Inducible co-stimulatory molecules participate in mesenteric vascular endothelial-mesenchymal transition and sclerosis of mesenteric vessels in spontaneously hypertensive rats / 南方医科大学学报

OBJECTIVE@#To investigate the correlation of inducible co-stimulatory molecules (ICOS) with mesenteric vascular endothelial- mesenchymal transition (EndMT) and sclerosis in spontaneously hypertensive rats (SHR).@*METHODS@#Twenty 4-week-old WKY rats and 20 SHRs of the same strain were both randomly divided into 4 groups for observation at 4, 6, 10 and 30 weeks of age. ICOS expression frequency in rat spleen CD4+T cells was analyzed using flow cytometry, and the expressions of ICOS, VE-cad, α-SMA and Col3 mRNA in rat mesentery were detected by RT-PCR. The distributions of ICOS, IL-17A and TGF-β in rat mesentery were detected by immunohistochemistry. The levels of IL-17A and TGF-β in rat plasma were measured using ELISA. The morphological changes of rat mesenteric vessels were observed with Masson staining. Spearman or Pearson correlation analyses were used to evaluate the correlation between ICOS expression and the expressions of the markers of vascular EndMT and sclerosis.@*RESULTS@#Compared with the control WKY rats, the SHRs began to show significantly increased systolic blood pressure and ICOS expression frequency on CD4+T cells at 6 weeks of age (P < 0.05). In the SHRs, the mRNA and protein expressions of ICOS, α-SMA, Col3, IL-17A and TGF-β in the mesentery were significantly higher than those in control group (P < 0.05), while the mRNA and protein expressions of VE-cad started to reduce significantly at 10 weeks of age (P < 0.05). The plasma levels of IL-17A and TGF-β were significantly increased in SHRs since 6 weeks of age (P < 0.05) with progressive worsening of mesenteric vascular sclerosis (P < 0.05). ICOS mRNA and protein expression levels in the mesenteric tissues of SHRs began to show positive correlations with α-SMA and Col3 expression levels and the severity of vascular sclerosis at 6 weeks of age (P < 0.05) and a negative correlation with VE-cad expression level at 10 weeks (P < 0.05).@*CONCLUSION@#ICOS play an important pathogenic role in EndMT and sclerosis of mesenteric vessels in essential hypertension by mediating related immune responses.

Intermittent heat exposure induces thoracic aorta injury in spontaneously hypertensive rats by activating the AMPK/mTOR/ULK1 pathway / 南方医科大学学报

OBJECTIVE@#To investigate the effects of different manners of heat exposure on thoracic aorta injury in spontaneously hypertensive rats (SHRs) and explore the underlying mechanism.@*METHODS@#Normal 6 to 7-week-old male SHRs were randomized into control group (cage at room temperature), intermittent heat exposure group (SHR-8 group, exposed to 32 ℃ for 8 h daily for 7 days) and SHR-24 group (with continuous exposure to 32 ℃ for 7 days). After the treatments, the pathologies of the thoracic aorta of the rats were observed with HE staining, and the expressions of Beclin1, LC3B and p62 were detected with Western blotting and immunofluorescence assay; TUNEL staining was used to observe cell apoptosis in the thoracic aorta, and the expressions of caspase-3, Bax, and Bcl-2 were detected using Western blotting. The effects of intraperitoneal injections of 3-MA (an autophagy agonist), rapamycin (an autophagy inhibitor) or compound C 30 min before intermittent heat exposure on the expressions of proteins associated with autophagy, apoptosis and the AMPK/mTOR/ULK1 pathway in the aorta were examined with immunohistochemistry.@*RESULTS@#In SHR-8 group, the rats showed incomplete aortic intima with disordered cell distribution and significantly increased expressions of Beclin1, LC3II/LC3I and Bax, lowered expressions of p62 and Bcl-2, and increased apoptotic cells in the thoracic aorta (P < 0.05). Pretreatment with 3-MA obviously inhibited the expressions of autophagy- and apoptosis-related proteins, whereas rapamycin promoted their expressions. Compared with the control group, the rats in SHR-8 group had significantly down-regulated p-mTOR and up-regulated p-AMPK and p-ULK1 expression of in the aorta; Treatment with compound C obviously lowered the expressions of p-AMPK and p-ULK1 and those of LC3B and Beclin1 as well.@*CONCLUSION@#In SHRs, intermittent heat exposure causes significant pathologies and promotes autophagy and apoptosis in the thoracic aorta possibly by activating the AMPK/mTOR/ULK1 pathway.

Involvement of Interleukin-1 β/Insulin-Like Growth Factor 1 in Ameliorating Effects of Electroacupuncture on Myocardial Fibrosis Induced by Essential Hypertension / 中国结合医学杂志

OBJECTIVE@#To investigate the effect of electroacupuncture (EA) at Neiguan (PC 6) on myocardial fibrosis in spontaneously hypertensive rats (SHRs), and to explore the contribution of interleukin-1 β (IL-1 β), insulin-like growth factor 1 (IGF-1), and transforming growth factor β 1 (TGF- β 1) to the effects.@*METHODS@#Nine 12-weeks-old Wistar Kyoto (WKY) male rats were employed as the normal group. Twenty-seven SHRs were equally randomized into SHR, SHR+EA, and SHR + sham groups. EA was applied at bilateral PC 6 once a day 30 min per day in 8 consecutive weeks. After 8-weeks EA treatment at PC 6, histopathologic changes of collagen type I (Col I), collagen type 1 (Col 1) and the levels of IGF-1, 1L-1 β, TGF- β 1, matrix metalloproteinase (MMP)-2 and MMP-9 were examined in myocardial tissure respectively.@*RESULTS@#After 8-weeks EA treatment at PC 6, the enhanced myocardial fibrosis in SHRs were characterized by the increased mean fluorescence intensity of Col I and Col 1 in myocardium tissue (P<0.01). All these abnormal alterations above in SHR + EA group was significantly lower compared with the SHR group (P<0.01). Meanwhile, the increased levels of IL-1 β, IGF-1, TGF-β 1 in serum or myocardial tissue of SHRs, diminished MMP 9 mRNA expression in SHRs were also markedly inhibited after 8 weeks of EA treatment (P<0.05 or P<0.01). Furthermore, the contents of IL-1 β, IGF-1, TGF-β 1 in myocardial tissue were positively correlated with the systolic blood pressure and hydroxyproline respectively (P<0.01).@*CONCLUSION@#EA at bilateral PC 6 could ameliorate cardiac fibrosis in SHRs, which might be mediated by regulation of 1L-1 β/IGF-1-TGF- β 1-MMP9 pathway.

Content determination of seven active components of Eucommiae Cortex in aortic vascular endothelial cells of spontaneously hypertensive rats by UPLC-MS/MS / 中国中药杂志

In the present study, the contents of seven active components [genipinic acid(GA), protocatechuic acid(PCA), neochlorogenic acid(NCA), chlorogenic acid(CA), cryptochlorogenic acid(CCA),(+)-pinoresinol di-O-β-D-glucopyranosid(PDG), and(+)-pinoresinol 4'-O-β-D-glucopyranoside(PG)] of Eucommiae Cortex in aortic vascular endothelial cells of spontaneously hypertensive rats(SHR) were simultaneously determined by ultra-high liquid chromatography-triple quadrupole mass spectrometry(UPLC-MS/MS). The qualified SHR models were selected. The primary aortic endothelial cells(VECs) of rats were separated and cultured by ligation and adherence, followed by subculture. After successful identification, an UPLC-MS/MS method for simultaneously determining the contents of GA, PCA, NCA, CA, CCA, PDG, PG in seven components of Eucommiae Cortex in VECs was established, including specificity, linearity, matrix effect, recovery, accuracy, precision and stability. The established method had the lo-west limit of quantification of 0.97-4.95 μg·L~(-1), accuracy of 87.26%-109.6%, extraction recovery of 89.23%-105.3%, matrix effect of 85.86%-106.2%, and stability of 86.00%-112.5%. Therefore, the established accurate UPLC-MS/MS method could rapidly and simultaneously determine the contents of the seven active components of Eucommiae Cortex in VECs of SHRs, which provided a refe-rence for the study of cellular pharmacokinetics of active components of Eucommiae Cortex extract.

Is the Wistar Rat a more Suitable Normotensive Control for SHR to Test Blood Pressure and Cardiac Structure and Function?

Abstract Background: There are divergences in the literature regarding the experimental model (Wistar-WIS or Wistar Kyoto-WKY) to be used as a Spontaneously Hypertensive Rat (SHR) control. The characterization of these models in terms of cardiovascular parameters provides researchers with important tools at the time of selection and application in scientific research. Objective: The aim of this study was to evaluate the use of WIS and WKY as a Spontaneously Hypertensive Rat (SHR) control by assessing the long-term behavior of blood pressure and cardiac structure and function in these strains. Methods: To this end, WIS, WKY, and SHR underwent longitudinal experiments. Blood pressure and body mass were measured every two weeks from the 8th to the 72nd. Echocardiographic analysis was performed in all groups with 16, 48, and 72 weeks of life. After having applied the normality test, the Two-Way ANOVA of repeated measures followed by the Tukey post hoc test was used. A significance level of 5% was established. Results: The WIS group showed higher body mass (p<0.05), while the WKY and SHR presented higher body mass variation over time (p<0.05). SHR exhibited increased values of systolic, diastolic, and mean blood pressure when compared to WKY and WIS, whereas the WKY generally showed higher values than WIS (p<0.05). Regarding the cardiac function, SHR showed reduced values, while the WKY presented an early decrease when compared to WIS with aging (p<0.05). Conclusion: WIS is a more suitable normotensive control for SHR than WKY in experiments to test blood pressure and cardiac structure and function.

Electroacupuncture Attenuated Phenotype Transformation of Vascular Smooth Muscle Cells via PI3K/Akt and MAPK Signaling Pathways in Spontaneous Hypertensive Rats / 中国结合医学杂志

OBJECTIVE@#To investigate whether the antihypertensive mechanism of electroacupuncture (EA) is associated with attenuating phenotype transformation of vascular smooth muscle cells (VSMCs) via phosphoinositide3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signaling pathways.@*METHODS@#Eight Wistar-ktoyo (WKY) rats were set as normal blood pressure group (normal group). A total of 32 spontaneous hypertensive rats (SHRs) were randomly divided into 4 groups using random number tables: a model group, an EA group, an EA+PI3K antagonist group (EA+P group), and an EA+p38 MAPK agonist+extracellular signal-regulated kinase (ERK) agonist group (EA+M group) (n=8/group). SHRs in EA group, EA+P group and EA+M group received EA treatment 5 sessions per week for continuous 4 weeks, while rats in the normal and model groups were bundled in same condition. The systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) of each rat was measured at 0 week and the 4th week. After 4-week intervention, thoracic aorta was collected for hematoxylin-eosin (HE) staining, immunohistochemistry [the contractile markers α-smooth muscle actin (α-SMA) and calponin and the synthetic marker osteopontin (OPN)] and Western blot [α-SMA, calponin, OPN, PI3K, phosphorylated-Akt (p-Akt), Akt, p-p42/44 ERK, total p42/44 ERK, p-p38 MAPK and total p38 MAPK].@*RESULTS@#EA significantly reduced SBP, DBP and MAP (P<0.01). HE staining showed that the wall thickness of thoracic aorta in EA group was significantly decreased (P<0.01). From results of immunohistochemistry and Western blot, EA increased the expression of α-SMA and calponin, and decreased the expression of OPN (P<0.01). In addition, the expression of PI3K and p-Akt increased (P<0.01), while the expression of p-p42/44 ERK and p-p38 MAPK decreased in EA group (P<0.01). However, these effects were reversed by PI3K antagonist, p38 MAPK agonist and ERK agonist.@*CONCLUSIONS@#EA was an effective treatment for BP management. The antihypertensive effect of EA may be related with inhibition of phenotypic transformation of VSMCs, in which the activation of PI3K/Akt and the repression of MAPK pathway were involved.

Metabolomic characteristics of spontaneously hypertensive rats under chronic stress and the treatment effect of Danzhi Xiaoyao Powder, a traditional Chinese medicine formula / 中西医结合学报

OBJECTIVE@#Numerous studies have demonstrated the close relationship between chronic stress and blood pressure (BP). Hypertensive subjects exhibit exaggerated reactions to stress, especially higher BP. The mechanisms by which stress affects pre-existing hypertension still need to be explored. Danzhi Xiaoyao Powder (DP), a historical traditional Chinese medicine formula, is a promising treatment for BP control in hypertensive patients under stress. The present study investigated the metabolomic disruption caused by chronic stress and the treatment effect and mechanism of DP.@*METHODS@#Spontaneously hypertensive rats (SHRs) were subjected to chronic restraint stress (CRS) for 4 weeks. BP was measured via the tail-cuff method, and anxiety-like behavior was quantified using the elevated-plus-maze test. Meanwhile, DP was administered intragastrically, and its effects were observed. Global metabolomic analysis was performed using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, followed by multivariate statistical analysis to detect differential metabolites and pathways.@*RESULTS@#DP alleviated the CRS-induced increase in BP and anxiety-like behavior. Systematic metabolic differences were found among the three study groups. A total of 29 differential plasma metabolites were identified in both positive- and negative-ion modes. These metabolites were involved in triglyceride metabolism, amino acid (phenylalanine, tryptophan, and glycine) metabolism, and steroid hormone pathways.@*CONCLUSION@#These findings expose the metabolomic disturbances induced by chronic stress in SHRs and suggest an innovative treatment for this disorder.

Influence of electroacupuncture on ghrelin and the phosphoinositide 3-kinase/protein kinase B/endothelial nitric oxide synthase signaling pathway in spontaneously hypertensive rats / 中西医结合学报

OBJECTIVE@#To investigate the influence of electroacupuncture (EA) on ghrelin and the phosphoinositide 3-kinase/protein kinase B/endothelial nitric oxide synthase (PI3K/Akt/eNOS) signaling pathway in spontaneously hypertensive rats (SHRs).@*METHODS@#Eight Wistar-Kyoto rats were used as the healthy blood pressure (BP) control (normal group), and 32 SHRs were randomized into model group, EA group, EA plus ghrelin group (EA + G group), and EA plus PF04628935 group (a potent ghrelin receptor blocker; EA + P group) using a random number table. Rats in the normal group and model group did not receive treatment, but were immobilized for 20 min per day, 5 times a week, for 4 continuous weeks. SHRs in the EA group, EA + G group and EA + P group were immobilized and given EA treatment in 20 min sessions, 5 times per week, for 4 weeks. Additionally, 1 h before EA, SHRs in the EA + G group and EA + P group were intraperitoneally injected with ghrelin or PF04628935, respectively, for 4 weeks. The tail-cuff method was used to measure BP. After the 4-week intervention, the rats were sacrificed by cervical dislocation, and pathological morphology of the abdominal aorta was observed using hematoxylin-eosin (HE) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of ghrelin, nitric oxide (NO), endothelin-1 (ET-1) and thromboxane A2 (TXA2) in the serum. Isolated thoracic aortic ring experiment was performed to evaluate vasorelaxation. Western blot was used to measure the expression of PI3K, Akt, phosphorylated Akt (p-Akt) and eNOS proteins in the abdominal aorta. Further, quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to measure the relative levels of mRNA expression for PI3K, Akt and eNOS in the abdominal aorta.@*RESULTS@#EA significantly reduced the systolic BP (SBP) and diastolic BP (DBP) (P < 0.05). HE staining showed that EA improved the morphology of the vascular endothelium to some extent. Results of ELISA indicated that higher concentrations of ghrelin and NO, and lower concentrations of ET-1 and TXA2 were presented in the EA group (P < 0.05). The isolated thoracic aortic ring experiment demonstrated that the vasodilation capacity of the thoracic aorta increased in the EA group. Results of Western blot and qRT-PCR showed that EA increased the abundance of PI3K, p-Akt/Akt and eNOS proteins, as well as expression levels of PI3K, Akt and eNOS mRNAs (P < 0.05). In the EA + G group, SBP and DBP decreased (P < 0.05), ghrelin concentrations increased (P < 0.05), and the concentrations of ET-1 and TXA2 decreased (P < 0.05), relative to the EA group. In addition, the levels of PI3K and eNOS proteins, the p-Akt/Akt ratio, and the expression of PI3K, Akt and eNOS mRNAs increased significantly in the EA + G group (P < 0.05), while PF04628935 reversed these effects.@*CONCLUSION@#EA effectively reduced BP and protected the vascular endothelium, and these effects may be linked to promoting the release of ghrelin and activation of the PI3K/Akt/eNOS signaling pathway.

Involvement of ET-1/eNOS in the ameliorating effect of electroacupuncture on cardiac dysfunction in rats with spontaneously hypertensive / 中国针灸

OBJECTIVE@#To observe the effect of electroacupuncture (EA) at "Neiguan" (PC 6) on cardiac function of ventriculus sinister in rats with spontaneously hypertensive (SHR), and to explore the mediation effect of endothelin-1 (ET-1)/endothelial nitric oxide synthase (eNOS).@*METHODS@#Six 12-week-old male Wistar Kyoto (WKY) rats were taken as the normal group. Eighteen 12-week-old SHR were randomly divided into a model group, an EA group and a sham EA group, 6 rats in each group. The rats in the EA group were treated with EA (disperse-dense wave, 2 Hz/15 Hz in frequency, 1 mA in current intensity) at "Neiguan" (PC 6), 30 min each time, once a day for 8 weeks. The rats in the sham EA group were treated with superficial needling at "Neiguan" (PC 6) with no electrical stimulation applied. After treatment, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were tested by echocardiographic analysis. The left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), heart rate (HR), the maximum rate of increase/decrease of left ventricular pressure (±dp/dtmax) were detected. The serum content of ET-1 was detected by ELISA. Western blot was used to evaluate the expression of ETAR, eNOS in myocardial tissue of left ventricular.@*RESULTS@#Compared with the normal group, LVEF, LVFS, +dp/dtmax/LVSP and -dp/dtmax/LVSP were decreased (P<0.01, P<0.05), while LVSP, LVEDP, +dp/dtmax and -dp/dtmax were increased (P<0.01) in the model group. Compared with the model group, LVEF, LVFS, +dp/dtmax/LVSP and -dp/dtmax/LVSP were increased (P<0.01, P<0.05), and LVSP and LVEDP were decreased (P<0.01) in the EA group. Compared with the normal group, the serum content of ET-1 and the expression of ETAR in myocardial tissue were increased (P<0.01), whereas expression of eNOS was decreased (P<0.01) in the model group. Compared with the model group, the serum content of ET-1 and the expression of ETAR in myocardial tissue were decreased (P<0.05), whereas expression of eNOS was increased (P<0.05) in the EA group.@*CONCLUSION@#EA intervention may alleviate hypertensive cardiac function damage by up-regulating the expression of eNOS protein in myocardial tissue, down-regulating the serum content of ET-1 and the expression of ETAR protein in myocardial tissue.

Interleukin-17A is closely correlated with the progression of renal epithelial-mesenchymal transition in spontaneously hypertensive rats / 南方医科大学学报

OBJECTIVE@#To explore the role of interleukin-17A (IL-17A) in renal epithelial- mesenchymal transition (EMT) in essential hypertensive nephropathy.@*METHODS@#Four-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (control group) were both randomized into 4 groups (n=5) for observation at 4, 6, 10 and 30 weeks of age. Blood pressure of the rats was monitored using a noninvasive tail artery blood pressure measurement instrument. The percentage of Th17 cells in the splenocytes was analyzed using flow cytometry. The mRNA and protein expression levels of IL-17A, iNOS, Arg-1, E-cadherin, and α-SMA in the kidneys of the rats were detected using RT-PCR and immunohistochemical staining, respectively, and plasma levels of IL-17A were regularly detected using ELISA.@*RESULTS@#At the age of 6 weeks, the SHRs began to show significantly higher blood pressure with greater Th17 cell percentage in the splenocytes and high renal expression and plasma level of IL-17A than WKY rats (P < 0.05 or P < 0.01). At 30 weeks, renal expression of E-cadherin mRNA and protein was significantly lower and the expression of Arg-1 mRNA and protein was significantly higher in SHR than in WKY rats (P < 0.01). Compared with the WKY rats, the SHRs showed significantly higher mRNA and protein expressions of iNOS at 6 and 10 weeks (P < 0.05 or 0.01) and higher α-SMA mRNA and protein expressions since 10 weeks of age (P < 0.05 or 0.01). In SHRs older than 10 weeks, renal IL-17A mRNA and protein expression levels were negatively correlated with those of E-cadherin (r=-0.731, P < 0.05; r=-0.827, P < 0.01) and positively correlated with those of α-SMA (r=0.658, P < 0.05; r=0.968, P < 0.01).@*CONCLUSION@#IL-17A is closely correlated with the progression of renal EMT in SHR and plays its role possibly by mediating M1/M2 polarization of renal infiltrating macrophages.

The effects of methanol extract of Galium verum L on cardiac redox state in hypertensive rats

Abstract The aim of this study was to assess the effects of methanol extract of G. verum on redox status of isolated heart of spontaneously hypertensive rats after ischemia. Twenty-four Wistar albino rats were divided into three groups: untreated control rats and rats that received 125 and 250 mg/kg G. verum extract for 4 weeks per os. Index of lipid peroxidation (measured as TBARS) and parameters of antioxidative defence system such as level of reduced glutathione (GSH) and activities of catalase (CAT) and superoxide dismutase (SOD) were spectrophotometrically determined in heart homogenate. The index of lipid peroxidation in heart tissue was lower in both treated groups compared to the control group. On the other hand, the activity of SOD was significantly higher after consumption of both doses, while the activity of CAT was significantly higher only after treatment with a higher dose of extract. Based on our results we might conclude that 4-week treatment with methanol extracts of G. verum has the potential to modulate myocardial redox signaling after ischemia, thus significantly alleviating cardiac oxidative stress and exerting dose-dependent antioxidant properties. Future studies are certainly necessary to fully clarify the role of this plant species in myocardial I-R injury.

Caracterização do tecido ósseo peri-implantar em ratas hipertensas e com deficiência de estrógeno, após ação sinérgica de losartan e alendronato de sódio / Characterization of peri-implant bone tissue in hypertensive and estrogen-deficient rats after the synergistic action of losartan and alendronate sodium

Introdução: Este estudo visou caracterizar morfológica e estruturalmente o tecido produzido na interface osso-implante em ratas espontaneamente hipertensas ovariectomizadas com implantes instalados em suas tíbias, e analisou como o tratamento associado de losartan sistêmico e alendronato de sódio local influenciou no reparo ósseo peri-implantar. Material e Métodos: Foram utilizadas ratas espontaneamente hipertensas (SHR) que receberam losartan (30 mg/kg, p.o.). Após uma semana, implantes de titânio tratados (Medens, Ribeirão Preto, São Paulo, Brazil) ou não com alendronato de sódio (ALE) foram instalados nas tíbias. Sessenta dias após a implantação, a estabilidade do implante foi avaliada pela medição de torque reverso, considerado como desfecho primário. A microtomografia computadorizada e a análise por confocal foram parâmetros secundários. Resultados: A ação sinérgica do losartan e do alendronato de sódio na superfície do implante aumentou o torque reverso no grupo SHR SHAM ALE. Enquanto a microtomografia também revelou maior extensão de contato entre osso e implante, volume ósseo e espessura trabecular nos animais SHR SHAM ALE. Por último, o losartan e o alendronato de sódio não alterou significativamente os parâmetros de osseointegração nas ratas ovariectomizadas. Conclusões: Os resultados apresentados sugerem que a ação sistêmica do losartan somada à atuação local do alendronato de sódio na superfície dos implantes melhoram os parâmetros de osseointegração em tíbias de ratas hipertensas e não ovariectomizadas(AU)

Background: This study aims to characterize morphologically and structurally the tissue produced at the bone-implant interface in spontaneously hypertensive ovariectomized rats that will have implants placed in their tibiae, and to analyze how the associated treatment of systemic losartan and local sodium alendronate might influence the peri-implant bone healing. Methods: They are used spontaneously hypertensive (SHR) rats that received losartan (30 mg/kg, p.o.). After one week, titanium implants treated (Medens, Ribeirão, São Paulo, Brazil) or not with sodium alendronate (ALE) were installed in the tibiae. Sixty days after implantation, implant stability was assessed by measuring the removal torque considered the primary end point. Computed tomography and confocal analysis were secondary parameters. Results: The synergistic action of losartan and sodium alendronate on the implant surface increased the reverse torque in the SHR SHAM ALE group. While microtomography also revealed a greater extent of contact between bone and implant, bone volume and trabecular thickness in SHR SHAM ALE animals. Finally, losartan and sodium alendronate did not significantly alter osseointegration parameters in ovariectomized rats. Conclusions: The results presented suggest that systemic losartan plus the local action of sodium alendronate on implants surface improves osseointegration parameters in tibias of hypertensives and non-ovariectomized rats(AU)

Tyrosine hydroxylase and ß2-adrenergic receptor expression in leukocytes of spontaneously hypertensive rats: putative peripheral markers of central sympathetic activity

The sympathetic nervous system (SNS) plays a fundamental role in the pathophysiology of cardiovascular diseases, including primary arterial hypertension. In this study, we aimed to investigate whether the expression of the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and the β2-adrenergic receptor (β2-AR) in immune cells from peripheral blood, reflect central SNS activity in spontaneously hypertensive rats (SHR). TH expression in the lower brainstem and adrenal glands and β2-AR expression in the lower brainstem were analyzed by western blot analyses. In the leukocytes, TH and β2-AR expression was evaluated by flow cytometry before and after chronic treatment with the centrally-acting sympathoinhibitory drug clonidine. Western blot analyses showed increased TH and β2-AR expression in the lower brainstem and increased TH in adrenal glands from SHR compared to normotensive Wistar Kyoto rats (WKY). Lower brainstem from SHR treated with clonidine presented reduced TH and β2-AR levels, and adrenal glands had decreased TH expression compared to SHR treated with vehicle. Flow cytometry showed that the percentage of leukocytes that express β2-AR is higher in SHR than in WKY. However, the percentage of leukocytes that expressed TH was higher in WKY than in SHR. Moreover, chronic treatment with clonidine normalized the levels of TH and β2-AR in leukocytes from SHR to similar levels of those of WKY. Our study demonstrated that the percentage of leukocytes expressing TH and β2-AR was altered in arterial hypertension and can be modulated by central sympathetic inhibition with clonidine treatment.

A method to assess heart rate variability in neonate rats: validation in normotensive and hypertensive animals

Several studies have focused on the heart rate variability (HRV) of murine species, while studies discussing HRV in murine neonates and infants remain scarce, since recording hemodynamic signals through invasive methods in small animals has been found to be quite challenging. Thus, this study aimed at describing and validating a novel method to assess HRV in newborn rats. An electrocardiogram (ECG) system was used to determine RR intervals in awake newborns and evaluate HRV in normotensive (Wistar) and hypertensive (SHR) neonate rats. After birth, ECG was recorded in the awake newborns, and they were allowed to rest on a heated surface, restricted only by the weight of the adhesive ECG electrodes. The electrodes were cut and adapted to provide more comfort to the animal, and gently placed on the newborn's skin. RR intervals were recorded over a 30-min period using an ECG system together with LabChart software (4 KHz). Three sequences of 5 min each from the ECG recording period were analyzed in time and frequency domains, using CardioSeries software. ECG data resulted in a clearly interpretable signal that was used to generate an RR interval sequence through time for the analysis of HRV. SHR neonates presented increased cardiac sympathovagal balance compared to Wistar neonates (low frequency/high frequency: 3.85±0.71 vs 0.90±0.09). In conclusion, the ECG setup here described may be used to record RR intervals to assess HRV in neonate rats, thus detecting early impairment of HRV in hypertensive newborns.

A via Nrf2 participa da maior modulação endotelial induzida pela prenhez sobre reatividade de aortas à fenilefrina / The Nrf2 pathway participates in the greater endothelial modulation induced by pregnancy on reactivity of aortas to phenylephrine

Alterações em diferentes vias de sinalização levam a disfunção vascular e endotelial e consequentemente a hipertensão. A hipertensão está relacionada diretamente com o aumento da produção de espécies reativas de oxigênio (ROS) e diminuição da biodisponibilidade de óxido nítrico (NO) nos vasos sanguíneos. A via do Nrf2 (fator nuclear eritróide 2) está envolvida nos mecanismos que levam ao aumento da biodisponibilidade vascular de NO, pois controla a expressão de enzimas antioxidantes. A ativação do Nrf2 é modulada por sua ligação com a Keap-1 (Kelch-like ECH-associated protein 1) e sua atividade é modulada pelo fator de transcrição Bach-1, que compete pelo mesmo sitio ativo no DNA com o Nrf2. Em ratas normotensas e em ratas espontaneamente hipertensas (SHR) é observada uma redução da pressão arterial ao final da prenhez, que tem sido associada à redução do estresse oxidativo e maior biodisponibilidade de NO. Com o aumento da biodisponibilidade de NO, é aumentada a modulação do endotélio sobre a reatividade vascular à agonistas vasoconstritores, como à fenilefrina (PE). Levantamos a hipótese que a prenhez altera a expressão e ou a atividade do Nrf2 e de seus inibidores Keap-1 e Bach-1 e que estas possíveis alterações estariam associadas à maior modulação endotelial sobre contração de aortas à PE. Para testarmos esta hipótese, a expressão de Nrf2, Keap-1 e Bach-1 e também das enzimas antioxidantes transcritas pelo Nrf2, como a NADP(H) quinona oxirredutase-1 (NQO1), SOD-1 e SOD-2 foram avaliadas em aortas de ratas prenhes e comparadas as aortas de ratas não-prenhes. A fim de identificarmos outros possíveis mecanismos alterados pela prenhez em ratas Wistar e SHR, avaliamos a expressão de NOXO-1, subunidade regulatória da NOX1 e de p47phox, subunidade regulatória de NOX2. A participação do Nrf2 na produção de NO endotelial em aortas de ratas prenhes, foi avaliada pela utilização de Brusatol, uma droga inibidora do Nrf2. Avaliamos também a participação do Nrf2 na reatividade de aortas de ratas prenhes à fenilefrina e à acetilcolina, utilizando o Brusatol. Todos os resultados foram comparados entre ratas não-prenhes normotensas (Wistar) e hipertensas (SHR) e entre ratas não-prenhes e prenhes nos grupos (análise de multivariância, post-test Tukey, p< 0,05). Os resultados mostraram que a expressão de Nrf2 está aumentada em aortas de ratas prenhes Wistar, apesar da expressão de Keap-1 e de Bach1 não estar alterada. Associado a expressão aumentada de Nrf2 observamos maior expressão de SOD-2, mas não de SOD-1 ou NQO1, em aortas de ratas prenhes. Em aortas de ratas SHR não prenhes, observamos entre todas as proteínas avaliadas, menor expressão de Bach-1 e de NQO1 quando comparadas às aortas de ratas normotensas. A prenhez reduziu ainda mais a expressão apenas de NQO1 em aortas de SHR. A prenhez reduziu a expressão de NOXO-1 e de p47phox em aortas de SHR, enquanto que em aortas de ratas Wistar reduziu apenas a expressão de NOXO-1. Os resultados obtidos neste estudo mostraram também que a incubação de HUVEC com Brusatol aumentou as concentrações intracelulares de ERO, mas não alterou as concentrações de NO, no entanto, reduziu significativamente a concentração de NOx estimulada pela ACh em aortas de ratas prenhes, Wistar ou SHR. Além disto, o Brusatol aumentou a reatividade à PE em aortas de ratas normotensas não prenhes e prenhes, igualando a reatividade de aortas de ratas prenhes as aortas de ratas não prenhes. No entanto, o Brusatol não alterou a reatividade de aortas de SHR, prenhes ou não-prenhes. Nenhum efeito significativo do Brusatol foi observado na reatividade à Acetilcolina em aortas de ratas Wistar ou SHR, prenhes ou não prenhes. Em conclusão, nossos resultados sugerem que a atividade da via de sinalização do Nrf2 está aumentada, favorecendo a maior atividade de enzimas antioxidantes como a SOD-2, que contribuiria para maior biodisponibilidade de NO e maior modulação endotélio-dependente da contração vascular à PE em aortas de ratas normotensas prenhes. No entanto, em aortas de SHR prenhes, este mecanismo parecer não ser mais importante que a redução da atividade de isoformas NOX e de suas subunidades regulatórias que contribuiria para menor geração de O2•- e consequentemente, maior biodisponibilidade de NO(AU)

Modifications in different signaling pathways lead to vascular and endothelial dysfunction and, consequently, hypertension. Hypertension is directly related to an increase in the production of reactive oxygen species (ROS) and a decrease in the bioavailability of nitric oxide (NO) in blood vessels. The Nrf2 (erythroid nuclear factor 2) pathway is involved in the mechanisms that lead to the increased vascular bioavailability of NO, as it controls the expression of antioxidant enzymes. The activation of Nrf2 is modulated by Keap-1 (Kelch-like ECH-associated protein 1) and its activity is modulated by the transcription factor Bach-1, which competes for the same active site in DNA with Nrf2. In normotensive rats and spontaneously hypertensive rats (SHR), a reduction in blood pressure at the end of pregnancy is observed, which has been associated with a reduction in oxidative stress and greater bioavailability of NO. This increased NO bioavailability has been associated with the higher endothelium modulation over blood vessel reactivity to vasoconstrictor agonists, such as phenylephrine (PE), observed in pregnant rats. We hypothesized that pregnancy alters the expression and/or activity of Nrf2 and its inhibitors Keap-1 and Bach-1 and that these changes are associated with greater endothelial modulation on the contraction of aortas to PE. To test this hypothesis, the expression of Nrf2, Keap-1 and Bach-1 and the antioxidant enzymes transcribed by Nrf2, such as NADP (H) quinone oxidoreductase-1 (NQO1), SOD-1 and SOD-2 were evaluated in aortas of pregnant rats and compared to aortas of non-pregnant rats. In order to identify other possible mechanisms altered by pregnancy in Wistar rats and SHR, we evaluated the expression of NOXO-1, NOX1 regulatory subunit and p47phox, NOX2 regulatory subunit. The role of Nrf2 in the production of endothelial NO in aortas of pregnant rats was evaluated by use of Brusatol, an inhibitor of Nrf2. We also evaluated the role of Nrf2 in the reactivity of aortas of pregnant rats to phenylephrine and acetylcholine, using Brusatol. All results were compared between normotensive (Wistar) and hypertensive (SHR) non-pregnant rats and between pregnant and non-pregnant rats in the groups (multivariate analysis, Tukey post-test, p< 0.05). The results showed that the expression of Nrf2 is increased in aortas of pregnant Wistar rats, although the expression of Keap-1 and Bach-1 is not altered. The increased expression of Nrf2 was associated with the greater expression of SOD-2, but not of SOD-1 or NQO1, in aortas of pregnant rats. In aortas of non-pregnant SHR rats, we observed among all evaluated proteins, lower expression of Bach-1 and NQO1 when compared to the aortas of normotensive rats. Pregnancy reduced even more the expression of NQO1 in SHR aortas. Pregnancy reduced the expression of NOXO-1 and p47phox in SHR aortas, whereas in aorta of Wistar rats it reduced only the expression of NOXO-1. The results obtained in this study also showed that the incubation of HUVEC with Brusatol increased the intracellular concentrations of ROS, but did not alter the concentrations of NO, however, Brusatol significantly reduced the concentration of NOx stimulated by ACh in aortas of pregnant rats, Wistar or SHR. Moreover, Brusatol increased the reactivity to PE in aortas of pregnant normotensive rats and pregnant, matching the reactivity of aortas of pregnant rats to aortas of non-pregnant rats. However, Brusatol did not alter the reactivity of pregnant or non-pregnant SHR aortas. No significant effect of Brusatol was observed in the reactivity to Acetylcholine in aortas of Wistar rats or SHR, pregnant or non-pregnant rats. In conclusion, our results suggest that the activity of the Nrf2 signaling pathway is increased, favoring the greater activity of antioxidant enzymes such as SOD-2, which would contribute to greater bioavailability of NO and greater endothelium-dependent modulation of vascular contraction to PE in aortas of pregnant normotensive rats. However, in pregnant SHR aortas, this mechanism appears to be no more important than the lower the activity of NOX isoforms and their regulatory subunits that would contribute to lower O2•- generation and, consequently, greater NO bioavailability(AU)

Thermoregulation in Hypertensive Rats during Exercise: Effects of Physical Training / Termorregulação durante o Exercício em Ratos Hipertensos: Efeitos do Treinamento Físico

Abstract Background: Spontaneously hypertensive rats (SHR) show deficit in thermal balance during physical exercise. Objective: To assess the effects of low-intensity physical exercise training on thermal balance of hypertensive rats undergoing an acute exercise protocol. Methods: Sixteen-week-old male Wistar rats and SHR were allocated into four groups: control Wistar rats (C-WIS), trained Wistar (T-WIS), control SHR (C-SHR) and trained SHR (T-SHR). Treadmill exercise training was performed for 12 weeks. Blood pressure, resting heart rate and total exercise time was measured before and after the physical exercise program. After the exercise program, a temperature sensor was implanted in the abdominal cavity, and the animals subjected to an acute exercise protocol, during which internal body temperature, tail skin temperature and oxygen consumption until fatigue were continuously recorded. Mechanical efficiency (ME), work, heat dissipation threshold and sensitivity were calculated. Statistical significance was set at 5%. Results: Physical training and hypertension had no effect on thermal balance during physical exercise. Compared with C-WIS, the T-WIS group showed higher heat production, which was counterbalanced by higher heat dissipation. Hypertensive rats showed lower ME than normotensive rats, which was not reversed by the physical training. Conclusion: Low-intensity physical training did not affect thermal balance in SHR subjected to acute exercise.

Resumo Fundamento: Ratos espontaneamente hipertensos (SHR) apresentam déficits no balanço térmico durante o exercício físico. Objetivo: Avaliar os efeitos do treinamento físico de baixa intensidade sobre o balanço térmico de ratos hipertensos submetidos a um protocolo de exercício físico agudo. Métodos: Ratos machos Wistar e SHR, com 16 semanas de idade, foram divididos em quatro grupos experimentais: Wistar controle (WIS-C), Wistar treinado (WIS-T), SHR controle (SHR-C) e SHR treinado (SHR-T). O treinamento físico em esteira rolante foi realizado durante 12 semanas. A pressão arterial, a frequência cardíaca de repouso e o tempo de exercício foram medidos previamente e após o programa de treinamento físico. Após o programa de treinamento físico, um sensor de temperatura foi implantado na região intraperitoneal e os ratos foram submetidos a um protocolo de exercício físico agudo com registros contínuos da temperatura corporal interna, temperatura da pele da cauda e do consumo de oxigênio até a fadiga. A eficiência mecânica (EM), o trabalho, o limiar e a sensibilidade para dissipação de calor foram calculados. Para as análises estatísticas o nível de significância adotado foi de 5%. Resultados: O treinamento físico e a hipertensão arterial não alteraram o balanço térmico durante o exercício físico. O grupo WIS-T quando comparado ao WIS-C, apresentou maior produção de calor, que foi contrabalanceado por uma maior dissipação de calor. Os animais hipertensos apresentaram menor EM em comparação aos animais normotensos, e o treinamento físico não foi capaz de reverter esta alteração. Conclusão: O treinamento físico de baixa intensidade não provocou alterações no balanço térmico de ratos hipertensos submetidos a um protocolo de exercício físico agudo.

Effects of Chronic Exposure to Mercury on Angiotensin-Converting Enzyme Activity and Oxidative Stress in Normotensive and Hypertensive Rats / Efeitos da Exposição Crônica ao Mercúrio sobre a Atividade da Enzima Conversora de Angiotensina e Estresse Oxidativo em Ratos Normotensos e Hipertensos

Abstract Background: Mercury's deleterious effects are associated with increased cardiovascular risk. Objective: To determine whether chronic exposure to inorganic mercury increases the activity of angiotensin-converting enzyme and its relationship with oxidative stress in several organs and tissues. Methods: We studied male Wistar and spontaneously hypertensive rats (SHR) (3-month-old) exposed or not to HgCl2 for 30 days. At the end of treatment, we investigated the following: changes in body weight, hemodynamic parameters, angiotensin-converting enzyme (ACE) activity and oxidative stress in the heart, aorta, lung, brain and kidney in hypertensive compared to normotensive animals. A value of p < 0.05 was considered significant. Results: Chronic exposure to HgCl2 did not affect weight gain in either group. Systolic blood pressure, measured weekly, did not increase in Wistar rats but showed a small increase in SHR rats. We also observed increases in left ventricular end-diastolic pressure and ACE activity in the plasma and hearts of normotensive rats. In the SHR+Hg group, ACE activity increased in plasma but decreased in kidney, lung, heart, brain and aorta. Oxidative stress was assessed indirectly by malondialdehyde (MDA) production, which increased in Hg-treated rats in both plasma and heart. In the SHR+Hg group, MDA increased in heart and aorta and decreased in lungs and brain. Conclusion: These results suggest that chronic exposure to inorganic mercury aggravates hypertension and produces more expressive changes in ACE activity and oxidative stress in SHRs. Such exposure affects the cardiovascular system, representing a risk factor for the development of cardiovascular disorders in normotensive rats and worsening of pre-existing risks for hypertension.

Resumo Fundamento: Os efeitos deletérios do mercúrio estão associados ao risco cardiovascular aumentado. Objetivo: Determinar se a exposição crônica ao mercúrio inorgânico aumenta a atividade da enzima conversora de angiotensina e sua relação com o estresse oxidativo em vários órgãos e tecidos. Métodos: Estudamos ratos Wistar e ratos espontaneamente hipertensos (SHR) (3 meses de idade) expostos ou não a HgCl2 por 30 dias. Ao final do tratamento, investigamos: alterações de peso, parâmetros hemodinâmicos, atividade da enzima conversora de angiotensina (ECA) e estresse oxidativo no coração, aorta, pulmão, cérebro e rim de animais hipertensos comparados a animais normotensos. Um valor de p < 0,05 foi considerado significativo. Resultados: A exposição crônica ao HgCl2 não afetou o ganho de peso em nenhum dos grupos. A pressão arterial sistólica, medida semanalmente, não aumentou em ratos Wistar, mas mostrou um pequeno aumento nos ratos SHR. Também observamos aumentos na pressão diastólica final do ventrículo esquerdo e na atividade da ECA no plasma e no coração de ratos normotensos. No grupo SHR + Hg, a atividade da ECA aumentou no plasma, mas diminuiu no rim, pulmão, coração, cérebro e aorta. O estresse oxidativo foi avaliado indiretamente pela produção de MDA, que aumentou nos ratos tratados com Hg tanto no plasma quanto no coração. No grupo SHR + Hg, o MDA aumentou no coração e na aorta e diminuiu nos pulmões e no cérebro. Conclusão: Estes resultados sugerem que a exposição crônica ao mercúrio inorgânico agrava a hipertensão e produz mudanças mais expressivas na atividade da ECA e no estresse oxidativo em SHRs. Essa exposição afeta o sistema cardiovascular, representando um fator de risco para o desenvolvimento de distúrbios cardiovasculares em ratos normotensos e para piorar riscos pré-existentes para hipertensão.

Papel dos receptores ß1 e ß2 adrenérgicos sobre a diferenciação osteoblástica de células mesenquimais estromais da medula óssea de ratos espontaneamente hipertensos / Role of ß1 and ß2 adrenergic receptor on bone marrow mesenquimal stem cells osteoblastic differentiation from hypertensive rats

Introdução: O remodelamento ósseo é um processo complexo que depende do balanço entre formação e reabsorção óssea, mecanismo regulado pelas células ósseas e fatores sistêmicos, como o Sistema Nervoso Simpático (SNS). Os mediadores deste sistema são capazes de regular o metabolismo ósseo através dos receptores adrenérgicos expressos na superfície dos osteoblastos. Entretanto, o papel dos receptores ß-adrenérgicos ainda não está totalmente elucidado no processo de diferenciação osteogênica. Objetivos: avaliar o papel dos receptores ß-adrenérgicos na diferenciação osteoblástica de células tronco mesenquimais da medula óssea de ratos normotensos e espontaneamente hipertensos (SHR). Métodos: Ratos machos Wistar e SHR (10 semanas) foram utilizados para a coleta da medula óssea a partir do fêmur, as quais foram plaqueadas em garrafas de cultivo celular e depois em placas de 24 poços, onde receberam o meio osteogênico (MO: MEM, mais 50 µg/mL de ácido ascórbico, 10 mM de ß-glicerofosfato e 10-8 M de dexametasona), e o tratamento com Isoprenalina (0,01 µM), Carvedilol (1 µM), antagonista adrenérgico não seletivo, ou Nebivolol (0,1 µM), antagonista ß1-adrenérgico. O ensaio de proliferação celular (MTT) e a atividade de fosfatase alcalina (Fal) foram realizados nos dias 7, 10 e 14. A mineralização foi avaliada no dia 14 através do vermelho de Alizarina. A expressão gênica dos marcadores osteogênicos e dos receptores ß1 e ß2 adrenérgicos foi avaliada no dia 7 por RT-PCR em tempo real. A atividade proteolítica da metaloproteinase de matriz (MMP-2) foi avaliada no mesmo período utilizando zimografia. As vias da MAPK também foram avaliadas ao final de 7 dias. Resultados: A Isoprenalina reduz a fosfatase alcalina na linhagem de células Wistar nos dois primeiros períodos, e ao final de 14 dias apresenta um aumento significativo. A adição dos -bloqueadores reverte tal resposta. Em SHR a Isoprenalina proporciona aumento da atividade de fosfatase alcalina no período intermediário. O Nebivolol inibe essa resposta no mesmo período e, em 7 dias, é capaz de reverter a redução causada pelo agonista. A Isoprenalina aumentou a expressão de todos os fatores de transcrição e o bloqueio dos receptores reverteu essa condição A Isoprenalina aumenta a expressão de Opn, Ocn e BSP nas células de animais Wistar, e em SHR aumenta apenas Ocn e o tratamento com Carvedilol corrige. A atividade de MMP-2 também foi reduzida pelo Nebivolol apenas no grupo Wistar. Além disso, o Nebivolol reduziu a expressão gênica do receptor ß1-adrenérgico. O ensaio de mineralização mostrou menor deposição mineral em Wistar. O Nebivolol também mediou a redução da fosforilação das vias da MAPK neste mesmo grupo de células. Conclusão: Nossos dados sugerem que o receptor ß1-adrenérgico pode estar envolvido na diferenciação osteogênica de células de ratos Wistar mas não em células de ratos SHR(AU)

Introduction: Bone remodeling is a complex process that depends on the balance between formation and resorption bone, a process which is regulated by bone cells and systemic factors, like the Sympathetic Nervous system (SNS). The mediators of these system are able to regulate bone metabolism through adrenergic receptors on the surface os the osteoblastos. However, the role of ß-adrenergic receptors is not clear in he osteogenic differentiation process. Thus, in this study we aimed to evaluate the role of B-adrenergic receptor on osteoblastic differentiation of bone marrow mesenchymal stem cells from normotensive and Spontaneously Hypertensive Rats (SHR). Methods: 70-days-old male Wistar and SHR rats were used for bone marrow collection from femurs, which was placed in cell culture flasks and after in to 24-well plates, where they received osteogenic medium (OM: MEN, plus 50 µg/mL ascorbic acid, 10 mM ß glycerophosphate, and 10-8 M dexamethasone) and the treatment with Isoprenaline (0.01 µM), Carvedilol (1µM), non-selective adrenergic receptor antagonist, or Nebivolol (0,1 µM), ß1-adrenergic receptor antagonist. Cell proliferation (MTT assay) and alkaline phosphatase specific activity (Alp) were analyzed at day 7, 10 and 14. Mineralization was evaluated at day 14, by Alizarin Red S. Gene expression of osteogenic markers and B1 and B2-adrenergic receptor were evaluated at day 7, by real time-RT-PCR. The proteolytic activity of matrix metalloproteinase 2 (MMP-2) were evaluated at day 7 using gelatin zymography. The MAPK pathway was evaluated at the same period. Results: Isoprenaline provides increased alkaline phosphatase activity in the intermediate period. The addition of Nebivolol includes this response over this same period and, within 7 days, was able to reverse the reduced agonist reduction. Isoprenaline increased expression of all transcription factors and receptor blockade reversed this condition Isoprenaline increases expression of Opn, Ocn and BSP in Wistar animal cells, and in SHR only increases Ocn and Carvedilol-corrected treatment. MMP-2 was reduced by Nebivolol treatment just at Wistar cells. Besides that, Nebivolol reduced Adrb1 gene expression at day 7 in Wistar group. Mineralization showed that Nebivolol reduced mineral deposition in Wistar. Nebivolol reduced MAPK proteins phosphorylation. Conclusion: Our results suggest that ß1 adrenergic receptor seems to be involved in the osteogenic differentiation of cells from Wistar rats but not in SHR cells(AU)

Pharmacological modulation of b-adrenoceptors as a new cardioprotective strategy for therapy of myocardial dysfunction induced by ischemia and reperfusion

Abstract Purpose: To evaluate the cardioprotective response of the pharmacological modulation of β-adrenergic receptors (β-AR) in animal model of cardiac ischemia and reperfusion (CIR), in spontaneously hypertensive (SHR) and normotensive (NWR) rats. Methods: CIR was induced by the occlusion of left anterior descendent coronary artery (10 min) and reperfusion (75 min). The SHR was treated with β-AR antagonist atenolol (AT, 10 mg/kg, IV) 5 min before CIR, and NWR were treated with β-AR agonist isoproterenol (ISO, 0.5 mg/kg, IV) 5 min before CIR. Results: The treatment with AT increased the incidence of VA, AVB and LET in SHR, suggesting that spontaneous cardioprotection in hypertensive animals was abolished by blockade of β-AR. In contrast, the treatment with ISO significantly reduced the incidence of ventricular arrhythmia, atrioventricular blockade and lethality in NWR (30%, 20% and 20%, respectively), suggesting that the activation of β-AR stimulate cardioprotection in normotensive animals. Serum CK-MB were higher in SHR/CIR and NWR/CIR compared to respective SHAM group (not altered by treatment with AT or ISO). Conclusion: The pharmacological modulation of β-AR could be a new cardioprotective strategy for the therapy of myocardial dysfunctions induced by CIR related to cardiac surgery and cardiovascular diseases.