Activation of TRPV1 improves natriuresis and salt sensitivity in high-fat diet fed mice.

Western diet (WD) intake increases morbidity of obesity and salt-sensitive hypertension albeit mechanisms are largely unknown. We investigated the role of transient receptor potential vanilloid 1 (TRPV1) in WD intake-induced hypertension. TRPV1-/- and wild-type (WT) mice were fed a normal (CON) or Western diet (WD) for 16-18 weeks. Mean arterial pressure (MAP) after normal sodium glucose (NSG) loading with or without L-NAME (a NO synthase inhibitor) or N-oleoyldopamine (OLDA, a TRPV1agonist) was not different between the two strains on CON.WT or TRPV1-/- mice fed WD had increased MAP after NSG, with a greater magnitude in TRPV1-/- mice. OLDA decreased while L-NAME increased MAP in WT-WD but not in TRPV1-/--WD mice. The urinary nitrates plus nitrites excretion (UNOx), an indicator of renal NO production, was increased in both strains on CON after NSG. TRPV1 ablation with WD intake abolished NSG-induced increment in UNOx. OLDA further increased while L-NAME prevented NSG-induced increment in UNOx in WT-WD mice. Urinary sodium excretion was increased in both strains on CON and in WT-WD mice but not in TRPV1-/--WD mice after NSG. OLDA further increased while L-NAME prevented NSG-induced increases in sodium excretion in WT-WD but not in TRPV1-/--WD mice. Thus, TRPV1 ablation increases salt sensitivity during WD intake possibly via impaired renal NO production and sodium excretion. Activation of TRPV1 enhances renal NO production and sodium excretion, resulting in prevention of increased salt sensitivity during WD intake.

Ablation of TRPV1 Abolishes Salicylate-Induced Sympathetic Activity Suppression and Exacerbates Salicylate-Induced Renal Dysfunction in Diet-Induced Obesity.

Sodium salicylate (SA), a cyclooxygenase inhibitor, has been shown to increase insulin sensitivity and to suppress inflammation in obese patients and animal models. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel expressed in afferent nerve fibers. Cyclooxygenase-derived prostaglandins are involved in the activation and sensitization of TRPV1. This study tested whether the metabolic and renal effects of SA were mediated by the TRPV1 channel. Wild-type (WT) and TRPV1-/- mice were fed a Western diet (WD) for 4 months and received SA infusion (120mg/kg/day) or vehicle for the last 4 weeks of WD feeding. SA treatment significantly increased blood pressure in WD-fed TRPV1-/- mice (p < 0.05) but not in WD-fed WT mice. Similarly, SA impaired renal blood flow in TRPV1-/- mice (p < 0.05) but not in WT mice. SA improved insulin and glucose tolerance in both WT and TRPV1-/- mice on WD (all p < 0.05). In addition, SA reduced renal p65 and urinary prostaglandin E2, prostaglandin F1α, and interleukin-6 in both WT and TRPV1-/- mice (all p < 0.05). SA decreased urine noradrenaline levels, increased afferent renal nerve activity, and improved baroreflex sensitivity in WT mice (all p < 0.05) but not in TRPV1-/- mice. Importantly, SA increased serum creatinine and urine kidney injury molecule-1 levels and decreased the glomerular filtration rate in obese WT mice (all p < 0.05), and these detrimental effects were significantly exacerbated in obese TRPV1-/- mice (all p < 0.05). Lastly, SA treatment increased urine albumin levels in TRPV1-/- mice (p < 0.05) but not in WT mice. Taken together, SA-elicited metabolic benefits and anti-inflammatory effects are independent of TRPV1, while SA-induced sympathetic suppression is dependent on TRPV1 channels. SA-induced renal dysfunction is dependent on intact TRPV1 channels. These findings suggest that SA needs to be cautiously used in patients with obesity or diabetes, as SA-induced renal dysfunction may be exacerbated due to impaired TRPV1 in obese and diabetic patients.

Knockout of TRPV1 Exacerbates Ischemia-reperfusion-induced Renal Inflammation and Injury in Obese Mice.

BACKGROUND/AIM: Transient receptor potential vanilloid type 1 (TRPV1) has anti-inflammatory properties. The present study aimed to investigate the role of TRPV1 in renal inflammatory responses and tissue injury following renal ischemia-reperfusion (I/R) in diet-induced obese mice. MATERIALS AND METHODS: TRPV1 knockout and wild type mice were fed a normal or western diet (WD) for 23 weeks and were then subjected to renal I/R injury. RESULTS: TRPV1 knockout mice showed enhanced WD-induced renal macrophage infiltration and collagen deposition. Knocking out TRPV1 exacerbated renal I/R-induced increase of malondialdehyde, interleukin-6, monocyte chemoattractant protein-1, and NF-ĸB in obese mice. Similar results were observed in the expression of phosphorylated Smad1 and Smad2/3. Blockade of calcitonin gene-related peptide (CGRP) receptors with CGRP8-37 worsened the I/R-induced renal inflammation and injury. CONCLUSION: Our data indicate that preserving TRPV1 expression and function may prevent renal I/R injury in obesity likely through alleviating inflammatory responses.

Protective Effects of TRPV1 Activation Against Cardiac Ischemia/ Reperfusion Injury is Blunted by Diet-Induced Obesity.

BACKGROUND: Activation of Transient Receptor Potential Vanilloid Subtype 1 (TRPV1) channels protects the heart from Ischemia/Reperfusion (I/R) injury through releasing Calcitonin Gene-Related Peptide (CGRP) and Substance P (SP). The current study aimed to study the cardioprotective effects of TRPV1 in obesity. METHODS: TRPV1 gene knockout (TRPV1-/-) and Wild-Type (WT) mice were Fed a High-Fat Diet (HFD) or a control diet or for 20 weeks, and then the hearts were collected for I/R injury ex vivo. The hearts were mounted on a Langendorff apparatus and subjected to ischemia (30 min) and reperfusion (40 min) after incubated with capsaicin (10 nmol/L), CGRP (0.1 µmol/L) and SP (0.1 µmol/L). Then, Coronary Flow (CF), left ventricular peak positive dP/dt (+dP/dt), Left Ventricular Developed Pressure (LVDP) and Left Ventricular End-Diastolic Pressure (LVEDP) were measured. RESULTS: HFD intake remarkably reduced CF, +dP/dt and LVDP and elevated LVEDP in both strains (P<0.05). Treatment with capsaicin decreased infarct size, increased CF, +dP/dt and LVDP, and decreased LVEDP in WT mice on control diet (P<0.05), but did not do so in other three groups. Treatment with CGRP and SP decreased infarct size in both strains fed with control diet (P<0.05). In contrast, not all the parameters of cardiac postischemic recovery in HFD-fed WT and TRPV1-/- mice were improved by CGRP and SP. CONCLUSION: These results suggest that HFD intake impairs cardiac postischemic recovery. HFDinduced impairment of recovery is alleviated by CGRP in both strains and by SP only in TRPV1-/- mice, indicating that the effects of CGRP and SP are differentially regulated during HFD intake.

Protease-activated receptor 2 protects against myocardial ischemia-reperfusion injury through the lipoxygenase pathway and TRPV1 channels.

This study tests the hypothesis that the lipoxygenase (LOX) pathway mediates protease-activated receptor (PAR) 2-induced activation of the transient receptor potential vanilloid receptor 1 (TRPV1) to protect the heart from ischemia/reperfusion (I/R) injury. SLIGRL, a PAR2 activating peptide, was administered prior to reperfusion following left anterior descending coronary artery ligation in wild type (WT) and TRPV1 knockout (TRPV1-/-) mice. In a Langendorffly perfused heart I/R model, hemodynamic parameters, including left ventricular end-diastolic pressure, left ventricular developed pressure, coronary blood flow and left ventricular peak +dP/dt were evaluated after I/R. SLIGRL reduced the cardiac infarct size in WT and TRPV1-/- mice with a greater effect in the former strain (P<0.05). SLIGRL increased plasma levels of calcitonin gene-related peptide (CGRP) and substance P in WT (both P<0.05) but not in TRPV1-/- mice. Pretreatment with CGRP8-37 (a CGRP receptor antagonist) or RP67580 (a neurokinin-1 receptor antagonist) alone had no effect on SLIGRL-induced cardiac protection in either strain. However, combined administration of CGRP8-37 and RP67580 abolished SLIGRL-induced cardiac protection in WT but not in TRPV1-/- mice. Nordihydroguaiaretic acid (a general LOX inhibitor) and baicalein (a 12-LOX inhibitor), but not indomethacin (a cyclooxygenase inhibitor) and hexanamide (a selective cytochrome P450 epoxygenase inhibitor), abolished the protective effects of SLIGRL in WT (all P<0.05) but not in TRPV1-/- hearts. These data suggested that PAR2, possibly via 12-LOX, activates TRPV1 and leads to CGRP and substance P release to prevent I/R injury in the heart, indicating that the 12-LOX-TRPV1 pathway conveys cardiac protection to alleviate myocardial infarction.

TRPV1 Mediates Glucose-induced Insulin Secretion Through Releasing Neuropeptides.

BACKGROUND/AIM: Transient receptor potential vanilloid 1 (TRPV1)-expressing sensory nerves innervate the pancreatic islets. Sensory neuropeptides, including calcitonin gene-related peptide (CGRP) and substance P (SP), participate in insulin secretion. This study aimed to investigate the role of TRPV1 in glucose-induced insulin secretion. MATERIALS AND METHODS: TRPV1-/- and wild-type (WT) mice were fed a normal diet for 24 weeks. Glucose tolerance and insulin secretion were measured at the end of the experiments. RESULTS: TRPV1-/- mice had greater impairments in glucose tolerance and higher decrease in glucose-induced insulin secretion than WT mice. Capsaicin (a TRPV1 agonist) increased insulin secretion in WT, but not in TRPV1-/- mice. Glucose-induced insulin secretion was blunted in TRPV1-/- mice, and was attenuated by AMG9810 (a TRPV1 inhibitor), CGRP8-37 (a CGRP receptor antagonist), or RP67580 (a NK-1 receptor antagonist) in WT mice. Glucose-induced SP and CGRP release from WT pancreas was higher than that from TRPV1-/- pancreas. CONCLUSION: TRPV1 mediates glucose-induced insulin secretion likely through CGRP and SP release.

TRPV1 protects renal ischemia-reperfusion injury in diet-induced obese mice by enhancing CGRP release and increasing renal blood flow.

BACKGROUND: Obesity is a major risk factor for end-stage renal disease. Using transient receptor potential vanilloid 1 knockout (TRPV1-/-) mice, we tested the hypothesis that TRPV1 protects against obesity-induced exacerbation of renal ischemia-reperfusion (I/R) injury. METHODS: TRPV1-/- and wild-type (WT) mice were fed a chow or Western diet (WD) for 22-23 weeks. After that, mice were subjected to renal I/R injury, and renal cortical blood flow (CBF) and medullary blood flow (MBF) were measured. RESULTS: The Western diet significantly increased body weight and fasting blood glucose levels in both TRPV1-/- and WT mice. WD-induced impairment of glucose tolerance was worsened in TRPV1-/- mice compared with WT mice. WD intake prolonged the time required to reach peak reperfusion in the cortex and medulla (both P < 0.05), decreased the recovery rate of CBF (P < 0.05) and MBF (P < 0.05), and increased blood urea nitrogen, plasma creatinine, and urinary 8-isoprostane levels after I/R in both mouse strains, with greater effects in TRPV1-/- mice (all P < 0.05). Renal I/R increased calcitonin gene-related peptide (CGRP) release in WT but not in TRPV1-/- mice, and WD attenuated CGRP release in WT mice. Moreover, blockade of CGRP receptors impaired renal regional blood flow and renal function in renal I/R injured WT mice. CONCLUSION: These results indicate that TRPV1 plays a protective role in WD-induced exacerbation of renal I/R injury probably through enhancing CGRP release and increasing renal blood flow.

Ablation of TRPV1 Elevates Nocturnal Blood Pressure in Western Diet-fed Mice.

BACKGROUND: This study tested the hypothesis that genetically ablation of transient receptor potential vanilloid type 1 (TRPV1) exacerbates impairment of baroreflex in mice fed a western diet (WD) and leads to distinct diurnal and nocturnal blood pressure patterns. METHODS: TRPV1 gene knockout (TRPV1-/-) and wild-type (WT) mice were given a WD or normal diet (CON) for 4 months. RESULTS: Capsaicin, a selective TRPV1 agonist, increased ipsilateral afferent renal nerve activity in WT but not TRPV1-/- mice. The sensitivity of renal sympathetic nerve activity and heart rate responses to baroreflex were reduced in TRPV1-/--CON and WT-WD and further decreased in TRPV1-/--WD compared to the WT-CON group. Urinary norepinephrine and serum insulin and leptin at day and night were increased in WT-WD and TRPV1-/--WD, with further elevation at night in TRPV1-/--WD. WD intake increased leptin, IL-6, and TNF-α in adipose tissue, and TNF-α antagonist III, R-7050, decreased leptin in TRPV1-/--WD. The urinary albumin level was higher in TRPV1-/--WD than WT-WD. Blood pressure was not different during daytime among all groups, but increased at night in the TRPV1-/--WD group compared with other groups. CONCLUSIONS: TRPV1 ablation leads to elevated nocturnal but not diurnal blood pressure, which is probably attributed to further enhancement of sympathetic drives at night.

Knockout of TRPV1 Exacerbates Left Ventricular Diastolic Dysfunction Induced by A High-fat Diet in Mice.

BACKGROUND: Transient Receptor Potential Vanilloid 1 (TRPV1) channels in sensory nerves have anti-oxidative properties and counteract obesity and diabetes that are associated with diastolic dysfunction with preserved ejection fraction. We tested the hypothesis that TRPV1 knockout exacerbates high-fat diet (HFD)-induced glucose intolerance and diastolic dysfunction. METHOD: Trpv1-/- and wild-type (WT) mice were fed chow diet or HFD for 20 weeks. Then, we performed the intraperitoneal glucose tolerance test, measured the heart function through transthoracic echocardiography and Langendorff heart perfusion system, analyzed cardiac histology, and measured the myocardial superoxide production and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. RESULTS: HFD increased body weight, heart weight, and levels of fasting glucose, insulin, and leptin in both strains, with no differences between two strains. HFD impaired glucose tolerance in both strains with a more profound effect on Trpv1-/- than WT mice. HFD increased left ventricular (LV) internal diameter in diastole in both strains, while increased LV posterior wall thickness in diastole in Trpv1-/- but not in WT mice. HFD increased LV end-diastolic pressure in both strains with a further increase in Trpv1-/- mice, while decreased -dP/dt in Trpv1-/- but not in WT mice. HFDinduced cardiac collagen deposition and superoxide production were enhanced in Trpv1-/- mice. HFD upregulated cardiac p22phox in both strains, while increased p47phox in Trpv1-/- but not in WT mice. CONCLUSION: In summary, TRPV1 knockout exacerbates HFD-induced glucose intolerance, cardiac oxidative stress and collagen deposition, leading to aggravated LV diastolic dysfunction.

Genetic ablation of TRPV1 exacerbates pressure overload-induced cardiac hypertrophy.

Transient receptor potential vanilloid 1 (TRPV1) channels expressed in sensory nerves may regulate vascular tone and cardiovascular function via their anti-inflammatory effects by releasing neuropeptide calcitonin gene-related peptide (CGRP). Inflammation plays a role in the progression of cardiac hypertrophy and TRPV1 activation may be key to cardiac inflammatory processes. The aim of this study was to test the hypothesis that TRPV1 modulates inflammatory processes to protect the heart from pressure overload-induced hypertrophy and inflammatory responses. Trpv1 knockout (Trpv1-/-) and wild-type (WT) mice were subjected to transverse aortic constriction (TAC) or sham operation. Four weeks after TAC, WT and Trpv1-/- mice had developed left ventricular (LV) hypertrophy with increased LV mass, fibrosis and infiltration of macrophages as well as increased secretion of tumor necrosis factor α, interleukin-6 from cardiac tissue (all P < 0.05), those were higher in Trpv1-/- than in WT mice with TAC (all P < 0.05). In addition, decreases of LV ejection fraction and fractional shortening were greater in Trpv1-/- than in WT mice (both P < 0.05). Moreover, atrial natriuretic peptide level was greater in Trpv1-/- than in WT mice with TAC (P < 0.05). Compared to sham control, TAC procedure significantly increased cardiac TRPV1 expression and CGRP release in WT mice (both P < 0.05), but not in Trpv1-/- mice. These results demonstrate that Trpv1 gene deletion results in excessive inflammation, exaggerates cardiac hypertrophy, and deteriorates cardiac function after TAC, which may be due to abnormal cardiac remodeling and decreased CGRP in the absence of TRPV1.

Cellular biophysical dynamics and ion channel activities detected by AFM-based nanorobotic manipulator in insulinoma ß-cells.

Distinct biochemical, electrochemical and electromechanical coupling processes of pancreatic ß-cells may well underlie different response patterns of insulin release from glucose and capsaicin stimulation. Intracellular Ca(2+) levels increased rapidly and dose-dependently upon glucose stimulation, accompanied with about threefold rapid increases in cellular stiffness. Subsequently, cellular stiffness diminished rapidly and settled at a value about twofold of the baseline. Capsaicin caused a similar transient increase in intracellular Ca(2+) changes. However, cellular stiffness increased gradually to about twofold until leveling off. The current study characterizes for the first time the biophysical properties underlying glucose-induced biphasic responses of insulin secretion, distinctive from the slow and single-phased stiffness response to capsaicin despite similar changes in intracellular Ca(2+) levels. The integrated AFM nanorobotics and optical investigation enables the fine dissection of mechano-property from ion channel activities in response to specific and non-specific agonist stimulation, providing novel biomechanical markers for the insulin secretion process. FROM THE CLINICAL EDITOR: This study characterizes the biophysical properties underlying glucose-induced biphasic responses of insulin secretion. Integrated AFM nanorobotics and optical investigations provided novel biomechanical markers for the insulin secretion process.

Nanomechanical analysis of insulinoma cells after glucose and capsaicin stimulation using atomic force microscopy.

AIM: Glucose stimulates insulin secretion from pancreatic islet ß cells by altering ion channel activity and membrane potential in the ß cells. TRPV1 channel is expressed in the ß cells and capsaicin induces insulin secretion similarly to glucose. This study aims to investigate the biophysical properties of the ß cells upon stimulation of membrane channels using an atomic force microscopic (AFM) nanoindentation system. METHODS: ATCC insulinoma cell line was used. Cell stiffness, a marker of reorganization of cell membrane and cytoskeleton due to ion channel activation, was measured in real time using an integrated AFM nanoindentation system. Cell height that represented structural changes was simultaneously recorded along with cell stiffness. RESULTS: After administration of glucose (16, 20 and 40 mmol/L), the cell stiffness was markedly increased in a dose-dependent manner, whereas cell height was changed in an opposite way. Lower concentrations of capsaicin (1.67 × 10(-9) and 1.67 × 10(-8) mol/L) increased the cell stiffness without altering cell height. In contrast, higher concentrations of capsaicin (1.67 × 10(-6) and 1.67 × 10(-7) mol/L) had no effect on the cell physical properties. CONCLUSION: A unique bio-nanomechanical signature was identified for characterizing biophysical properties of insulinoma cells upon general or specific activation of membrane channels. This study may deepen our understanding of stimulus-secretion coupling of pancreatic islet cells that leads to insulin secretion.

Protease-activated receptor 2-mediated protection of myocardial ischemia-reperfusion injury: role of transient receptor potential vanilloid receptors.

Activation of the protease-activated receptor 2 (PAR2) or the transient receptor potential vanilloid type 1 (TRPV1) channels expressed in cardiac sensory afferents containing calcitonin gene-related peptide (CGRP) and/or substance P (SP) has been proposed to play a protective role in myocardial ischemia-reperfusion (I/R) injury. However, the interaction between PAR2 and TRPV1 is largely unknown. Using gene-targeted TRPV1-null mutant (TRPV1(-/-)) or wild-type (WT) mice, we test the hypothesis that TRPV1 contributes to PAR2-mediated cardiac protection via increasing the release of CGRP and SP. Immunofluorescence labeling showed that TRPV1 coexpressed with PAR2, PKC-epsilon, or PKAc in cardiomyocytes, cardiac blood vessels, and perivascular nerves in WT but not TRPV1(-/-) hearts. WT or TRPV1(-/-) hearts were Langendorff perfused with the selective PAR2 agonist, SLIGRL, in the presence or absence of various antagonists, followed by 35 min of global ischemia and 40 min of reperfusion (I/R). The recovery rate of coronary flow, the maximum rate of left ventricular pressure development, left ventricular end-diastolic pressure, and left ventricular developed pressure were evaluated after I/R. SLIGRL improved the recovery of hemodynamic parameters, decreased lactate dehydrogenase release, and reduced the infarct size in both WT and TRPV1(-/-) hearts (P < 0.05). The protection of SLIGRL was significantly surpassed for WT compared with TRPV1(-/-) hearts (P < 0.05). CGRP(8-37), a selective CGRP receptor antagonist, RP67580, a selective neurokinin-1 receptor antagonist, PKC-epsilon V1-2, a selective PKC-epsilon inhibitor, or H-89, a selective PKA inhibitor, abolished SLIGRL protection by inhibiting the recovery of the rate of coronary flow, maximum rate of left ventricular pressure development, and left ventricular developed pressure, and increasing left ventricular end-diastolic pressure in WT but not TRPV1(-/-) hearts. Radioimmunoassay showed that SLIGRL increased the release of CGRP and SP in WT but not TRPV1(-/-) hearts (P < 0.05), which were prevented by PKC-epsilon V1-2 and H-89. Thus our data show that PAR2 activation improves cardiac recovery after I/R injury in WT and TRPV1(-/-) hearts, with a greater effect in the former, suggesting that PAR2-mediated protection is TRPV1 dependent and independent, and that dysfunctional TRPV1 impairs PAR2 action. PAR2 activation of the PKC-epsilon or PKA pathway stimulates or sensitizes TRPV1 in WT hearts, leading to the release of CGRP and SP that contribute, at least in part, to PAR2-induced cardiac protection against I/R injury.

N-oleoyldopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1.

N-oleoyldopamine (OLDA), a bioactive lipid originally found in the mammalian brain, is an endovanilloid that selectively activates the transient receptor potential vanilloid type 1 (TRPV1) channel. This study tests the hypothesis that OLDA protects the heart against ischemia and reperfusion (I/R) injury via activation of the TRPV1 in wild-type (WT) but not in gene-targeted TRPV1-null mutant (TRPV1(-/-)) mice. Hearts of WT or TRPV1(-/-) mice were Langendorffly perfused with OLDA (2 x 10(-9) M) in the presence or absence of CGRP8-37 (1 x 10(-6) M), a selective calcitonin gene-related peptide (CGRP) receptor antagonist; RP-67580 (1 x 10(-6) M), a selective neurokinin-1 receptor antagonist; chelerythrine (5 x 10(-6) M), a selective protein kinase C (PKC) antagonist; or tetrabutylammonium (TBA, 5 x 10(-4) M), a nonselective K(+) channel antagonist, followed by 35 min of global ischemia and 40 min of reperfusion (I/R). Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), coronary flow (CF), and left ventricular peak positive dP/dt (+dP/dt) were evaluated after I/R. OLDA improved recovery of cardiac function after I/R in WT but not TRPV1(-/-) hearts by increasing LVDP, CF, and +dP/dt and by decreasing LVEDP. CGRP8-37, RP-67580, chelerythrine, or TBA abolished the protective effect of OLDA in WT hearts. Radioimmunoassay showed that the release of substance P (SP) and CGRP after OLDA treatment was higher in WT than in TRPV1(-/-) hearts, which was blocked by chelerythrine or TBA. Thus OLDA exerts a cardiac protective effect during I/R injury in WT hearts via CGRP and SP release, which is abolished by PKC or K(+) channel antagonists. The protective effect of OLDA is void in TRPV1(-/-) hearts, supporting the notion that TRPV1 mediates OLDA-induced protection against cardiac I/R injury.

TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice.

Although the transient receptor potential vanilloid type 1 (TRPV1)-containing afferent nerve fibers are widely distributed in the heart, the relationship between TRPV1 function and cardiac ischemic preconditioning (PC) has not been well defined. Using TRPV1 knockout mice (TRPV1(-/-)), we studied the role of TRPV1 in PC-induced myocardial protection. Hearts of gene-targeted TRPV1-null mutant (TRPV1(-/-)) or wild-type (WT) mice were Langendorffly perfused in the presence or absence of CGRP(8-37), a selective calcitonin gene-related peptide (CGRP) receptor antagonist; or RP-67580, a selective neurokinin-1 receptor antagonist when hearts were subjected to three 5-min periods of ischemia PC followed by 30 min of global ischemia and 40 min of reperfusion (I/R). PC before I/R decreased left ventricular (LV) end-diastolic pressure and increased LV developed pressure, coronary flow (CF), peak-positive maximum rate of rise of LV pressure in WT mice (PC-WT) compared with PC-TRPV1(-/-), TRPV1(-/-), or WT hearts (P < 0.05), and PC also decreased LV end-diastolic pressure in PC-TRPV1(-/-) compared with TRPV1(-/-). CGRP(8-37) or RP-67580 abolished PC-induced protection in WT but not TRPV1(-/-) hearts (P < 0.05). Moreover, PC decreased lactate dehydrogenase release and infarct size in PC-WT compared with PC-TRPV1(-/-), TRPV1(-/-), or WT hearts, and it also lowered these parameters in PC-TRPV1(-/-) compared with TRPV1(-/-) hearts (P < 0.05). Radioimmunoassay showed that the release of substance P and CGRP after PC was higher in WT hearts than in TRPV1(-/-) hearts (P < 0.05), which was attenuated by capsazepine in WT but not TRPV1(-/-) hearts. Thus PC-induced protection of the heart was impaired in TRPV1(-/-) hearts, indicating that TRPV1 contributes to the beneficial effects of preconditioning against I/R injury through release substance P and CGRP.

Effects of simvastatin on activities of endogenous antioxidant enzymes and angiotensin-converting enzyme in rat myocardium with pressure-overload cardiac hypertrophy.

AIM: To investigate effects of simvastatin (Sim) on the activities of antioxidant enzymes and angiotensin-converting enzyme in rat myocardium with pressure-overload cardiac hypertrophy. METHODS: Left ventricular hypertrophy (LVH) was induced by partly constricting rat abdominal aorta between the left and right renal artery. Rats were given ig Sim 1.8 and 3.6 mg . kg-1 . d-1 for 8 weeks following 6 weeks aortic constriction. Activities of antioxidant enzymes and angiotensin-converting enzyme, and lipid peroxidation of left ventricular (LV) tissue were determined. RESULTS: Contents of angiotensin II and thiobarbituric acid reactive substances (TBARS), and activity of ACE in LVH group (n = 8) were increased by 163 %, 90 %, and 130 %, respectively (P < 0.01)compared with sham-operated group (n = 7), and were decreased by 30 %, 37 %, and 51 %, respectively (P < 0.01) in high dosage Sim treatment group (n = 9) compared with LVH group. Activities of catalase and glutathione peroxidase of LV tissue in LVH group were decreased by 29 % and 23 % (P < 0.01) compared with sham-operated group, and were increased by 32 % and 22 % (P < 0.01) in high dosage Sim treatment group compared with LVH group. Activity of Cu, Zn-superoxide dismutase (SOD) of LV tissue was increased by 33 % in LVH group compared with sham-operated group. Sim treatment did not significantly affect activity of Cu,Zn-SOD. CONCLUSION: Alteration of redox status in myocardium is associated with cardiac hypertrophy and inhibitory effects of Sim on cardiac hypertrophy in rats model might be linked to its antioxidant effects.