Conventional and advanced echocardiographic assessment of systolic function in dogs sedated with dexmedetomidine or acepromazine.

Dexmedetomidine and acepromazine, sedatives commonly used in dogs have opposite vascular effects, resulting in afterload increase and decrease, respectively. This could variably affect systolic myocardial function. Previous echocardiographic studies assessing the cardiovascular effects of these drugs used conventional echocardiography, while advanced techniques such as speckle tracking echocardiography (STE) and tissue Doppler imaging (TDI), which are known to provide a more accurate assessment of systolic function, have been rarely used for this aim. Moreover, in the few studies using advanced techniques, the drugs where combined with opioids. Therefore, the main objective of this prospective study was to assess systolic myocardial function by conventional and advanced echocardiography (STE and TDI), in dogs sedated exclusively with dexmedetomidine or acepromazine not combined with other drugs. Twenty healthy dogs were randomly divided into two groups, Group A (acepromazine, 20 µg/kg IM), and Group D (dexmedetomidine, 5 µg/kg IM), cardiovascular parameters were assessed before sedation (T0), and thirty minutes afterwards (T1). Systolic arterial pressure and heart rate decreased in both groups at T1 as compared to T0. Only one conventional echocardiographic raw variable (left ventricular internal dimension in systole) and three out of five advanced echocardiographic variables (radial TDI systolic velocities at the epicardial region of the left ventricular free wall, longitudinal TDI systolic velocities of the septal mitral valve annulus and the STE-derived left ventricular global strain), were affected in Group D. A systolic impairment was observed in Group D and better estimated by advanced echocardiography. In Group A, only the end diastolic voume index (conventional echocardiography) was decreased. Both protocols seem to induce echocardiographic changes more likely secondary to their vascular action.

AZP2006, a new promising treatment for Alzheimer's and related diseases.

Progranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aß1-42 and in two different pathological animal models of Alzheimer's disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.

Successful transcatheter pulmonary valve implantation in a dog: first clinical report.

Transcatheter pulmonary valve (TPV) implantation is a therapeutic approach approved by the United States Food and Drug Administration for human patients with failing pulmonary conduits in 2010 and for failing bioprosthetic surgical pulmonary valves in 2017. We report here the first successful transcatheter implantation of a stented valve in a pulmonary position in a dog with congenital pulmonary valve disease. A 3-year-old, 10.9 kg, client-owned Beagle dog was referred for a follow-up visit after a percutaneous balloon valvuloplasty performed 22 months before for treatment of a severe type A valvular pulmonary stenosis. The Doppler-derived peak pressure gradient was 348 mmHg before the procedure and 66 mmHg 24 h after. The dog was lethargic. Echocardiography revealed a mild pulmonary stenosis (pressure gradient-43 mmHg), severe pulmonary regurgitation, and secondary severe right ventricular and right atrial dilation. Worsening of right heart dilation was observed 2 months later despite medical therapy. A TPV implantation was performed using a prestented Melody bovine jugular bioprosthetic valve. The dog recovered uneventfully and was discharged 10 days after the procedure. Right heart dilation resolved within 15 days. The dog was doing well 7 months after valve implantation. This case demonstrates that TPV implantation with a stented valve is technically feasible in dogs with severe pulmonary valve disease. Stringent postoperative care, with particular attention to thrombosis and infectious endocarditis, and appropriate sizing and positioning of the valve stent are keys to the success of this procedure.

Comparison of tibial anatomical-mechanical axis angle between predisposed dogs and dogs at low risk for cranial cruciate ligament rupture.

The purpose of this prospective, radiographic, descriptive study was to compare measurements of tibial anatomical-mechanical axis angle (AMA-angle), tibial plateau angle (TPA), relative tibial tuberosity width (rTTW) and Z-angle from mediolateral radiographs of the tibia between two canine breeds (72 dogs) not predisposed to cranial cruciate ligament rupture (CCLR) and those from a consecutive series of 185 large dogs and 17 West Highland white terriers (WHWT) diagnosed with unilateral, surgically confirmed CCLR. Correlations among these measurements were determined, and levels of inter- and intra-observer variability among and within three observers for each measurement were established using Kendall's coefficient of concordance. Breed had a significant effect on AMA-angle. The median AMA-angle of the subject population of large dogs affected by CCLR was 2.80° (range 1.09°-5.21°); for the WHWT, it was 6.34° (range 5.68°-8.88°); and for the clinically normal dogs, it was 0.74° (range 0.00°-5.40°). In the CCLR group, AMA-angle and TPA were strongly correlated (r=0.745; p<0.0001). A receiver operating characteristic (ROC) curve analysis showed that an AMA-angle higher than 1.87° had a sensitivity of 0.941 (95% confidence interval [CI]: 0.898-0.966) and a specificity of 0.965 (95% CI: 0.919-0.987) for predicting CCLR and was more accurate than TPA, rTTW and Z-angle at predicting CCLR (p<0.0001). Good inter- and intra-observer agreement was found for all measurements. The highly significant difference in AMA-angle found between clinically normal dogs and dogs with CCL injury suggests that AMA-angle magnitude may be a clinically relevant predisposing factor for the development of canine CCLR.

Differences between coagulation and cytokine profiles in dogs of different ages.

In human medicine, age is a risk factor for thromboembolic diseases associated with hypercoagulable and antifibrinolytic states, but information in veterinary medicine is limited. This study compared the thromboelastometric (TEM) profiles of two groups of dogs of distinct ages. Ten healthy old (>10 years) Beagles and 10 healthy young (<3 years) Beagles were recruited. White blood cell counts and haematocrit were significantly lower in the old group compared to the young group, and fibrinogen, total proteins, globulins and monocyte chemoattractant protein-1 plasma concentrations were significantly higher in the old group. Comparisons of the TEM profiles indicated a hypercoagulable profile and a decrease in fibrinolytic activity in all old Beagles. The findings support the need to consider age as a possible risk factor for thrombosis in dogs.

Evaluation of arterial blood gases and arterial blood pressures in brachycephalic dogs.

BACKGROUND: Brachycephalic dogs (BD) are prone to congenital upper airway obstruction (brachycephalic syndrome, BS). In humans suffering from sleep apnea, upper airway obstruction is known to cause hypertension. There is no information regarding the influence of BS in dogs on cardiorespiratory physiology. HYPOTHESIS: BD are prone to lower P(a) O(2), higher P(a) CO (2), and hypertension compared with meso- or dolicocephalic dogs (MDD). ANIMALS: Eleven BD and 11 MDD. METHODS: After a questionnaire was completed by the owner, a physical examination was performed. Height and thoracic circumferences were measured. Arterial blood gases, electrolyte concentrations, and packed cell volume (PCV) were measured. Systolic (SAP), mean (MAP), and diastolic (DAP) arterial blood pressure recordings were performed. RESULTS: A total of 7 French and 4 English bulldogs met the inclusion criteria. The control group consisted in 6 Beagles, 2 mixed breed dogs, 1 Staffordshire Bull Terrier, 1 Parson Russell Terrier, and 1 Australian Cattle Dog. Statistically, BD had lower P(a) O(2), higher P(a) CO2, and higher PCV when compared with controls (86.2 ± 15.9 versus 100.2 ± 12.6 mmHg, P = .017; 36.3 ± 4.6 versus 32.7 ± 2.6 mmHg, P = .019; 48.2 ± 3.5 versus 44.2 ± 5.4%, P = .026, respectively). Also, they had significantly higher SAP (177.6 ± 25.0 versus 153.5 ± 21.7 mmHg, P = .013), MAP (123.3 ± 17.1 versus 108.3 ± 12.2 mmHg, P = .014), and DAP (95.3 ± 19.2 versus 83.0 ± 11.5 mmHg, P = .042). BD with a P(a) CO (2) >35 mmHg were significantly older than those with a P(a) CO (2) ≤35 mmHg (58 ± 16 and 30 ± 11 months, P = .004). CONCLUSION: Results of this study suggest that some BD are prone to lower P(a) O(2), higher P(a) CO (2), and hypertension when compared with MDD. Age may be a contributing factor.

Effects of postoperative ketamine infusion on pain control and feeding behaviour in bitches undergoing mastectomy.

OBJECTIVES: To determine if ketamine administered to bitches at the end of a mastectomy, followed by a six-hour constant rate infusion (CRI), improved postoperative opioid analgesia and feeding behaviour. METHODS: The bitches were randomised into three groups: the placebo group received 0.09 ml/kg isotonic saline intravenously followed by a six-hour CRI of 0.5 ml/kg/hour, the low-dose ketamine received 150 microg/kg ketamine intravenously followed by a six-hour CRI of 2 microg/kg/minute and the high-dose ketamine group received 700 microg/kg ketamine intravenously followed by a six-hour CRI of 10 microg/kg/minute. Any additional opioids given were recorded at the time of extubation and at intervals after extubation. Food intake was evaluated eight (T8) and 20 (T20) hours after extubation by measuring the per cent coverage of basal energy requirements (BER). RESULTS: No significant difference was observed for opioid requirements between the three groups. The mean percentages of BER coverage did not differ significantly at T8 but the difference between the high-dose and low-dose ketamine groups (P=0.014), and the high-dose ketamine and placebo groups (P=0.038) was significant at T20. CLINICAL SIGNIFICANCE: This study demonstrated that 700 microg/kg ketamine given intravenously postoperatively followed by a six-hour ketamine CRI of 10 microg/kg/minute improved patient feeding behaviour.

Increased monoamine oxidase and semicarbazide-sensitive amine oxidase activities in white adipose tissue of obese dogs fed a high-fat diet

Adipocytes express two types of amine oxidases: the cell surface semicarbazidesensitive amine oxidase (SSAO) and the mitochondrial monoamine oxidase (MAO). In human abdominal subcutaneous adipose tissue, it has been reported that SSAO substrates stimulate glucose transport and inhibit lipolysis while MAO activity is decreased in obese patients when compared to age-matched controls. However, no information has been reported on visceral WAT. To further investigate the obesity-induced regulations of MAO and SSAO in white adipose tissue (WAT) from different anatomical locations, enzyme activities and mRNA abundance have been determined on tissue biopsies from control and high-fat fed dogs, an obesity model already described to be associated with arterial hypertension and hyperinsulinemia. MAO activity was increased in the enlarged omental WAT of diet-induced obese dogs, but not in their mesenteric WAT, another intra-abdominal fat depot. Subcutaneous WAT did not exhibit any change in MAO activity, as did the richest MAO-containing tissue: liver. Similarly, SSAO was increased in omental WAT of diet-induced obese dogs, but was not modified in other WAT and in aorta. The increase in SSAO activity observed in omental WAT likely results from an increased expression of the AOC3 gene since mRNA abundance and maximal benzylamine oxidation velocity were increased. Finally, plasma SSAO was decreased in obese dogs. Although the observed regulations differ from those found in subcutaneous WAT of obese patients, this canine model shows a tissue- and site-specific regulation of peripheral MAO and SSAO in obesity (AU)

Los adipocitos expresan dos tipos de amino-oxidasa: la amino oxidasa sensible a semicarbazida de la superficie celular (SSAO) y la monoamino oxidasa mitocondrial (MAO). En el tejido adiposo subcutáneo abdominal de humanos se ha descrito que los sustratos de la SSAO estimulan el transporte de glucosa e inhiben la lipólisis, mientras que la actividad MAO disminuye en pacientes obesos cuando se compara con controles de su propia edad. Sin embargo, no existe información sobre lo que ocurre en el tejido adiposo visceral. Se investiga, por tanto, sobre la influencia de la obesidad en la regulación de la MAO y SSAO en el tejido adiposo blanco (WAT) de diferentes localizaciones anatomicas, su actividad enzimatica y la riqueza de RNAm en biopsias tisulares procedentes de perros control y tratados con dieta rica en grasa. Este modelo de obesidad ya había sido previamente descrito asociado a hipertensión arterial e hiperinsulinemia. La actividad MAO se incrementó en WAT omental hipertrofiado de perros tratados con dieta rica en grasa, pero este efecto no se apreciaba en su correspondiente tejido adiposo mesentérico, otro depósito graso intra-abdominal. En el tejido adiposo subcutáneo no se pusieron de manifiesto cambios en la actividad MAO, ni tampoco en un tejido como el hígado, muy rico en MAO.De forma similar, la actividad SSAO se incrementó en el WAT omental de perros con obesidad inducida por la dieta, pero no se modificaba en otros WAT y en la aorta. El incremento encontrado en la actividad de la SSAO en el WAT (..) (AU)

Increased monoamine oxidase and semicarbazide-sensitive amine oxidase activities in white adipose tissue of obese dogs fed a high-fat diet.

Adipocytes express two types of amine oxidases: the cell surface semicarbazide-sensitive amine oxidase (SSAO) and the mitochondrial monoamine oxidase (MAO). In human abdominal subcutaneous adipose tissue, it has been reported that SSAO substrates stimulate glucose transport and inhibit lipolysis while MAO activity is decreased in obese patients when compared to age-matched controls. However, no information has been reported on visceral WAT. To further investigate the obesity-induced regulations of MAO and SSAO in white adipose tissue (WAT) from different anatomical locations, enzyme activities and mRNA abundance have been determined on tissue biopsies from control and high-fat fed dogs, an obesity model already described to be associated with arterial hypertension and hyperinsulinemia. MAO activity was increased in the enlarged omental WAT of diet-induced obese dogs, but not in their mesenteric WAT, another intra-abdominal fat depot. Subcutaneous WAT did not exhibit any change in MAO activity, as did the richest MAO-containing tissue: liver. Similarly, SSAO was increased in omental WAT of diet-induced obese dogs, but was not modified in other WAT and in aorta. The increase in SSAO activity observed in omental WAT likely results from an increased expression of the AOC3 gene since mRNA abundance and maximal benzylamine oxidation velocity were increased. Finally, plasma SSAO was decreased in obese dogs. Although the observed regulations differ from those found in subcutaneous WAT of obese patients, this canine model shows a tissue- and site-specific regulation of peripheral MAO and SSAO in obesity.

Insulin downregulates M(2)-muscarinic receptors in adult rat atrial cardiomyocytes: a link between obesity and cardiovascular complications.

OBJECTIVE: To determine whether decreased cardiac parasympathetic activity observed in obesity is due to insulin-induced alterations in cardiac M(2)-muscarinic receptors and/or adenylyl cyclase activity. DESIGN AND METHODS: After incubation with increasing concentrations of insulin, adult rat atrial cardiomyocytes were assayed for M(2)-muscarinic receptor binding density and affinity, and for M(2)R mRNA expression using RT-PCR analysis. Forskolin-stimulated adenylyl cyclase activity and its inhibition by carbachol were also assayed, as was endothelial nitric oxide synthase mRNA expression. The effects of insulin on M(2)-muscarinic receptor density and mRNA expression levels were analyzed using the insulin signaling inhibitors rapamycin, wortmanin and PD 098059. RESULTS: Insulin induces a concentration- and time-dependent decrease in expression of the M(2)R mRNA, and in [(3)H]N-methylscopolamine binding by the receptor. These effects on the M(2)R mRNA levels and on [(3)H]N-methylscopolamine binding were prevented by PD 98059, but not by wortmanin or rapamycin. Basal and forskolin-induced cAMP production did not differ, but the inhibition of forskolin-simulated enzyme activity by carbachol was blunted by insulin. No change in the mRNA levels for endothelial nitric oxide synthase was observed. CONCLUSION: In rat atrial cardiomyocytes, insulin markedly alters both the M(2)-muscarinic receptor density, and its mRNA expression through transcriptional regulation and adenylyl cyclase activity. These data suggest that the obesity-associated decrease in cardiac parasympathetic tone may be related to hyperinsulinemia, which could directly contribute to cardiovascular morbidity in obese patients.

Comparison of whole blood and plasma potassium concentrations in dogs using the Reflovet system.

BACKGROUND: The Reflovet system is designed for chemical analysis of whole blood. However, plasma or serum is recommended for potassium analysis because of possible interference from RBC potassium. Because RBC potassium concentration is low in most canine erythrocytes, however, there should be little or no interference. OBJECTIVE: The objective of this study was to compare potassium results obtained in whole blood and in plasma from dogs using the Reflovet system. METHODS: Blood samples were collected from 104 dogs into lithium-heparin tubes. The potassium concentration was measured in whole blood, and subsequently the PCV was measured. Samples were centrifuged and the potassium concentration was measured in plasma. Comparisons were made using Deming's regression and Bland-Altman difference plots. RESULTS: There was very good correlation between results of potassium measurements in whole blood and plasma (r = 0.93). Potassium values were moderately lower in whole blood: Potassium(blood) = 0.912 x Potassium(plasma)+ 0.119. Hemolysis had a negligible effect on the results, but the difference increased with the PCV value. In more than 90% of samples, the difference between the 2 measurements was

[Study of ventricular repolarization in an experimental model of arterial hypertension associated with obesity]. / Etude de la repolarisation ventriculaire dans un modèle expérimental d'HTA associée à l'obésité.

UNLABELLED: High fat diet (HFD) in dogs is associated with obesity and hypertension (HTN) but also with a significant and early decrease in heart rate variability (HRV). Decreased HRV has been shown to be a good predictor of sudden cardiac death due mainly to arrhythmic event. The aim of this work was to investigate the changes in ventricular repolarization through 24 hours EKG recordings in dogs with hypertension and rendered obese by 20 weeks of HFD. This was achieved through 24 hour EKG recording analysis of QT parameters. The aims of this work was i) feasibility of this method in dogs and ii) identification of potential arrhythmic risk factors that could explain overmortality during obesity. METHOD: Six dogs received a high fat diet (HFD) ad libitum during 20 weeks. A 24 hour EKG recording was realized just before and after 20 weeks of HFD. The following parameters studying QT interval were collected: QT interval lasting from the beginning of the Q wave to the apex (QTa) and to the end of the T wave (QTe), QT intervals plotted against RR intervals and two regression lines were calculated characterized by their slope and intersection with the Y axis, QT dispersion (longest minus shortest QT interval for each RR value) as well as the difference of QT interval between night and day at a fixed RR value considered as a marker of the sympathovagal balance. Our results show that HFD significantly increased body weight, blood pressure, heart rate, left ventricular mass and insulinemia. QT dispersion was increased in a non-significant manner both during day (+35%) and night (16%) for QTa and only during day for QTe (+27%). This increased dispersion of QT was not associated to any increase of QT interval. There was no effect of HFD on QT dynamicity parameter nor on the night-day difference at any RR interval from 300 to 1,300 ms. CONCLUSION: HFD tend increase QT dispersion without any effect on QT interval. These results are compatible with a heterogeneous repolarization probably related to abnormal autonomic nervous system tone. This study could partly explain occurrence of lethal arrhythmias during obesity which might lead to overmortality of obese patients. These results are different for QTa and QTe, but these two parameters are characterizing different type of ventricular cells. This study confirms the feasibility of this method in an experimental model, but results need to be validated in larger groups and in human.

[Early atrial gene regulation of obesity-related arterial hypertension]. / Modifications précoces du transcriptome auriculaire dans l'hypertension artérielle associée à l'obésité chez le chien.

High fat diet (HFD) induces both arterial hypertension and tachycardia in dogs. Changes in heart rate occur early and are in part due to a decrease in the parasympathetic drive to the heart secondary to down-regulation of atrial muscarinic M2 receptors (Pelat et al. Hypertension 1999; 340: 1066-72). These data suggest that HFD is able to modify genic expression at atrial level. Thus, the aim of this work was to perform a systematic study of the genic expression profile in dogs made obese and hypertensive by 9 weeks of HFD. Blood pressure and heart rate were measured by telemetry implanted 15 days before starting regimen in 6 HFD and in 6 control dogs. HFD was the normal canine diet administered to controls but mixed with 300 g of beef fat. At the end of the experience, animals were sacrified and right atria were collected. Gene regulation was assessed in pooled tissue samples from both groups using suppressive substractive hybridization and microarray analysis. Genes with induction or repression rates of at least 20% when compared to controls were sequenced. As previously reported HFD induced a significant increase in body weight, blood pressure and heart rate when compared to controls. The results of SSH experiments led to the identification of 32 genes which are differentially regulated in atria from HFD dogs. Most are genes encoding proteins which have been previously shown to be regulated during various cardiopathies (MMP9, Na/K-ATPase 3...). These changes indicate the existence of early remodeling processes of atrial myocardium secondary to HFD. Other group of genes encodes proteins with no role identified in heart up today (lec-3, ERK-3, TRIP1, nucleophosmin...) or which function remains totally unknown. This work confirms that HFD is associated with early changes in gene expression in atrium. These changes are unlikely to be related to ventricular hypertrophy which is observed only during long-term HFD. Further studies are necessary to demonstrate the role of these modifications in the pathophysiological mechanisms leading to the increase in heart rate in this model of obesity-related arterial hypertension.

The accuracy of the i-STAT portable analyser for measuring blood gases and pH in whole-blood samples from dogs.

To assess the suitability of the i-STAT portable analyser for use by non-laboratory personnel, we measured blood gases and pH in venous blood samples from 100 dogs. Deming's regression and bias plots were used to compare i-STAT results with those obtained by laboratory professionals using two different autocalibrated benchtop analysers. Overall accuracy of the portable analyser proved excellent for pH, pO(2), and pCO(2) (r=0.978, 0.968 and 0.997, respectively), with Deming's regression slopes close to 1.00 (0.96, 0.97 and 1.08 for pH, pO(2), and pCO(2), respectively) and intercepts close to zero (0.28, 0.47 kPa and 0.46 kPa for pH, pO(2), and pCO(2), respectively). The accuracy of the i-STAT was also satisfactory for calculated parameters: bicarbonates, total CO(2), base excess and oxygen saturation. Our findings show this portable analyser to be a valid substitute for expensive benchtop analysers in situations requiring mobility, or when small numbers of tests are to be performed by users not specialized in laboratory techniques.

Changes in vascular alpha 1- and alpha 2-adrenoceptor responsiveness by selegiline treatment.

Pharmacoepidemiological studies have reported an excess of mortality with selegiline, a MAO B inhibitor used in the treatment of Parkinson's disease. The mechanism of this putative adverse effect remains unknown but an interaction with the sympathetic nervous system was suggested. The aim of the present study was to investigate the influence of selegiline (10 mg/daily, orally during one week) on vascular alpha1- and alpha2-adrenoceptor responsiveness in conscious unrestrained dogs. Selegiline significantly increased resting values of both systolic and diastolic blood pressures and noradrenaline plasma levels (HPLC) without changing heart rate. Moreover, spectral analysis of systolic blood pressure (Fast Fourier Transformation) showed that selegiline increased the relative energy of a low frequency band without modifying the total spectrum. ED 50 calculated from dose-pressor response curves with phenylephrine (after beta-blockade by propranolol), an index of alpha1-adrenoceptor response or with noradrenaline (after alpha1- and beta blockade by prazosin plus propranolol), an index of alpha2-adrenoceptor response, were significantly higher after selegiline. Selegiline failed to modify the number of platelet alpha2-adrenoceptors measured by [(3)H] RX 821002 binding. Yohimbine-induced increase in noradrenaline release was significantly more marked after selegiline. These results support the evidence that selegiline induces a vascular alpha1- and alpha2-adrenoceptor-hyposensitivity that can be explained by the increase in noradrenaline release elicited by the drug.

Impaired atrial M(2)-cholinoceptor function in obesity-related hypertension.

The aim of this study was to investigate the activity of the parasympathetic limb of the baroreflex arch in a canine model of obesity-related hypertension. Twelve male beagle dogs were randomized into 2 groups. Six dogs were fed with normal canine food and 6 were submitted to a 10-week high-fat diet (HFD). We have evaluated the consequences of HFD on heart rate (HR) and blood pressure (BP) circadian cycles and methylscopolamine dose-response curves. Binding of [(3)H]-AF-DX 384 and adenylyl cyclase activity were investigated to determine the density and functionality of M(2)-cholinoceptors on right atrial membranes from control and HFD dogs. HFD induced a significant increase in body weight (15+/-1 vs 12+/-1 kg), systolic BP (161+/-5 vs 145+/-4 mm Hg), diastolic BP (92+/-3 vs 79+/-2 mm Hg), and HR (96+/-4 vs 81+/-3 bpm). Circadian rhythms of HR and BP observed in the baseline period were abolished after 9 weeks of HFD. After propranolol (1 mg/kg) pretreatment, the dose of methylscopolamine able to induce 50% maximum tachycardia was significantly increased after 9 weeks of HFD (7.4+/-0.3 vs 4.7+/-0.1 microg/kg). In the control group, the experimental period failed to modify these parameters. The numbers of M(2)-cholinoceptors measured in right atrial membranes were significantly lower in HFD than in control groups (54+/-6 vs 27+/-6 fmol/mg protein). The ability of carbachol to inhibit isoproterenol-stimulated adenylyl cyclase activity was significantly lower in HFD than in control groups (IC(50)=47+/-12 vs 6.4+/-1.4 micromol/L). However, the basal activity of adenylyl cyclase was unchanged by HFD. HFD decreases M(2)-cholinoceptor number and function in cardiomyocytes. This could explain the abolition of circadian rhythm of HR and the changes in chronotropic effect brought about by methylscopolamine.

Changes in short-term variability of blood pressure and heart rate during the development of obesity-associated hypertension in high-fat fed dogs.

OBJECTIVE: To investigate the nature and time course of autonomic nervous system changes elicited by a 21-week ad libitum high-fat diet (HFD) in dogs. RESULTS: The HFD increased body weight (+22.0+/-2.8% at week 21) with an abdominal circumference gain significantly more elevated than the thoracic one. The increases in insulin and free fatty acid plasma levels were correlated with body weight changes. Systolic and diastolic blood pressures and heart rate significantly increased (+23+/-6, +28+/-5 and 19+/-9% respectively). Arterial hypertension was characterized by an increase in cardiac output (+22.3+/-7.7%), in left ventricular mass (+18.1+/-5.0% at week 21) and a decrease in spontaneous baroreflex efficiency (-55+/-6%). The time course of autonomic changes (using spectral analysis of systolic blood pressure and heart rate) showed the existence of time-dependent modifications, which were linked with food intake. The initial rise in arterial blood pressure during body weight increment (observed between the 1st and 8th week of HFD) was associated with a transient increase in the low frequency band of systolic blood pressure variability and noradrenaline plasma levels associated with a long-lasting decrease in the high frequency band of heart rate variability. Early changes in short-term variability were significantly correlated with free fatty acid plasma levels. In contrast, the steady-state of obesity-related hypertension was associated with a decreased high frequency band of heart rate variability, without significant changes in noradrenaline plasma levels. CONCLUSIONS: This study shows that the HFD induces abdominal obesity, hyperinsulinaemia and arterial hypertension, with a left ventricular hypertrophy associated with a biphasic changes in autonomic activity: an early and long-lasting decrease in parasympathetic nervous system activity and an early but transient increase in sympathetic activity. The present data suggest that autonomic nervous system changes are dependent on the time course of obesity development.

Peripheral cardiovascular actions of SR 58611 A, a beta 3-adrenoceptor agonist, in the dog: lack of central effect.

In order to investigate the putative role of beta3-adrenoceptors in central and peripheral cardiovascular regulations, the effects of intracisternal (i.c.) and intravenous (i.v.) injections of SR 58611 A (10, 50, 100 and 200 nmol kg-1), a selective beta3-adrenoceptor agonist, were investigated in chloralose anaesthetized dogs. In normal dogs, i.v. SR 58611 A (100 and 200 nmol kg-1) induced a dose-dependent increase in heart rate with no change in blood pressure. After i.c. injection, SR 58611 A failed to modify blood pressure and heart rate (except at the highest dose 200 nmol kg-1 which induced a positive chronotropic effect). The positive chronotropic effect of SR 58611 A (200 nmol kg-1) appeared earlier and was significantly more pronounced after i.v. than i.c. administration. The positive chronotropic effect of i.v. SR 58611 A (200 nmol kg-1) was reduced by pretreatment with beta-adrenoceptor antagonists [propranolol, nadolol, bupranolol or the beta3-adrenoceptor selective antagonist, SR 59230 A (2 mg kg-1 i.v.)] and suppressed after sinoaortic denervation (i.e. after removal of vagal tone to the heart). These experiments do not show evidence for a primary central cardiovascular effect of SR 58611 A. The positive chronotropic effect of i.v. SR 58611 A is mainly of peripheral origin and can be attributed to a baroreceptor-mediated reflex due to the beta3-adrenoceptor mediated vasodilation with an increase in sympathetic tone and a reduction in vagal tone to the heart.

[Twenty-four hour time and frequency domain variability of systolic blood pressure and heart rate in an experimental model of arterial hypertension plus obesity]. / Variabilité temporelle et fréquentielle de la pression artérielle et de la fréquence cardiaque au cours du nycthémère dans un modèle expérimental d'hypertension artérielle avec obésité.

Modifications of heart rate (HR) and systolic blood pressure (SBP) variabilities (V) have been reported in the human syndrome arterial hypertension plus insulin-resistance. The aim of this study was to characterize the 24 h SBPV and HRV in both time and frequency domains during weight increase in dogs fed ad libitum with a high fat diet. Implantable transmitter units for measurement of blood pressure and heart rate were surgically implanted in five beagle male dogs. BP and HR were continuously recorded using telemetric measurements during 24 hours, before and after 6 and 9 weeks of hypercaloric diet in quiet animals submitted to a 12h light-dark cycle. To study nychtemeral cycle of SBP and HR, two periods were chosen: day (from 6.00 h to 19.00 h) and night (from 23.00 h to 6.00 h). Spontaneous baroreflex efficiency was measured using the sequence method. Spectral variability of HR and SBP was analyzed using a fast Fourier transformation on 512 consecutive values and normalized units of low (LF: 50-150 mHz, reflecting sympathetic activity) and high (HF: respiratory rate +/- 50 mHz, reflecting parasympathetic activity) frequency bands were calculated. The energy of total spectrum (from 0.004 to 1 Hz) was also studied. Body weight (12.4 +/- 0.9 vs 14.9 +/- 0.9 kg, p < 0.05). SBP (132 +/- 1 vs 147 +/- 1 mmHg, p < 0.05) significantly increased after 9 weeks of hypercaloric diet. A nycthemeral HR rhythm was present at baseline (day: 79 +/- 1 vs night: 71 +/- 1 bpm) but not after 9 weeks (day: 91 +/- 4 bpm ; night: 86 +/- 2 bpm). Concomitantly, the efficiency of spontaneous baroreflex decreased at 6 weeks (36 +/- 1 vs 42 +/- 2 mmHg/ms, p < 0.05). A significant decrease in HF energy of HRV was found after 6 but not after 9 weeks. LF energy of SBPV was increased at 6 but not at 9 weeks (table). [table: see text] In conclusion, this study shows that an hyperlipidic and hypercaloric diet induces transient variations in autonomic nervous system activity which could be the physiopathological link between obesity, insulin-resistance and arterial hypertension.

[Functional decoupling of left ventricular beta-adrenoceptor in a canine model of obesity-hypertension]. / Découplage fonctionnel des récepteurs beta-adrénergiques ventriculaires gauches dans un modèle canin d'obésité-hypertension.

OBJECTIVE: To assess cardiac beta-adrenoceptors (beta-AR) in an obesity-hypertension model. METHODS: Six male beagle dogs (aged 35 +/- 5 months) receiving during 30 weeks a high-fat diet with 60% uncooked beef fat were compared to 6 normal beagle dogs. With right auricular and left ventricular samples we analysed cardiac beta-AR density through binding study using [125I]-cyanopindolol. beta 1 and beta 2 densities were obtained by competition with CGP 20712A. Affinity state of beta-AR was assessed by competition with isoproterenol. Noradrenaline plasma level was assayed by HPLC. Left ventricular mass (LV mass) was measured by echocardiography. Results are expressed as mean +/- SE. All comparisons were performed using a variance analysis (*: p < 0.05). RESULTS: Systolic blood pressure was significantly higher in obesses (245 +/- 8 vs 197 +/- 10 mmHg in controls). Diastolic blood pressure did not differed between both groups (93 +/- 3 vs 84 +/- 3 mmHg in controls). Noradrenaline plasma levels were similar in both groups (276 +/- 30 vs 235 +/- 50 pg/mL in controls). Obesses were characterized by higher LV mass (80 +/- 24 vs 67 +/- 15 g in controls*). Right auricular and left ventricular beta-AR densities were not different in obesses (57 +/- 6 and 67 +/- 4 fmoles/mg protein) and in controls (68 +/- 7 and 63 +/- 9 fmoles/mg protein). The beta 1-AR proportion was the same in obesses and controls in right auricule (63 +/- 4 vs 64 +/- 3% in controls) and left ventricule (59 +/- 3 vs 60 +/- 4% in controls). The proportion of beta-AR receptors in a high affinity state was similar in right auricular samples (69 +/- 4 vs 67 +/- 3%) in controls) but was significantly different in left ventricule (28 +/- 6 vs 74 +/- 6%) in controls). CONCLUSION: Left ventricular beta-adrenoceptors came under a specific desensibilisation independent of plasma noradrenaline levels. This functional decoupling of beta-adrenoceptors may account for the progressive systolic dysfunction of hypertensive cardiomyopathy.