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(Hypertension. 1999;34:1066-1072.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Impaired Atrial M₂-Cholinoceptor Function in Obesity-Related Hypertension

Michel Pelat; Patrick Verwaerde; Christelle Merial; Jean Galitzky; Michel Berlan; Jean-Louis Montastruc; Jean-Michel Senard

From Laboratoire de Pharmacologie Médicale et Clinique, INSERM U317, Faculté de Médecine, 37 allées Jules Guesde 31073 Toulouse Cedex, France.

Correspondence to Michel Pelat, Laboratoire de Pharmacologie Médicale et Clinique, INSERM U317, Faculté de Médecine, 37 allées Jules Guesde 31073 Toulouse Cedex, France. E-mail pharmed{at}cict.fr

Abstract—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 [³H]-AF-DX 384 and adenylyl cyclase activity were investigated to determine the density and functionality of M₂-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 µg/kg). In the control group, the experimental period failed to modify these parameters. The numbers of M₂-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 (IC₅₀=47±12 vs 6.4±1.4 µmol/L). However, the basal activity of adenylyl cyclase was unchanged by HFD. HFD decreases M₂-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.

Key Words: obesity • receptors, muscarinic • diet • adenylyl cyclase

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