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.
Pelat
M
M
Laboratoire de Pharmacologie Médicale et Clinique, INSERM U317, Faculté de Médecine, 37 allées Jules Guesde 31073 Toulouse Cedex, France. pharmed@cict.fr
Verwaerde
P
P
Merial
C
C
Galitzky
J
J
Berlan
M
M
Montastruc
J L
JL
Senard
J M
JM
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006325:Heart Atria / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D019832:N-Methylscopolamine / Q000494:pharmacology; D009765:Obesity / Q000503:physiopathology*; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000378:metabolism; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000502:physiology*
D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C065959:AFDX 384; D010890:Pirenzepine; D000262:Adenylyl Cyclases; D019832:N-Methylscopolamine