Impaired atrial M2-cholinoceptor function in obesity-related hypertension

被引:45
作者
Pelat, M [1 ]
Verwaerde, P [1 ]
Merial, C [1 ]
Galitzky, J [1 ]
Berlan, M [1 ]
Montastruc, JL [1 ]
Senard, JM [1 ]
机构
[1] Fac Med Toulouse, INSERM, U317, Lab Pharmacol Med & Clin, F-31073 Toulouse, France
关键词
obesity; receptors; muscarinic; diet; adenylyl cyclase;
D O I
10.1161/01.HYP.34.5.1066
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
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 [H-3]-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 mu g/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 (IC50=47+/-12 vs 6.4+/-1.4 mu mol/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.
引用
收藏
页码:1066 / 1072
页数:7
相关论文
共 42 条
[1]   RELATIVE DENSITIES OF MUSCARINIC CHOLINERGIC AND BETA-ADRENERGIC RECEPTORS IN THE CANINE SINOATRIAL NODE AND THEIR RELATION TO SITES OF PACEMAKER ACTIVITY [J].
BEAU, SL ;
HAND, DE ;
SCHUESSLER, RB ;
BROMBERG, BI ;
KWON, B ;
BOINEAU, JP ;
SAFFITZ, JE .
CIRCULATION RESEARCH, 1995, 77 (05) :957-963
[2]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[3]   Cardiac muscarinic receptors decrease with age -: In vitro and in vivo studies [J].
Brodde, OE ;
Konschak, U ;
Becker, K ;
Rüter, F ;
Poller, U ;
Jakubetz, J ;
Radke, J ;
Zerkowski, HR .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (02) :471-478
[4]  
Caulfield MP, 1998, PHARMACOL REV, V50, P279
[5]  
CHASSAING C, 1976, J PHARMACOL-PARIS, V7, P609
[6]   Association between high heart rate and high arterial rigidity in normotensive and hypertensive subjects [J].
Cunha, RS ;
Pannier, B ;
Benetos, A ;
Siche, JP ;
London, GM ;
Mallion, JM ;
Safar, ME .
JOURNAL OF HYPERTENSION, 1997, 15 (12) :1423-1430
[7]  
DEIGHTON NM, 1990, N-S ARCH PHARMACOL, V341, P14
[8]  
FABER A, 1924, SCAND ARCH PHYSL, V45, P198
[9]  
FUKAMAUCHI F, 1993, MOL PHARMACOL, V44, P940
[10]   Validation of a telemetry system for measurement of blood pressure, electrocardiogram and locomotor activity in beagle dogs [J].
Gelzer, ARM ;
Ball, HA .
CLINICAL AND EXPERIMENTAL HYPERTENSION, 1997, 19 (07) :1135-1160