Reduced muscarinic cholinoceptor density and sensitivity in various models of experimental cardiac hypertrophy.
1. In the present study we investigated functional and binding characteristics of muscarinic receptors in experimental cardiac hypertrophy. 2. As models of cardiac hypertrophy we used hearts of spontaneously hypertensive rats (SHR) and Wistar rats with surgically induced abdominal aorta stenosis (ASR). Wistar Kyoto rats (WKY) and sham operated Wistar rats were used as respective controls. 3. The hypertrophy was more pronounced in hearts of ASR compared to SHR, although the mean arterial pressure was found to be lower. 4. Isolated, perfused Langendorff heart preparations (paced with 5 Hz) from both groups of hypertrophied hearts were less sensitive to the muscarinic agonists oxotremorin and methacholine (P < 0.05, all n = 6) when compared with control organs. The maximal reduction in contractile force induced by methacholine was 59.3 +/- 4.5% in SHR and 41.6 +/- 3.4% in ASR hearts versus 26.4 +/- 4.1% and 25.0 +/- 2.6% in control organs, respectively. 5. The density (fmol/mg protein-1) of muscarinic receptors in membrane homogenates of hearts from SHR (127.6 +/- 11.5) was unchanged, whereas in hearts from ASR (221.0 +/- 8.9) it was found to be reduced (P < 0.05) when compared to the respective controls (142.5 +/- 14.7 and 308.8 +/- 16.1, respectively, all n = 6). 6. From the present data we conclude that cardiac hypertrophy results in a loss of sensitivity towards muscarinic receptor stimulation. A corresponding reduction of left ventricular receptor density could only be demonstrated in massively hypertrophied hearts of ASR.
Mertens
M J
MJ
Department of Pharmacotherapy, University of Amsterdam, Netherlands.
Batink
H D
HD
Mathy
M J
MJ
Pfaffendorf
M
M
van Zwieten
P A
PA
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics; D066298:In Vitro Techniques; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D010095:Oxotremorine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000032:analysis*
D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D016210:Methacholine Chloride; D010095:Oxotremorine