Release of N-[3H]methylscopolamine from isolated guinea pig atria is controlled by diffusion and rebinding.
This study attempts to analyze the inter-relationship between the slow fading of muscarinic antagonist action observed in isolated tissue preparations upon washout and the dissociation kinetics at the receptor level. Isolated guinea pig left atria stimulated electrically at 3 Hz were equilibrated with N-[3H]methylscopolamine ([3H]NMS) and the time course of release of [3H]NMS was studied. In parallel experiments, the fading of the antimuscarinic action of NMS was monitored by repeated determinations of the negative inotropic effect of oxotremorine. In comparison, the dissociation of [3H]NMS from muscarinic receptors was recorded in a membrane suspension of guinea pig right atria. Having been equilibrated at 10(-8) M [3H]NMS, the atria released [3H]NMS extremely slowly, when transferred into a drug-free washout bath: not even half of the initially bound [3H]NMS was lost within 3 hr. With a corresponding time course, 10(-8) M oxotremorine regained its negative inotropic action. In contrast, when 10(-4) M unlabeled NMS was present in the washout bath, it took only 5 min for the [3H]NMS binding to fall by 50%. Similarly, in a membrane-suspension of guinea pig right atria, the half-life time of the [3H]NMS receptor complexes amounted to about 5 min. It is concluded that the dissociation of NMS from its receptor sites proceeds with a half-life time of 5 min in intact atria as well as in the cardiac membrane suspension.(ABSTRACT TRUNCATED AT 250 WORDS)
Lüllmann
H
H
Department of Pharmacology, University of Kiel, West Germany.
Mohr
K
K
Pfeffer
J
J
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004058:Diffusion; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D019832:N-Methylscopolamine; D010095:Oxotremorine / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000493:pharmacokinetics*; D013997:Time Factors
D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D010095:Oxotremorine; D002217:Carbachol; D019832:N-Methylscopolamine