In human atrial and ventricular myocardium, the muscarinic cholinoceptor (M-cholinoceptor) populations were characterized by means of radioligand binding (with [N-methyl-3H]-scopolamine ([3H]-NMS) as the ligand) and functional experiments (negative inotropic effect of carbachol on isolated electrically driven right atrial and left papillary muscle preparations). (1) Binding of [3H]-NMS to human atrial and ventricular membranes was rapid, reversible and saturable (KD-values: 0.5-1.0 nmol/l). The maximal number of [3H]-NMS binding sites, however, was approximately 2.5-fold higher in right and left atrial membranes (200-250 fmol [3H]-NMS specifically bound/mg protein) than in right and left ventricular membranes (80-100 fmol/mg protein). (2) M-cholinoceptor antagonists inhibited [3H]-NMS binding to right atrial and left ventricular membranes with steep, monophasic competition curves indicating interaction with a single class of binding sites. In both tissues the order of potency was: atropine greater than AF-DX 116 greater than hexahydrosiladifenidol (HHSiD) greater than pirenzepine. (3) On isolated electrically driven right atrial and left papillary muscle preparations (with force of contraction enhanced by 10(-5) mol/l isoprenaline), carbachol (10(-8)-10(-4) mol/l) caused concentration-dependent decreases in force of contraction; the pD2-value for carbachol was 6.65 +/- 0.09 (n = 8, atria) and 6.62 +/- 0.08 (n = 10, papillary muscles). In both tissues M-cholinoceptor antagonists antagonized the negative inotropic effect of carbachol with an order of potency: atropine greater than AF-DX 116 greater than HHSiD greater than pirenzepine, identical to that obtained in radioligand binding experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
In 44 patients undergoing coronary artery bypass grafting, the effect of chronic administration of the fi-adrenoceptor antagonists sotalol, propranolol, pindolol, metoprolol and atenolol on fiadrenoceptor density in right atria (containing 70% PB-and 30% P2-adrenoceptors) and in lymphocytes (having only f2-adrenoceptors) was studied.2 fl-Adrenoceptor density in right atrial membranes and in intact lymphocytes was assessed by (-)[1225I]-iodocyanopindolol (ICYP) binding; the relative amount of right atrial P,-and #2-adrenoceptors was determined by inhibition of ICYP binding by the selective #2-adrenoceptor antagonist ICI 118,551 and analysis of the resulting competition curves by the iterative curve fitting programme LIGAND. 3 With the exception of pindolol, all f-adrenoceptor antagonists increased right atrial ,Badrenoceptor density compared to that observed in atria from patients not treated with fadrenoceptor antagonists. 4 All f-adrenoceptor antagonists increased right atrial fi-adrenoceptor density; on the other hand, only sotalol and propranolol also increased right atrial f2-adrenoceptor density, whereas metoprolol and atenolol did not affect it and pindolol decreased it. 5 Similarly, in corresponding lymphocytes, only sotalol or propranolol increased fi2-adrenoceptor density, while metoprolol and atenolol did not affect it and pindolol decreased it.6 It is concluded that P-adrenoceptor antagonists subtype-selectively regulate cardiac and lymphocyte ,B-adrenoceptor subtypes. The selective increase in cardiac fi1-adrenoceptor density evoked by metoprolol and atenolol may be one of the reasons for the beneficial effects observed in patients with end-stage congestive cardiomyopathy following intermittent treatment with low doses of selective fl-adrenoceptor antagonists.
In patients suffering from end-stage congestive cardiomyopathy, cardiac beta 1-adrenoceptor function is markedly reduced, whereas cardiac beta 2-adrenoceptor function is nearly normal. To determine whether beta 1-adrenoceptor function is impaired in heart failure selectively, beta 1- and beta 2-adrenoceptor density and functional responsiveness in the right and left atria and the left papillary muscles from patients with mitral valve disease (functional class III to IV) were studied. In all three tissues concomitantly beta 1- and beta 2-adrenoceptor density gradually declined when the degree of heart failure increased from functional class III to IV. This decrease in beta 1- and beta 2-adrenoceptor density was accompanied by similar decreases in the contractile response of isolated electrically driven right atrial and left ventricular papillary muscles to beta-adrenergic agonists. It is concluded that a decrease in cardiac beta-adrenoceptor function is a general phenomenon in heart failure, and its extent is related to the degree of heart failure. However, in contrast to congestive cardiomyopathy, in mitral valve disease the decrease in cardiac beta-adrenoceptor function is due to a concomitant decrease in beta 1- and beta 2-adrenoceptors.
1 In 64 patients undergoing coronary artery bypass grafting the effects of chronic fl1-adrenoceptor antagonist (metoprolol, atenolol, bisoprolol) treatment on right atrial fi-adrenoceptor and muscarinic M2-receptor number and functional responsiveness were investigated.2 The fil-adrenoceptor antagonists increased right atrial fl,-adrenoceptor number, did not affect fl2-adrenoceptor number, and decreased muscarinic M2-receptor number. 3 Concomitantly, activation of right atrial adenylate cyclase by 1OuM GTP, 10pM isoprenaline and 1 UM forskolin was enhanced and inhibition by 100pM carbachol was diminished. 4 On isolated, electrically driven right atria the 6,1-adrenoceptor-mediated positive inotropic effect of noradrenaline was -even with fil-adrenoceptor number increased -not altered, while the fi2-adrenoceptor-mediated effect of procaterol was markedly enhanced. However, the carbachol-induced negative inotropic effect was decreased.5 It is concluded that chronic fl1-adrenoceptor antagonist treatment increases fil-adrenoceptor number and concomitantly sensitizes f2-adrenoceptor function, but desensitizes muscarinic M2-receptor function in the human heart.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.