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.

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A significant proportion of early graft occlusions after aortocoronary revascularization using autologous saphenous vein grafts (SVG) are due to mechanical and/or metabolic or biochemical endothelial lesions. The morphological examination of the endothelium, usually carried out using light microscopy or by various types of scanning electron microscopy (SEM), does not give any indication of the functioning of the endothelium (E). Functionally intact E is capable of producing endothelium-derived relaxing factor (EDRF); a practicable in vitro test is the relaxation of pre-contracted vein segments (VS) in response to acetylcholine (ACh) application. To study the effect of the solution used to rinse and store the SVG between removal and implantation on the functional characteristics of the E, we performed in vitro tests on macroscopically intact VS removed from the saphenous vein of 30 male patients who underwent elective CABG surgery. Isolated VS rings were incubated for 60 min in heparinized whole blood (HWB), Bretschneider's cardioplegic solution (HTK), human albumin solution (HAS), or Ringer's solution (RS) and compared with the results obtained immediately after the removal of untreated control samples (C) taken from the same patients. After equilibration in carbogen aerated Krebs-Henseleit solution and precontraction by 3 x 10(-7) M noradrenaline (NE), relaxation induced by 10(-6) M ACh was measured. Only the samples stored in HWB (13.4 +/- 0.4 mN) showed similar maximal contractions with NE to those in the control group (14.4 +/- 0.5 mN), i.e. all those segments which showed both contractions with NE and relaxation with ACh.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to determine whether the primary use of a phosphodiesterase-III (PDE) inhibitor as monotherapy for severe cardiac low-output states (LOS) is in fact practicable, we investigated the haemodynamic effects of amrinone and enoximone in a prospective randomized study. After elective CABG, AVR, or MVR, patients with cardiac LOS were given amrinone (n = 10) or enoximone (n = 9). Following bolus saturation (1.0-2.0 mg/kg [XA = 1.4] or 0.5-1 mg/kg [XE = 0.9] in total), a dose of 5-10 microgram/kg/min was given by infusion. The standard monitoring program included discontinuous haemodynamic measurements (Swan-Ganz) over a maximum time period of 48 hours, arterial and venous blood-gas analyses, and clinical chemistry. The preoperative clinical and haemodynamic status of the enoximone (E) group (55% CABG patients; MPAP 27 +/- 2.5 mmHg, PCWP 20 +/- 2.9 mmHg, PVR 201 +/- 35 dyn.s.cm-5) was considerably worse than that of the amrinone (A) group (70% CABG patients; MPAP 23 +/- 2.3 mmHg, PCWP 16 +/- 3.5 mmHg, PVR 153 +/- 28 dyn.s.cm-5). Both PDE inhibitor preparations led to a significant increase in cardiac index (from 1.9 +/- 0.1 to 2.5 +/- 0.12 L/min/m2 (A) and from 1.98 +/- 0.1 to 2.6 +/- 0.18 L/min/m2 (E) within 30 minutes, accompanied by a simultaneous decrease in filling pressures and vascular resistances. For up to 2 hours, 3/10 (A) and 2/9 (E) patients required additional positive inotropic support with adrenaline. There were no significant differences between the two groups at any time.(ABSTRACT TRUNCATED AT 250 WORDS)

To study beta-adrenoceptor antagonist-induced changes in human vascular beta-adrenoceptors, we determined the effects of chronic treatment with different beta-adrenoceptor antagonists without intrinsic sympathomimetic activity (ISA) on beta 2-adrenoceptor density (assessed by (-)-[125I]-iodopindolol binding) in human saphenous vein membranes obtained from patients undergoing coronary artery bypass grafting. In patients chronically treated with the non-selective beta-adrenoceptor antagonists propranolol or sotalol, the density of saphenous vein beta 2-adrenoceptors was significantly higher than in control (i.e. patients not treated with beta-adrenoceptor antagonists), whereas in patients chronically treated with the selective beta 1-adrenoceptor antagonists metoprolol or bisoprolol it was not different from control. It is concluded that beta-adrenoceptor antagonists without ISA increase human saphenous vein beta 2-adrenoceptors in a subtype-selective fashion.