Beta-receptor Blocking Properties Research Articles

PF9404C, a new slow NO donor with beta receptor blocking properties.

1. PF9404C is the S-S diesteroisomer of a novel blocker of beta adrenergic receptors with vasodilatory properties. It causes a concentration-dependent relaxation of rat aorta helical strips pre-contracted with 10(-6) M noradrenaline (NA; IC(50) 33 nM). It was equipotent to nitroglycerin (NTG; IC(50) 49 nM), but much more potent than isosorbide dinitrate (ISD; IC(50) 15,000 nM). 2. Oxyhaemoglobin (10 microM) shifted to the right the concentration-response curve for the relaxation induced by PF9404C (IC(50) 530 nM) or NTG (IC(50) 61 nM). 3. Either methylene blue (MB) or ODQ (1 microM each) largely prevented the vasorelaxing responses to increasing concentrations of PF9404C or NTG. 4. In rat aorta smooth muscle cells, PF9404C increased the formation of cyclic GMP from 3 pmol mg(-1) protein in basal conditions, to 53 pmol mg(-1) protein in 10 microM PF9404C. Neither metoprolol nor carvedilol enhanced cyclic GMP. 5. In the electrically driven guinea-pig left atrium, PF9404C blocked the inotropic effects of isoprenaline in a concentration-dependent manner. Its IC(50) (30 nM) was similar to that for S-propranolol (22.4 nM) and lower than the IC(50)s for metoprolol (120 nM) and atenolol (192 nM). The beta-adrenergic ligand (-)-[(3)H]-CGP12177 (0.2 nM) was displaced from its binding to rat brain membranes with K(i) of 7 nM, 17 nM, 170 nM and 1.2 microM respectively for PF9404C, S-(-)propranolol, metoprolol, and atenolol. 6. The data are consistent with the idea that the S-S diesteroisomer PF9404C, is a potent vasorelaxing agent, as well as a blocker of cardiac beta adrenergic receptors. The mechanism of its vasorelaxing effects involves the slow generation of NO. This molecule can, therefore, exhibit antihypertensive and cardioprotective actions through a double mechanism, NO donation and beta blockade.

新β遮断薬Acebutololのβ<SUB>1</SUB>選択性に関する生化学的研究

Effects of acebutolol on carbohydrate and lipid metabolism in rats and on adenylate cyclase of heart and liver in dogs were investigated to determine the beta receptor blocking properties of the compound. Acebutolol exhibited the beta blocking activity and inhibited the increase of serum lactate concentration induced by adrenaline. This inhibition was about one-sixth as potent as that of propranolol. In hyperglycemic and free fatty acid effects of adrenaline, acebutolol inhibited the adrenaline-induced free fatty acid increase more effectively than hyperglycemia induced by adrenaline. In the inhibition of stimulated adenylate cyclase activity in the heart and liver, acebutolol was more active on the heart than on liver. Relative beta1 specificity of acebutolol was 93.2. Inhibition of propranolol on adenylate cyclase activity was more potent than that of acebutolol on both tissues, but showed no specificity. These results suggest that acebutolol is beta1 selective, although its beta blocking potency is less than that of propranolol.

Anti-arrhythmic, local anaesthetic, and adrenergic blocking activity of some beta-receptor antagonists.

1. The antagonistic effect of the beta-receptor blocking compounds propranolol, Ph QA 33 and INPEA on ouabain-induced cardiac fibrillations in guinea-pigs was compared with their local anaesthetic and beta-receptor blocking properties.2. All three compounds were found capable of increasing the tolerance to ouabain and of reversing ouabain-induced fibrillations, the ED50 being 0.3 mg/kg intravenously, 0.5 mg/kg intravenously, and 1.5 mg/kg intravenously, respectively for propranolol, Ph QA 33 and INPEA.3. Propranolol and Ph QA 33 were found to be moderate to strong local anaesthetics while INPEA had a considerably weaker though significant effect.4. The order of potency as beta-receptor blocking compounds was propranolol >/= Ph QA 33 >> INPEA, the latter compound being less than 1% as active as propranolol.5. Despite the surprising finding that INPEA was effective against non-catecholamine-induced arrhythmias, the results support the general assumption that the anti-arrhythmic effect of beta-receptor blocking compounds is related to their local anaesthetic action rather than to their beta-blocking ability.