Some effects of nipradilol, a β‐antagonist possessing a nitroxy group, on smooth muscle of the pig coronary artery

Abstract

1 The effects of nipradilol, a ,B-adrenoceptor antagonist which possesses a nitroxy group, on cytosolic Ca2+ concentration ([Ca2+i) and on tension development were simultaneously measured by front-surface fluorometry and fura-2-loaded strips in the proximal portion of pig coronary arteries.2 Nipradilol reduced in a concentration-dependent manner both the [Ca2+]i and tension, irrespective of whether the strips were unstimulated or exposed to either high K+ or histamine containing solutions. However, both in the case of contractions induced by high K+-depolarization and histamine stimulation, for a given [Ca2+]i elevation the tension which developed in the presence of nipradilol was smaller than that generated in its absence, so that the [Ca2 +]i-tension curves during the contraction were shifted to the right.3 In the absence of extracellular Ca2 , the [Ca2i], elevation due to the release of Ca2+ from histaminesensitive store was inhibited by nipradilol. Nipradilol had no effect on the [Ca2+]i elevation due to the release of Ca2+ from caffeine-sensitive stores; however, it did inhibit the caffeine-induced increase in tension. A derivative of nipradilol, which lacked a nitroxy molecule (Nip(-N)), had no effect on the At lower concentrations, nipradilol acted as a fl-blocker, the IC50 value being smaller than that of Nip(-N), and at higher concentrations, it acted as a nitrovasodilator. 5 Thus, it is suggested that, at lower concentrations, nipradilol, an antianginal drug, acts as a ,Badrenoceptor antagonist. At higher concentrations, it relaxes the proximal portion of the coronary artery by directly reducing [Ca2']i and the Ca2+-sensitivity of the myofilaments, apparently due to the presence of the nitroxy molecule.

Relative Importance of Calcium-activated Potassium Channels in Nipradilol-induced Aortic Relaxation in Rats

“…Nipradilol is a vasodilating beta-blocker that contains a nitroxy group. In the present study desnitronipradilol, a nipradilol analogue without a nitroxy group, had virtually no relaxing effects on the rat aortic ring precontracted with norepinephrine, thus confirming the pervious finding that these actions of nipradilol require a nitroxy group [2,3].…”

“…Nipradilol (CAS 81486-22-8) is a vasodilating betablocker with a nitroxy group [1], which has been used for the treatment of essential hypertension. The mechanisms for nipradilol-induced vasorelaxation have been shown to involve cyclic GMP (guanosine monophosphate) generation [2] and reduction in intracellular calcium ions and calcium sensitivity of the myofilament [3]. Because these actions of nipradilol require a nitroxy group [2,3], the drug may well be considered to have nitroglycerin (CAS 55-63-0)-like effects.…”

“…The mechanisms for nipradilol-induced vasorelaxation have been shown to involve cyclic GMP (guanosine monophosphate) generation [2] and reduction in intracellular calcium ions and calcium sensitivity of the myofilament [3]. Because these actions of nipradilol require a nitroxy group [2,3], the drug may well be considered to have nitroglycerin (CAS 55-63-0)-like effects. However, there is a study which demonstrated a smaller contribution of cyclic GMP generation through activation of soluble guanylate cyclase to nipradilol-induced than nitroglycerin-induced relaxation in the rabbit aorta [2].…”

β‐Adrenoceptor Blocking Activities Of Nipradilol And Its Optical Isomers In Pig Coronary Artery

“…Nipradilol is a potent non‐selective β‐adrenoceptor blocking agent with nitrovasodilating properties 1–3 and, therefore, has been used for the treatment of essential hypertension 4 and angina pectoris 5,6 . The clinical use of an agent such as nipradilol, which possesses both β‐adrenoceptor blocking and vasodilator activity, 7 is considered to be an attractive approach because the β‐adrenoceptor antagonism of nipradilol can cooperate with its vasodilator action for therapeutic efficacy. Namely, β‐adrenoceptor antagonists can block the reflex tachycardia that is caused by the vasodilating effect of the nitroxy group, while the nitroxy group can alleviate the increase in coronary vascular resistance associated with β‐adrenoceptor blockade 8…”