Norio Taira

Nicorandil as a hybrid between nitrates and potassium channel activators

Nicorandil, although structurally a nitrate, differs from classic nitrates in several respects. It preferentially dilates resistive vessels. Its effect on venous return in dogs is not unanimously a decrease but rather an increase. In high doses or concentrations it suppresses myocardial contraction and ventricular automaticity, nearly sparing sinoatrial nodal automaticity and atrioventricular nodal conduction. It shortens the effective refractory period of myocardium. These cardiac effects of nicorandil have been explained by its mechanism of action as a potassium (K) channel activator. However, what part of the vascular effects of nicorandil this mechanism is responsible for has not been determined. BRL 34915 and pinacidil, nonnitrate vasodilators with a K-channel activator action, have essentially the same cardiovascular profile as nicorandil in isolated, blood-perfused canine heart preparations. In anesthetized, open-chest dogs the 2 K-channel activators decreased systemic blood pressure and increased venous return and cardiac output without elevating heart rate, unless the cardiodepressant effect emerged. The increase in venous return or cardiac output survived elimination of baroceptor functions. These results taken together with previous results on nicorandil suggest the following: (1) The property of nicorandil as a resistive vessel dilator highly selective for vasculature originates in its mechanism of action as a K-channel activator. The nonunanimous effect of nicorandil on venous return is a result of the opposing actions as a capacitive (action as a nitrate) and a resistive vessel dilator. Nicorandil, with its hybrid nature, is advantageous over specific K-channel activators and classic nitrates in therapeutic implications.

PHARMACOLOGICAL PROFILE OF A NEW CORONARY VASODILATOR DRUG, 2‐NICOTINAMIDOETHYL NITRATE (SG‐75)

1. In anaesthetized, open‐chest dogs, 2‐nicotinamidoethyl nitrate (SG‐75) administered intravenously (0.3–1 mg/kg) or intraduodenally (3 mg/kg) produced decreases in systemic blood pressure, coronary resistance, heart rate and an increase in coronary sinus outflow, but virtually no change in myocardial oxygen consumption and atrioventricular conduction. The effects of SG‐75 administered intraduodenally emerged within a few minutes after dosing and lasted over about 1 h.

Differences in cardiovascular profile among calcium antagonists

Calcium antagonists constitute a group of organic compounds with diverse chemical structures. Although their main pharmacodynamic actions are vasodilatation and myocardial depression, they are not uniform in producing these effects. Based on comparison of the potencies in producing negative inotropic, chronotropic and dromotropic effects to the coronary vasodilator potency of individual calcium antagonists determined by use of isolated, blood-perfused papillary muscle, sinoatrial node and atrioventricular node preparations of dogs, calcium antagonists are classified into 2 major groups. The dihydropyridines, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, PN 200-110 (isradipine) and PY 108-068, are generally far more potent in producing coronary vasodilatation than in producing negative inotropic, chronotropic and dromotropic (first-degree atrioventricular block) effects, although there are minor differences among them. The non-dihydropyridine calcium antagonists, verapamil, diltiazem, KB-944, bepridil and MCI-176, are nearly equipotent in producing coronary vasodilatation and a negative dromotropic effect, although all of them are less potent in producing negative inotropy. The non-dihydropyridine calcium antagonists can be further divided into 2 subgroups. Verapamil, diltiazem and KB-944 are nearly equipotent in producing negative dromotropic and chronotropic effects. Bepridil and MCI-176 are less potent in producing negative chronotropy than in producing negative dromotropy.

Similarity and dissimilarity in the mode and mechanism of action between nicorandil and classical nitrates: an overview.

Nicorandil, which is structurally a nitrate and also a nicotinamide, differs from classical nitrates such as nitroglycerin and isosorbide dinitrate in the following respects. It dilates preferentially resistive vessels (arterioles); and it produces the increase in potassium conductance in the membranes of cardiac and some vascular smooth muscle cells that is responsible for its negative inotropic and chronotropic and vasodilator effects. Nicorandil has the following characteristics of a nitrate. (a) It is capable of dilating large conductive coronary arteries, although the effect is weaker than that of classical nitrates. (b) It is capable of reducing venous return, although this effect is less pronounced than that of classical nitrates, (c) It produces an increase in intracellular cyclic guanosine-3′,5′-monophosphate (cyclic GMP) in vascular smooth muscle. The activity of nicorandil to increase the membrane potassium conductance resides in the nicotinamide moiety. However, this activity is greatly enhanced by the presence of the nitrate group at an appropriate distance from the nicotinamide group. The nitrate moiety per se has also its own action. The presence of these two pharmacologically active groups in the molecule appears to cause nicorandil to have rather complex cardiovascular actions.

Effects on atrio-ventricular conduction of calcium-antagonistic coronary vasodilators, local anaesthetics and quinidine injected into the posterior and the anterior septal artery of the atrio-ventricular node preparation of the dog

SummaryThe effects on atrio-ventricular (A-V) conduction and blood flow of calcium-antagonists (verapamil, nifedipine and diltiazem), local anaesthetics (procaine and lidocaine) and quinidine were investigated in the isolated, cross-circulated A-V node preparation of the dog. The drugs were injected individually into the posterior septal artery (PSA) through which the upper part of the A-V node is mainly perfused or into the anterior septal artery (ASA) through which the lower part of the node and the more distal conduction system are perfused. Single injections into the PSA of nifedipine (0.3–10 μg), verapamil (1–30 μg), diltiazem (1–30 μg), quinidine (30–300 μg), lidocaine (100 μg–1 mg) and procaine (300 μg–3 mg) produced a dose-related increase in the A-V conduction time and with higher doses of these drugs a second or third degree block of A-V conduction occurred. Nifedipine (0.3–30 μg) and verapamil (1–100 μg) injected into the ASA scarcely affected A-V conduction. Quinidine (30 μg–1 mg) and lidocaine (100 μg–3 mg) injected into the ASA prolonged the A-V conduction time in a dose-related manner, although the effects were less prominent than those produced upon injection into the PSA. High doses of quinidine (3 mg) and lidocaine (3–10 mg) injected into the ASA altered the shape of ventricular bipolar electrograms and prolonged the time interval between an electrogram of the right bundle branch and that of the ventricle. The results are consistent with the hypothesis that in excitation of A-V nodal cells a slow calcium current rather than a fast sodium current plays an important role and that in the His-Purkinje-ventricular system the fast sodium current is predominant. Single injections of the 6 drugs into the PSA produced a doserelated increase in blood flow through the PSA. All drugs but nifedipine increased the blood flow in almost the same dose range that caused impairment of A-V conduction. Nifedipine was 10 times more potent in increasing the blood flow than in impairing A-V conduction.

Cytoplasmic calcium and the relaxation of canine coronary arterial smooth muscle produced by cromakalim, pinacidil and nicorandil

1 In order to investigate the vasodilator mechanisms of the K+ channel openers, cromakalim, pinacidil and nicorandil, we measured changes in cytoplasmic Ca2+ concentration ([Ca2+]i) simultaneously with force by a microfluorimetric method using fura‐2, a calcium indicator, in canine coronary arterial smooth muscle cells. 2 The three K+ channel openers all produced a concentration‐dependent reduction of [Ca2+]j in 5 and 30mM KCl physiological salt solution (PSS) but failed to affect [Ca2+]i in 45 and 90 mM KC1‐PSS. 3 Cromakalim only partly inhibited (‐45%) the 30 mM KCl‐induced contractures, whereas pinacidil and nicorandil nearly abolished contractions produced by 45 mM, 90 mM and 30 mM KC1‐PSS. 4 Tetrabutylammonium (TBA), a nonselective K+ channel blocker, or glibenclamide, a supposed adenosine 5′‐triphosphate (ATP)‐sensitive K+ channel blocker, abolished the reduction of [Ca2+]i caused by the three K+ channel openers and the relaxant effect of cromakalim, whereas they only slightly attenuated the relaxant effects of pinacidil and nicorandil. 5 The increase in [Ca2+]i produced by 45 or 90 mM KCl‐PSS in the presence of pinacidil or nicorandil was abolished by 10−5m verapamil, indicating that the increase in [Ca2+]i was caused by the influx of extracellular Ca2+ and that pinacidil and nicorandil did not affect the voltage‐dependent Ca2+ channel directly. 6 The [Ca2+]i‐force relationship in the presence of cromakalim was not distinguishable from that of control. 7 The [Ca2+]i‐force curve was shifted to the right by pinacidil and nicorandil. 8 These results show that cromakalim is a more specific K+ channel opener than pinacidil and nicorandil, and that vasodilatation produced by cromakalim in this study is predominantly a result of a reduction of [Ca2+]i due to the closure of voltage‐dependent Ca2+ channels by hyperpolarization. In contrast, additional mechanisms are involved in the vasodilator actions of pinacidil and nicorandil. One of these is related to a reduction in the sensitivity of contractile proteins to Ca2+. The latter mechanism of nicorandil is akin to that of nitroglycerin. K+ channels opened by these K+ channel openers may be ATP‐sensitive ones which are blocked by glibenclamide.

Nitroglycerin relaxes canine coronary arterial smooth muscle without reducing intracellular Ca2+ concentrations measured with fura‐2

1 Changes in cytoplasmic Ca2+ concentration ([Ca2+]i) were measured simultaneously with force by a microfluorometric method using a calcium indicator, fura‐2, in canine coronary arterial smooth muscle cells. 2 Depolarization by high (30–90 mm) KCl‐physiological salt solution (PSS) produced concentration‐dependent increases in force and [Ca2+]i. 3 The KCl‐induced increase in [Ca2+]i was abolished by Ca2+‐free conditions and almost abolished by verapamil 10−5m, suggesting that it was entirely due to the increased Ca2+ influx through voltage‐dependent Ca2+ channels. 4 The [Ca2+]i‐force relationship in the presence of verapamil was not distinguishable from that of control. 5 Nitroglycerin produced a concentration‐dependent, reversible contraction of the coronary artery that had been contracted by high KC1‐PSS, without reduction of the increased [Ca2+]i. 6 The KCl‐induced increase in [Ca2+]i was not affected by nitroglycerin and in the presence of nitroglycerin it was abolished by 10−5m verapamil suggesting that it was caused by the influx of extracellular Ca2+. 7 The [Ca2+]i‐force curve was shifted to the right by nitroglycerin. 8 It is likely that nitroglycerin relaxes the coronary arterial smooth muscle by reducing the amount of myosin light chain phosphorylation even in the presence of raised [Ca2+]i produced by increased Ca2+ influx following depolarization.

Coronary Vasodilator and Cardiac Effects of Optical Isomers of Verapamil in the Dog

Summary Coronary vasodilator and cardiac effects of (-) and (+) verapamil were investigated in two kinds of canine heart preparations. When administered intravenously to anesthetized open-chest dogs, (-) verapamil was only 1.5–2 times as potent as (+) verapamil in increasing coronary sinus outflow and in decreasing mean arterial pressure and coronary resistance. However, (-) verapamil was about 5 times as potent in producing a negative chronotropic effect, about 10 times as potent in producing a negative dromotropic effect, and about 15 times as potent in decreasing myocardial oxygen consumption as (+) verapamil. When injected into the anterior septal artery in the isolated, blood-perfused papillary muscle preparation of the dog, (-) verapamil was about 15 times as potent as (+) verapamil in producing a negative inotropic effect. However, in increasing blood flow through the anterior septal artery (-) verapamil was only about 2.5 times as potent as (+) verapamil. These results indicate that in equieffective doses in producing coronary vasodilatation (+) verapamil is far less cardiodepressant than the (-) isomer.

ASSESSMENT OF THE EFFECTS OF VASOACTIVE INTESTINAL PEPTIDE (VIP) ON BLOOD FLOW THROUGH AND SALIVATION OF THE DOG SALIVARY GLAND IN COMPARISON WITH THOSE OF SECRETIN, GLUCAGON AND ACETYLCHOLINE

1 The vascular bed of the submandibular gland in situ was perfused with blood through the glandular artery at a constant pressure in anaesthetized dogs. All drugs were administered intra‐arterially. 2 Vasoactive intestinal peptide (VIP), secretin and acetylcholine produced a dose‐dependent increase in blood flow through the artery (vasodilatation) but glucagon was almost ineffective. 3 Dose‐blood flow response curves for VIP and secretin were parallel, and VIP was about 100 times as potent as secretin on a molar basis. Dose‐blood flow response curves for acetylcholine were flatter than those for VIP and secretin. Acetylcholine was approximately as potent as secretin on a molar basis. 4 No tachyphylaxis developed to the vasodilator action of VIP. 5 The vasodilator responses to VIP and to electrical stimulation of the chordolingual nerve were scarcely modified by (—)‐hyoscyamine in doses that fully antagonized the vasodilator response to acetylcholine. 6 VIP, secretin and glucagon were ineffective in eliciting salivary secretion. 7 The possibility that VIP is released from parasympathetic vasodilator nerves and mediates the atropine‐resistant vasodilatation in the dog submandibular gland is discussed.

Role of the peripheral vasculature in changes in venous return caused by isoproterenol, norepinephrine, and methoxamine in anesthetized dogs.

We studied effects on venous return of α-and β-adrenergic agonists in anesthetized dogs. Blood from the superior and inferior venae cavae (venous return) was drained at the level of the tricuspid valve into a reservoir, from which blood was pumped into the right atrium at a constant rate. Isoproterenol infused into the ascending aorta or the right atrium increased the venous return and heart rate and decreased systemic blood pressure. The increase in venous return produced by isoproterenol given into the right atrium was not significantly different from that produced by isoproterenol administered into the ascending aorta, although the increase in heart rate was more marked with the latter route of administration. Norepinephrine infused into the ascending aorta increased the systemic blood pressure, venous return, and heart rate. Methoxamine infused into the ascending aorta increased the systemic blood pressure and decreased the venous return but produced no change in heart rate. Isoproterenol increased the venous return even when the sinoaortic baroreceptor reflex was eliminated. Propranolol abolished the increase in venous return caused by isoproterenol and reversed the increase in venous return caused by norepinephrine. The results suggest that a decrease in venous resistance mediated through a β-adrenergic mechanism is important in increasing venous return, whereas an increase in venous resistance mediated through an α-adrenergic mechanism is responsible for a decrease in venous return.