Cardiotonic activity of amrinone--Win 40680 [5-amino-3,4'-bipyridine-6(1H)-one].

Abstract

SUMMARYThe cardiotonic activity of a new, noncatechol, nonglycoside agent, amrinone, waa investigated in vitro and in anesthestized and unanesthetized dogs. Amrinone (3-1000 /ig/ml) caused a dose-dependent increase in papillary muscle developed tension and df/dt without significant changes in duration of the contractile cycle or time-to-peak tension. Amrinone induced slight increases in right atrial rate with no changes in electrophysiological properties of the cat papillary muscle or dog Purkinje fibers. In anesthetized dogs, intravenous bolus injections of amrinone at doses ranging from 1 to 10 mg/kg caused increases in cardiac contractile force and left ventricular dp/dt max with relatively small changes in heart rate and blood pressure. No significant changes in lead II ECG were observed. In unanesthetized dogs, intravenous infusion of amrinone (10-100 /ig/kg per min) caused increases in left ventricular dp/dt max and only small changes in heart rate and blood pressure. Amrinone, tested orally in this model at doses of 2-10 mg/kg, produced a positive inotropic effect with a rapid onset and long duration of action. The inotropic response to amrinone was not blocked by propranolol, dibenzyline, chlorisondamine, atropine, metiamide, or reserpine. Amrinone's inotropic response was not associated with significant alterations in cardiac norepinephrine, phosphodiesterase, cyclic AMP, or Na + ,K + -activated ATPase. Ore Res 45: 666-677, 1979 A LARGE number of agents have positive inotropic effects on the heart. However, of these, only two classes of compounds have been found to be useful in the treatment of heart failure in man. The cardiac glycosides have enjoyed a valued position for nearly 200 years in spite of the fact that they have a narrow therapeutic range, and digitalis intoxication is one of the most common drug-induced adverse reactions in this country (Mason et al., 1971;Beller et al., 1971;Doherty and Kane, 1975). The catecholamines have limitations in that they are arrhythmogenic, are chronotropic, have a short duration of action, and cannot be given orally (Goldberg, 1968). Dopamine (Goldberg, 1974;Beregovich et al., 1974) and the synthetic catecholamine, amine dobutamine (Tuttle and Mills, 1975;Goldberg et al, 1977), both of which have been introduced recently for clinical use, suffer from most of the same drawbacks as the older catecholamines. Other inotropic agents, such as glucagon (Farah and Tuttle, 1960;Glick et al., 1968) has proved of value in the management of congestive heart failure (Cohn and Franciosa, 1977;Mehta, 1977).The development of an orally active non-catechol and non-glycoside cardiotonic agent has been the goal of this laboratory for several years (Alousi and Farah, 1975;Alousi et al., 1978;Farah and Alousi, 1978). Amrinone (Win 40680), a 5-amino-3,4'-bipyridine-6(lH)-one, is a novel chemical entity with rather unique cardiac inotropic properties Farah and Alousi, 1978). In this report, the action of amrinone on the heart is studied in several models, and in light of these res...

Differential effects of OPC‐18790, amrinone and dobutamine on cardiac function and energy metabolism in the guinea‐pig isolated ischaemic heart

“…Increases in HR induced by amrinone (Alousi et al, 1979;Zannad et al, 1983;Sato et al, 1986) and dobutamine (Tuttle & Mills, 1975;Sonnenblick et al, 1979) have been reported previously and lack of direct chronotropic effect of OPC-18790 is also consistent with a previously reported action in canine isolated right atria (Hosokawa et al, 1992). From the parameters of cardiac energetics elucidated by 3'P-MRS signals, it is shown that amrinone and dobutamine aggravate the cardiac energetic state, namely increase Pi, decrease PCr and ATP and cause further acidification of intracellular pH, with an increase in LVdP/dt (Figure 4).…”

“…Therefore, the usefulness of these drugs in the ischaemic heart is determined by the balance of these actions. In fact, deleterious effects of positive inotropic stimulation in ischaemic hearts have been reported (Rude et al, 1980;Pozen et al, 1981 (Taira, 1987), many are guanosine 3': 5'-cyclic monophosphate (cyclic GMP)-inhibited phosphodiesterase (cGI-PDE) inhibitors such as amrinone (Alousi et al, 1979). Recently, we described a new compound, OPC-18790 [(± )-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2-(lH)-quinolinone] (Fujioka et al, 1992) which is a Author for correspondence.…”

Interaction of amrinone with endogenous adenosine in guinea‐pig atria

“…Amrinone (5-amino-3,4-bipyridin-6(l H)-one; Win 40680) decreases peripheral vascular resistance and increases cardiac output and contractility in a variety ofin vitro and in vivo preparations (Benotti et al, 1978;Alousi & Farah, 1978;LeJemtel et al, 1979;Klein et al, 1981;Ward et al, 1983;Toda et al, 1984).…”

Effects of Dopamine, Dobutamine, Amrinone and Milrinone on Regional Blood Flow in Isoflurane Anesthetized Dogs

“…Selective phosphodiesteraseIII (PDEIII) inhibitors such as amrinone (AM) and milrinone (ML) increase the intracellular concentration of cyclic adenosine-3, 5-cyclic monophosphate (cAMP) [8] by inhibiting PDEIII, which is a splitting enzyme of cAMP [37] and increase myocardial contractility without activation of adrenergic receptors [1,2]. Therefore PDEIII inhibitors might act effectively even in the case that CAs do not act adequately due to adrenergic receptor down regulation [6].…”