Cardiovascular Pharmacology

Fawaz, G.

doi:10.1146/annurev.pa.03.040163.000421

Cited by 17 publications

(6 citation statements)

References 42 publications

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“…The lack of significant effects by amrinone on cardiac output of the normal (nonfailing) heart was similar to that of the cardiac glycosides (Cotton and Stopp, 1958;Cotton and Moran, 1961). It is well established that increased inotropy alone would not lead necessarily to increased cardiac output, since other factors such as preload, afterload, and heart rate are important contributors to changes in this parameter (Fawaz, 1963). Amrinone produced a typical positive inotropic effect in pentobarbital-induced heart failure in dogs.…”

Section: Discussionmentioning

confidence: 99%

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

Alousi¹,

Farah²,

Lesher³

et al. 1979

Circulation Research

219

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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...

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Section: Discussionmentioning

confidence: 99%

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

Alousi¹,

Farah²,

Lesher³

et al. 1979

Circulation Research

219

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“…The hypotension which occurs during acute treatment is due to a reduction in the capacity of vasoconstrictor nerves to mediate the usual reflex compensations when the erect posture is assumed. As a consequence venous return and cardiac output fall and hypotension results (FAWAZ, 1963).…”

Section: Effects Due To Administration In Vivo A) Consequences Of Adrmentioning

confidence: 99%

Adrenergic Neuron Blocking Drugs

Maxwell¹,

Wastila²

1977

Antihypertensive Agents

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“…According to these authors the a-methylated sympathomimetic amines first release noradrenaline from the stores, then block their own entry as well as that of subsequent doses of noradrenaline and other indirectly acting sympathomimetic amines into the stores. We have also used similar arguments to explain certain actions of guanethidine, cocaine and indirectly acting sympathomimetic amines (Fawaz, 1963).…”

Section: Discussionmentioning

confidence: 99%

The Tachyphylaxis Caused by Mephentermine and Tyramine

Fawaz

Simaan

1965

British Journal of Pharmacology and Chemotherapy

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The sympathomimetic action of mephentermine, like that of tyramine, is considerably reduced by procedures that deplete noradrenaline stores, such as administration of reserpine. We have, however, observed important differences between these two sympathomimetic amines in the speed with which tachyphylaxis to the pressor action develops, in their behaviour in dogs treated with reserpine before and after infusions of noradrenaline and in their action on the heart-lung preparation. Blaschko (1962) and Day & Rand (1963) concluded that the differences in behaviour, with regard to tachyphylaxis, between tyramine and a-methylated sympathomimetic amines could be explained by the resistance of the latter to attack by monoamine oxidase. The experiments reported in this paper suggest a more complex situation. METHODSMongrel dogs weighing 8 to 12 kg were anaesthetized with chloralose (150 mg/kg). In the heart-lung preparations the experimental dogs were anaesthetized with pentobarbitone (30 to 40 mg/kg) and the donors with chloroform. The blood pressure was measured from a common carotid artery by a mercury manometer and both cervical vagosympathetic trunks were cut. Heart rates were measured from electrocardiograph records. The heart-lung preparations were of the conventional type (Fawaz & Simaan, 1963). Reserpine was given as intraperitoneal injections of0.5 mg/kg 48 hr and 24 hr before the experiment; such animals usually required less anaesthetic. Noradrenaline was estimated by the method described by Fawaz & Simaan (1963). Noradrenaline was used as the bitartrate, tyramine as the hydrochloride and mephentermine (Wyamine) as sulphate, and the doses quoted are expressed in terms of the bases. Injections into anaesthetized dogs were intravenous. RESULTSThe action of tyramine and mephentermine in dogs treated with reserpineIn twelve dogs not treated with reserpine, the first injection of tyramine (2 mg) caused a rise in arterial pressure of 63±6.8 mm Hg (mean and standard error). In sixteen similar dogs mephentermine (4 mg) caused a mean rise of 70±5.7 mm Hg. But the intravenous injection of either tyramine or mephentermine caused only a slight rise in arterial blood pressure in dogs treated with reserpine (Table 1). When 2 mg of noradrenaline was infused over 50 min and tyramine (2 mg) or mephentermine (4 mg) was injected 5 to 10 min after the end of the infusion (when the blood pressure had reached a steady level), the pressor action was fully restored. The pressor action of mephentermine after the infusion was even greater than in normal dogs. These results are in harmony with those of Burn & Rand (1958) on spinal cats treated with reserpine. After the infusion of noradrenaline a

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Cardiovascular Pharmacology

Cited by 17 publications

References 42 publications

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

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

Adrenergic Neuron Blocking Drugs

The Tachyphylaxis Caused by Mephentermine and Tyramine

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