Biochemical Studies on the Mechanism of Cardiotonic Activity of MDL 17,043

Kariya, Takashi; Wille, Louis J.; Dage, Richard C.

doi:10.1097/00005344-198205000-00024

Cited by 155 publications

(32 citation statements)

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“…However this enzyme exists as at least three isoenzymes, of which the most important, with regard to positive inotropic stimulation, is that described as PDE-III. Several potent inotropes, including milrinone, MDL-17043 and Cl-914, have been identified which show a marked selectivity for this isoenzyme (Kariya et al, 1982;Bristol et al, 1984;Weishaar et al, 1985). More recently both sulmazole (Bristol et al, 1984) and BW A746C (Hayes et al, 1986) have been found to have some selectivity for the PDE-III isoenzyme.…”

Section: Discussionmentioning

confidence: 99%

A comparative study of the cardiovascular and biochemical actions of the imidazo [4,5b] pyridine sulmazole and an imidazo [4,5c] pyridine analogue, BW A746C

Allan

Cambridge

Follenfant

et al. 1988

British J Pharmacology

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A comparative study of the cardiovascular and biochemical actions of the imidazo [4,5b] pyridine sulmazole and an imidazo [4,5c] 2 In anaesthetized guinea-pigs, dogs and primates, a bolus i.v. injection of BWA746C, (0.001-1.0 mg kg-') caused a significant, dose-related increase in ventricular dP/dt, and reduction in diastolic blood pressure, with small increases in heart rate. In these species, a significantly higher dose of BW A746C was required to lower blood pressure by 30% from basal, than was needed to raise ventricular dP/dt by 50% over basal.3 In anaesthetized guinea-pigs and dogs, bolus i.v. injections of sulmazole (0.1-10.0mg kg-')caused similar effects to those observed with BW A746C. In these species, however, there was no significant difference between the dose of sulmazole required to lower blood pressure by 30% from basal and that required to raise ventricular dP/dt by 50%. 4 In conscious dogs, i.v. infusion of BW A746C (to a total dose of 0.3 mg kg-') caused a significant increase in ventricular dP/dt, but no significant change in either diastolic blood pressure or heart rate. 5 In cell-free biochemical assays, there were no clear differences between the observed activities of BW A746C and sulmazole. Both compounds are cyclic nucleotide phosphodiesterase inhibitors with similar potencies and selectivities for the Type III enzyme (IC-, BW A746C = 3.0 ± 0.5 x 10-'M, sulmazole 5.0 ± 1.9 x 10-' M). The compounds had little or no effects on sarcolemmal Na+/ K+-ATPase, Ca"+ ATPase or Na+/Ca2" exchange, and sulmazole, but not BW A746C, had a small, stimulatory effect on myofibrillar ATPase.6 In anaesthetized guinea-pigs and dogs, BW A746C was significantly more potent as a positive inotrope than sulmazole. In contrast with sulmazole, BW A746C produced its inotropic effects at significantly lower doses than those required to reduce diastolic blood pressure. This was also apparent from the results obtained in the anaesthetised primates and the conscious dogs. It was therefore concluded that the inotropic/vasodilator profile of BW A746C favours its positive inotrope activity.This profile cannot be explained on the basis of any biochemical differences from sulmazole.

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Section: Discussionmentioning

confidence: 99%

A comparative study of the cardiovascular and biochemical actions of the imidazo [4,5b] pyridine sulmazole and an imidazo [4,5c] pyridine analogue, BW A746C

Allan

Cambridge

Follenfant

et al. 1988

British J Pharmacology

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“…Recently, orally active positive Inotropic com pounds have been developed which have beta -sympathom1metic (1-4) or phosphodies terase inhibiting action (5)(6)(7)(8)(9), and these agents are structurally unrelated to cardiac gly cosides. Denopamine, a newly synthesized phenylethanolamine derivative, is the former type of cardiotonic agent.…”

Section: Abstract-positive Chrono and Inotropic Responses To Denopamimentioning

confidence: 99%

Pharmacological analysis of positive chrono- and inotropic responses to denopamine (TA-064) in dog cross-circulated atrial and ventricular preparations.

et al. 1990

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Abstract-Positive chrono and inotropic responses to denopamine (TA-064, (-) (R)-1-(p-hydroxyphenyl)-2- [(3,4-dimethoxyphenethyl)amino] ethanol), a new and orally active cardiotonic agent, were investigated in the canine isolated right atrial or left ventricular preparation which was cross-circulated with blood from another support dog. Denopamine dose-dependently increased the sinus rate, right atrial and left ventricular contractile force. Denopamine was one to two orders of mag nitude less potent than isoproterenol. The positive chrono and inotropic effects of denopamine in isolated, blood-perfused right atria were dose-dependently in hibited by treatment with propranolol and atenolol. The effects of denopamine were only slightly attenuated by ICI 118,551 in doses which completely suppressed the positive chrono and inotropic effects of procaterol. The increases in sinus rate and atrial contractility induced by denopamine were partially but significantly attenuated by treatment with imipramine in a dose which suppressed the effects of tyramine and potentiated the effects of norepinephrine. These results indicate that denopamine is a highly selective beta-1 adrenoceptor agonist in isolated, blood perfused dog heart preparations, and they also suggest a mild catecholamine releasing activity through tyramine-like action in isolated right atria.Congestive heart failure is characterized by a state of insufficient cardiac output to fulfill the metabolic requirements of the body. One of the therapies for congestive heart failure is augmenting the cardiac pumping function (positive Inotropic action). Cardiac gly cosides are the drugs used for producing Positive inotropic effects, but their effec tiveness and safety remain controversial be cause of their toxicity. Some catecholamines such as dopamine and dobutamine, which have a strong positive inotropic effect, are clinically available only by intravenous ad ministrations. Therefore, potent positive Ino tropic drugs which are orally active and pos sess a wide margin of safety are of great interest in the treatment of heart failure.Recently, orally active positive Inotropic com pounds have been developed which have beta -sympathom1metic (1-4) or phosphodies terase inhibiting action (5-9), and these agents are structurally unrelated to cardiac gly cosides. Denopamine, a newly synthesized phenylethanolamine derivative, is the former type of cardiotonic agent. Ikeo et al. (10) have reported that, administered parenterally or orally, denopamine induced a significant dose-dependent increase in contractile force and dp/dtmax in the left ventricle with a little change in heart rate in anesthetized and con scious dogs.The cardiotonic effects of denopamine with a weak arrhythmogenic ac tivity were also demonstrated in guinea pigs, rabbits, cats, monkeys, rats and pigs (11)(12)(13)(14). Kino et al. (15) have revealed that the in travenous infusion of denopamine produced a To whom correspondence should be addressed.marked increase in dp/dtmax in the left ventri cle without sig...

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“…Recent data, however, suggests that selective inhibition of PDE enzyme F-III which is relatively specific for cyclic AMP is more closely correlated with the inotropic action of the newer agents, e.g. amrinone and milrinone than to effects on adrenosine receptors (Kariya et al, 1982). The action of PDE inhibitors on intracellular cyclic AMP are not tissue selective and, therefore, significant vasodilatation can be expected with these drugs.…”

Section: -Adrenoceptor Partial Agonistsmentioning

confidence: 99%

Myocardial beta‐adrenoceptor function and regulation in heart failure: implications for therapy.

Barnett

1989

Brit J Clinical Pharma

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Biochemical Studies on the Mechanism of Cardiotonic Activity of MDL 17,043

Cited by 155 publications

References 0 publications

A comparative study of the cardiovascular and biochemical actions of the imidazo [4,5b] pyridine sulmazole and an imidazo [4,5c] pyridine analogue, BW A746C

A comparative study of the cardiovascular and biochemical actions of the imidazo [4,5b] pyridine sulmazole and an imidazo [4,5c] pyridine analogue, BW A746C

Pharmacological analysis of positive chrono- and inotropic responses to denopamine (TA-064) in dog cross-circulated atrial and ventricular preparations.

Myocardial beta‐adrenoceptor function and regulation in heart failure: implications for therapy.

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