Cardiovascular Effects of a New Positive Inotropic Agent, (−)-(R)-1-(p-Hydroxyphenyl)-2-[(3,4-Dimethoxyphenethyl) Amino]-Ethanol (TA-064) in the Anesthetized Dog and Isolated Guinea Pig Heart

Nagao, Taku; Ikeo, Tomihiro; Murata, Shigeru; Sato, Masanori; Nakajima, Hiromichi

doi:10.1254/jjp.35.415

Cited by 53 publications

(32 citation statements)

References 19 publications

(2 reference statements)

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Section: Discussionsupporting

confidence: 94%

“…In our study, denopamine dose-dependently in creased the sinus rate, atrial and ventricular contractility in isolated dog heart preparations and the effects of denopamine at higher doses lasted more than 10 min. It has been reported that the positive inotropic activity of denop amine was 1 /60-1 /300 that of isoproterenol in many species (12,28), and these results are consistent with our findings.Denopamine produced a potent positive inotropic effect without affecting systemic blood pressure (12), and it has also been shown that the increases in heart rate and myocardial oxygen consumption by denop amine were rather weak (27). Nagao et al (12) also reported that the positive inotropic effect of denopamine was more pronounced than the positive chronotropic effect, com pared with those of isoproterenol.…”

supporting

confidence: 94%

“…Denopamine produced a potent positive inotropic effect without affecting systemic blood pressure (12), and it has also been shown that the increases in heart rate and myocardial oxygen consumption by denop amine were rather weak (27). Nagao et al (12) also reported that the positive inotropic effect of denopamine was more pronounced than the positive chronotropic effect, com pared with those of isoproterenol.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Abstract-positive Chrono and Inotropic Responses To Denopamimentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 94%

supporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Abstract-positive Chrono and Inotropic Responses To Denopamimentioning

confidence: 99%

mentioning

confidence: 99%

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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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Sympathomimetics and Vasopressin

Lerche

2024

Pharmacology in Veterinary Anesthesia and Analgesia

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Clinicopharmacological studies of a newly synthesized cardiotonic agent (TA‐064) in patients with congestive heart failure

Bito

Kinoshita

Mashiro

et al. 1988

Clinical Cardiology

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Summary:In animal experiments, a new inotropic agent, (-)-(R)-1 -@-hydroxphenyl)-2-[(3,4-dimethoxyphen-etyl)amino]ethanol, designated TA-064 was found to possess a more positive inotropic than chronotropic action. Its effectiveness and lack of significant toxicity make it beneficial for clinical use as a cardiotonic in human heart failure. The effects of TA-064 were investigated in patients with various types of heart disease (n=29). Cardiac output increased, left ventricular end-systolic dimension decreased, and left ventricular fractional shortening increased for 15 minutes after a single intravenous dose (1 mg). The plasma level of TA-064 at the cessation of infusion was 61.1 f49.6 ng/ml and thereafter declined biexponentially. After a single oral dose (10 mg), TA-064 appeared in the plasma at 30 minutes and reached its peak levels of 13.7k5.6 n g / d at 60 minutes. Seven hours later, the plasma level was 5.9 f 3.1 n g / d which was considered to be within the effective range according to the results after intravenous administration. In conclusion, minimal effective plasma levels of TA-064 are obtained by oral administration of 10 mg three times a day.

show abstract

Cardiovascular Effects of a New Positive Inotropic Agent, (−)-(R)-1-(p-Hydroxyphenyl)-2-[(3,4-Dimethoxyphenethyl) Amino]-Ethanol (TA-064) in the Anesthetized Dog and Isolated Guinea Pig Heart

Cited by 53 publications

References 19 publications

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

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

Sympathomimetics and Vasopressin

Clinicopharmacological studies of a newly synthesized cardiotonic agent (TA‐064) in patients with congestive heart failure

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