Interaction of phentolamine and noradrenaline on myocardial contractility and adenyl cyclase activity

Rabinowitz, Babeth; Parmley, William W.; Bonnoris, George; Chuck, Leonard; Kligerman, Miriam

doi:10.1093/cvr/8.2.243

Cited by 12 publications

(7 citation statements)

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“…Clearly, however, the dominant factor would likely be a-activation. These findings are consistent with observations in isolated cat papillary muscle showing that phentolamine attenuates the increase in both force and adenylate cyclase activ- ity induced by norepinephrine (Rabinowitz, 1974). Similar findings have been reported for guinea pig atrial muscle (Govier et al, 1966).…”

Section: Discussionsupporting

confidence: 92%

“…Further evidence for this assumption is provided by the demonstration that methoxamine in suitable concentrations elicits substantial increases in force development in cat RV papillary muscle and rat atrium (Rabinowitz et al, 1974(Rabinowitz et al, , 1975. Moreover, we have recently reported dose-related increases of left ventricular contractility in the lamb, as judged by changes in dP/dt max and LV function curves .…”

Section: Discussionmentioning

confidence: 83%

“…Earlier findings that phentolamine reduced inotropic responses to agents with combined a-and /?-stimulating properties (NE, epinephrine, phenylephrine) in at least two species (Govier et al, 1966;Rabinowitz et al, 1974) suggest the presence of a physiologically significant concentration of a-receptors in myocardium. Further evidence for this assumption is provided by the demonstration that methoxamine in suitable concentrations elicits substantial increases in force development in cat RV papillary muscle and rat atrium (Rabinowitz et al, 1974(Rabinowitz et al, , 1975.…”

Section: Discussionmentioning

confidence: 95%

“…It probably is not mediated by an increase in adenylate cyclase activity (Rabinowitz et al, 1974(Rabinowitz et al, , 1975Schumann et al, 1975). Moreover, in contrast with the /8-adrenergic system, activation of a-receptors induces little reduction of time-to-peak tension, and relaxation time is lengthened (Rabinowitz et al, 1975).…”

Section: Discussionmentioning

confidence: 98%

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Contribution of alpha-adrenoceptor activation to the pathogenesis of norepinephrine cardiomyopathy.

Downing¹,

Lee²

1983

Circulation Research

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Graded doses of norepinephrine and methoxamine were given to rabbits over a standard 90-minute infusion period to assess their potential for inducing myocardial injury. Lesions of myofiber necrosis and leukocytic infiltration were graded semiquantitatively in animals killed 2 days later. A close correlation was found between the dose of norepinephrine and the histological score (r = 0.912, P less than 0.001). Mean arterial pressure rose from 100 mm Hg to a maximum of 129 mm Hg, and averaged 115 mm Hg during infusion of 2 micrograms/min per kg. However, heart rate fell from 287 beats/min to average 208 beats/min. The pressure-rate product, an index of metabolic demand, showed no significant change and did not differ from saline-infused controls. Beta-adrenergic blockade with practolol (4 mg/kg) or propranolol (1 mg/kg) failed to significantly reduce cardiac injury with norepinephrine. However, alpha-adrenoceptor blockade with phentolamine (10 mg), alone or in combination with either of the beta-antagonists, markedly reduced lesion formation as reflected by the histological score (P less than 0.02). Administration of the alpha-agonist methoxamine produced dose-related increases in the intensity of myocardial injury (r = 0.938, P less than 0.01), morphologically identical with those resulting from norepinephrine. Hemodynamic changes also were comparable. Phentolamine markedly reduced methoxamine injury. It may be concluded from these studies that norepinephrine cardiomyopathy results in large part from activation of the alpha-adrenergic system in the rabbit model. Ischemia or a supply-demand mismatch are unlikely mechanisms. We speculate that alterations in myofiber Ca++ translocation, uptake, and binding induced by alpha 1-receptor activation may contribute to membrane damage.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 98%

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Contribution of alpha-adrenoceptor activation to the pathogenesis of norepinephrine cardiomyopathy.

Downing¹,

Lee²

1983

Circulation Research

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“…P-Adrenoceptor stimulation was achieved by using isoprenaline. Rabinowitz et al (1974) found no effect of phentolamine either on isoprenaline induced increase in force of contraction or on isoprenaline activated adenylate cyclase in cat heart. Wenzel & Su (1966) found, however, that a-adrenoceptor blockers potentiated the inotropic response of isoprenaline on rat ventricle strips.…”

Section: Adequacy Of B-adrenoceptor Stirnulationmentioning

confidence: 63%

Differences between α‐Adrenergic and β‐Adrenergic Inotropic Effects in Rat Heart Papillary Muscles

Skomedal

Osnes

Øye

1982

Acta Pharmacologica et Toxicologica

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a-And p-adrenergic inotropic effects have been shown to be qualitatively different. In order to further characterize these differences we compared the mechanical responses to a-and P-adrenoceptor stimulation, respectively, in electrically driven left ventricular papillary muscles from rat heart. The muscles were stimulated by either isoprenaline (p-adrenoceptor stimulation), phenylephrine in the presence of propranolol (a-adrenoceptor stimulation) or phenylephrine alone (combined aand p-adrenoceptor stimulation). Isometric tension (T), rate of rise and decline of tension (first derivative=T') and rate of transition from tension rise to tension decline (negative part of second derivative=T") were recorded. These recordings disclosed qualitative differences between the a-and p-inotropic response both in dose-response and time course experiments. Maximal p-adrenoceptor stimulation caused a small increase in T,,, (I8 %), intermediate increases in T',,, (45%) and T',,, (68%) and a considerable increase in T",,, (145%) ("/I-type" effect). Maximal aadrenoceptor stimulation increased all qualities by about the same degree (23-24%) ("a-type" effect). While padrenoceptor stimulation gave a dose-dependent and pronounced increase in the ratio T",,n/T',,, (relaxationonset index), a-adrenoceptor stimulation decreased it to subcontrol values and phenylephrine alone gave a small dose-dependent increase at higher doses. The time course of the a-adrenoceptor stimulation was characterized by a transient decrease in all qualities followed by an increase which reached maximum at 4-5 min. p-Adrenoceptor stimulation gave a monophasic response which reached maximum after 1-2 min. Phenylephrine alone gave mainly an "a-type" effect although T",,. increased significantly more in the absence than in the presence of propranolol and T,,n/T',ax showed a small increase which developed slowly. Thus p-adrenoceptor stimulation activated relaxation compared to contraction by a higher degree than did a-adrenoceptor stimulation. This probably reflects different mechanisms of action. While the a-effect may rely primarily on an increased calcium influx, the p-effect probably is the final result of several subcellular effects of cyclic AMP. Key-words:Rat hearta-adrenergic effectsp-adrenergic effectscyclic AMPrat. W h e n Ahlquist classified adrenergic receptors in 1948, he designated the stimulating receptors in heart P-adrenergic according t o t h e o r d e r of potency of a number of agonists (Ahlquist 1948). p-Receptors were regarded a s t h e sole adrenoceptors in heart muscle for m a n y years, although Nickerson (1949) had published results indicating an a-adrenergic inotropic effect in frog heart. In 1966,Wenzel & Su, however, claimed t h a t ventricle strips from rat heart contained both aa n d P-adreno-ceptors a s recorded by inotropic effects. Later

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Effects of Beta- and Alpha-Adrenoceptor Activators and Adrenergic Transmitter Releasing Agents on the Mechanical Activity of the Heart

Scholz¹

1980

Adrenergic Activators and Inhibitors

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Interaction of phentolamine and noradrenaline on myocardial contractility and adenyl cyclase activity

Cited by 12 publications

References 0 publications

Contribution of alpha-adrenoceptor activation to the pathogenesis of norepinephrine cardiomyopathy.

Contribution of alpha-adrenoceptor activation to the pathogenesis of norepinephrine cardiomyopathy.

Differences between α‐Adrenergic and β‐Adrenergic Inotropic Effects in Rat Heart Papillary Muscles

Effects of Beta- and Alpha-Adrenoceptor Activators and Adrenergic Transmitter Releasing Agents on the Mechanical Activity of the Heart

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