Effects of chlorpromazine, d,1-propranolol, and d-propranolol in the isolated rat heart: Modification of the response to isoprenaline and glucagon

Langslet, A

doi:10.1016/0014-2999(71)90168-3

Cited by 12 publications

(5 citation statements)

References 16 publications

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“…This may be related to an increasing amount of Ca" mobilization which involves increasing numbers of calmodulin molecules. The present findings are in agreement with the observations on isolated perfused rat heart that chlorpromazine 3 X I@ mol/l, which also is able to block Ca+'-calmodulin (Levin & Weiss 1979), did not change the contractile response to 1.8XIO-* molh isoprenaline (Langslet 1971;Langslet & 0ye 1972), and that trifluoperazine (1c5 mol/l) had no effect on the inotropic response to 3X 16' mol/l and 3 X 10' mol/l isoprenaline (Werth et al 1982).…”

Section: Influence Of Trifluoperazine On 8-adrenergic Effectssupporting

confidence: 93%

Effects of Trifluoperazine on β‐Adrenergic Responses of Rat Papillary Muscle: Related to Calmodulin?

Aass

Skomedal

Osnes

1983

Acta Pharmacologica et Toxicologica

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The P-adrenergic stimulation of cardiac contraction and relaxation is related to an augmented Ca" oscillation mediated by CAMP. This Cat+ mobilization may secondarily involve calmodulin in a way modulating the mechanical responses. We tested this possibility by studying interferences of trifluoperazine (which is able to block Caw-calmodulin) with P-adrenergic responses in rat heart papillary muscles. Trifluoperazine up to Ic5 mol/l did not change the basal function.mol/l trifluoperazine augmented the contractile response to isoprenaline above lo' mol/l. The inotropic effects of isoprenaline below 16' mol/l and of the partial P-agonist prenalterol were not influenced by trifluoperazine. mol/l trifluoperazine attenuated the stimulation of initial relaxation by isoprenaline in the entire concentration range. Thus this P-adrenergic response was more sensitive to trifluoperazine than the contractile response. But trifluoperazine only slightly and non-significantly attenuated the stimulation of initial relaxation by prenalterol. From experiments on broken cell preparations the present results can be explained in terms of calmodulin blockade and thus inhibition of Cat+ efflux across the sarcolemma and of Ca" uptake by the sarcoplasmic reticulum. Trifluoperazine effects unrelated to calmodulin can hardly account for the results. Thus a full P-agonist can apparently mobilize enough Ca" to activate calmodulin systems important for the final effects on the contraction-relaxation cycle.

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Section: Influence Of Trifluoperazine On 8-adrenergic Effectssupporting

confidence: 93%

Effects of Trifluoperazine on β‐Adrenergic Responses of Rat Papillary Muscle: Related to Calmodulin?

Aass

Skomedal

Osnes

1983

Acta Pharmacologica et Toxicologica

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“…In the present study, all hearts were paced thus negating rate influenced changes. Chloropromazine at concentrations greater than 10~5 M also was reported to produce concentration-dependent decreases in contractility in isolated rat ventricles, which were paced (Langslet, 1971). The magnitude of the decreases was not stated, making direct comparison between those results and ours difficult.…”

Section: Discussionmentioning

confidence: 73%

Regulation of phosphorylase kinase in rat ventricular myocardium. Role of calmodulin.

Werth¹,

Hathaway²,

Watanabe³

1982

Circulation Research

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Conversion of phosphorylase b to a which is catalyzed by the enzyme phosphorylase kinase is known to require Ca++. Trifluoperazine, an inhibitor of calmodulin-dependent enzymes, was utilized in the present study to clarify the role in vivo of calcium-calmodulin regulation of phosphorylase kinase. Twenty-minute preperfusion of isolated rat ventricles with 10(-5) M trifluoperazine had no effect on basal levels of phosphorylase a but significantly attenuated phosphorylase activation induced by either calcium (3.75 mM) or isoproterenol (3 x 10(-9) M, 3 x 10(-8) M). The positive inotropic effect of both agents and cyclic adenosine 3',5'-monophosphate (cAMP) levels were not altered by trifluoperazine in the perfused hearts. In addition, no effects of 10(-5) M trifluoperazine were noted on beta-adrenergic receptor binding of [3H](+/-)carazolol or on adenylate cyclase activity. In vitro studies with partially purified rat cardiac phosphorylase kinase demonstrated 1.5- to 3-fold stimulation by exogenous calmodulin. The addition of 10(-5) M trifluoperazine prevented calmodulin stimulation but had little effect on activity in the absence of exogenous calmodulin. The present results suggest that reversible binding of calcium-calmodulin may represent a physiological means for regulating phosphorylase kinase activity in rat cardiac muscle.

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“…But the inotropic effect of isoprenaline at the concentrations used in the present study (as well as higher concentrations) was completely blocked by propranolol in perfused rat hearts (LaRaiaeta1. 1968;Langslet 1971), in rat atria (Refsum, unpublished results), and in rat papillary muscle (Skomedal, unpublished results). Moreover the inotropic effect of isoprenaline was competitively blocked by p-blockers (Govier 1968;Refsum & Landmark 1972).…”

Section: Discussionmentioning

confidence: 90%

Qualitative Differences between β‐Adrenergic and α‐Adrenergic Inotropic Effects in Rat Heart Muscle

Osnes

Refsum

Skomedal

et al. 1978

Acta Pharmacologica et Toxicologica

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If β‐ and α‐adrenergic inotropic effects are cyclic AMP dependent and cyclic AMP independent, respectively, they may be qualitatively different. The inotropic effects of β‐receptor stimulation (isoprenaline) and α‐receptor stimulation (phenylephrine combined with propranolol) were characterized in isolated perfused rat hearts, rat atria and rat papillary muscles. The β‐effect reached its maximum before the α‐effect. The α‐effect followed a three‐phasic time‐course indicating both stimulatory and inhibitory components. The aortic pressure wave (perfused heart) indicated a shorter contraction phase after β‐stimulation than after α‐stimulation. The time to peak tension (atrium, papillary muscle) was relatively shorter after isoprenaline than after α‐stimulation, which tended to prolong it. The contraction‐relaxation cycles (atrium, papillary muscle) were examined by recording the isometric tension (T), its first (T′) and second (T″) derivatives, α‐ and β‐stimulation both increased Tmax, T′max (maximal rate of tension rise), T′min, (maximal rate of tension decline) and T″min (maximal rate of transition from rise to decline of tension). Isoprenaline increased Tmin, (papillary muscle) and T″min (atrium, papillary muscle) relatively more than did α‐stimulation, i.e. the relaxing processes were activated relatively more by β‐stimulation. The results indicate different mechanisms for the two adrenergic inotropic effects. The relatively larger activation of relaxation by β‐stimulation is assumed to be caused by cyclic AMP.

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Effects of chlorpromazine, d,1-propranolol, and d-propranolol in the isolated rat heart: Modification of the response to isoprenaline and glucagon

Cited by 12 publications

References 16 publications

Effects of Trifluoperazine on β‐Adrenergic Responses of Rat Papillary Muscle: Related to Calmodulin?

Effects of Trifluoperazine on β‐Adrenergic Responses of Rat Papillary Muscle: Related to Calmodulin?

Regulation of phosphorylase kinase in rat ventricular myocardium. Role of calmodulin.

Qualitative Differences between β‐Adrenergic and α‐Adrenergic Inotropic Effects in Rat Heart Muscle

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