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The effects of adrenergic amines and theophylline on contractile force and cyclic AMP Martinez, Terry T.

Abstract

Time response studies of the effects of norepinephrine and phenylephrine revealed that both agonists caused an increase in cyclic AMP levels prior to increases in contractile force. Norepinephrine caused a nearly six fold increase in cyclic AMP, whereas phenylephrine produced only a 50% increase in the nucleotide. Pretreatment with reserpine did not affect the norepinephrine cyclic AMP response; however, the phenylephrine cyclic AMP response was abolished. Reserpine pretreatment did not significantly affect the contractile responses of either amine. In the presence of propranolol, norepinephrine was found to have the ability to produce an increase in contractile force in which cyclic AMP was apparently not involved. The time course of the contractile response induced by adrenergic amines was found to be remarkably influenced by the chronotropic response in spontaneously beating preparations while the cyclic AMP response was not greatly affected. This difference in the contractile response may be due to the ability of the chronotropic response to influence the flux of calcium through the cell membrane. At 37° C phentolamine was found to have no effect on the isoproterenol dose-response curve. Phentolamine did, however, cause the norepinephrine log dose-response (LDR) curve to shift to the right and the maximum response was attenuated. Phentolamine competitively antagonized the phenylephrine LDR curve. Propranolol caused a shift to the right of the isoproterenol LDR curve. In the presence of propranolol the efficacy of of isoproterenol was increased, which may be related to the ability of propranolol to antagonize binding and sequestration of internal free calcium. Propranolol competitively antagonized only the second component of phenylephrine activity which was probably due to catecholamine release. At 22° C phentolamine was found to produce an apparent nonspecific, noncompetitive antagonism of the inotropic response to isoproterenol, norepinephrine and phenylephrine. This apparent blockade was found to be related to the ability of phentolamine to increase the inotropic effect of low temperature so as to leave little room within the limits of contractility for the agonist to produce a positive inotropic response. The efficacy of all the amines appeared to be increased in the presence of propranolol which was found to antagonize the inotropic effects of low temperature and thus leave more room within the limits of contractility for an amine to produce an inotropic response. The cyclic AMP response was found to be blocked by propranolol at 37° C, 22° C, and 17° C. Phentolamine did not block the cyclic AMP response at any temperature tested. Exposure to phenoxy-benzamine 17° C for 45 minutes before testing at 37° C did not significantly affect either the contractile response or the cyclic AMP response from control experiments. It is therefore concluded that there is no interconversion of alpha and beta adrenergic receptors mediated by temperature. The interpretation of the effects of adrenergic antagonists at low temperature is complicated by their ability to modify the inotropic effect of temperature alone. Theophylline alone produced! a 50% increase in cyclic AMP levels, however, this response was abolished in reserpine pretreated tissue. In addition, theophylline was found to exert a direct contractile effect which was unrelated to cyclic AMP. The effect of theophylline on cyclic AMP appeared to be additive with the norepinephrine and phenylephrine responses. The effect of theophylline on amine-induced cardiac cyclic AMP and contractile force showed no correlation between the contractile and the cyclic AMP effects at the different times tested. It therefore seems logical that the cardiac effects of theophylline are not mediated through cyclic AMP. These results support the view that the methylxanthines exert their effects on heart through changes in calcium metabolism.

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