John H. McNeill

Histamine effects on cardiac contractility, phosphorylase and adenyl cyclase.

Abstract Histamine was found to produce a positive inotropic effect and to activate the enzyme glycogen phosphorylase in isolated, perfused guinea pig hearts. Both effects were greatly enhanced by theophylline and proved resistant to blockade by tripelennamine. Histamine stimulated cardiac adenyl cyclase and this stimulation also proved resistant to blockade by antihistamines whereas stimulation of the enzyme by epinephrine was blocked by propranolol. Betazole and a triazole derivative, both analogs of histamine, also increased adenyl cyclase activity but were less effective than histamine and more effective than epinephrine. The combined effects of maximum doses of betazole or the triazole derivative and epinephrine were greater than that obtained with either drug alone. Betazole decreased the histamine stimulation of adenyl cyclase. The data suggest that there are separate receptors for histamine and epinephrine on cardiac adenyl cyclase and that stimulation of adenyl cyclase could account for the cardiac actions of histamine. The data also confirm reports that the cardiac histamine receptor differs from other histamine receptors.

Ephedrine-adrenergic amine interaction of heart phosphorylase, adenyl cyclase and amine uptake☆☆☆

Abstract Ephedrine is known to interact with other adrenergic amines by enhancing the effect of direct acting amines in low doses and by blocking the effect in high doses. In the present study ephedrine in low doses enhanced the effect of norepinephrine on rat cardiac phosphorylase a . Higher doses of ephedrine blocked the norepinephrine response. Ephedrine was found to cause a parallel shift in the dose-response curve obtained with isoproterenol on cardiac phosphorylase a . Ephedrine also shifted the dose-response curve obtained with tyramine to the right and depressed the maximal response obtained with tyramine. Ephedrine was found to decrease amine uptake as measured by the formation of labelled octopamine from labelled tyramine. Ephedrine also blocked the stimulatory effects of epinephrine on rat adenyl cyclase. It is concluded that the effects of ephedrine can be explained on the basis that ephedrine blocks amine uptake and also can occupy and block β-adrenergic receptors.

Amine-induced cardiac phosphorylase A after reserpine-triiodothyronine pretreatment☆

Abstract Both reserpine and triiodothyronine pretreatment greatly enhanced the noradrenaline- and isoproterenol-induced activation of rat cardiac phosphorylase. When both pretreatment were combined the resulting potentiation was greater than that produced by either pretreatment alone indicating that different mechanisms of action are involved for each drug. Atropine pretreatment had no effect on the noradrenaline response in animals pretreated with reserpine, trilodothyronine or a combination of both drugs. Atropine pretreatment did increase the noradrenaline effect in hyperthyroid animals pretreated with propranolol thus indicating that part of the blocking action of propranolol in the hyperthyroid animals is due to an increase in vagal tone.

Glycogen phosphorylase levels in spontaneously beating turtle hearts.

Abstract 1. 1. The total activity of glycogen phosphorylase and the percentage of the enzyme in the active form (per cent phosphorylase a ) was determined at various stages of the contraction cycle in the heart of the turtle. 2. 2. Enzyme activity did not vary throughout the contraction cycle. 3. 3. Total enzyme activity in the turtle heart was less than that found in mammalian hearts but the turtle heart had a significantly greater level of phosphorylase a .

Thyroxine-induced supersensitivity to histamine and norepinephrine activation of cardiac phosphorylasea

Abstract The interaction between thyroid hormone and the adrenergic amines on the activation of the cardiac enzyme glycogen phosphorylase has been well documented ( Frazer et al. 1969; , Hess and Shanfeld 1965; , Hornbrook and Brody 1963; Hornbrook et al. 1965; , McNeill 1969 , McNeill and Brody 1968) . The mechanism of the enhancement is not understood but it does not involve blockade of catecholamine uptake ( McNeill and Brody 1968) , cyclic AMP formation ( Frazer et al. 1969; McNeill and Brody 1968) , adenyl cyclase stimulation or sensitization ( McNeill et al. 1969) , or phosphodiesterase inhibition ( Levey and Epstein 1968; ,McNeill et al. 1971). An increase in the activity of phosphorylase b kinase may, however, be a factor in the enhancement of adrenergic amine-induced activation of phosphorylase by thyroid hormone Frazer et al. 1969; . It is also not known whether the enhancement of drug-induced enzyme activation by thyroid hormone is specific for the adrenergic amines. This is probably due to the lack of non-adrenergic agonists capable of stimulating the enzyme. It has been demonstrated that histamine will increase the activity of cardiac phosphorylase (McNeill and Schulze, in press; Muschek and McNeill 1971 a and b; Poch and Kukovetz 1967). Therefore the present study was undertaken to investigate the interaction between thyroid hormone and histamine on guinea pig cardiac phosphorylase a . The results indicate that thyroid hormone can enhance both histamine and norepinephrine-induced activation of cardiac phosphorylase a . Possible mechanisms of this interaction are discussed.