ELECTROPHARMACOLOGICAL ANALYSIS OF THE ACTIONS OF HISTAMINE IN CARDIAC TISSUE

The effects of histamine in cardiac muscle of the guinea pig were resolved into actions at H1 and H2 receptors and compared with the effects and interactions of adrenergic agonists and antagonists. Using intracellular recording techniques and drug administration by superperfusion, right atrial muscle fibres and papillary muscle fibres from both ventricles were studied in vitro in conditions where the fast Na+-current system was presumably inactivated by depolarization with high [K+] perfusion. Application of histamine or the H2 agonist, 4-methyl-histamine, and of isoproterenol permitted restoration of action potential activity in such fibres which were otherwise incapable of generating action potentials following intense (> 100 times threshold) electrical stimulation. The above effects of histamine and 4-methyl-histamine were antagonized by metiamide; propranolol antagonized only the effects of isoproterenol. Perfusion with high [Ca2+] increased, while application of D 600 (an inhibitor of Ca2+ movements) reduced, the restorative effect of 4-methyl-histamine, implicating the involvement of a Ca2+-current system in the ionic events following H2 receptor activation. Specific α or H1 receptor agonists (methoxamine and 2-(2-pyridyl)-ethylamine) did not exhibit any restorative action. Applications of methoxamine, in the presence of a β blocker, increased the duration of action potentials without affecting their amplitude; this effect could be blocked with phentolamine. On the other hand, the H1 receptor agonist reduced the duration of ventricular action potentials; this effect could be antagonized by concomitant perfusion of promethazine. Although the effects of the H1 receptor agonist were demonstrated to be different from those of the α receptor agonist, the data suggest that histamine may cause its positive inotropic and chronotropic effects in the heart by activating H2 receptors in a manner analogous to that of β-adrenergic agents.