Tobias O. Yellin

ICI 125,211: A new gastric antisecretory agent acting on histamine H2-receptors

In vitro, ICI 125,211 competitively antagonized the action of dimaprit on guinea pig atrium with an apparent dissociation constant of 1.5 × 10−8M (pA2 = 7.8). In vivo, the histamine dose-response curve in conscious gastric fistula beagles was shifted rightward in parallel without change in the maximal response by intravenous infusions of ICI 125,211 at doses of 0.01 and 0.03 umol/kg/hr (estimated pA2 = 7.3). Our data show that this new drug is at least 10x more potent than cimetidine as an inhibitor of gastric secretion in the dog. ICI 125,211, which is an orally effective antisecretory agent in man and devoid of antiandrogenic activity, is the most potent selective H2-blocker described to date.

Relationship between anti-diarrheal activity and binding to calmodulin

Several neuroleptics known to bind to calmodulin were tested for anti-diarrheal activity and were compared with the opiate anti-diarrheals loperamide and diphenoxylate. All inhibited the intestinal fluid secretion induced by 16,16-dimethyl prostaglandin E2 and castor oil-induced diarrhea in rats as a function of dose, the order of potency being loperamide approximately equal to diphenoxylate greater than chlorpromazine greater than promethazine greater than amitriptyline. The opiates loperamide and diphenoxylate were found to compete with [3H]trifluoperazine binding to calmodulin in the presence of calcium. These opiates were approximately 3 times more potent inhibitors of [3H]trifluoperazine binding than chlorpromazine. A positive correlation between calmodulin binding and anti-diarrheal activity was demonstrated.

Differences in the interaction of histamine H2 receptor antagonists and tricyclic antidepressants with adenylate cyclase from guinea pig gastric mucosa.

The interaction of adenylate cyclase with histamine H2 receptor agents and with tricyclic antidepressants was studied in guinea pig gastric mucosal membranes. The H2 receptor antagonist tiotidine acted as a competitive inhibitor of histamine-stimulated adenylate cyclase. The tricyclic antidepressants imipramine and amitryptyline were also competitive inhibitors. The dissociation constant of imipramine was the same whether histamine or dimaprit was used to activate the enzyme. In membrane preparations that had been stored frozen, there was a marked increase in the concentration of histamine or dimaprit required to cause half-maximal enzyme stimulation, and the dissociation constants of some classical H2 receptor antagonists were greatly increased. In contrast, the dissociation constants of the antidepressants were either unchanged or decreased. These results suggest that antidepressants are potent blockers of H2 receptors in gastric mucosal membranes, but there are differences between antidepressants and classical H2 receptor antagonists in their interaction with H2 receptors.

Regulation by monovalent cations of histamine H2 receptor-coupled adenylate cyclase from guinea pig fundic gastric mucosa

In thoroughly washed guinea pig fundic gastric mucosal membranes, NaCl markedly potentiates the maximal histamine-stimulated adenylate cyclase activity and increases the concentration of histamine required for half-maximal effect (EC50). The apparent dissociation constants for the antagonists cimetidine and metiamide are only slightly increased in the presence of NaCl. Potassium chloride does not change the histamine EC50 but does increase the maximal histamine-stimulated adenylate cyclase activity. These results suggest that Na and K ions may play an important role in the regulation of histamine-sensitive adenylate cyclase in gastric mucosa. The effect of the Na ion appears to be more specific for histamine H2 receptor agonists than for antagonists.

Interaction of α-adrenergic imidazolines with cardiac histamine H2-receptors

Abstract We have investigated in the isolated, perfused guinea pig heart whether the α-adrenergic imidazolines, tolazoline and tetrahydrozoline stimulate histamine H 2 -receptors directly or via the release of endogenous histamine. At 30°C neither tolazoline nor tetrahydrozoline released histamine. However, both increased heart rate, contractility, and decreased coronary vascular resistance as a function of dose. The H 2 -receptor antagonists cimetidine and tiotidine blocked the effects of tolazoline and tetrahydrozoline. The actions of tetrahydrozoline were confined to its l-isomer. At 37°C tolazoline, but not tetrahydrozoline, released histamine into the coronary perfusate. The maximum tolazoline-induced change in heart rate was 2.5–3.0 times greater than tetrahydrozolines, in distinct contrast to their identical effect at 30°C. All other responses to the two drugs were the same at 30 and 37°C. Our results suggest that tolazoline and tetrahydrozoline directly stimulate histamine H 2 -receptors. Because of the differences in the structures of imidazolines and histamine, these findings have implications for the current hypothesis regarding histamine H 2 -receptor activation.