On the topically effective ocular hypotensive properties of ICI 147,798, a natriuretic beta-adrenoceptor antagonist, in rabbits.

The ocular antihypertensive effects of ICI 147,798, a natriuretic, non-selective beta-blocker lacking local anaesthetic and intrinsic sympathomimetic activities, were evaluated in unanaesthetized rabbits with water-load-induced ocular hypertension. The racemate was approximately 20 times more potent as a beta-blocker than its d-isomer. The magnitude of reductions in intraocular pressure (IOP) elicited by both compounds was equal following topical administration of an equal dose-concentration (100-300 microliters, 0.5% or 0.75%) to one or both eyes, and the activities were similar to those obtained with timolol. A five-hour duration of the IOP lowering effect was achieved by ICI 147,798 and timolol in this rabbit model. ICI d-147,798 exhibited a shorter duration, which could be prolonged by increasing the concentration of the ophthalmic solution. Timolol caused a pronounced reduction of isoproterenol-induced tachycardia after a single dose (200 microliters, 0.5%) or by repeating the dose twice a day for four consecutive days. Following the same dose regimen, neither ICI 147,798 nor its d-isomer significantly altered the heart rate response produced by isoproterenol. These findings indicate that ICI 147,798, while effective as a potential antiglaucoma agent, does not display the characteristics of beta-blockers on heart rate effects noted with timolol. The results also cast some doubt on the contention that the IOP lowering effect of certain beta-blockers is predominantly determined by specific blockade of beta-adrenoceptors.

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.