Protection against aspirin-induced human gastric mucosal injury by bosentan, a new endothelin-1 receptor antagonist.

Background: Gastric ulceration induced by aspirin and by non-steroidal anti-inflammatory drugs (NSAIDs) is a major clinical problem. The mechanism of injury is unclear. There is evidence that NSAID-induced injury may cause endothelin activation.

Haemodynamics, cardiac conduction and pharmacokinetics of mibefradil (Ro 40-5967), a novel calcium antagonist.

Objectives: Mibefradil (Ro40-5967) is a chemically novel non-dihydropyridine calcium antagonist. In this phase II study we compared its acute and chronic effects on blood pressure, heart rate and atrioventricular conduction (electrocardiographic PQ interval) with those of verapamil and diltiazem.

Patients And Methods: After a 4-week placebo run-in, 18 patients with mild to moderate essential hypertension were given single doses of mibefradil (150 mg), slow-release (SR) verapamil (240 mg), diltiazem (240 mg) and placebo at weekly intervals; pharmacokinetics and the effects on blood pressure, heart rate and PQ interval were studied on four 10-h study days.

Dissociation between reperfusion induced arrhythmias and increases in ventricular alpha 1 receptor density in the anaesthetised rat.

Using anaesthetised rats we have assessed (1) whether the density of alpha 1 adrenergic receptors increases during coronary artery occlusion, (2) whether any change in density can be associated with the onset of reperfusion induced ventricular fibrillation, and (3) whether alpha 1 blockade with prazosin modifies the incidence of reperfusion induced ventricular fibrillation. The incidence of fibrillation upon reperfusion after 3, 5, 10, 20 and 30 min occlusion was 20, 75, 50, 16 and 10% (n = 10-12 in each group) respectively. alpha 1 Receptor density was measured using [3H]-prazosin in non-ischaemic and ischaemic tissue obtained after 0, 5 and 30 min ischaemia.

Allopurinol and reperfusion-induced arrhythmias: increased protection by simultaneous administration of anti-oxidant enzymes.

We have assessed whether the xanthine oxidase inhibitor, allopurinol, can afford maximal protection against the formation of reperfusion-induced arrhythmias or whether the addition of free radical scavengers and anti-oxidants can increase this protection. Using an anesthetized rat preparation with transient coronary artery occlusion, we have compared the ability of allopurinol pretreatment alone to that of a combination therapy of allopurinol, superoxide dismutase, and catalase to reduce the incidence of reperfusion-induced arrhythmias. While both regimes reduced the incidence of reperfusion-induced ventricular fibrillation (from 87% to 40%, p less than 0.

Reperfusion-induced arrhythmias: a study of the role of xanthine oxidase-derived free radicals in the rat heart.

We have assessed whether oxygen-derived free radicals produced by xanthine oxidase may be an important trigger mechanism in the genesis of reperfusion-induced arrhythmias. We have examined (i) the effects of inhibition of xanthine oxidase by both folic acid solution and amflutizole; (ii) the effects of the inhibitor of xanthine dehydrogenase to xanthine oxidase conversion, soybean trypsin inhibitor; (iii) the effects of administration of superoxide dismutase and catalase, both singly and in combination and (iv) in an isolated rat heart preparation we have investigated the ability of free radical scavengers to reduce reperfusion arrhythmias caused by the infusion of xanthine oxidase and hypoxanthine. The prior administration of folic acid solution, amflutizole, superoxide dismutase, catalase, and superoxide dismutase plus catalase all reduced the incidence of reperfusion-induced arrhythmias and resultant mortality, caused by reperfusion after a transient period of coronary artery occlusion in the anaesthetised rat.