Converting enzyme inhibitors and the interaction between kinins and eicosanoids

Inhibitors of the angiotensin-converting enzyme (ACE = kininase II) by definition have a dual action: prevention of angiotensin II generation and inhibition of kinin degradation. Although the first mechanism is generally accepted, it may not by itself be sufficient to explain the acute blood pressure-lowering action of these compounds. Studies in experimental and clinical hypertension, including the use of selective angiotensin II and bradykinin receptor antagonists, suggest additional vasodilator, non-renin-dependent mechanisms in their action on blood flow and blood pressure. Inhibition of kinin degradation by ACE inhibitors will amplify kinin-mediated reactions on local vessel tone, in particular, if kinin generation is stimulated or this situation is experimentally mimicked by addition of exogenous bradykinin. The acute blood pressure-lowering action of ACE inhibitors is inhibited by indomethacin-type cyclooxygenase inhibitors, suggesting a contribution of bradykinin-induced release of vasodilator prostaglandins to their action. Bradykinin stimulates the phospholipase-dependent release of arachidonic acid from membrane phospholipids, allowing for subsequent generation of its metabolites, the eicosanoids. This stimulation is receptor-mediated and involves one or more types of B2 receptors, coupled via G-proteins to intracellular messenger systems that control cytosolic calcium levels. Bradykinin-induced changes in vessel tone are transient, caused by a rapidly developing tachyphylaxis at the receptor level. The potent vasodilator action of systemic bradykinin administration is not consistently reflected in studies performed on isolated blood vessels. This is probably due to the indirect nature of kinin-mediated vasomotor responses, i.e., the release of vasoactive mediators, most notably the eicosanoids and endothelium-derived relaxing factor (EDRF).(ABSTRACT TRUNCATED AT 250 WORDS)