Plasma and vascular kinins stimulate the production of endothelium-derived nitric oxide, prostacyclin and hyperpolarizing factor (which regulates the function of vascular smooth muscle), and endothelial interactions with blood cells. The role of kinins in vasomotion is determined by the rate of production of the peptides by kininogenases and their degradation by kininases, in particular angiotensin-converting enzyme (ACE). Acute increases in plasma kinin levels during exercise or myocardial ischemia indicate that the metabolism of the peptides is fine tuned to the systemic or local metabolic demands. The release of endothelial vasodilators is impaired (or counterbalanced by the release of chemical or functional antagonists) in atherosclerosis, hypertension, diabetes, subarachidonic hemorrhage, and following postischemic injury. ACE-inhibitors potentiate the action of kinins and normalize endothelial function. In septic shock, hypotension triggered by overproduction of kinins leads to cardiovascular impairment and end-organ damage. Thus the balance in the metabolism of kinins modulates the control of blood flow by the endothelium.

Experiments were designed to determine whether or not indapamide, an antihypertensive agent with vasodilator properties, inhibits endothelium-dependent contractions. Rings of aortae with and without endothelium from spontaneously hypertensive rats (SHR) were suspended in conventional organ chambers for the measurement of isometric force. Acetylcholine and adenosine diphosphate-beta-S in the presence of a nitric oxide synthase inhibitor, caused endothelium-dependent contractions, which were inhibited by indapamide. The compound (10(-4) M) also slightly reduced the contractions of rings without endothelium evoked by U-46,619, which activates thromboxane-endoperoxide receptors. These results demonstrate that indapamide inhibits endothelium-dependent contractions in the SHR aorta, and suggest that the inhibition is due, at least in part, to the action of the drug on the hypertensive vascular smooth muscle.