1. Impaired endothelium-dependent relaxation has been previously demonstrated in blood vessels of hypertensive rats and in humans with essential hypertension. Arteries from spontaneously hypertensive rats have been shown to produce, in response to high concentrations of acetylcholine, a vasoconstrictor substance called endothelium-derived contracting factor, the production of which can be inhibited by indomethacin or other cyclo-oxygenase inhibitors, suggesting that it is a prostanoid. The mechanisms involved in endothelium-dependent relaxation of human arteries are unclear, and the potential generation of endothelium-derived contracting factor by endothelium in human hypertension has not been established.

2. We investigated the effects of acetylcholine on precontracted small arteries dissected from gluteal subcutaneous fat biopsies from normotensive subjects and subjects with borderline and mild essential hypertension. Vessels from normotensive subjects and those from borderline hypertensive patients, precontracted by noradrenaline, were relaxed completely by acetylcholine, whereas those from patients with mild essential hypertension relaxed slightly but significantly less, indicating that generation of endothelium-derived relaxing factor (endothelium-derived nitric oxide) was only minimally reduced or that production of minor amounts of endothelium-derived contracting factor occurred in small arteries from these hypertensive subjects. This impairment of endothelium-dependent relaxation was not corrected by indomethacin, which indicated that the contribution of endothelium-derived contracting factor, if any, was minimal in this subset of essential hypertensive patients. In contrast, mesenteric small arteries of adult spontaneously hypertensive rats presented strong contractions in response to the higher concentrations of acetylcholine, which were abolished by exposure to indomethacin.

3. The relaxation induced by acetylcholine in arteries from both hypertensive and normotensive humans was partially blunted (by 30%) by pretreatment with 0.1 mmol/l NG-nitro-l-arginine methyl ester or NG-nitro-monomethyl-l-arginine (inhibitors of nitric oxide synthase) and by 10 μmol/l Methylene Blue (a blocker of soluble guanylate cyclase), indicating the role of endothelium-derived nitric oxide and the generation of its intracellular second messenger cyclic guanosine monophosphate in acetylcholine-induced relaxation. The remaining relaxation elicited by acetylcholine could be blocked with 30 mmol/l KCl or with 10 μmol/l ouabain (inhibitor of Na+, K+-ATPase), and, when combined with NG-nitro-l-arginine methyl ester, these interventions abolished acetylcholine-induced relaxation. Tolbutamide at 2 mmol/l or 10 μmol/l glyburide (blockers of ATP-sensitive potassium channels) partially inhibited NG-nitro-l-arginine methyl ester-resistant endothelium-dependent relaxation. Apamin (a blocker of small-conductance calcium-activated potassium channels), which has been shown to block NG-nitro-l-arginine methyl ester-resistant endothelium-dependent relaxation in rat arteries, was without effect. Charybdotoxin (blocker of large-conductance calcium-activated potassium channels) displaced to the right the responses to acetylcholine, in the absence and presence of NG-nitro-l-arginine methyl ester and/or tolbutamide.

4. In conclusion, in contrast to mesenteric small arteries from spontaneously hypertensive rats, which produce endothelium-derived contracting factor, subcutaneous small arteries from subjects with mild essential hypertension appear not to do so in significant amounts. Thirty per cent of the relaxation induced by acetylcholine in human small arteries is mediated by release of endothelium-derived nitric oxide, whereas more than 60% is the result of release of another agent, perhaps the putative endothelium-derived hyperpolarizing factor, which may act in part by opening ATP-sensitive potassium channels and large-conductance calcium-activated potassium channels. Endothelium-dependent relaxation induced by acetylcholine was normal in borderline hypertensive subjects and only slightly abnormal in the mildly hypertensive patients studied.

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