The relative importance of nitric oxide and nitric oxide‐independent mechanisms in acetylcholine‐evoked dilatation of the rat mesenteric bed

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Abstract
The relative contribution of nitric oxide (NO) to acetylcholine‐induced smooth muscle relaxation was investigated in the rat perfused mesenteric vasculature and in isolated segments of second, third and fourth order arterial branches. The EC50 values and maximal relaxation to acetylcholine were not significantly different in the sequential arterial branches, being approximately 0.05 μm and 85%, respectively. The NO synthase inhibitor L‐NG‐nitro‐L‐arginine methyl ester (L‐NAME; 100 μm) reduced acetylcholine‐evoked endothelium‐dependent dilatation and relaxation in the perfused mesenteric bed and in isolated arterial segments. The maximum response to acetylcholine in both preparations was reduced by between 35% to 40% while the EC50 values were increased by 5–6 fold. L‐NAME had no effect on basal smooth muscle tone in either case. In contrast, endothelium‐dependent dilatation of the perfused mesenteric bed evoked by A23187 (0.002–20 nmol), was unaffected by exposure to L‐NAME. The EC50 values and maximal responses elicited by A23187 (20 nmol) before and after exposure to L‐NAME were 0.96 ± 0.5 nmol and 67.0 ± 7.0% (n = 4), and 0.7 ± 0.4 nmol and 70.0 ± 5.0% (n = 4; P > 0.01), respectively. Perfusion of the isolated mesenteric bed with raised K+‐Krebs buffer (25 μm) had no effect on basal tone, but reduced the amplitude of both acetylcholine‐ and A23187‐evoked dilatation. The maximum responses to acetylcholine (2 μmol) and A23187 (20 nmol) were reduced from 67.5 ± 7.3% and 65.4 ± 8.2% to 18.9 ± 11.0% (n = 5; P < 0.01) and 13.5 ± 12.0% (n = 4; P < 0.01), respectively. Exposure of the mesenteric bed to L‐NAME in the presence of raised K+‐Krebs further reduced the maximal response elicited by acetylcholine to only 8.9 ± 2.8% (n = 4; P < 0.01). These results indicate that acetylcholine‐evoked vasodilatation of the rat mesenteric vasculature is mediated by both NO‐dependent and ‐independent mechanisms. The relative contribution made by these mechanisms does not appear to differ in sequential branches of the mesenteric artery. In contrast, A23187‐evoked vasodilatation appears to be mediated predominantly by a NO‐independent mechanism which is sensitive to increases in the extracellular potassium concentration and may reflect the action of endothelium‐derived hyperpolarizing factor (EDHF).

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