Nitric oxide-dependent and -independent mechanisms account for gender differences in vasodilation to acetylcholine

The purpose of this study was to examine the mechanism of enhanced endothelium-dependent dilation in arteries from female rats compared with arteries from males. Isolated mesenteric resistance arteries ( approximately 250 microm) from sexually mature male and female Sprague-Dawley rats were pressurized and outer diameter was measured. Arteries from females were more sensitive to the endothelium-dependent vasodilator acetylcholine (Ach) compared with those from males (-log EC(50): male = 6.74 +/- 0.06; female = 6.96 +/- 0.06; P =.037). After incubation with N(omega)-nitro-L-arginine (100 microM) or apamin (30 nM), there was no longer a gender difference in midrange sensitivity to ACh. In contrast, at higher concentrations of ACh, N(omega)-nitro-L-arginine had a greater inhibitory effect in the males than in the females. Indomethacin (10 microM) decreased sensitivity to ACh in arteries from both males and females, but did not alter the maximal response or eliminate the gender difference. Finally, there was no gender difference in vasodilation to the nitric oxide (NO) donor spermine-NO complex, nor did apamin alter the spermine-NO complex response. In conclusion, mesenteric arteries from female rats are more sensitive to ACh than those from males. An enhanced contribution of an apamin-sensitive K(Ca) channel on the endothelium of female arteries appears to be responsible for the augmented ACh-stimulated NO production compared with that of males. In addition, ACh stimulates the production of a non-NO, noncyclooxygenase, endothelium-derived hyperpolarizing factor to a greater extent in females compared with males.