Human eNOS gene delivery attenuates cold-induced elevation of blood pressure in rats

We previously showed that chronic cold exposure inhibits endothelial nitric oxide synthase ( eNOS) expression and decreases nitric oxide (NO) production. The aim of the present study was to evaluate the possible role of the NO system in the development of cold-induced hypertension (CIH) by testing the hypothesis that adenoviral delivery of human eNOS gene increases NO production and attenuates CIH in rats. The effect of in vivo delivery of adenovirus carrying human eNOS full-length cDNA (rAdv.heNOS) on CIH was tested using four groups of Sprague-Dawley rats (6 rats/group). Blood pressure ( BP) did not differ among the four groups during the control period at room temperature (24 degrees C). Two groups of rats received intravenous injection of rAdv.heNOS (1 X 10(9) plaque- forming units/rat), and the other two groups received the same dose of rAdv.LacZ to serve as controls. After gene delivery, one rAdv.heNOS-treated group and one rAdv. LacZ-treated group were exposed to cold (6 degrees C) while the remaining groups were kept at 24 degrees C. We found that the BP of the rAdv. LacZ group increased significantly within 1 wk of exposure to cold and reached a peak level at week 5 (152.2 +/- 6.4 mmHg). In contrast, BP (118.7 +/- 8.4 mmHg) of the cold-exposed rAdv.heNOS group did not increase until 5 wk after exposure to cold. The rAdv.heNOS increased plasma and urine levels of NO significantly in cold-exposed rats, which indicates that eNOS gene transfer increased NO production. Notably, rAdv.heNOS decreased plasma levels of norepinephrine and plasma renin activity in cold-exposed rats, which suggests that eNOS gene transfer may decrease the activities of the sympathetic nervous system and the renin-angiotensin system. Immunohistochemical analysis showed that the transferred human eNOS was expressed in both endothelium and adventitia of mesenteric arteries. We conclude that 1) eNOS gene transfer attenuates CIH by increasing NO production and inhibiting the sympathetic nervous system and the renin-angiotensin system; and 2) the NO system appears to mediate this nongenetic, nonpharmacological, nonsurgical model of hypertension.