Vascular structure and expression of endothelin-1 gene in L-NAME-treated spontaneously hypertensive rats.

Inhibition of nitric oxide synthase by L-arginine analogues is associated with elevation of blood pressure in rats. Deoxycorticosterone acetate (DOCA)-salt hypertensive rats and DOCA-salt-treated spontaneously hypertensive rats (SHR) overexpress the endothelin-1 gene in blood vessels, and this is associated with severe vascular hypertrophy, whereas SHR do not overexpress endothelin-1 and exhibit limited vascular hypertrophy. In this study malignant hypertension was induced in SHR by chronic administration of the L-arginine analogue NG-nitro-L-arginine methyl ester (L-NAME), a potent inhibitor of nitric oxide synthase, to determine whether malignant hypertension would result in endothelin-1 gene overexpression in blood vessels and in greater severity of vascular hypertrophy, as found in malignant DOCA-salt-treated SHR. L-NAME treatment induced malignant hypertension in SHR, with a systolic blood pressure of 246 +/- 2 mm Hg, compared with 211 +/- 2 mm Hg (P < .01) in untreated SHR. Plasma renin activity was very high in L-NAME-treated SHR, and their plasma immunoreactive endothelin concentration was slightly but significantly elevated (P < .01). After 3 weeks of treatment, aortic and to a lesser degree mesenteric artery weights were significantly increased in L-NAME-treated SHR compared with untreated SHR. However, cardiac weight and the media cross-sectional area or media width-to-lumen diameter ratio of small arteries from the coronary, renal, mesenteric, or femoral vasculature were not increased in L-NAME-treated SHR in comparison with untreated SHR. The abundance of endothelin-1 mRNA measured by Northern blot analysis was significantly increased in L-NAME-treated SHR in aorta and with less magnitude in the mesenteric arterial tree. The absence of accentuation of cardiac and small artery hypertrophy in malignant hypertension in L-NAME-treated SHR, despite enhanced expression of the endothelin-1 gene in blood vessels, may suggest a direct or indirect inhibitory effect of L-NAME on cardiovascular growth, probably independent of its effects on nitric oxide synthase, counterbalanced in aorta and large mesenteric arteries by the hypertrophic effect of enhanced vascular endothelin-1 gene expression. These results also suggest a role for blood pressure and potentially for nitric oxide in the regulation of endothelin-1 gene expression in blood vessels.