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 associa ted with elevation of blood pressure in rats. Deoxycorticosterone acet ate (DOCA)-salt hypertensive rats and DOCA-salt-treated spontaneously hypertensive rats (SHR) overexpress the endothelin-1 gene in blood ves sels, and this is associated with severe vascular hypertrophy, whereas SHR do not overexpress endothelin-1 and exhibit limited vascular hype rtrophy. In this study malignant hypertension was induced in SHR by ch ronic administration of the L-arginine analogue N-G-nitro-L-arginine m ethyl 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 vascul ar hypertrophy, as found in malignant DOCA-salt-treated SHR. L-NAME tr eatment induced malignant hypertension in SHR, with a systolic blood p ressure of 246+/-2 mm Hg, compared with 211+/-2 mm Hg (P<.01) in untre ated SHR. Plasma renin activity was very high in L-NAME-treated SHR, a nd their plasma immunoreactive endothelin concentration was slightly b ut significantly elevated (P<.01). After 3 weeks of treatment, aortic and to a lesser degree mesenteric artery weights were significantly in creased in L-NAME-treated SHR compared with untreated SHR. However, ca rdiac weight and the media cross-sectional area or media width-to-lume n diameter ratio of small arteries from the coronary, renal, mesenteri c, or femoral vasculature were not increased in L-NAME-treated SHR in comparison with untreated SHR. The abundance of endothelin-1 mRNA meas ured by Northern blot analysis was significantly increased in L-NAME-t reated SHR in aorta and with less magnitude in the mesenteric arterial tree. The absence of accentuation of cardiac and small artery hypertr ophy in malignant hypertension in L-NAME-treated SHR, despite enhanced expression of the endothelin-1 gene in blood vessels, may suggest a d irect or indirect inhibitory effect of L-NAME on cardiovascular growth , probably independent of its effects on nitric oxide synthase, counte rbalanced in aorta and large mesenteric arteries by the hypertrophic e ffect of enhanced vascular endothelin-1 gene expression. These results also suggest a role for blood pressure and potentially for nitric oxi de in the regulation of endothelin-1 gene expression in blood vessels.