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Endothelin (ET)-1 is a potent vasoconstrictor with profibrotic and proinflammatory effects. Increasing evidence suggests that ET-1 and its cognate receptors are involved in a variety of progressive renal disorders, including diabetes, hypertension and glomerulonephritis. Several laboratory studies have demonstrated elevated expression of ET-1, which colocalizes with glomerular and tubulointerstitial injury, in addition to enhanced urinary excretion. Moreover, ET-1 expression correlates with disease severity and renal function. With the availability of ET receptor antagonists, a pathogenetic role has been further corroborated in animal models, demonstrating both structural and functional improvement. Thus, antagonizing the ET system may be useful in major renal pathologies associated with glomerular and tubulointerstitial damage.

Background: Although endothelin I (ET-1) is a very potent vasoconstrictor, ET-1 transgenic (ET-1 tg) mice are not hypertensive. This might be due to higher bioavailability of nitric oxide (NO) in ET-1 tg, which counteracts the effect of vasoconstrictors. We hypothesized lower angiotensin II (Ang II) sensitivity of afferent arterioles in ET-1 tg., Methods: Afferent arterioles were manually dissected and microperfused. Changes of the luminal diameter due to application of vasoactive substances were used for assessment of the reactivity of afferent arterioles. We investigated the effect of L-NAME, an unspecific NO synthase inhibitor, on basal tone, and the sensitivity of afferent arterioles to Ang II with and without pre-treatment with L-NAME. The renin-angiotensin-system was characterized by expression analysis of angiotensin-receptors and renin at the mRNA level., Results: L-NAME reduced afferent arterioles diameters similarly in ET-1 tg and wild-types (WT). Ang II sensitivity determined by calculation of EC50 for Ang II was less in ET-1 tg compared with WT (P<0.05). Ang II reduced luminal diameters to a lesser extent in ET-1 tg compared to WT (P<0.05). After pre-treatment with L-NAME, Ang II sensitivity and maximum constriction of afferent arterioles were similar in ET-1 tg and WT. The expression of renin- and Ang II-receptor-mRNA in the kidney did not differ between either group., Conclusion: The loss of differences in the maximum constriction and Ang II sensitivity of afferent arterioles between ET-1 tg and WT in the absence of NO suggests pronounced NO effects in afferent arterioles of ET-1 tg. This might contribute to the maintenance of normal renal arteriolar tone in ET-1 tg mice.