Interaction between endothelin and nitric oxide in sympathetic nerve modulation in hypertensive rats

To test the hypothesis that endothelin (ET) and nitric oxide (NO) interact in modulating the sympathetic nervous system in conscious rats, as they do in the endothelium, mean arterial pressure (MAP), heart rate, and renal sympathetic nerve activity (RSNA) were recorded in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) given losartan and compared before and during intravenous infusion of an NO synthase inhibitor, L-NMMA (0.25 mg/kg/min). The slope of the relation between RSNA and MAP to blood pressure reduction was increased in the presence of L-NMMA (from 0.6 +/- 0.1 to 2.8 +/- 0.2), suggesting that endogenous NO suppresses the reflex increase in RSNA. Since NO inhibits ET production in the endothelium, we speculated that the increase in MAP-RSNA slope was due partly to an unmasking of ET, and thus recorded MAP, heart rate, and RSNA during intravenous infusions of both L-NMMA and the ET-type-A-receptor antagonist BQ-485 (0.10 mg/kg/min). The slope decreased significantly in SHR when BQ-485 was added (1.5 +/- 0.2), but not in WKY, implying that unmasked ET enhanced the sympathetic increase via ETA receptors in hypertensive rats. An ETB-receptor antagonist potentiated the sympathetic response only in WKY rats. These results suggest that NO suppressed the reflex increase in RSNA to blood pressure reduction, while ET uncovered by L-NMMA enhanced the sympatho-activation, indicating an interaction between ET and NO in modulating the sympathetic nervous system in conscious hypertensive animals in vivo. In contrast, the interaction was not observed in normotensive rats.