Office of Naval Research Contract N00014-88-c-0118 Technical Report 94-10 Endothelial Receptor a Blockade Alters the Hemodynamic Response to Nitric Oxide Inhibition in the Rat

We have examined the extent to which the systemic and renal vasoconstriction induced by nitric oxide (NO) inhibition in vivo are mediated by endothelin (ET). We examined'the effects of BQ610, a specific ET-A receptor antagonist, following NO inhibition with L-NAME in the anesthetized rat. Mean arterial pressure (MAP) increased following L-NAME infusion from 107±2 to 133+3 mmHg (p<0.05 vs baseline period) and then fell to 115+3mmHg following administration of BQ610 (p<0.05 vs LNAME and baseline periods). Systemic vascular resistance (SVR) increased from 1.26±0.06 to 2.17±0.18 mmHg/ml/min/300g following L-NAME (p<0.05 vs baseline period) and then fell to 1.69±0.12 mmHg/ml/min/300g after BQ610 (p<0.05 vs L-NAME and baseline periods). The increase in renal vascular resistance (RVR) from 6.4±0.4 to 13.7±1.4 mmHg/ml/min/300g induced by L-NAME (p<0.05 vs baseline period) was reduced to 11.1+1.0 mmHg/ml/min/300g by BQ610 (p<0.05 vs L-NAME and baseline periods). The extent to which BQ610 reversed the L-NAME induced increases in RVR and SVR was comparable (RVR by 40±9% ; SVR by 52±7%). GFR and renal blood flow (RBF) were both reduced by L-NAME, but neither value increased following BQ610, possibly because the renal vasodilation induced by ET-A blockade was offset by the concomitant reduction in MAP and renal perfusion pressure. In summary, ET, acting via the ET-A receptor, partially contributes to the systemic and renal hemodynamic vasoconstrictor and hypertensive effects of NO inhibition.