The sympathetic nervous system facilitates endothelin-1 effects on venous tone

The effects of endothelin-1 (ET-1) or normal saline (0.9% NaCl) on mean arterial pressure (MAP), heart rate (HR) and mean circulatory filling pressure (MCFP), an index of body venous tone, were studied in 10 groups (n = 6 each) of conscious, unrestrained rats continuously i.v. infused with vehicle, verapamil, both hexamethonium and verapamil, phentolamine or, both phentolamine and verapamil. Infusion (i.v.) of normal saline into the five control groups did not significantly alter MAP, HR or MCFP. Cumulative i.v. bolus of ET-1 (0.8, 1.6, 3.2, 6.4, 12.8 and 19.4 x 10(-10) mol/kg) reduced HR in all five treatment groups and dose-dependently increased MAP in the presence of either vehicle or phentolamine, but did not affect MAP in the groups treated with verapamil. The ability of ET-1 to reduce HR in verapamil-treated rats, despite the absence of a pressor response, suggests that ET-1 is negatively chronotropic. ET-1 alone slightly increased MCFP and it did not alter MCFP in the presence of phentolamine. In the presence of verapamil, ET-1 markedly raised MCFP, and this was abolished by concurrent treatment with either hexamethonium or phentolamine. Therefore, ET-1 markedly elevates venous tone in the presence of verapamil via reflex-mediated increase in sympathetic nerve activity and the activation of alpha adrenoceptors.