EFFECTS OF N-G-MONOMETHYL-L-ARGININE, INDOMETHACIN, AND ASPIRIN ON THE VASODEPRESSOR RESPONSE TO LOW-DOSES OF ENDOTHELIN-1 AND ENDOTHELIN-3IN RATS

Low doses (less than or equal to 100 pmol/kg) of endothelin-l (ET-1) a nd endothelin-3 (ET-3) elicited a fall in mean arterial pressure (MAP) and a dose-related reduction in hindquarter vascular resistance in an esthetized rats. The depressor response to low doses of ET-1 or ET-3 w as short-lived (about 10 sec) and reversible. High doses (greater than or equal to 200 pmol/kg) of ET-1 and ET-3 elicited a biphasic respons e; an initial fall in MAP followed by a gradual increase in MAP. The p resser response to large doses of ET-3 was less than that to large dos es of ET-1. On the other hand, the depressor response to low doses of ET-3 was similar to that to low doses of ET-1. Both ET-1 and ET-3 at l ow doses exhibited primarily a vasodilatory activity. Pretreatment wit h N-G-monomethyl-L-arginine (L-NMMA), a compound that inhibits nitric oxide (NO) production by endothelial cells, attenuated the hypotensive and hindquarter vasodilating effects of low doses of these isopeptide s, indicating that the hindquarter vasodilating responses to these pep tides depend upon the release of NO from endothelial cells. On the oth er hand, pretreatment with either aspirin or indomethacin did not alte r the hypotensive or the hindquarter vasodilating effects of either ET -1 or ET-3, indicating that cycloxygenase products may not be involved in the vasodepressive mechanisms of these peptides. L-NMMA attenuated the vasodilating effects of these peptides, but did not completely in hibit the response, suggesting that NO production by endothelial cells plays only a partial role in the vasodilation of ET in vivo. Although endothelin per se is a potent vasoconstrictor, this peptide also has vasodilatory activity in vivo due to the interaction between endotheli um derived relaxing factor and other vasoactive substances to regulate vascular tone in regional criculation.