Effect of intrathecal administration of ET-1, ET-3 and ET(16-21) on blood pressure and micturition reflex in anesthetized rats

In urethane-anesthetized rats, intrathecal administration of endothelin-1 (ET-1), endothelin-3 (ET-3) (3-100 pmol/rat) or the C-terminal hexapeptide ET(16-21) (10-100 nmol/rat) dose-dependently increased mean blood pressure (MBP) and suppressed the supraspinal micturition reflex (SMR). ET(16-21), at 100 nmo-, produced a pressor response comparable to that induced by ET-1 at 100 pmol. Guanethidine and hexamethonium pretreatment significantly reduced the increase of MBP induced by ET-1 but was inactive in antagonizing inhibition of SMR. Neither naloxone nor adrenalectomy were effective in preventing the responses to ET-1. The high degree of lethality (60-100%), observed with ET-1 (10-100 pmol), was not reduced by guanethidine, naloxone, adrenalectomy or by hexamethonium. ET-3, at 100 pmol or 1 nmol, induced death in about 50% of cases. The symptoms before death were reduction of the respiratory rate followed by respiratory arrest. These findings indicate that the pressor response to intrathecally-administered endothelins involves activation of sympathetic preganglionic elements; induction of secretion of catecholamines from adrenal glands was excluded. Lethality and inhibition of SMR does not involve opioids, sympathetic activation or release of catecholamines from the adrenal glands.