Mechanisms of big endothelin-1-induced diuresis and natriuresis

Endothelin-1 (ET-1) at high concentrations has marked antidiuretic and anti natriuretic activities, whereas its precursor, big endothelin-1 (big ET-1), has surprisingly potent diuretic and natriuretic actions. The mechanisms u nderlying the excretory effects of big ET-1 have not been fully elucidated. To explore these mechanisms, we examined the effects of a highly selective ET, antagonist (A-192621.1), a calcium channel blocker (verapamil), a nitr ic oxide synthase inhibitor (N-nitro-L-arginine methyl ester [L-NAME]), and a cyclooxygenase inhibitor (indomethacin) on the systemic and renal action s of big ET-1 in anesthetized rats. An intravenous bolus injection of incre mental doses of big ET-1 (0.3, 1.0, and 3.0 nmol/kg) produced a significant hypertensive effect that was dose dependent and prolonged (from 113+/-7 mm Hg to a maximum of 148+/-6 mm Hg). The administration of big ET-1 induced marked diuretic and natriuretic responses (urinary flow rate increased from 8.5+/-1 to 110+/-14 mu L/min, and fractional excretion of sodium increased from 0.38+/-0.13% to 7.51+/-1.24%). Glomerular filtration rate and renal p lasma flow significantly decreased only at the highest dose of big ET-1. Pr etreatment with A-192621.1 (3 mg/kg plus 3 mg . kg(-1) . h(-1)) significant ly abolished the diuretic (17+/-5 mu L/min to a maximum of 19+/-3 mu L/min) and natriuretic (0.29+/-0.1% to a maximum of 1.93+/-0.37%) responses induc ed by big ET-1. Moreover, A-192621.1 potentiated the decline in glomerular filtration rate and renal plasma flow and the increase in mean arterial blo od pressure produced by the low doses of big ET-1. Similar to A-192621.1, p retreatment with a nitric oxide synthase inhibitor (L-NAME, 10 mg/kg plus 5 mg . kg(-1) . h(-1)) significantly: and comparably reduced the diuretic an d natriuretic actions of big ET-1 and augmented the hypoperfusion/ hypofilt ration and systemic vasoconstriction induced by high doses of the peptide. Pretreatment with verapamil (2 mg . kg(-1) . h(-1)) slightly inhibited the diuretic/natriuretic effects of the high-dose big ET-1 and completely preve nted the increase in mean arterial blood pressure provoked by the peptide. Unlike verapamil and L-NAME, only indomethacin administration was associate d with significant natriuretic/diuretic responses and did not influence the presser effect and renal actions of big ET-1. Taken together, these result s suggest that big ET-1-induced diuretic and natriuretic responses are medi ated mainly by stimulation of nitric oxide production coupled to ETB recept or subtype activation.