Mechanisms of big endothelin-1-induced diuresis and natriuresis : role of ET(B) receptors.
Endothelin-1 (ET-1) at high concentrations has marked antidiuretic and antinatriuretic activities, whereas its precursor, big endothelin-1 (big ET-1), has surprisingly potent diuretic and natriuretic actions. The mechanisms underlying 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(B) antagonist (A-192621.1), a calcium channel blocker (verapamil), a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester [L-NAME]), and a cyclooxygenase inhibitor (indomethacin) on the systemic and renal actions of big ET-1 in anesthetized rats. An intravenous bolus injection of incremental 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 microL/min, and fractional excretion of sodium increased from 0.38+/-0.13% to 7.51+/-1.24%). Glomerular filtration rate and renal plasma flow significantly decreased only at the highest dose of big ET-1. Pretreatment with A-192621.1 (3 mg/kg plus 3 mg. kg(-1). h(-1)) significantly abolished the diuretic (17+/-5 microL/min to a maximum of 19+/-3 microL/min) and natriuretic (0. 29+/-0.1% to a maximum of 1.93+/-0.37%) responses induced 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 blood pressure produced by the low doses of big ET-1. Similar to A-192621.1, pretreatment with a nitric oxide synthase inhibitor (L-NAME, 10 mg/kg plus 5 mg. kg(-1). h(-1)) significantly and comparably reduced the diuretic and natriuretic actions of big ET-1 and augmented the hypoperfusion/hypofiltration 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 prevented the increase in mean arterial blood pressure provoked by the peptide. Unlike verapamil and L-NAME, only indomethacin administration was associated with significant natriuretic/diuretic responses and did not influence the pressor effect and renal actions of big ET-1. Taken together, these results suggest that big ET-1-induced diuretic and natriuretic responses are mediated mainly by stimulation of nitric oxide production coupled to ET(B) receptor subtype activation.
Hoffman
A
A
Department of Vascular Surgery, Rambam Medical Center, Haifa, Israel. ahofman@rambam.health.gov.il
Abassi
Z A
ZA
Brodsky
S
S
Ramadan
R
R
Winaver
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009318:Natriuresis / Q000187:drug effects* / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D011498:Protein Precursors / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D014554:Urination / Q000187:drug effects / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology
C120508:A 192621; D002121:Calcium Channel Blockers; D002317:Cardiovascular Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D011453:Prostaglandins; D011498:Protein Precursors; D011759:Pyrrolidines; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D009569:Nitric Oxide; D014700:Verapamil; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin