K+ channel blockers: natriuretic potency correlates to vascular ATP-sensitive K+ channel blockade.
Using analogs of known vascular ATP-sensitive K+ channel (KATP) blockers, we identified compounds with a wide range of potencies (over 500-fold) in their capacity to block the hypotensive response of 0.2 mg/kg pinacidil in rats. The most potent of these, U-97025E, belongs to a newly disclosed class of compounds, the cyanoguanidines. U-97025E at 0.04 mg/kg blocked 50% of the depressor response induced by 0.2 mg/kg pinacidil. The maximal natriuresis induced by U-97025E (0.4 mg/kg i.v.) increased Na+ excretion by approximately 60%. This natriuresis is of the same magnitude as that induced by thiazide without any effect on K+ excretion. We found a high degree of correlation between natriuretic potency and the capacity to block the blood pressure lowering effects of pinacidil, both among closely related analogs and dissimilar compounds. These findings imply an obligatory rather than incidental relationship between vascular KATP blockade and natriuresis. The exact molecular link of the vascular and renal effects remains to be determined.
Clark
M A
MA
Pharmacia & Upjohn, Inc., Kalamazoo, MI, USA. michael.a.clark@am.pnu.com
Lawson
J A
JA
Ludens
J H
JH
D018528:ATP-Binding Cassette Transporters; D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D054086:KATP Channels; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D020110:Pinacidil / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017207:Rats, Sprague-Dawley
D018528:ATP-Binding Cassette Transporters; D000959:Antihypertensive Agents; D006146:Guanidines; D054086:KATP Channels; D009570:Nitriles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C119464:U 97025E; C092520:uK-ATP-1 potassium channel; D020110:Pinacidil