Forskolin and calcium: interactions in the control of renin secretion and perfusate flow in the isolated rat kidney.
Forskolin (activator of adenyl cyclase), high concentrations of K+ and high renal perfusion pressure (manoeuvres known to increase Ca2+ permeability), and calmidazolium (the specific blocker of calmodulin) were used to investigate the mechanisms whereby adenosine 3',5'-phosphate (cyclic AMP) and Ca2+ interact to control renin secretion and perfusate flow in the isolated perfused rat kidney. Forskolin stimulated renin secretion and caused vasodilation in a dose-dependent manner in medium containing 5 mM-Ca2+. Reducing the Ca2+ concentration to 1.25 mM did not affect the renin stimulatory response but blunted the vasodilation. High K+ concentration reversed the forskolin-induced renin secretion and vasodilation. Conversely, forskolin reversed the high K+-induced renin inhibition of renin secretion and vasoconstriction. These effects of forskolin and high K+ were absent when Ca2+ was withheld from the perfusion medium. High renal perfusion pressure also reversed the forskolin-induced renin secretion. Calmidazolium prevented the inhibition mediated by high K+ and high perfusion pressure and thereby restored the forskolin-induced stimulation. Calmidazolium also caused a prompt and marked vasoconstriction. The calmidazolium-induced stimulation of renin secretion was Ca2+-dependent since the drug was ineffective in the absence of Ca2+. On the other hand, the prompt and potent vasoconstriction was present even in the Ca2+-free medium. These results support the hypothesis that cyclic AMP stimulates renin secretion by a mechanism which involves a lowering of membrane permeability to Ca2+ in addition to lowering cytosolic Ca2+ concentration. High K+ and high renal perfusion pressure inhibit renin secretion by raising the membrane permeability to Ca2+, thereby raising the intracellular Ca2+ concentration which then inhibits renin secretion by a calmodulin-dependent process. A further general conclusion from these studies is that membrane permeability to Ca2+ and cellular Ca2+ concentration are of central importance in the control of renin secretion and renal blood flow.
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D008297:Male; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000378:metabolism*; D013997:Time Factors
D002147:Calmodulin; D007093:Imidazoles; D005576:Colforsin; C031938:calmidazolium; D000242:Cyclic AMP; D012083:Renin; D011188:Potassium; D002118:Calcium