Mechanism of action of angiotensin II and bradykinin on prostaglandin synthesis and vascular tone in the isolated rat kidney. Effect of Ca++ antagonists and calmodulin inhibitors.
We have studied the effect of angiotensin II and bradykinin on prostaglandin output and vascular tone during extracellular calcium depletion and administration of calcium antagonists and calmodulin inhibitors to elucidate the mechanism of action in the isolated rat kidney perfused with Tyrode's solution. Administration of angiotensin II (0.028-0.28 nmol) or bradykinin (0.28-2.8 nmol) enhanced the output of prostaglandin E2 and 6-keto-prostaglandin F1 alpha in a dose-dependent manner. Angiotensin II, but not bradykinin, produced renal vasoconstriction. Omission of calcium from the medium or infusion of calcium entry blockers, diltiazem (60 microM), or nimodipine (47 microM), failed to alter prostaglandin output elicited by angiotensin II or bradykinin; however, the effect of angiotensin II to produce renal vasoconstriction was inhibited. If calcium was omitted from the medium, the intracellular calcium antagonists, 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (23 microM), dantrolene sodium (31 microM), or ryanodine (2 microM), attenuated prostaglandin output caused by angiotensin II but not bradykinin. Calmodulin inhibitors, trifluoperazine (2 microM), napthalene sulfonamide hydrochloride (2 microM), or calmidazolium (2 microM), diminished prostaglandin output elicited by angiotensin II, but not that caused by bradykinin. Trifluoperazine, but not naphthalene sulfonamide or calmidazolium, attenuated the renal vasoconstrictor effect of angiotensin II. Prostaglandin output induced by angiotensin II and bradykinin were inhibited by mepacrine and indomethacin, whereas, the prostaglandin output caused by exogenous arachidonic acid (33 nmol) was abolished by indomethacin but was unaltered by mepacrine, calcium antagonists, and calmodulin inhibitors. From these data, we conclude that angiotensin II produces renal vasoconstriction by a mechanism dependent on extracellular calcium but not calmodulin, whereas angiotensin II-induced prostaglandin output depends on intracellular calcium and calmodulin. In contrast, bradykinin appears to stimulate prostaglandin synthesis by a calcium/calmodulin-independent mechanism.
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D003620:Dantrolene / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology; D015232:Dinoprostone; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D009539:Nicotinic Acids / Q000494:pharmacology; D009553:Nimodipine; D011458:Prostaglandins E / Q000096:biosynthesis*; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012433:Ryanodine / Q000494:pharmacology; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D002121:Calcium Channel Blockers; D002147:Calmodulin; D007093:Imidazoles; D009539:Nicotinic Acids; D011458:Prostaglandins E; D013449:Sulfonamides; D000804:Angiotensin II; D012433:Ryanodine; D014268:Trifluoperazine; D000001:Calcimycin; C031938:calmidazolium; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D009553:Nimodipine; D015121:6-Ketoprostaglandin F1 alpha; D005707:Gallic Acid; C017967:W 7; D004110:Diltiazem; D003620:Dantrolene; D011796:Quinacrine; D015232:Dinoprostone; D001920:Bradykinin; D002118:Calcium; D007213:Indomethacin