Reversal of renal and smooth muscle actions of the thromboxane mimetic U-44069 by diltiazem.
U-44069 is a stable prostaglandin (PG) H2 analogue and a potent vasoconstrictor. Its in vivo and in vitro actions mimic those of thromboxane A2. We have studied the effects of the calcium antagonist diltiazem upon the vasoconstriction induced by U-44069 using isolated rat aortic smooth muscle and isolated perfused rat kidney (IPRK). The administration of 10(-6)M U-44069 elicited maximally effective contractions in isolated aortic rings and increased 45Ca uptake from a control value of 285 +/- 6 mumol/kg to 344 +/- 8 mumol/kg. Diltiazem reduced U-44069-induced tension development and 45Ca uptake of isolated aortic smooth muscle 73 +/- 2 and 91 +/- 3%, respectively. The dose dependency of each of these effects of diltiazem was similar (EC50 = 369 nM and 334 nM for tension and 45Ca flux, respectively). When administered to the IPRK, 10(-6) M U-44069 caused a 82 +/- 3% decrease in glomerular filtration rate (GFR) and a 80 +/- 4% decrease in filtration fraction but reduced renal perfusate flow (RPF) only 13 +/- 8% (P less than 0.005). Diltiazem completely reversed the actions of U-44069 on the IPRK (EC50 = 288 nM and 323 nM for GFR and RPF, respectively). Diltiazem thus inhibited U-44069-induced tension development and 45Ca uptake by vascular smooth muscle and increased GFR within identical dose ranges. The contractile response of isolated rat glomeruli was also assessed. U-44069 reduced the volume of isolated glomeruli, but this action was neither prevented nor reversed by diltiazem. These results are consistent with the hypothesis that diltiazem increased GFR by inhibiting U-44069-induced Ca influx at preglomerular vessels.
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D004110:Diltiazem / Q000494:pharmacology*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors*; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D001552:Benzazepines; D011450:Prostaglandin Endoperoxides, Synthetic; C028429:U 44069; D004110:Diltiazem; D002118:Calcium