INHIBITION OF NITRIC-OXIDE, BRADYKININ, AND PROSTAGLANDINS IN NORMAL RATS

We assessed the vasodilator effect of endothelium-derived nitric oxide by inhibiting its formation with N(G)-monomethyl L-arginine (LNMMA) on systemic and regional hemodynamics in conscious, normotensive rats, using the radioactive microsphere technique. In rats injected with 10 mg/kg LNMMA (n = 8), mean blood pressure increased by 16.2 +/- 2.6 mm Hg, and heart rate decreased by 54.3 +/- 16.7 beats per minute. In comparison with rats injected with 5% dextrose (n = 14), cardiac index was lower by 35.6% (p < 0.01), and total peripheral vascular resistance was higher by 51.6% (p < 0.01); regional blood flows were lower and vascular resistance higher in most organs. Changes were significant in the heart, kidney, stomach, large intestine, skin, and adrenals (p < 0.05). Preinjection of 100 mg/kg L-arginine prevented the pressor response but only partially attenuated the other hemodynamic effects of LNMMA. Combination of LNMMA with the bradykinin antagonist (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg)trifluoroacetic acid (50-mu-g/min for 5 minutes) did not produce systemic or regional effects different from those obtained with LNMMA alone. Combination of LNMMA with indomethacin (10 mg/kg) resulted in additional changes in the cerebral circulation, blood flow decreasing by an additional 44.2% (p < 0.01) and vascular resistance increasing by 75.3% (p < 0.01) compared with changes produced by LNMMA alone. The data suggest that endothelium-derived nitric oxide contributes differently to the resting vascular tone of various vascular beds; it mediates most of the vasodilator effects of bradykinin and partly those of prostaglandins, but the effect of the latter on the cerebral circulation is not nitric oxide dependent.