FUNCTIONAL INTEGRITY OF THE CENTRAL AND SYMPATHETIC NERVOUS SYSTEMS IS A PREREQUISITE FOR PRESSOR AND TACHYCARDIC EFFECTS OF DIPHENYLENEIODONIUM, A NOVEL INHIBITOR OF NITRIC-OXIDE SYNTHASE

The pressor and tachycardic effects of diphenyleneiodonium (DPI), a no vel inhibitor of endothelial nitric oxide synthase with chemical struc ture different from those of N(G)-substituted Arg analogs, were studie d in pentobarbital-anesthetized rats. Bolus injections of DPI (0.05-1. 6 mg/kg i.v.) caused transient (1-2 min in duration) and dose-dependen t increases in mean arterial pressure (MAP) with ED50 of 0.22 +/- 0.02 mg/kg and maximum effect (E(max)) of 58 +/- 3 mm Hg, and heart rate ( HR) with ED50 of 0.26 +/- 0.03 mg/kg and E(max) of 60 +/- 5 beats/min. Pretreatments with tetrodotoxin, reserpine, guanethidine, mecamylamin e, but not atropine, rauwolscine, captopril nor L-Arg, attenuated the MAP and HR responses to DPI. Phentolamine and prazosin attenuated the MAP but not HR response whereas propranolol attenuated the HR but not MAP response of DPI. Pithing abolished, whereas spinal cord transectio n reduced, the MAP and HR responses to DPI. Pithing did not alter the pressor response but blocked the reflex bradycardic response to N(G)-n itro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. B olus injection of a single dose of DPI (1.6 mg/kg i.v.) or N(G)-nitro- L-arginine increased MAP, but only DPI caused immediate and large incr eases (> 1 ng/ml) in plasma norepinephrine, epinephrine and moderate i ncrease in dopamine; pretreatment with reserpine attenuated, whereas p ithing abolished these increases. The increases in plasma norepinephri ne and epinephrine by DPI were positively correlated to increases in M AP and HR. The results demonstrate that DPI, unlike N(G)-substituted A rg analogs, produces pressor and tachycardic effects via indirect acti vation of the sympathetic nervous system.