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 novel inhibitor of endothelial nitric oxide synthase with chemical structure different from those of NG-substituted Arg analogs, were studied 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-dependent increases in mean arterial pressure (MAP) with ED50 of 0.22 +/- 0.02 mg/kg and maximum effect (Emax) of 58 +/- 3 mm Hg, and heart rate (HR) with ED50 of 0.26 +/- 0.03 mg/kg and Emax of 60 +/- 5 beats/min. Pretreatments with tetrodotoxin, reserpine, guanethidine, mecamylamine, 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 transection reduced, the MAP and HR responses to DPI. Pithing did not alter the pressor response but blocked the reflex bradycardic response to NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. Bolus injection of a single dose of DPI (1.6 mg/kg i.v.) or NG-nitro-L-arginine increased MAP, but only DPI caused immediate and large increases (> 1 ng/ml) in plasma norepinephrine, epinephrine and moderate increase in dopamine; pretreatment with reserpine attenuated, whereas pithing abolished these increases. The increases in plasma norepinephrine and epinephrine by DPI were positively correlated to increases in MAP and HR. The results demonstrate that DPI, unlike NG-substituted Arg analogs, produces pressor and tachycardic effects via indirect activation of the sympathetic nervous system.
Wang
Y X
YX
Department of Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Pang
C C
CC
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D002395:Catecholamines / Q000097:blood; D002490:Central Nervous System / Q000502:physiology*; D003655:Decerebrate State; D006339:Heart Rate / Q000187:drug effects; D019001:Nitric Oxide Synthase; D009861:Onium Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000601:surgery; D013564:Sympathetic Nervous System / Q000502:physiology*; D013610:Tachycardia / Q000139:chemically induced*; D013779:Tetrodotoxin / Q000494:pharmacology
D002395:Catecholamines; D009861:Onium Compounds; D013779:Tetrodotoxin; C007517:diphenyleneiodonium; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases