Sodium nitroprusside potentiates the depressor response to the phosphodiesterase inhibitor zaprinast in rats.
To determine if the presence of an activator of guanylate cyclase alters the depressor response to a selective inhibitor of low Km cyclic GMP (cGMP) phosphodiesterase (PDE), zaprinast (3-30 mg/kg) was given i.v. to conscious, spontaneously hypertensive rats during a steady state of i.v. infusion of sodium nitroprusside (15 micrograms/kg per min). Sodium nitroprusside significantly increased the magnitude of the depressor response to zaprinast. In contrast, fenoldopam (20 micrograms/kg per min), an activator of adenylate cyclase, did not affect the depressor response to zaprinast. Zaprinast (10 mg/kg) significantly decreased mean arterial pressure (MAP) in rats given an infusion of sodium nitroprusside, an activator of soluble guanylate cyclase, at doses of 15 and 25 micrograms/kg per min but not at a dose of 5 micrograms/kg per min. However, in rats given atrial natriuretic peptide (ANP; 0.5, 1 and 2 micrograms/kg per min), an activator of particulate guanylate cyclase, zaprinast (10 mg/kg) did not affect MAP. In contrast to the potentiation of the depressor response to zaprinast, sodium nitroprusside (15 micrograms/kg per min) significantly attenuated the reductions in MAP produced by CI-930, a selective inhibitor of low Km cAMP PDE. It is concluded that sodium nitroprusside, but not ANP or fenoldopam, potentiates the depressor response to zaprinast. Furthermore, the potentiation of the depressor response to zaprinast is dependent upon the dose of sodium nitroprusside and is selective for zaprinast; the depressor response to CI-930 is attenuated by sodium nitroprusside.
Dundore
R L
RL
Department of Cardiovascular Pharmacology, Sterling Research Group, Rensselaer, NY 12144.
Pratt
P F
PF
Hallenbeck
W D
WD
Wassey
M L
ML
Silver
P J
PJ
Buchholz
R A
RA
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018818:Fenoldopam; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011688:Purinones / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR
D015259:Dopamine Agents; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011724:Pyridazines; D009599:Nitroprusside; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D009320:Atrial Natriuretic Factor; C042528:4,5-dihydro-6-(4-(imidazol-1-yl)phenyl)-5-methyl-3(2H)-pyridazinone; C011145:zaprinast; D018818:Fenoldopam