A structurally novel stimulator of guanylate cyclase with long-lasting hypotensive activity in the dog.
Studies were undertaken to characterize the activity of diphenyliodonium hexafluorophosphate (DIFP) as a structurally novel stimulator of soluble guanylate cyclase from rat lung and make comparisons to the activity of sodium nitroprusside (SNP). In addition, the effects of these two compounds on several cardiovascular parameters in anesthetized dogs were determined. DIFP stimulated guanylate cyclase activity within the same concentration range (10-300 microM) as SNP, causing a maximal 2-3-fold activation. The activities of both SNP and DIFP were dependent on the presence of dithiothreitol and inhibited by methylene blue. In anesthetized dogs, DIFP (i.v.) elicited a dose-related, long-lasting fall (greater than 3 h) in mean arterial pressure (MAP) which was accompanied by a reduction in total peripheral resistance and a transient rise in cardiac output. These effects on MAP were similar to those of SNP except they were of a much longer duration. In addition, both SNP and DIFP produced slight bradycardia and reduced negative dP/dt. These results suggest that DIFP and SNP, while structurally dissimilar, activate guanylate cyclase by a related mechanism which may be involved in vascular relaxation leading to reduced blood pressure.
Pettibone
D J
DJ
Sweet
C S
CS
Risley
E A
EA
Kennedy
T
T
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005292:Ferricyanides / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D006847:Hydrocarbons, Iodinated / Q000494:pharmacology*; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology*; D009861:Onium Compounds; D013997:Time Factors
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D005292:Ferricyanides; D006847:Hydrocarbons, Iodinated; D009861:Onium Compounds; C031291:diphenyliodonium; D009599:Nitroprusside; D006162:Guanylate Cyclase