A structurally novel stimulator of guanylate cyclase with long-lasting hypotensive activity in the dog

Abstract

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 effectsof these two compounds on several cardiovascular parameters in anesthetized dogs were determined. DIFP stipulated guanylate cyclase activity within the same concentration range (10–300 μM) 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 (> 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. The e 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.