title: Inhibition of low Km cGMP phosphodiesterases and Ca+(+)-regulated protein kinases and relationship to vasorelaxation by cicletanine.
abstract: In the present studies we sought to determine if cicletanine, which is an antihypertensive agent of unknown mechanism, could alter cGMP metabolism via inhibition of cGMP phosphodiesterases (PDE) in vascular smooth muscle. Cicletanine was determined to be a mixed (competitive, noncompetitive) inhibitor of both calmodulin-regulated and cGMP-specific PDEs from monkey aortic smooth muscle with Ki values of 450 to 700 microM. Cicletanine also potentiated vasorelaxation by the guanylate cyclase activators sodium nitroprusside and atrial natriuretic peptide in isolated rat aortas. Potentiation was not dependent upon the contractile agonists nor was it indomethacin-sensitive. Neither potentiation nor inhibition of cGMP PDEs was stereoselective. Methylene blue attenuated a component of cicletanine-induced vasorelaxation, but did not completely obviate relaxation. Both cicletanine and the cGMP-PDE inhibitor zaprinast potentiated sodium nitroprusside-mediated cGMP formation and relaxation, although the increase in cGMP content was markedly greater with zaprinast compared to cicletanine. In further studies, cicletanine did not potentiate cGMP activation of cGMP-dependent protein kinase, but did inhibit calmodulin-activated myosin light chain kinase and protein kinase C at relatively high concentrations (approximately 1 mM). In summary, these data demonstrate that cicletanine inhibits vascular cGMP PDEs, potentiates vasorelaxation, and to a limited extent, cGMP formation by guanylate cyclase activators in vascular smooth muscle. However, these relationships for cicletanine are dissimilar from the reference cGMP PDE inhibitor, zaprinast. Thus, other mechanisms may also contribute to the vasorelaxant action of cicletanine.
authors.affiliation: Department of Cardiovascular Pharmacology, Sterling Research Group, Rensselaer, New York 12144.
authors.forename: P J
authors.initials: PJ
authors.lastname: Silver
authors.forename: B
authors.initials: B
authors.lastname: O'Connor
authors.forename: W R
authors.initials: WR
authors.lastname: Cumiskey
authors.forename: G
authors.initials: G
authors.lastname: Van Aller
authors.forename: L T
authors.initials: LT
authors.lastname: Hamel
authors.forename: R G
authors.initials: RG
authors.lastname: Bentley
authors.forename: E D
authors.initials: ED
authors.lastname: Pagani
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology*; D002147:Calmodulin / Q000494:pharmacology; D006152:Cyclic GMP / Q000032:analysis; D004232:Diuretics / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D008297:Male; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051381:Rats; D011919:Rats, Inbred Strains; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000959:Antihypertensive Agents; D002147:Calmodulin; D004232:Diuretics; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009599:Nitroprusside; C038068:cicletanine; D009219:Myosin-Light-Chain Kinase; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006152:Cyclic GMP; D002118:Calcium