Cardiac and vascular responses of isolated rat tissues treated with diterpenes from Sinularia flexibilis (coelenterata: octocorallia).
The marine environment is a rich source of compounds with cardiovascular activity. This study characterizes the cardiac and vascular responses in isolated rat tissues of flexibilide, dihydroflexibilide and sinulariolide, three diterpenes isolated from the soft coral Sinularia flexibilis. On rat left ventricular papillary muscles, dihydroflexibilide and flexibilide showed similar potencies (-log EC50 = 4.69 +/- 0.05 and 4.66 +/- 0.06, respectively); the maximal response to dihydroflexibilide of 1.4 +/- 0.2 mN was 35 +/- 7% that of calcium chloride in the same muscles. All diterpenes relaxed rat thoracic aortic rings precontracted with KC1 (100 mM) with similar potencies (flexibilide, -log EC50 = 4.17 +/- 0.06). Flexibilide was further characterized and shown to increase force in isolated rat left atria by 0.8 +/- 0.5 mN at 1 x 10(-4) M, to increase rate of contraction in isolated rat right atria by 18 +/- 5 beta/min at 3 x 10(-5) M and to completely relax endothelium-denuded rat thoracic aortic rings (-log EC50 = 4.14 +/- 0.05). Toxicity as indicated by the occurrence of ectopic beats was not observed with the diterpenes at concentrations which produced complete relaxation of blood vessels, maximal positive inotropic activity and minor positive chronotropic responses. Thus, these compounds may be useful lead compounds in the search for improved treatment of cardiovascular disease, especially heart failure.
Aceret
T L
TL
Department of Molecular Sciences, James Cook University of North Queensland, Townsville, QLD, Australia.
Brown
L
L
Miller
J
J
Coll
J C
JC
Sammarco
P W
PW
D000818:Animals; D001011:Aorta / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction; D010210:Papillary Muscles / Q000187:drug effects; D011161:Porifera / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar
D004224:Diterpenes; D007783:Lactones; C027469:flexibilide; C050253:sinulariolide