Mechanisms underlying the cardiovascular effects of a labdenic diterpene isolated from Moldenhawera nutans in normotensive rats.
Cardiovascular effects of Labd-8 (17)-en-15-oic acid (Labd-8), a labdenic diterpene isolated from methanolic extract of Moldenhawera nutans were investigated in normotensive rats. Additionally, this study examined the role of autonomic nervous system in the mediation of these cardiovascular effects. In pentobarbital-anesthetized rats, bolus intravenous (i.v.) injection of Labd-8 (1-10 mg/kg) induced dose-dependent hypotensive and tachycardiac responses. After cervical bivagotomy, hypotensive responses to Labd-8 were significantly enhanced whereas the tachycardia was completely abolished. In conscious rats, Labd-8 (1-10 mg/kg, i.v.) also decreased blood pressure and increased heart rate in a dose-dependent manner. Pretreatment with methylatropine (1 mg/kg, i.v.) or propranolol (2 mg/kg, i.v.) significantly reduced the tachycardia evoked by Labd-8 without affecting the hypotension. Blockade of ganglionic neurotransmission with hexamethonium (30 mg/kg, i.v.) reduced and abolished the hypotensive and tachycardic effects of Labd-8, respectively. However, hypotensive effects of Labd-8 were not reduced by pretreatment with N(w)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg, i.v.), a nitric oxide synthase inhibitor. In rat endothelium-containing aorta preparations, Labd-8 (1-1000 micro g/ml) induced a concentration-dependent reduction of potassium (60 mM)-induced contraction [IC(50) (geometric mean +/-95% confidence interval)=313.6 (191.4-513.8) micro g/ml], an effect that remained unaffected [IC(50)=440.8 (225.1-863.3) micro g/ml] by removal of vascular endothelium. These results show that i.v. treatment with Labd-8-induced dose-dependent hypotensive and tachycardiac effects in both conscious and anesthetized rats. The tachycardia is mediated reflexly through inhibition of vagal and activation of sympathetic drive to the heart. The hypotension is mainly due to withdrawal of sympathetic tone to the vasculature and also partly to an active vascular relaxation. Released nitric oxide from vascular endothelial cells is not involved in the mediation of Labd-8-induced hypotension.