Mechanisms underlying the cardiovascular effects of a labdenic diterpene isolated from Moldenhawera nutans in normotensive rats

Abstract

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.

Cardiovascular effects of a labdenic diterpene isolated fromMoldenhawera nutansin conscious, spontaneously hypertensive rats

“…Rats were anesthetized with intraperitoneal injection of sodium pentobarbital (50 mg/kg), and catheters (PE-10 fused to PE-50) were implanted in the abdominal aorta (for the recording of arterial blood pressure) and in the inferior vena cava (for drug administration) through the left femoral artery and vein, respectively, as described previously (Lahlou et al, 2007;de Siqueira et al, 2014). Twenty-four hours later, baseline MAP and HR were recorded on a Gilson model 5/6H polygraph (Medical Electronics Inc., Middletown, WI), as described previously (Lahlou et al, 2007).…”

“…Twenty-four hours later, baseline MAP and HR were recorded on a Gilson model 5/6H polygraph (Medical Electronics Inc., Middletown, WI), as described previously (Lahlou et al, 2007). The maximal changes in MAP and HR caused by i.v.…”

“…We have first reported in conscious rats the dose-dependent decreases in mean arterial pressure (MAP) and increases in heart rate (HR) caused by the intravenous (i.v.) injection of labd-8 (Lahlou et al, 2007). As the hypotension was only reduced by blockade of ganglionic neurotransmission with hexamethonium, it was suggested that this response is partly due to withdrawal of sympathetic tone to the vasculature and partly to an active vascular relaxation (Lahlou et al, 2007).…”

“…injection of labd-8 (Lahlou et al, 2007). As the hypotension was only reduced by blockade of ganglionic neurotransmission with hexamethonium, it was suggested that this response is partly due to withdrawal of sympathetic tone to the vasculature and partly to an active vascular relaxation (Lahlou et al, 2007). Indeed, labd-8 also relaxed rat-isolated aortic preparations contracted with KCl in a concentration-dependent manner.…”

“…Furthermore, the role of the autonomic nervous system in the mediation of cardiovascular responses to labd-8 was assessed in SHRs. (David et al, 1998;Lahlou et al, 2007), which achieved a purity grade of 99.5% w/w as determined by GC/MS analysis. Moreover, spectral analysis and NMR evaluation served to elucidate the molecular structure of labd-8 (David et al, 1998 …”