CARDIOVASCULAR ACTIVITIES OF ANDROGRAPHIS PANICULATA AND ITS DITERPRENOID CONSTITUENTS

Abstract

This thesis describes the cardiovascular activities of Andrographis paniculata and its diterpenoids, DA and DDA, in normotensive and hypertensive rats, isolated rat thoracic aortae and right atria, as well as human umbilical endothelial cells. DA and DDA are firstly examined for their antihypertensive effects. The first chapter is a literature review on blood pressure regulation, antihypertensive agents and A. paniculata. The second chapter describes the chemicals, animals and methods used in this study. The first section of Chapter three reportts the in viva studies of antihypertensive activities of aqueous extract of A. paniculata (WE) and its three semi-purified fractions, ethyl acetate (FA), n-butanol (FB) and water (FC), in conscious SHR and WKY rats, and anaesthetized SD rats. WE exhibited a definite hypotensive effect on the SBP in SHR and WKY rats when infused intraperitoneally for 13 days by osmotic pumps. The decrease in plasma ACE activity and kidney free radical levels were found to be two of the possible mechanisms of hypotensive action in the SHR. FA elicited no drop in the mean arterial blood pressure (MAP) of anaesthetized rats, while WE, FB and FC produced a significant fall in MAP without significant change in heart rate (HR). The hypotensive substance(s) in WE was found to be concentrated in FB. Pharmacological antagonist studies were thus performed using FB. The results suggested that its hypotensive action was mediated through ?-adrenoceptors, autonomic ganglion and histaminergic receptors. These may be the common mechanisms of hypotensive action of WE in conscious SHR and WKY rats. Section two of Chapter four reports the cardiovascular activities of DA and DDA in anaesthetized SD rats, isolated rat aorta and right atria, and endothelial cells. Five main diterpenoid constituents isolated from A. paniculata, DA, DDA, andrographolide, andrographiside and neoandrographolide, were screened for their hypotensive activities in anaesthetized SD rats. DA and DDA caused a significant fall in MAP and HR, while the rest did not affect MAP and HR. Both DA and DDA produced vasorelaxation in isolated aorta through nitric oxide (NO) synthase and NO activation of guanylyl cyclase pathway, and the blockade of Ca2+ influx through voltage- and receptor-operated Ca2+ channels. The involvement of NO in their vasorelaxation is further supported by their stimulation of NO production in human endothelial cells. The reduction in MAP, vasorelaxation and stimulant effect on NO production caused by DDA are more potent than those of DA. DDA was also examined in the anaesthetized SD rat and isolated right atria. The results demonstrated that the hypotensive effect of DDA appeared to be mediated through ?- adrenoceptors, autonomic ganglion receptor and ACE inhibitory activity. The bradycardia induced by DDA in vivo and in vitro may contribute to its hypotensive action as well.