Activation of Nitric Oxide/cGMP/PKG Signaling Cascade Mediates Antihypertensive Effects of Muntingia calabura in Anesthetized Spontaneously Hypertensive Rats

Abstract

We previously reported that the leaf extract of Muntingia calabura L. (Tiliaceae) exerts a potent hypotensive effect in the normotensive rats. The antihypertensive activity of this plant extract, however, is currently unknown. In the present study, we investigated the antihypertensive effects of the n-butanol soluble fraction (BSF) from methanol leaf extract of M. calabura in spontaneously hypertensive rats (SHR), and delineated is underlying mechanisms. The intravenous bolus administration of the BSF (10-100 mg/kg) of M. calabura produced biphasic dose-related antihypertensive and bradycardiac effects in SHR. The BSF-induced initial cardiovascular depressive effects lasted for 10 min, and the delayed effects commenced 40 min and lasted for at least 120 min postinjection. These cardiovascular depressive effects of BSF treatments were greater in SHR than in normotensive Wistar-Kyoto (WKY) rats. Both the initial and delayed antihypertensive and bradycardiac effects of BSF (25 mg/kg, i.v.) in SHR, were significantly blocked by pretreatment with a nonselective nitric oxide (NO) synthase (NOS) inhibitor, a soluble guanylyl cyclase (sGC) inhibitor, or a protein kinase G (PKG) inhibitor. Moreover, the initial effects of BSF in SHR were inhibited by pretreatment with a selective endothelial NOS (eNOS) inhibitor; whereas the delayed effects were attenuated by a selective inducible NOS (iNOS) inhibitor. These results indicate that the BSF from the leaf of M. calabura elicited both transient and delayed antihypertensive and bradycardiac actions in SHR, which might be mediated through NO generated respectively by eNOS and iNOS. Furthermore, activation of sGC/cGMP/PKG signaling pathway may participate in the M. calabura-induced biphasic cardiovascular effects.