Cardiovascular effects of ethanol extract of Rubus chingii Hu (Rosaceae) in rats: an in vivo and in vitro approach.

Rubus chingii Hu (Rosaceae) is an important traditional Chinese medicine that has been used to improve function of the kidney and treat excessive polyuria. However, the effects of Rubus chingii on the cardiovascular system and its pharmacological mechanisms of action have not been studied. The aim of the present study was to evaluate the cardiovascular effects of ethanol extract of Rubus chingii (ERC) in rats. The changes in systolic blood pressure and heart rate of rats and vascular tone of aortic rings in in vitro were measured using pressure transducer and force transducer, respectively, connected to a multichannel recording system. ERC decreased systolic blood pressure and heart rate in a concentration-dependent manner. ERC induced vasorelaxation in a concentration-dependent manner. The ERC-induced vasorelaxation was not observed in the absence of the endothelium. The vasorelaxant effect of ERC was significantly attenuated by inhibition of endothelial NO synthase (eNOS), soluble guanylyl cyclase (sGC), or Ca(2+) entry from extracellular sources with L-NAME, ODQ, diltiazem, or extracellular Ca(2+) depletion, respectively. Similarly, an inhibition of Akt with wortmannin attenuated the ERC-induced vasorelaxation. Modulators of the store-operated Ca(2+) entry, thapsigargin, Gd(3+), and 2-aminoethyl diphenylborinate markedly attenuated the ERC-induced vasorelaxation. Furthermore, 4-aminopyridine an inhibitor of voltage-dependent K(+) (KV) channel, significantly attenuated the ERC-induced vasorelaxation. However, tetraethylammonium and glibenclamide, had no significant effect on the ERC-induced vasorelaxation. Indomethacin, atropine, and propranolol had no effects on the ERC-induced vasorelaxation. The present study demonstrates that ERC induces vasorelaxation via endothelium-dependent two-step signaling: an activation of the Ca(2+)-eNOS-NO signaling in the endothelial cells and then subsequent stimulation of the NO-sGC-cGMP-KV channel signaling in the vascular smooth muscle cells. The Akt-eNOS pathway is also suggested to be involved in this relaxation. Also, the findings suggest that the ERC-induced vasorelaxation is closely related to the hypotensive action of the agent.