Investigation of the pronounced synergism between prostaglandin E2 and other constrictor agents on rat femoral artery.

This study investigates the pronounced synergism between the weak contractile action of prostaglandin E(2) (PGE(2)) and strong actions of phenylephrine, U-46619 and K(+) on rat isolated femoral artery. The potency ranking for synergism was SC-46275 (prostanoid receptor agonist selectivity: EP(3)>>EP(1))=sulprostone (EP(3)>EP(1))>17-phenyl PGE(2) (EP(1)>EP(3)). The novel EP(3) antagonist L-798106 (0.2-1microM) blocked the enhanced action of sulprostone (pA(2)=7.35-8.10), while the EP(1) antagonist SC-51322 (1microM) did not (pA(2)<6.0). Matching responses to priming agent and priming agent/sulprostone were similarly suppressed by nifedipine (300nM) and the selective Rho-kinase inhibitors H-1152 (0.1-1microM) and Y-27632 (1-10microM). Our findings implicate an EP(3) receptor in the prostanoid component of contractile synergism. While the synergism predominantly operates through a Ca(2+) influx-Rho-kinase pathway, the EP(3) receptor does not necessarily transduce via Rho-kinase.

Mechanisms underlying the vasorelaxing effects of butylidenephthalide, an active constituent of Ligusticum chuanxiong, in rat isolated aorta.

Butylidenephthalide (BDPH) is one of the most potent vasorelaxants isolated from Ligusticum chuanxiong Hort. The objective of the current study is to investigate the underlying vasorelaxation mechanisms in rat aorta. In 9,11-dideoxy-9alpha,11alpha-methanoepoxyprostaglandin F(2alpha) (U46619) precontracted preparations, endothelium removal, the nitric oxide (NO) synthase inhibitor Nomega-nitro-l-arginine methyl ester (l-NAME) and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) partially inhibited the BDPH relaxation response to a similar extent. The cyclooxygenase inhibitor indomethacin, beta-adrenoceptor antagonist propranolol, adenylate cyclase inhibitors 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22536) and 2',5'-dideoxyadenosine, and K(+) channel blocker tetraethylammonium had no effect. BDPH produced full relaxation against contractions induced by KCl and U46619 in the presence of the l-type voltage-operated Ca(2+) channel (Ca(v) 1.2) blocker nifedipine. In a receptor-operated Ca(2+) channel protocol where contraction was mediated by Ca(2+) re-addition in the presence of U46619 and nifedipine, BDPH produced relaxation. In the absence of extracellular Ca(2+), BDPH inhibited contractions induced by phorbol-12,13-dibutyrate and U46619. Our results suggest that BDPH-mediated vasorelaxation comprises both endothelium-dependent (NO) and independent components. It is suggested that BDPH acting through an inhibitory mechanism downstream to l-type voltage-operated and prostanoid TP receptor-operated Ca(2+) channels operating late in the contractile pathway.

Synergistic interaction between the Ligusticum chuanxiong constituent butylidenephthalide and the nitric oxide donor sodium nitroprusside in relaxing rat isolated aorta.

ETHNOPHARMACOLOGICAL RELEVANCE: Ligusticum chuanxiong Hort. (Umbelliferae), a traditional Chinese medicinal herb, is often prescribed together with nitric oxide donors for treating coronary heart diseases such as angina in China; however, studies concerning their pharmacological interaction are scarce. AIM OF THE STUDY: The objective of the present study was to examine the interaction between the Ligusticum chuanxiong major active constituent butylidenephthalide (BDPH) and the nitric oxide donor sodium nitroprusside (SNP) in vasorelaxation. MATERIALS AND METHODS: Vasorelaxation was examined in rat isolated aorta using an organ bath system. RESULTS: BDPH and SNP interacted synergistically under 9,11-dideoxy-9alpha,11alpha-methanoepoxyprostaglandin H2 (U-46619)-induced tone. This synergism became greater with increasing U-46619 concentrations where Ca2+ sensitization contributed more significantly, and less when U-46619 was replaced with phenylephrine where participation of Ca2+ sensitization was minimal. BDPH-SNP synergism remained intact in the absence of external Ca2+, indicating that regulation of Ca2+ influx was not a requirement for the manifestation of this interaction. CONCLUSIONS: The present study demonstrated the synergistic relaxation between BDPH and SNP in rat isolated aorta. This interaction is related to an enhancement of the effectiveness of SNP in producing relaxation under tone induced mainly by Ca2+ sensitization.