RESUMEN
We examined the inhibitory effects of α-linolenic acid (ALA) on the contractions of pig coronary arteries. ALA concentration-dependently inhibited the contractions elicited by U46619 and prostaglandin F2α without affecting those elicited by 80 mM KCl, histamine, acetylcholine, and serotonin. ALA rightward shifted the concentration-response curve of U46619, and Schild plot analysis revealed that ALA competitively antagonized U46619. Furthermore, ALA inhibited the increase in intracellular Ca2+ concentration caused by TP receptor stimulation but not that caused by FP receptor stimulation. These results suggest that ALA behaves as a selective antagonist of TP receptors in coronary arteries.
Asunto(s)
Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Calcio , Vasos Coronarios , Receptores de Tromboxanos , Ácido alfa-Linolénico , Animales , Vasos Coronarios/efectos de los fármacos , Ácido alfa-Linolénico/farmacología , Porcinos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Calcio/metabolismo , Receptores de Tromboxanos/antagonistas & inhibidores , Receptores de Tromboxanos/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Dinoprost/farmacología , Contracción Muscular/efectos de los fármacosRESUMEN
We studied the inhibitory actions of docosahexaenoic acid (DHA) on the contractions induced by carbachol (CCh), angiotensin II (Ang II), and bradykinin (BK) in guinea pig (GP) gastric fundus smooth muscle (GFSM), particularly focusing on the possible inhibition of store-operated Ca2+ channels (SOCCs). DHA significantly suppressed the contractions induced by CCh, Ang II, and BK; the inhibition of BK-induced contractions was the strongest. Although all contractions were greatly dependent on external Ca2+, more than 80% of BK-induced contractions remained even in the presence of verapamil, a voltage-dependent Ca2+ channel inhibitor. BK-induced contractions in the presence of verapamil were not suppressed by LOE-908 (a receptor-operated Ca2+ channel (ROCC) inhibitor) but were suppressed by SKF-96365 (an SOCC and ROCC inhibitor). BK-induced contractions in the presence of verapamil plus LOE-908 were strongly inhibited by DHA. Furthermore, DHA inhibited GFSM contractions induced by cyclopiazonic acid (CPA) in the presence of verapamil plus LOE-908 and inhibited the intracellular Ca2+ increase due to Ca2+ addition in CPA-treated 293T cells. These findings indicate that Ca2+ influx through SOCCs plays a crucial role in BK-induced contraction in GP GFSM and that this inhibition by DHA is a new mechanism by which this fatty acid inhibits GFSM contractions.
Asunto(s)
Angiotensina II , Bradiquinina , Carbacol , Ácidos Docosahexaenoicos , Fundus Gástrico , Contracción Muscular , Músculo Liso , Animales , Cobayas , Ácidos Docosahexaenoicos/farmacología , Bradiquinina/farmacología , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Músculo Liso/metabolismo , Carbacol/farmacología , Contracción Muscular/efectos de los fármacos , Angiotensina II/farmacología , Fundus Gástrico/efectos de los fármacos , Fundus Gástrico/fisiología , Fundus Gástrico/metabolismo , Verapamilo/farmacología , Calcio/metabolismo , Masculino , Humanos , Canales de Calcio/metabolismo , Células HEK293 , Bloqueadores de los Canales de Calcio/farmacología , Imidazoles/farmacologíaRESUMEN
This study was performed to elucidate whether eicosapentaenoic acid (EPA) suppresses spasm-prone blood vessel contractions induced by a thromboxane mimetic (U46619) and prostaglandin F2α (PGF2α) and determine whether the primary target of EPA is the prostanoid TP receptor. Accordingly, we assessed: (1) the tension changes in porcine basilar and coronary arteries, and (2) changes in the Fura-2 (an intracellular Ca2+ indicator) fluorescence intensity ratio at 510 nm elicited by 340/380 nm excitation (F340/380) in 293T cells expressing the human TP receptor (TP-293T cells) and those expressing the human prostanoid FP receptor (FP-293T cells). EPA inhibited both porcine basilar and coronary artery contractions induced by U46619 and PGF2α in a concentration-dependent manner, but it did not affect the contractions induced by 80 mM KCl. EPA also inhibited the increase in F340/380 induced by U46619 and PGF2α in TP-293T cells. In contrast, EPA showed only a marginal effect on the increase in F340/380 induced by PGF2α in FP-293T cells. These findings indicate that EPA strongly suppresses the porcine basilar and coronary artery contractions mediated by TP receptor and that inhibition of TP receptors partly underlies the EPA-induced inhibitory effects on these arterial contractions.