RESUMEN
L-arginine has been proposed to be the precursor of the endothelium-derived relaxing factor. In this study, we evaluated the pulmonary vascular effects of L-arginine-HCl and its benzoyl derivative N-alpha-benzoyl-L-arginine ethyl ester (BAEE) in the rat, in comparison with other vasodilators such as acetylcholine and sodium nitroprusside. In isolated pulmonary artery rings incubated with indomethacin (10 microM) and precontracted with phenylephrine (2 microM), BAEE (10(-6)-10(-5) M) significantly (P less than .05) relaxed the rings more than L-arginine. This effect was potentiated by the endothelium (P less than .05). The relaxing effect of BAEE (ED50 = 2.1 X 10(-6) M) and acetylcholine (ED50 = 2.4 X 10(-7) M) was significantly less potent than that of sodium nitroprusside (ED50 = 1.1 X 10(-8) M). Moreover, pretreatment with the soluble guanylate cyclase inhibitors methylene blue (10(-5) M) and hemoglobin (10(-5) M) antagonized BAEE-induced relaxation in intact pulmonary rings but had no effect on the relaxation elicited with atrial natriuretic peptide. In the isolated lung preparations perfused with the endoperoxide analog U46619 (5-10 nmol/min), sodium nitroprusside (10(-10)-10(-8) M) elicited potent vasodilation (ED50 = 2.8 X 10(-9) mol) whereas no vasodilation was observed with acetylcholine (10(-8)-10(-5) mol). BAEE (10(-6)-10(-5) M) decreased in a dose-dependent manner pulmonary perfusion pressure, and similar doses of L-arginine showed only a mild vasodilating effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Arginina/análogos & derivados , Vasodilatadores/farmacología , Acetilcolina/farmacología , Animales , Arginina/farmacología , Presión Sanguínea/efectos de los fármacos , Hemoglobinas/farmacología , Técnicas In Vitro , Pulmón/efectos de los fármacos , Masculino , Azul de Metileno/farmacología , Óxido Nítrico/metabolismo , Perfusión , Arteria Pulmonar/efectos de los fármacos , RatasRESUMEN
Rats exposed to 20 Gy whole-body irradiation demonstrated a depressed aortic responsiveness to the thromboxane mimic, U46619, 48 h postirradiation. The mechanism for this observed response was investigated. Shielding the abdominal aorta attenuated this altered vascular reactivity. Since this suggests that radiation exposure induces local changes in the aorta, vascular smooth muscle function was assessed with cumulative concentrations of KCl. Radiation-induced smooth muscle damage was insufficient to account for the decreased reactivity to U46619. Next, calcium availability for vascular smooth muscle function was evaluated and found not to be responsible for the radiation-induced depression in aortic responsiveness. Finally, the role that cyclooxygenase products play in the depressed contractile response was investigated. Indomethacin treatment prior to and for 48 h after irradiation attenuated the altered vascular reactivity to U46619. These data suggest that a radiation-induced increase in cyclooxygenase products may play a role in the decreased aortic reactivity to the thromboxane mimic.
Asunto(s)
Aorta Abdominal/efectos de los fármacos , Endoperóxidos de Prostaglandinas Sintéticos/farmacología , Irradiación Corporal Total , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animales , Aorta Abdominal/efectos de la radiación , Radioisótopos de Cesio , Rayos gamma , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/efectos de la radiación , Prostaglandina-Endoperóxido Sintasas/fisiología , Ratas , Ratas EndogámicasRESUMEN
In the presence of indomethacin, arachidonic acid relaxes precontracted rings of rat aorta only when the endothelium is intact. Arachidonate-induced, endothelium-dependent relaxation is potentiated by superoxide dismutase. In contrast, linoleic acid (LA) contracts endothelium-intact and -denuded rings. Arachidonate is metabolized in endothelial cells by both cyclo-oxygenase and 15-lipoxygenase. Therefore, we determined the vasodilatory effect of 15-lipoxygenase products. The products generated by soybean lipoxygenase (SLO) from arachidonate in the bioassay bath relax precontracted, de-endothelialized ring segments of rat aorta. This relaxation is potentiated by superoxide dismutase and is more prominent when high concentrations of SLO are used. The main metabolites recovered from the bioassay bath were 5,15-dihydroperoxyeicosatetraenoic acid and 8,15-dihydroperoxyeicosatetraenoic acid. At lower concentrations of SLO the degree of relaxation is less and the major product is 15-hydroperoxyeicosatetraenoic acid. LA is metabolized by SLO to 13-hydroperoxyoctadecadienoic acid. The relaxation induced by the incubation of LA with SLO in endothelium-denuded rings is less than that obtained with arachidonic acid. In endothelium-denuded rings that were precontracted with phenylephrine authentic 15-hydroperoxyeicosatetraenoic acid did not induce clear effect (at 40 microM 15-hydroperoxide caused relaxation, whereas at 15 microM induced small contraction) and 13-hydroperoxyoctadecadienoic acid of LA induced contraction. Neither 5,15-dihydroperoxyeicosatetraenoic acid nor 8,15-dihydroperoxyoctadecadienoic acid (1-15 microM) induced a well defined relaxation. This study indicates that arachidonic acid is metabolized by SLO to a vasodilatory compound(s) that is possibly derived from 15-hydroperoxyeicosatetraenoic acid.
Asunto(s)
Araquidonato 15-Lipooxigenasa/fisiología , Araquidonato Lipooxigenasas/fisiología , Ácidos Araquidónicos/metabolismo , Ácidos Araquidónicos/farmacología , Leucotrienos , Peróxidos Lipídicos/farmacología , Vasodilatación/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Ácido Araquidónico , Endotelio/fisiología , Ácido Linoleico , Ácidos Linoleicos/farmacología , Masculino , Ratas , Ratas Endogámicas , Superóxido Dismutasa/farmacologíaRESUMEN
Segments of rat aortic arch were studied to determine the existence of sexual dimorphism. The influence of the endothelium in mediating gender differences in contractility (maximum tension, Tmax) and sensitivity (ED50) to prostaglandin F2 alpha was measured. This was done in both intact and denuded vascular ring preparations which were dissected from adult male and female rats. Group I comprised untreated male and female rats; Groups II and III were treated with testosterone (10 mg/kg i.m.) or 17 beta-estradiol (2.5 mg/kg i.m.), respectively, on days 1, 3 and 6 and sacrificed on day 7. Intact vascular ring preparations from untreated females were significantly less sensitive (P less than .01) and less contractile (P less than .025) than those from the males. After the intimal surface of the aortic arch rings was rubbed the rings from females exhibited a significant increase in Tmax. However, in vessels from males endothelial denudation had no effect on either Tmax or ED50. Testosterone treatment of female rats significantly increased Tmax (P less than .01) and decreased the ED50 (P less than .01) when compared to rings from untreated females. Testosterone treatment did not significantly affect either parameter in vessels from females which had been rubbed. Testosterone treatment also had no significant effect in either intact or rubbed vessels from males. Estrogen treatment significantly increased the Tmax (P less than .05) of intact vessels from females and had no effect on other vessel segments. Thus, the gender difference in Tmax may relate to an attenuating effect of the endothelium on contractility in the rings from females.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Endotelio/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Prostaglandinas F/farmacología , Factores Sexuales , Animales , Aorta/citología , Aorta/efectos de los fármacos , Dinoprost , Femenino , Masculino , Contracción Muscular/efectos de los fármacos , Ratas , Testosterona/farmacologíaRESUMEN
The pulmonary arteries of rats were studied in order to determine the existence of sexual dimorphism. Gender differences, in the sensitivity (EC50) and maximum contractility (Tmax) of ring preparations of the main pulmonary arteries of adult male and female rats, were evaluated with the synthetic endoperoxide analog [(15S)]-hydroxy-11 alpha,9 alpha-(epoxymethano)-prosta-5Z, 13E-dienoic acid,] (U46619) and norepinephrine. There were no significant gender differences in the Tmax values obtained with either U46619 or norepinephrine. However, when the intimal surface of vessel segments from female rats was rubbed, U46619 but not norepinephrine elicited a significantly lower Tmax. In contrast, no change in Tmax was observed with denuded vessel segments from males. Removal of the endothelium did not significantly affect the EC50 of U46619 or norepinephrine in segments from either sex. The inhibitory effect of verapamil on the U46619-induced contractile response was studied on both intact and denuded vessels from rats of both gender. The Tmax of intact vessels from males but not females was significantly attenuated by verapamil (P less than .05). The EC50 values with verapamil were not significantly different in any of the vessel preparations. We suggest that the endothelium of the pulmonary artery of female rats significantly potentiates the contractile response to U46619 and attenuates the inhibitory effect of verapamil.