Postnatal maturation in nitric oxide-induced pulmonary artery relaxation involving cyclooxygenase-1 activity.

The maturation in the vasodilator response to nitric oxide (NO) in isolated intrapulmonary arteries was analyzed in newborns and 15- to 20-day-old piglets. The vasodilator responses to NO gas but not to the NO donor sodium nitroprusside increased with age. The inhibitory effects of the superoxide dismutase inhibitor diethyldithiocarbamate and xanthine oxidase plus hypoxanthine and the potentiation induced by superoxide dismutase and MnCl(2) of NO-induced vasodilatation were similar in the two age groups. Diphenyleneiodonium (NADPH oxidase inhibitor) potentiated the response to NO, and this effect was more pronounced in the older animals. The nonselective cyclooxygenase inhibitors indomethacin and meclofenamate and the preferential cyclooxygenase-1 inhibitor aspirin augmented NO-induced relaxation specifically in newborns, whereas the selective cycloxygenase-2 inhibitor NS-398 had no effect. The expressions of alpha-actin, cycloxygenase-1, and cycloxygenase-2 proteins were similar, whereas Cu,Zn-superoxide dismutase decreased with age. Therefore, the present data suggest that the maturational increase in the vasodilatation of NO in the pulmonary arteries during the first days of extrauterine life involves a cycloxygenase-dependent inhibition of neonatal NO activity.

Respuesta de las arterias pulmonares de lechón al óxido nítrico y a dadores de óxido nítrico: Evolución con la edad postnatal y modulación por el estrés oxidativo / Nitric oxide- and nitric oxide donor-induced responses in piglet pulmonary arteries: Postnatal maturation and modulation by oxidative stress

En el presente estudio hemos analizado la influencia de la edad postnatal y los cambios en el nivel de estrés oxidativo sobre la vasodilatación pulmonar in vitro inducida por el NO endógeno, el NO exógeno y donadores de NO. Se han utilizado las arterias pulmonares procedentes de lechones de 1 día y de 2 semanas de edad para el registro de la fuerza contráctil. En las arterias pulmonares de lechones de 1 y 15 días de edad, el estrés oxidativo basal modula la acción vasodilatadora del NO, siendo la NAD(P)H oxidasa de la adventicia la principal fuente endógena del anión superóxido. La vasodilatación inducida por el NO de origen endotelial y por el NO exógeno aumenta con la edad, posiblemente por un incremento en la actividad de la ciclooxigenasa-1 en los primeros momentos de vida extrauterina que modularía el efecto vasodilatador del NO. Finalmente, encontramos que el NO y los donadores de NO, SNAP y nitroprusiato (SNP), difieren en la cinética y distribución regional de la liberación del NO, lo que influye en la susceptibilidad para la inactivación por el anión superóxido y por la oxihemoglobina (AU)

Endothelium-independent vasodilator effects of the flavonoid quercetin and its methylated metabolites in rat conductance and resistance arteries.

The flavonoid quercetin is metabolized into isorhamnetin, tamarixetin, and kaempferol, the vascular effects of which are unknown. In the present study, the effects of quercetin and its metabolites were analyzed on isometric tension in isolated rat thoracic and abdominal aorta, in isolated intact and beta-escin-permeabilized iliac arteries, and on perfusion pressure in the isolated mesenteric resistance vascular bed. In noradrenaline-precontracted vessels, the four flavonoids produced a vasodilator effect, which was inversely correlated with the diameter of the vessel studied; i.e., quercetin, isorhamnetin, tamarixetin, and kaempferol were 5-, 25-, 4-, and 6-fold, respectively, more potent in the resistance mesenteric bed (-log IC(50) = 5.35 +/- 0.15, 5.89 +/- 0.11, 5.34 +/- 0.10, and 5.66 +/- 0.06, respectively) than in the thoracic aorta (-log IC(50) = 4.68 +/- 0.08, 4.61 +/- 0.08, 4.73 +/- 0.11, and 4.81 +/- 0.13, respectively; n = 4-6). The vasodilator responses of quercetin and isorhamnetin were not significantly modified after removal of the endothelium in the thoracic aorta or in the mesenteric bed. Furthermore, the guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 10(-6) M), the adenylate cyclase inhibitor SQ22536 [9-(tetrahydro-2-furanyl)-9H-purin-6-amine; 10(-6) M], KCl (40 mM), or ouabain (10(-3) M) had no effect on isorhamnetin-induced vasodilation in the mesenteric bed. In permeabilized iliac arteries stimulated with Ca(2+) (pCa of 5.9), isorhamnetin was also significantly more potent (-log IC(50) = 5.27 +/- 0.15) than quercetin (-log IC(50) = 4.56 +/- 0.15). In conclusion, quercetin and its metabolites showed vasodilator effects with selectivity toward the resistance vessels. These effects are not due to or modulated by endothelial factors and are unrelated to changes in cytosolic Ca(2+).

Cardiovascular effects of isorhamnetin and quercetin in isolated rat and porcine vascular smooth muscle and isolated rat atria.

Isorhamnetin and quercetin produced endothelium-independent vasodilator effects in rat aorta, rat mesenteric arteries, rat portal vein and porcine coronary arteries. The effects of the two flavonoids were similar in arteries stimulated by noradrenaline, KCl, U46619 or phorbol esters but the two flavonoids were more potent in the coronary arteries than in the aorta. At high concentrations, they also induced a positive inotropic effect in isolated rat atria. Therefore, at least part of the in vivo effects of quercetin may result from its conversion to isorhamnetin which is the main metabolite of quercetin found in plasma. The arterial, venous and coronary vasodilator effects may contribute to the protective effects of flavonoids in ischaemic heart disease observed in epidemiological studies.