Involvement of TP and EP₃ Receptors in Vasoconstrictor Responses to Isoprostanes in Pulmonary Vasculature

Abstract

Although isoprostanes generally act on smooth muscle via TXA 2 -selective prostanoid receptors (TPs), some suggest other prostanoid receptors or possibly even a novel isoprostaneselective receptor might be involved. We studied contractions to several isoprostanes in porcine pulmonary vasculature using organ bath techniques. 8-iso-prostaglandin E 2 (PGE 2 ) was the most potent and efficacious of the isoprostanes, with a log EC 50 of Ϫ7.0 Ϯ 0.2 in the pulmonary artery and Ϫ6.8 Ϯ 0.2 in the pulmonary vein. The responses to all the isoprostanes were essentially completely blocked by the TP receptor antagonist Ϫ5 M] but were antagonized by the less selective DP/EP 1 /EP 2 antagonist AH6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid; 10 Ϫ5 M) or by cyclopiazonic acid (10 Ϫ5 M; depletes the internal Ca 2ϩ store). Our data indicate that, whereas 8-iso-PGE 2 constricts pulmonary vasculature primarily through TP receptors, a substantial portion of this response is also directed through EP 3 receptors or possibly a novel isoprostane receptor.Isoprostanes are metabolites of polyunsaturated fatty acids, such as arachidonic acid, and are produced by peroxidative attack of lipid membranes. They accumulate to substantial levels in a wide variety of clinical and experimental settings associated with oxidative stress, including systemic and pulmonary (Jankov et al., 2000) hypertension, and during exposure to agents that are associated with hypertension, such as subpressor doses of angiotensin II (Haas et al

Age-Related Differences in Vasoconstrictor Responses to Isoprostanes in Piglet Pulmonary and Mesenteric Vascular Smooth Muscle

“…In addition, Belik et al (9) have shown that the 1-wk-old rat pulmonary vascular response to 8-iso-PGF2␣ is clearly distinct from the adult. This age-dependent difference in force development was similar to the pattern previously described during stimulation of rat pulmonary artery with other agonists, including the TxA 2 analog U46619, which appears to act via the same receptor as 8-iso-PGF 2␣ (9,21). No study has characterized the response to isoprostanes in neonatal systemic vessels.…”

“…Another point of interest is that some of the F-ring isoprostanes, such as 8-iso-PGF 2␣ and 8-iso-PGF 2␤ , produced, in our experiments, levels of contraction that are comparable with those induced by the E-ring isoprostanes. In contrast, in the porcine adult pulmonary vessels, F-ring isoprostanes induced markedly weaker contractions than E-ring isoprostanes (21,26). Finally, Janssen and Tazzeo (21) observed that, although the contractions induced in adult porcine PA and PV by 8-iso-PGE 1 , 8-iso-PGF 1␣ , 8-iso-PGF 2␣ , and 8-iso-PGF 2␤ were essentially completely prevented by TP receptor blockade, 8-iso-PGE 2 was able to evoke substantial contraction of PV in the maintained presence of TP receptor blockade.…”

“…Finally, Janssen and Tazzeo (21) observed that, although the contractions induced in adult porcine PA and PV by 8-iso-PGE 1 , 8-iso-PGF 1␣ , 8-iso-PGF 2␣ , and 8-iso-PGF 2␤ were essentially completely prevented by TP receptor blockade, 8-iso-PGE 2 was able to evoke substantial contraction of PV in the maintained presence of TP receptor blockade. Moreover, their data suggest that, in the adult porcine PV, 8-iso-PGE 2 can also act upon another type of excitatory receptor, likely EP 3 receptors or a unique isoprostane receptor (21). Our data do not allow us to speculate on the presence of these putative isoprostane receptors.…”

Vasodilatory and Electrophysiological Actions of 8-iso-Prostaglandin E2 in Porcine Coronary Artery

“…Many have described contractile responses to isoprostanes in a wide variety of arterial beds, generally via stimulation of thromboxane A 2 receptors (TP receptors), which then enhance the Ca 2ϩ -sensitivity of the contractile apparatus through some mechanism that is largely dependent on tyrosine kinase activation (Janssen, 2001). They may also cause vasoconstriction through an action on PGE 2 -selective (EP) receptors coupled to release of internally sequestered Ca 2ϩ (Janssen and Tazzeo, 2002). More recently, some have identified important vasodilatory actions of isoprostanes (Jourdan et al, 1997;Janssen et al, 2000;Janssen et al, 2001); however, the signaling mechanisms underlying those inhibitory responses have not been investigated.…”

Mecanismos celulares que influenciam a sinalização por receptores 1-adrenérgicos na carótida contra-lateral à lesão por cateter balão

“…Alguns isoprostanos possuem propriedades vasoconstritoras (JANSSEN et al, 2001;JANSSEN, TAZZEO, 2002;YI et al, 2006), enquanto outros são vasodilatadores ZHANG et al, 2005 (WEI et al, 1996). Ao ativar canais para potássio, agentes oxidantes promovem hiperpolarização e fechamento de canais para cálcio dependentes de voltagem, resultando na diminuição do influxo de cálcio (SCHACH et al, 2007).…”