Differential effects of 5,6-EET on segmental pulmonary vasoactivity in the rabbit

Abstract

In the rabbit, 5,6-epoxyeicosatrienoic acid (EET) was reported both to dilate and to constrict pulmonary blood vessels. We propose that these seemingly contradictory results could be explained by differences in responses to 5,6-EET in large-conductance pulmonary arteries (PA) compared with smaller PA and resistance vessels. Thus we found that in rings of extralobar PA [>2-mm outside diameter (OD)], in which active tension had been increased with PGF(2alpha), 5,6-EET produced relaxation in a concentration- and cyclooxygenase (COX)-dependent manner. In contrast, 5,6-EET increased tension in intralobar (1- to 2-mm OD) PA. Small extralobar PA (2- to 2.5-mm OD) exhibited intermediate responses. In the intact lung, the net effect of 5,6-EET (1 x 10(-8)-1 x 10(-5) M) was an increase in pulmonary vascular resistance (PVR) from 13.0 +/- 0.5 to 47.8 +/- 4.6 mmHg. 100 ml(-1) x min(-1) (EC(50) 5.9 +/- 1.7 x 10(-7) M). The increase in PVR was accompanied by a 10-fold increase in perfusate thromboxane (TX)B(2) concentration. The 5,6-EET-induced increase in PVR was prevented with indomethacin (100 microM), a cyclooxygenase inhibitor, or ONO-3708 (20 microM), a TX/PGH(2) (TP) receptor antagonist, but not with OKY-046 (700 microM), a TX synthase inhibitor. These results demonstrate that although 5,6-EET dilates large extralobar PA segments in a COX-dependent manner, in the intact rabbit lung 5,6-EET produces constriction that requires synthesis of a COX-dependent agonist of the TP receptor other than TX.

Cyclooxygenase (COX)-1 and COX-2 Participate in 5,6-Epoxyeicosatrienoic Acid-Induced Contraction of Rabbit Intralobar Pulmonary Arteries

“…Of these regioisomers, 5,6-EET has been reported to be the most abundant metabolite synthesized in rabbit lung (Zeldin et al, 1995), and it is the most potent pulmonary vasoconstrictor (Zhu et al, 2000). Although EETs relax most blood vessels in the systemic circulation, they contract intralobar segments of pulmonary arteries (PA) (Schwartzman et al, 1985;Zhu et al, 2000;Stephenson et al, 2003;Losapio et al, 2005) and increase pulmonary vascular resistance in isolated perfused lungs (Stephenson et al, 2003). Recently, the importance of this finding was illustrated in a report by Pokreisz et al (2006), who demonstrated that inhibition of epoxygenase activity significantly reduced acute hypoxic pulmonary vasoconstriction (HPV) and chronic hypoxia-induced pulmonary vascular remodeling in a mouse model of hypoxia-induced pulmonary hypertension.…”

Emerging role of epoxyeicosatrienoic acids in coronary vascular function

“…The sEH inhibitors may also have detrimental effects on the pulmonary circulation, as EETs constrict the pulmonary vasculature [88][89][90][91] in most, but not all [92,93], animal models studied. The effects of EETs on the human pulmonary circulation remain unknown and future studies are needed to determine how sEH inhibition may alter vasomotor tone in this vascular bed.…”

ω3 and ω6 CYP450 Eicosanoid Derivatives: Key Lipid Mediators in the Regulation of Pulmonary Hypertension

“…The mechanism of EET-induced vasodilation has been studied extensively and is dependent on the hyperpolarisation of vascular smooth muscle cells (Gebremedhin et al, 1992, Hecker et al, 1994, Campbell et al, 1996, Eckman et al, 1998, Morin et al, 2007a resulting from EETinduced opening of smooth muscle cell potassium channels (Campbell et al, 1996, Zou et al, 1996, Eckman et al, 1998, Gebremedhin et al, 1998, Hayabuchi et al, 1998, Morin et al, 2007a. Although EETs also reduce tension in non-resistant extralobar pulmonary artery (PA) segments (Stephenson et al, 1998, Stephenson et al, 2003, all four EET regioisomers have been observed to be vasoconstrictors in small-diameter intralobar PA segments in rabbits and rats (Yaghi et al, 2001. Because EETs also increase vascular resistance (and decrease compliance) in isolated perfused rabbit lungs (Stephenson et al, 2003), the predominant activity of EETs in lung vessels appears to be vasoconstriction.…”

“…Although EETs also reduce tension in non-resistant extralobar pulmonary artery (PA) segments (Stephenson et al, 1998, Stephenson et al, 2003, all four EET regioisomers have been observed to be vasoconstrictors in small-diameter intralobar PA segments in rabbits and rats (Yaghi et al, 2001. Because EETs also increase vascular resistance (and decrease compliance) in isolated perfused rabbit lungs (Stephenson et al, 2003), the predominant activity of EETs in lung vessels appears to be vasoconstriction. These data are supported by the observation that inhibition of epoxygenase activity with specific pharmacological inhibitors attenuates PA tension to phenylephrine (Zhu et al, 2000a), suggesting that endogenous EETs participate in -adrenergic contraction of the pulmonary vasculature.…”

“…Of the four EET regioisomers, 5,6-EET is also the most potent, albeit labile, constrictor of rabbit pulmonary arteries (Zhu et al, 2000b). The 5,6-EET-induced contraction of rabbit PA requires intact endothelium, cyclooxygenase activity, and activation of the thromboxane/endoperoxide (TP) receptor (Zhu et al, 2000b, Stephenson et al, 2003. Moreover data suggest that 5,6-EET induces contraction in intralobar PA by increasing Rho-kinase activity, thus phosphorylating MLC and increasing Ca 2+ sensitivity of the contractile apparatus in rabbit lung (Losapio et al, 2005).…”