Prostacyclin release and receptor activation: differential control of human pulmonary venous and arterial tone

Abstract

1 In human pulmonary vascular preparations, precontracted arteries were more sensitive to the relaxant effect of acetylcholine (ACh) than veins (pD 2 values: 7.2570.08 (n ¼ 23) and 5.9270.09 (n ¼ 25), respectively). Therefore, the role of prostacyclin (PGI 2 ) was explored to examine whether this mediator may be responsible for the difference in relaxation. 2 In the presence of the cyclooxygenase (COX) inhibitor, indomethacin (INDO), the ACh relaxations were reduced in arteries but not in veins. On the contrary, an inhibitor (L-NOARG) of the nitric oxide synthase blocked preferentially the relaxation in veins. 3 A greater release of 6-keto-PGF 1a , the stable metabolite of PGI 2 , was observed in arterial preparations than in venous preparations when stimulated with either ACh or arachidonic acid (AA). 4 Exogenous PGI 2 produced a reduced relaxant effect in the precontracted vein when compared with the artery. In the presence of the EP 1 -receptor antagonist AH6809, the PGI 2 relaxation of veins was similar to arteries. 5 In veins, AA (0.1 mM) produced a biphasic response, namely, a contraction peak (0.4-0.5 g) followed by a relaxation. These contractions in venous preparations were abolished either in the absence of endothelium or in the presence of INDO or an EP 1 -receptor antagonist (AH6809, SC19220). In the arterial preparations AA induced only relaxations. 6 In both vascular preparations, COX-1 but not the COX-2 protein was detected in microsomal preparations derived from homogenized tissues or freshly isolated endothelial cells. 7 The differential vasorelaxations induced by ACh may be explained, in part, by a more pronounced production and release of PGI 2 in human pulmonary arteries than in the veins. In addition, while PGI 2 induced relaxation by activation of IP-receptors in both types of vessels, a PGI 2 constrictor effect was responsible for masking the relaxation in the veins by activation of the EP 1 -receptor.

Altered reactivity to norepinephrine through COX-2 induction by vascular injury in hypercholesterolemic rabbits

“…In the present study, whereas unstimulated samples did not exhibit significant differences in terms of prostanoid release, NE increased the release of PGI 2 only in aorta from atherosclerotic rabbits. Similar activation of COX after NE stimulation has also been observed in previous studies of systemic and pulmonary vessels (13,22).…”

Participation of Prostacyclin in Endothelial Dysfunction Induced by Aldosterone in Normotensive and Hypertensive Rats

“…In this sense, it has been described that EP 1 and EP 3 receptors bound IP ligands such as iloprost with K i values comparable to those for IP receptor. 38,39 In addition, the participation of vasoconstrictor derivated from cytochrome P450 family can also be proposed because the presence of the cytochrome P450 inhibitor ABZ reversed the alterations in ACh relaxation in both strains. 40 Because PGI 2 synthase is a member of the P450 family, 38 it could be postulated that the effect of ABZ is mediated by PGI 2 synthesis inhibition.…”

Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

“…The observation that the COX inhibitor indomethacin reduces ACh relaxation in isolated human pulmonary artery but not in the pulmonary vein supports little role of PGI 2 in relaxation of pulmonary vein. In contrast, NO seems to be the sole endothelium-derived vasorelaxant released by ACh in porcine pulmonary artery (Lawrence et al, 1998;Norel et al, 2004). In canine pulmonary vessels, PGI 2 does not contribute to endothelium-dependent relaxation in the large arterial rings but has an important vasodilator effect in the small microvessels.…”

“…For example, in rat aorta precontracted with norepinephrine, the relaxation induced by lower concentrations of PGI 2 is likely to involve IP receptors, whereas the decreased relaxation in response to higher PGI 2 concentrations is abolished by the TP receptor antagonist 7-(3-((2-((phenylamino)carbonyl)hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid (SQ29548), suggesting that at higher concentrations, PGI 2 binds to TP receptor (Williams et al, 1994). In addition, exogenous PGI 2 causes less relaxation in isolated human pulmonary veins than arteries precontracted with noradrenaline, probably because of activation of EP1 receptor; in the presence of the EP1 receptor antagonist 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809), PGI 2 -induced relaxation in the veins is similar to that in the arteries (Norel et al, 2004). In addition to EP1 and TP receptors, some PGI 2 analogs may target EP3 receptor and cause VSM contraction.…”