Relaxation of isolated human pulmonary muscle preparations with prostacyclin (PGI2) and its analogs

1 Iloprost and cicaprost (IP-receptor agonists) induced relaxations in the histamine-(50 mM) contracted human bronchial preparations (pD 2 values, 6.63+0.12 and 6.86+0.08; E max values, 90+04 and 65+08% of the papaverine response for iloprost (n=6) and cicaprost (n=3), respectively).2 Prostaglandin E 2 (PGE 2 ) and misoprostol (EP-receptor agonist) relaxed the histamine-contracted human bronchial preparations (pD 2 values, 7.13+0.07 and 6.33+0.28; E max values, 67+04 and 57+08% of the papaverine response for PGE 2 (n=14) and misoprostol (n=4), respectively). In addition, both relaxations were inhibited by AH6809 (DP/EP 1 /EP 2 -receptor antagonist; 3 mM; n=5 ± 6). 3 The PGE 2 -induced relaxations of human bronchial preparations were not modi®ed by treatment with AH23848B (TP/EP 4 -receptor antagonist; 30 mM; n=4). 4 The contracted human bronchial preparations were signi®cantly relaxed by prostaglandin D 2 (PGD 2 ) or by BW245C a DP-receptor agonist. However, these responses did not exceed 40% of the relaxation induced by papaverine. In addition, the relaxations induced by PGD 2 were signi®cantly inhibited by treatment with a DP-receptor antagonist BWA868C (0.1 mM; n=3). 5 These data suggest that the relaxation of human isolated bronchial preparations induced by prostanoids involved IP-, EP 2 -and to a lesser extent DP-receptors but not EP 4 -receptor.

Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Prostanoid receptors involved in the relaxation of human bronchial preparations

Norel

Walch

Labat

et al. 1999

“…The relaxations observed with iloprost and cicaprost, two IP-receptor selective agonists (SchroÈ r et al, 1981;StuÈ rzebecher et al, 1985), indicate the presence of IP-receptor in human pulmonary arterial preparations. These results are in agreement with the data previously reported by Haye-Legrand et al (1987). In addition, results (present report) suggest that PGE 1 Figure 2 Schild-plot analysis of the antagonism by BWA868C of relaxant concentration-eect curves to PGD 2 in veins derived from four human lung samples.…”

Section: Discussionsupporting

confidence: 83%

Prostanoid receptors involved in the relaxation of human pulmonary vessels

Walch

Labat

Gascard

et al. 1999

111

1 To characterize the prostanoid receptors on human pulmonary smooth muscle involved in vasodilatations, isolated arteries and veins were contracted with norepinephrine (10 mM) and vessels were subsequently challenged with dierent prostanoid-receptor agonists in the absence or presence of selective antagonists. 2 Prostaglandin D 2 (PGD 2 ) and the selective DP-receptor agonist, BW245C, induced relaxations in the contracted human pulmonary venous preparations. The pD 2 values were: 6.88+0.11 (n=17) and 7.31+0.12 (n=5), respectively. The relaxant responses induced by PGD 2 were reduced by the selective DP-receptor antagonist, BWA868C, and the estimated pA 2 value was 7.84+0.16 (n=4). PGD 2 and BW245C did not relax contracted human pulmonary arteries. 3 The selective IP-receptor agonists, iloprost and cicaprost, both induced relaxations in the contracted human vascular preparations. The pD 2 values for iloprost were: 7.84+0.08 (n=6) and 8.25+0.06 (n=4) and for cicaprost: 8.06+0.12 (n=5) and 8.11+0.09 (n=5) in arteries and veins respectively. 4 Prostaglandin E 2 (PGE 2 ) and the EP 2 /EP 3 -receptor agonist, misoprostol, partially relaxed the contracted venous preparations and the pD 2 values were: 8.10+0.15 (n=15) and 6.24+0.33 (n=3), respectively. These relaxations suggest the presence of an EP receptor in the human pulmonary veins. The contracted human pulmonary arteries did not relax when challenged with PGE 2 . 5 In human pulmonary venous preparations, the PGE 2 -induced relaxations were neither modi®ed by treatment with TP/EP 4 -receptor antagonist, AH23848B (10 and 30 mM, n=6), nor by the DP/ EP 1 /EP 2 -receptor antagonist, AH6809 (3 mM, n=6). 6 These data suggest that the relaxation induced by prostanoids involved DP-, IP-receptors and to a lesser extent an EP-receptor on human pulmonary venous smooth muscle. In contrast, only the IPreceptor is involved in the prostanoid induced relaxations on human pulmonary arterial smooth muscle.

“…The absolute values of maximum responses to the agonists showed large interindividual variability, as previously reported (Haye-Legrand et al, 1987). Thus the maximum response to 5-HT obtained in control tissues at the end of the CRC was 1.63+0.23 g (n/p=28/20) in artery and 1.76+0.21 g (n/p=26/ 25) in vein preparations.…”

Section: Contractile Responses Of 5-ht Receptor Agonistssupporting

confidence: 50%

Characterization of 5‐HT receptors on human pulmonary artery and vein: functional and binding studies

Cortijo

Martı́-Cabrera

Bernabeu

et al. 1997

1 This study aimed to investigate the 5-hydroxytryptamine (5-HT) receptors mediating contraction of ring preparations isolated from human pulmonary arteries and veins. In functional studies, the responses to 5-HT, sumatriptan, ergotamine, serotonin-O-carboxymethyl-glycyl-tyrosinamide (SCMGT), a-methyl 5-HT (a-Me) and 2-methyl 5-HT (2-Me) were studied with WAY100635, GR127935, ritanserin, zacopride and SB204070 as antagonists. 2 All agonists produced concentration-dependent contractions of human pulmonary artery and vein preparations. The order of potency (7log EC 50 values) was ergotamine (6.88)45-HT (6.41)5SCMGT (6.20)=sumatriptan (6.19) 5a-Me (6.04) in the artery, and ergotamine (7.84)45-HT (6.96)4suma-triptan (6.60)=a-Me (6.56)4SCMGT (6.09) in the vein. The potency of each agonist, except for SCMGT, was greater in vein than in artery preparations. Contractile responses to 5-HT were similar in intact and endothelium-denuded preparations but responses to sumatriptan were enhanced in artery rings without endothelium. 3 GR127935 (1 nM to 0.5 mM) produced an unsurmountable antagonism of the response to 5-HT, sumatriptan, ergotamine and SCMGT. Ritanserin (1 nM to 1 mM) also reduced the maximum contractile responses to 5-HT, ergotamine and a-Me in artery and vein preparations without aecting those to sumatriptan and SCMGT. In endothelium-denuded preparations, surmountable antagonism of sumatriptan by GR127935 (in the presence of ritanserin) and of a-Me by ritanserin (in the presence of GR127935) allowed for the calculation of the apparent pK B values of GR127935 (9.17+0.11 in artery and 9.11+0.05 in vein) and ritanserin (8.82+0.09 in artery and 8.98+0.12 in vein). 4 WAY100635 (1 nM to 1 mM), zacopride (1 nM to 1 mM), or SB204070 (1 nM) did not signi®cantly alter the concentration-response curves for 5-HT, sumatriptan, ergotamine, SCMGT or 2-Me in human pulmonary artery or vein thus indicating that 5-HT 1A , 5-HT 3 and 5-HT 4 receptors are presumably not involved in the contractile response to these agonists. 5 Binding studies using selective radioligands for dierent 5-HT receptors could not detect the presence of 5-HT 1A receptor binding in human pulmonary blood vessels whereas the 5-HT 1B/1D radioligand [ 3 H]-5-CT signi®cantly labelled a population of speci®c binding sites in both vessel types. The presence of 5-HT 2A receptors could also be inferred from the level of binding of [ 3 H]-ketanserin to membranes obtained from human pulmonary vessels, although signi®cance could not be reached for arteries. 5-HT 4 speci®c receptor binding was scarce in veins and absent in the case of arteries. 6 These ®ndings indicate that the human pulmonary artery and vein have a mixed functional population of 5-HT 1B/1D and 5-HT 2A receptors mediating the contractile response to 5-HT which is consistent with results of the binding studies.