Pharmacologic characterization of the contractile activity of peptide leukotrienes in guinea-pig pulmonary artery.
The actions of the peptide leukotrienes (LT) LTC4, LTD4 and LTE4 and phenylephrine (PE) were studied in isolated left branches of the guinea-pig pulmonary artery (GPPA). Indomethacin 5 x 10(-6) M enhanced both the potency and maximal response of all agonists, but the effect on LTD4 and LTE4 was larger. The influence of indomethacin suggests the release of an endogenous vasodilating cyclooxygenase product in GPPA. In the presence of indomethacin the rank-order of potency was LTC4 greater than LTD4 greater than LTE4 greater than or equal to PE with respective pD2 values of 7.65, 7.39, 6.35 and 6.26. All further studies were carried out in the presence of 5 x 10(-6) M indomethacin. Removal of the endothelium further increased both potency (greater than 3-fold) and the maximal response of all agonists tested, indicating that a non-cyclooxygenase endothelium-dependent relaxing factor may be present in GPPA. In separate studies, GPPA was demonstrated capable of metabolizing 3H-LTC4 to 3H-LTD4 by an L-serine borate inhibitable gamma-glutamyl transpeptidase. In contrast, relatively little formation of 3H-LTE4 was apparent either from 3H-LTC4 or 3H-LTD4. The LTD4-selective antagonists, LY 171,883 and ICI 198,615 had -log molar KB values of 6.07 +/- 0.14 and 9.38 +/- 0.32, respectively, against LTD4 in the absence of endothelium. The ability of LY 171,883 to antagonize LTC4 was eliminated in the presence of 45 mM serine borate in endothelium denuded tissues. LT receptors in GPPA appear to be heterogeneous and similar to guinea pig airway receptors.
Fedyna
J S
JS
Department of Pharmacology, ICI Americas Inc., Wilmington, DE 19897.
Snyder
D W
DW
Aharony
D
D
Redkar-Brown
D
D
Krell
R D
RD
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001881:Borates / Q000494:pharmacology; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000502:physiology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D012694:Serine / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
D000098:Acetophenones; D001881:Borates; D007191:Indazoles; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D013777:Tetrazoles; C040900:serine-borate complex; C054217:ICI 198615; D010656:Phenylephrine; D012694:Serine; C044660:LY 171883; D007213:Indomethacin