Pulmonary vascular reactivity: effect of PAF and PAF antagonists.
We investigated the effects of two different platelet-activating factor (PAF) antagonists, SRI 63-441 and WEB 2086, on PAF-, angiotensin II-, and hypoxia-induced vasoconstrictions in isolated rat lungs perfused with a physiological salt solution. Bolus injection of PAF (0.5 micrograms) increased pulmonary arterial and microvascular pressures and caused lung edema. Both SRI 63-441, a PAF-analogue antagonist, and WEB 2086, a thienotriazolodiazepine structurally unrelated to PAF, completely blocked PAF-induced vasoconstriction and lung edema at 10(-5) M. At a lower concentration (10(-6) M), WEB 2086 was more effective than SRI 63-441. WEB 2086 also blocked the pulmonary vasodilation induced by low-dose PAF (15 ng) in blood-perfused lungs preconstricted with hypoxia. SRI 63-441 and CV 3988 (another PAF analogue antagonist), but not WEB 2086, caused acute pulmonary vasoconstriction at 10(-5) M and severe lung edema at a higher concentration (10(-4) M). PAF-induced but not SRI- or CV-induced pulmonary vasoconstriction and edema were inhibited by WEB 2086. In addition, SRI 63-441 potentiated angiotensin II- and hypoxia-induced vasoconstrictions. This effect of SRI 63-441 is not due to PAF receptor blockade because 1) addition of PAF (1.6 nM) to the perfusate likewise potentiated angiotensin II-induced vasoconstriction and 2) WEB 2086 did not cause a similar response. We conclude that both SRI 63-441 and WEB 2086 are effective inhibitors of PAF actions in the rat pulmonary circulation. However, antagonists with structures analogous to PAF (SRI 63-441 and CV 3988) can have significant pulmonary vasoactive side effects.
Chen
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CR
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver 80262.
Voelkel
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NF
Chang
S W
SW
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D010742:Phospholipid Ethers / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects*; D011654:Pulmonary Edema / Q000503:physiopathology; D011806:Quinolinium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D001381:Azepines; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D011806:Quinolinium Compounds; D014230:Triazoles; C050531:SRI 63-441; C052518:WEB 2086; D000804:Angiotensin II; C037913:CV 3988