Pulmonary vascular reactivity: effect of PAF and PAF antagonists.

Abstract

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.

• Authors: C R Chen, N F Voelkel, S W Chang
• Journal: Journal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 73 Issue 5 Pg. 1762-9 (Nov 1992) ISSN: 8750-7587 [Print] United States
• PMID: 1474049 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Azepines
• Phospholipid Ethers
• Platelet Activating Factor
• Quinolinium Compounds
• Triazoles
• SRI 63-441
• WEB 2086
• Angiotensin II
• CV 3988

Topics

• Angiotensin II (pharmacology)
• Animals
• Azepines (pharmacology)
• Hypoxia (physiopathology)
• In Vitro Techniques
• Male
• Phospholipid Ethers (pharmacology)
• Platelet Activating Factor (antagonists & inhibitors, pharmacology)
• Pulmonary Circulation (drug effects)
• Pulmonary Edema (physiopathology)
• Quinolinium Compounds (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Triazoles (pharmacology)
• Vasoconstriction (drug effects)
• Vasodilation (drug effects)