Putative mechanism of hypotensive action of platelet-activating factor in dogs.
We examined the mechanism(s) of hypotensive action of platelet-activating factor (PAF) in anesthetized dogs. PAF (0.5 micrograms/kg i.v.) caused a biphasic hypotension; the first phase was transient and was accompanied by a decrease in systemic vascular resistance and an increase in cardiac output. Aspirin-DL-lysine, a cyclooxygenase inhibitor, had no effect on this phase. The second phase was characterized by a sustained hypotension caused by a reduction in cardiac output and was accompanied by an increase in systemic and pulmonary vascular resistance. The plasma concentrations of 6-ketoprostaglandin F1 alpha and thromboxane B2 also increased. These changes were markedly attenuated by aspirin. Both atrial pressures decreased during the second phase, thereby indicating that the PAF-induced reduction in cardiac output was related to a hindrance in venous return. The hematocrit increased, and aspirin did not affect this change. The extravasation of plasma probably plays a minor role, whereas venodilation would be the primary mechanism of the second-phase hypotension. S-1452, a prostaglandin H2/thromboxane A2 antagonist, abolished the PAF-induced pulmonary vasoconstriction but did not block the hypotensive action of PAF. OKY-046, a thromboxane A2 synthetase inhibitor, almost completely abolished the PAF-induced pulmonary vasoconstriction and the increase in plasma thromboxane B2 level, whereas it potentiated the hypotension and the increase in the plasma concentrations of prostaglandins; aspirin abolished this potentiation. These results suggest that PAF causes hypotension by two different mechanisms: 1) dilatation of resistance vessels independent of prostaglandins and 2) reduction of venous return due to venodilation, as mediated by prostaglandin(s).
Yamanaka
S
S
Department of Pharmacology, Osaka City University Medical School, Japan.
Miura
K
K
Yukimura
T
T
Okumura
M
M
Yamamoto
K
K
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D007022:Hypotension / Q000139:chemically induced*; D008297:Male; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011453:Prostaglandins / Q000097:blood; D013928:Thromboxane A2 / Q000097:blood; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014680:Veins / Q000187:drug effects
D010972:Platelet Activating Factor; D011453:Prostaglandins; D013928:Thromboxane A2; D001241:Aspirin