Site of action of calcium channel blockers in inhibiting endogenous pyrogen fever in rats.
We have demonstrated that the Ca2+ channel blocker verapamil, administered intravenously, exerts an antipyretic effect on the febrile responses of rats to intravenously injected endogenous pyrogen (EP). We have also shown that the same intravenous dose of verapamil is ineffective in blocking fevers induced by the microinjection of exogenous prostaglandin E (PGE) into the organum vasculosum laminae terminalis (OVLT) of rats. Experiments were conducted to determine whether the site of this verapamil antipyresis was in the OVLT itself. The febrile responses of six male Sprague-Dawley rats to EP were determined at thermoneutrality. Verapamil (10 micrograms/rat) was microinjected directly into the OVLT, and the febrile responses to the EP dose were redetermined 15-30 min later. In every case the EP fevers were attenuated after verapamil pretreatment. Intra-OVLT injections of verapamil alone were without effect on body temperature. When the same dose of verapamil was injected into the OVLT 15 min before the injection of PGE into the same site, it had no effect on the ensuing PGE-induced fever. In view of the fact that less than 1/250th of the effective systemic dose of verapamil, when injected into the OVLT, was equally effective in blocking the EP fevers, we conclude that verapamil acts within the OVLT to block fever rather than peripherally. Furthermore, because verapamil administered into the OVLT does not block PGE fevers, it is unlikely that PGE produces fever by acting as a Ca2+ ionophore on hypothalamic neurons.
Stitt
J T
JT
John B. Pierce Foundation Laboratory, Yale University School of Medicine, New Haven, Connecticut 06519.
Shimada
S G
SG
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005334:Fever / Q000139:chemically induced / Q000517:prevention & control*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D008845:Microinjections; D010740:Phospholipases / Q000378:metabolism; D011458:Prostaglandins E / Q000494:pharmacology; D011749:Pyrogens / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013238:Stereotaxic Techniques; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D007375:Interleukin-1; D011458:Prostaglandins E; D011749:Pyrogens; C008270:leukocyte endogenous mediator; D014700:Verapamil; D010740:Phospholipases