Cardiovascular effects of Sar-[D-Phe8]des-Arg9-bradykinin, a metabolically protected agonist of B1 receptor for kinins, in the anesthetized rabbit pretreated with a sublethal dose of bacterial lipopolysaccharide.
We investigated the mechanism of the hypotensive effect of Sar-[D-Phe8]des-Arg9-bradykinin (BK) in lipopolysaccharide-treated anesthetized rabbits. The study involved pharmacokinetic and hemodynamic measurements and tests of antagonism with various drugs. The rate of elimination of Sar-[D-Phe8]des-Arg9-BK from the rabbit plasma was slower than that of Lys-BK, a naturally occurring B1 agonist. The amplitude of the hypotensive effect of Sar-[D-Phe8]des-Arg9-BK was not affected by pretreatment with indomethacin, diclofenac, dazmegrel, NG-nitro-L-arginine, glibenclamide, MK-886, BN-50739, atropine or propranolol, but its duration was shortened by indomethacin and diclofenac. Sar-[D-Phe8]des-Arg9-BK-induced hypotension was associated with decreases of total peripheral resistance, cardiac output, carotid, mesenteric and femoral blood flow, transient reductions followed by secondary increases of vascular resistance in the carotid and femoral beds, reductions of central venous pressure, but no change of hematocrit. Animal pretreatment with diclofenac or hexamethonium abolished the secondary increases of carotid bed vascular resistance caused by the B1 agonist. These and other results suggest that peripheral vasodilation leading to a decrease of total peripheral resistance and a decrease of cardiac output may both contribute consecutively to the hypotensive effect of Sar-[D-Phe8]des-Arg9-BK in this animal model. Inappropriate compensatory responses to arterial hypotension, prostaglandin release, and slow rate of elimination of Sar-[D-Phe8]des-Arg9-BK from the rabbit plasma, may all be at the basis of the prolonged duration of the hypotension caused by the B1 agonist.
Audet
R
R
Centre de recherche (Université Laval), Hôtel-Dieu de Québec, Canada.
Rioux
F
F
Drapeau
G
G
Marceau
F
F
D000758:Anesthesia; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006221:Halothane / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D011817:Rabbits; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000819:agonists*
D008070:Lipopolysaccharides; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; C072121:bradykinin, Sar-(D-Phe(8))des-Arg(9); D009569:Nitric Oxide; D001920:Bradykinin; D006221:Halothane