CARDIOVASCULAR EFFECTS OF SAR-[D-PHE(8)]DES-ARG(9)-BRADYKININ, A METABOLICALLY PROTECTED AGONIST OF B-1 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-Phe( 8)]des-Arg(9)-bradykinin (BK) in lipopolysaccharide-treated anesthetiz ed rabbits. The study involved pharmacokinetic and hemodynamic measure ments and tests of antagonism with various drugs. The rate of eliminat ion of Sar-[D-Phe(8)]des-Arg(9)-BK from the rabbit plasma was slower t han that of Lys-BK, a naturally occurring B-1 agonist. The amplitude o f the hypotensive effect of Sar-[D-Phe(8)]des-Arg(9)-BK was not affect ed by pretreatment with indomethacin, diclofenac, dazmegrel, N-G-nitro -L-arginine, glibenclamide, MK-886, BN-50739, atropine or propranolol, but its duration was shortened by indomethacin and diclofenac. Sar-[D -Phe(8)]des-Arg(9)-Bk-induced hypotension was associated with decrease s of total peripheral resistance, cardiac output, carotid, mesenteric and femoral blood flow, transient reductions followed by secondary inc reases of vascular resistance in the carotid and femoral beds, reducti ons of central venous pressure, but no change of hematocrit. Animal pr etreatment with diclofenac or hexamethonium abolished the secondary in creases of carotid bed vascular resistance caused by the B-1 agonist. These and the other results suggest that peripheral vasodilation leadi ng to a decrease of total peripheral resistance and a decrease of card iac output may both contribute consecutively to the hypotensive effect of Sar-[D-Phe(8)]des-Arg(9)-BK in this animal model. Inappropriate co mpensatory responses to arterial hypotension, prostaglandin release, a nd slow rate of elimination of Sar-[D-Phe(8)]des-Arg(9)-BK from the ra bbit plasma, may all be at the basis of the prolonged duration of the hypotension caused by the B-1 agonist.