Sar-[D-Phe8]-des-Arg9-Bradykinin

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.[Pubmed:8996175]

J Pharmacol Exp Ther. 1997 Jan;280(1):6-15.

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.

International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences.[Pubmed:15734727]

Pharmacol Rev. 2005 Mar;57(1):27-77.

Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.

Development and in vivo evaluation of metabolically resistant antagonists of B1 receptors for kinins.[Pubmed:8392550]

J Pharmacol Exp Ther. 1993 Jul;266(1):192-9.

The B1 receptors for kinins are selectively stimulated by bradykinin (BK) and Lys-BK metabolites that do not have the C-terminal arginine, des-Arg9-BK and Lys-des-Arg9-BK, respectively. B1 receptors mediate a definite subset of the cardiovascular effects of kinins in normal and septic animals. We have studied the metabolism of the best selective B1 antagonist, Lys[Leu8]des-Arg9-BK, in order to support the rational design of new antagonists that have increased metabolic stability. The affinity of the new compounds was evaluated using the pA2 scale and was based on the antagonism of the contractile effect of kinins in the rabbit isolated aortic preparation. Acetylation of the alpha-amino group of the N-terminal Lys residue provided an excellent protection from the degradation by rabbit blood plasma. This and the inhibitory effect of amastatin on the metabolism of Lys[Leu8]des-Arg9-BK indicated that aminopeptidase M (AmM) is the major route of inactivation for this class of peptides in plasma. Various other modifications afforded a more or less complete resistance to purified angiotensin I converting enzyme (ACE). One analog, Ac-Lys[MeAla6, Leu8]des-Arg9-BK, was found resistant to the above-mentioned enzymes and to neutral endopeptidase-24.11 extracted from rabbit kidney. This antagonist, although 100 times less potent than the parent peptide Lys[Leu8]des-Arg9-BK on the rabbit aortic preparation, was equipotent in vivo against the hypotensive effect of a B1 agonist in lipopolysaccharide-treated rabbits, and unlike the original compound, its effect was persistent after the end of the infusion. Ac-Lys[MeAla6, Leu8]des-Arg9-BK does not antagonize B2 receptors either in vitro or in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypotensive effects of Lys-des-Arg9-bradykinin and metabolically protected agonists of B1 receptors for kinins.[Pubmed:1662280]

J Pharmacol Exp Ther. 1991 Dec;259(3):997-1003.

B1 receptors for kinins are selectively stimulated by bradykinin (BK) or Lys-BK (kallidin) fragments without the C terminal arginine residue. The present study was performed using an established in vivo model of B1 receptor-mediated cardiovascular action. Rabbits pretreated with bacterial lipopolysaccharide (LPS) (25 micrograms/kg) and anesthetized 5 h later exhibit acute and transient hypotension in response to intra-arterial boluses of B1 receptor agonists. The naturally occurring B1 agonist Lys-des-Arg9-BK was more potent than des-Arg9-BK in the in vivo model, but the effect of either natural sequence was brief. Evidence derived from previous in vitro experiments suggests these peptides may be substrates for angiotensin I converting enzyme (ACE). In addition, Lys-des-Arg9-BK is hydrolyzed in vitro by aminopeptidase M. Therefore, we tested the hypotensive effects of Lys-des-Arg9-BK analogs selectively protected against ACE activity (Lys-[D-Phe8]des-Arg9-BK) or against both ACE and aminopeptidase M (Sar-[D-Phe8]des-Arg9-BK). Both analogs were found to elicit a biphasic response consisting of a brief hypotensive effect followed by a prolonged hypotensive state. Indomethacin prevented only the second, prolonged phase of the hypotension induced by the metabolically protected analogs. The duration of hypotensive episodes induced by Lys-des-Arg9-BK was increased in rabbits pretreated with either captopril, an ACE inhibitor, or the aminopeptidase M inhibitor amastatin, consistent with the prolonged effect of metabolically protected analogs. An infusion of the B1 agonist Sar-[D-Phe8]des-Arg9-BK (1 microgram/min) in lipopolysaccharide-pretreated rabbits led to a very important and persistent hypotensive state that was not prevented by indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)