Hypotensive effects of Lys-des-Arg9-bradykinin and metabolically protected agonists of B1 receptors for kinins.
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)
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Centre de recherche de l'Hôtel-Dieu de Québec, Université Laval, Canada.
deBlois
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Marceau
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D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D002319:Cardiovascular System / Q000187:drug effects; D005260:Female; D007022:Hypotension / Q000139:chemically induced*; D007609:Kallidin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D007705:Kinins / Q000009:adverse effects / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D011453:Prostaglandins / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011817:Rabbits; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter / Q000502:physiology*
D007705:Kinins; D008070:Lipopolysaccharides; D011453:Prostaglandins; D011480:Protease Inhibitors; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter; C072121:bradykinin, Sar-(D-Phe(8))des-Arg(9); D007609:Kallidin; C052787:kallidin, des-Arg(10)-; D001920:Bradykinin