Receptor mechanism of thrombin-mediated pulmonary vasodilation in neonates.
A recently identified peptide sequence exposed after proteolytic cleavage of the NH2-terminus of the thrombin receptor mimics some cellular effects of alpha-thrombin. To determine whether a proteolytic action of thrombin is required for vasoactivity, we examined the vascular effects of modified thrombins and synthetic NH2-terminus peptide sequences of the thrombin receptor (TRPs) in isolated piglet lungs. Lungs of piglets 1-6 days old were perfused with recirculating Ringer-albumin solution at a constant flow of 60 ml/min. We measured the pulmonary artery pressure (Ppa) and segmental distribution of pulmonary vascular resistance (using the double occlusion method) in response to injections of human alpha-thrombin, modified thrombins, and TRP-14 and TRP-7 (i.e., 14 and 7 amino acid NH2-terminus peptides of the cleaved thrombin receptor). alpha-Thrombin produced a rapid and transient decrease in Ppa; the magnitude and duration [time for one-half recovery (t1/2 R)] of the vasodilation responses were concentration dependent [t1/2 R values of 1.4 +/- 0.1 and 3.3 +/- 2.4 min (mean +/- SE) at concentrations of 10(-10) and 10(-9) M, respectively]. The vasodilation was due primarily to a decrease in precapillary resistance. Proteolytically active, but binding-impaired gamma-thrombin was a less potent vasodilator and proteolytically inactive D-phenylalanyl-prolyl-arginine-chloromethyl ketone (PPACK)-alpha-thrombin did not induce vasodilation. TRP-14 was also a pulmonary vasodilator with a t1/2R value of 0.8 +/- 0.09 min at a concentration of 10(-7) M; both TRP-14 and TRP-7 were approximately 3-log less potent than equimolar alpha-thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)
Pinheiro
J M
JM
Department of Pediatrics, Albany Medical College of Union University, New York 12208.
Andersen
T T
TT
Malik
A B
AB
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D018179:Receptors, Thrombin / Q000737:chemistry / Q000502:physiology*; D013552:Swine; D013917:Thrombin / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*
D009842:Oligopeptides; D010446:Peptide Fragments; D018179:Receptors, Thrombin; C083977:phenylalanyl-leucyl-leucyl-arginyl-asparagine; D013917:Thrombin