title: Bradykinin -induced vasodilatation: Role of age, ACE1-inhibitory peptide, mas- and bradykinin receptors.
abstract: Bradykinin exerts its vascular actions via two types of receptors, the non-constitutively expressed bradykinin receptor type 1 (BR1) and the constitutive type 2 receptor (BR2). Bradykinin-induced vasorelaxation is age-dependent, a phenomenon related to the varying amounts of BR1 and BR2 in the vasculature. Isoleucine-proline-proline (Ile-Pro-Pro), a bioactive tripeptide, lowers elevated blood pressure and improves impaired endothelium-dependent vasorelaxation in hypertensive rats. It inhibits angiotensin converting enzyme 1 (ACE1). Other mechanisms of action have also been postulated. The aims of the study were to clarify the underlying mechanisms of the age-dependency of bradykinin-induced vasodilatation such as the roles of the two bradykinin receptors, the mas-receptor and synergism with Ile-Pro-Pro. The vascular response studies were conducted using mesenteric artery and aorta rings from normotensive 6 wk. (young) and 22 wk. (old) Wistar rats. Cumulative dosing of acetylcholine, bradykinin and angiotensin(1-7) (Ang(1-7))were tested in phenylephrine-induced vasoconstriction with or without 10min pre-incubation with antagonists against BR1-, BR2- or mas-receptors, Ang(1-7) or ACE1-inhibitors captopril and Ile-Pro-Pro. The bradykinin-induced vasorelaxation in vitro was age-dependent and it was improved by pre-incubation with Ile-Pro-Pro, especially in old rats with endothelial dysfunction. The mas-receptor antagonist, D-Pro7-Ang(1-7) abolished bradykinin-induced relaxation totally. Interestingly, BR1 and BR2 antagonists only slightly reduced bradykinin-induced vasorelaxation, as an evidence for the involvement of other mechanisms in addition to receptor activation. In conclusion, bradykinin-induced vasorelaxation was age-dependent and Ile-Pro-Pro improved it. Mas receptor antagonist abolished relaxation while bradykinin receptor antagonist only slightly reduced it, suggesting that bradykinin-induced vasorelaxation is regulated also by other mechanisms than the classical BR1/BR2 pathway.
authors.affiliation: Faculty of Medicine, Pharmacology, University of Helsinki, P.O. Box 63, 00014 University of Helsinki, Finland. Electronic address: aino.siltari@helsinki.fi.
authors.forename: A
authors.initials: A
authors.lastname: Siltari
authors.affiliation: Faculty of Medicine, Pharmacology, University of Helsinki, P.O. Box 63, 00014 University of Helsinki, Finland.
authors.forename: R
authors.initials: R
authors.lastname: Korpela
authors.affiliation: Faculty of Medicine, Pharmacology, University of Helsinki, P.O. Box 63, 00014 University of Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Vapaatalo
mesh_terms: D000803:Angiotensin I / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000235:genetics / Q000378:metabolism; D002216:Captopril / Q000008:administration & dosage; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000187:drug effects / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000187:drug effects / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D043562:Receptors, G-Protein-Coupled; C489032:isoleucyl-prolyl-proline; D000803:Angiotensin I; D002216:Captopril; C118790:angiotensin I (1-7); D001920:Bradykinin
keywords: ACE-inhibition; Ageing; Bioactive peptides; Bradykinin; Ile-Pro-Pro; Vascular function; Vasodilatation