title: Addition of angiotensin II receptor antagonist to an ACE inhibitor in heart failure improves cardiovascular function by a bradykinin-mediated mechanism.
abstract: Whether cardiovascular responses to bradykinin are augmented by additional treatment with angiotensin II receptor antagonism (ATRA) to angiotensin-converting enzyme inhibition (ACEI) in congestive heart failure (CHF) is unknown. To clarify the level and functional effects of endogenous bradykinin in CHF with combined ATRA and ACEI, 35 dogs were assigned to the following treatment protocols: 1). rapid ventricular pacing (240 bpm), 2). concomitant ATRA (TCV116, 1.5 mg x kg-1.day-1) and rapid pacing, 3). concomitant ACEI (enalapril 1.9 mg x kg-1.day-1) and rapid pacing, 4). concomitant combined ATRA (TCV116, 0.75 mg x kg-1.day-1) and ACEI (enalapril 0.95 mg x kg-1.day-1) and rapid pacing, and 5). sham-operated control. Plasma bradykinin levels were increased and B(2) receptors were synergistically upregulated in CHF groups treated with combined ATRA and ACEI compared with those treated with ATRA or ACEI alone. HOE-140 (0.3 mg/kg), a bradykinin B(2) receptor antagonist, produced an increase in total systemic resistance and a decrease in left ventricular contractility in CHF with combined therapy compared with either monotherapy. Thus, endogenous bradykinin partially contributes to the synergistic improvement of cardiovascular function in CHF with additional treatment with ATRA to ACEI.
authors.affiliation: First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Koji
authors.forename: Katsuya
authors.initials: K
authors.lastname: Onishi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Dohi
authors.forename: Ryuji
authors.initials: R
authors.lastname: Okamoto
authors.forename: Masaki
authors.initials: M
authors.lastname: Tanabe
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kitamura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
authors.forename: Naoki
authors.initials: N
authors.lastname: Isaka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nobori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakano
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001920:Bradykinin / Q000097:blood*; D065168:Bradykinin Receptor Antagonists; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006333:Heart Failure / Q000188:drug therapy*; D008297:Male; D043782:Receptor, Bradykinin B2; D011945:Receptors, Angiotensin / Q000378:metabolism; D018002:Receptors, Bradykinin / Q000096:biosynthesis
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D043782:Receptor, Bradykinin B2; D011945:Receptors, Angiotensin; D018002:Receptors, Bradykinin; D001920:Bradykinin