title: Angiotensin-converting enzyme inhibition, but not AT(1) receptor blockade, in the solitary tract nucleus improves baroreflex sensitivity in anesthetized transgenic hypertensive (mRen2)27 rats.
abstract: Transgenic hypertensive (mRen2)27 rats overexpress the murine Ren2 gene and have impaired baroreflex sensitivity (BRS) for control of the heart rate. Removal of endogenous angiotensin (Ang)-(1-7) tone using a receptor blocker does not further lower BRS. Therefore, we assessed whether blockade of Ang II with a receptor antagonist or combined reduction in Ang II and restoration of endogenous Ang-(1-7) levels with Ang-converting enzyme (ACE) inhibition will improve BRS in these animals. Bilateral solitary tract nucleus (nTS) microinjections of the AT(1) receptor blocker, candesartan (CAN, 24 pmol in 120 nl, n=9), or a peptidic ACE inhibitor, bradykinin (BK) potentiating nonapeptide (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro; BPP9α, 9 nmol in 60 nl, n=12), in anesthetized male (mRen2)27 rats (15-25 weeks of age) show that AT(1) receptor blockade had no significant effect on BRS, whereas microinjection of BPP9α improved BRS over 60-120 min. To determine whether Ang-(1-7) or BK contribute to the increase in BRS, separate experiments using the Ang-(1-7) receptor antagonist D-Ala(7)-Ang-(1-7) or the BK antagonist HOE-140 showed that only the Ang-(1-7) receptor blocker completely reversed the BRS improvement. Thus, acute AT(1) blockade is unable to reverse the effects of long-term Ang II overexpression on BRS, whereas ACE inhibition restores BRS over this same time frame. As the BPP9α potentiation of BK actions is a rapid phenomenon, the likely mechanism for the observed delayed increase in BRS is through ACE inhibition and elevation of endogenous Ang-(1-7).
authors.affiliation: Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1032, USA.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Isa
authors.forename: Amy C
authors.initials: AC
authors.lastname: Arnold
authors.forename: Brian M
authors.initials: BM
authors.lastname: Westwood
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
authors.forename: Debra I
authors.initials: DI
authors.lastname: Diz
mesh_terms: D000758:Anesthesia; D000803:Angiotensin I / Q000037:antagonists & inhibitors / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017704:Baroreflex / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008845:Microinjections; D009842:Oligopeptides; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D055647:Rats, Transgenic; D017552:Solitary Nucleus / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D065168:Bradykinin Receptor Antagonists; D009842:Oligopeptides; D010446:Peptide Fragments; D013777:Tetrazoles; C015623:Arg-Pro-Gln-Ile-Pro-Pro; D000803:Angiotensin I; C118790:angiotensin I (1-7); C081643:candesartan; D001920:Bradykinin