title: Enhanced cAMP-induced nitric oxide-dependent coronary dilation during myocardial stunning in conscious pigs.
abstract: The goal of the current study was to determine the effects of cAMP-mediated coronary reactivity in conscious pigs with stunned myocardium induced by 1.5 h coronary stenosis (CS) and 12 h coronary artery reperfusion (CAR). Domestic swine (n = 5) were chronically instrumented with a coronary artery blood flow (CBF) probe, hydraulic occluder, left ventricular pressure gauge, wall-thickening crystals in the ischemic and nonischemic zones, and a coronary sinus catheter. The hydraulic occluder was inflated to induce a CS with a stable 38 +/- 1% reduction in CBF for 1.5 h. Before flow reduction and during CAR, cAMP-induced coronary vasodilation was investigated by forskolin (20 nmol. kg(-1). min(-1)). Enhanced CBF responses [+62 +/- 9%, P < 0.05, compared with pre-CS (+37 +/- 3%)] were observed for forskolin at 12 h after CAR as well as for bradykinin and reactive hyperemia. With the use of a similar protocol during systemic nitric oxide (NO) synthase inhibition with N(omega)-nitro-L-arginine (30 mg. kg(-1). day(-1) for 3 days), the enhanced CBF responses to forskolin, bradykinin, and reactive hyperemia were not observed after CS. Isolated microvessel preparations from pigs (n = 8) also demonstrated enhanced NO production to direct stimulation of adenylyl cyclase with forskolin (+71 +/- 12%) or NKH-477 (+60 +/- 10%) and administration of 8-bromo-cAMP (+74 +/- 13%), which were abolished by protein kinase A or NO synthase inhibition. These data indicate that cAMP stimulation elicits direct coronary vasodilation and that this action is amplified in the presence of sustained myocardial stunning after recovery from CS. This enhanced cAMP coronary vasodilation is mediated by an NO mechanism that may be involved in myocardial protection from ischemic injury.
authors.affiliation: Cardiovascular Research Institute and Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Kudej
authors.forename: X P
authors.initials: XP
authors.lastname: Zhang
authors.forename: B
authors.initials: B
authors.lastname: Ghaleh
authors.forename: C H
authors.initials: CH
authors.lastname: Huang
authors.forename: J B
authors.initials: JB
authors.lastname: Jackson
authors.forename: A B
authors.initials: AB
authors.lastname: Kudej
authors.forename: N
authors.initials: N
authors.lastname: Sato
authors.forename: S
authors.initials: S
authors.lastname: Sato
authors.forename: D E
authors.initials: DE
authors.lastname: Vatner
authors.forename: T H
authors.initials: TH
authors.lastname: Hintze
authors.forename: S F
authors.initials: SF
authors.lastname: Vatner
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D005576:Colforsin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003243:Consciousness; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D003327:Coronary Disease / Q000378:metabolism / Q000503:physiopathology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008833:Microcirculation / Q000502:physiology; D017682:Myocardial Stunning / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D010101:Oxygen Consumption / Q000502:physiology; D013552:Swine; D013873:Thionucleotides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology; D017725:Ventricular Pressure / Q000502:physiology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D013873:Thionucleotides; D014665:Vasodilator Agents; D005576:Colforsin; D019335:Nitroarginine; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016957:adenosine-3',5'-cyclic phosphorothioate; D009569:Nitric Oxide; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D000262:Adenylyl Cyclases; D019331:NG-Nitroarginine Methyl Ester