title: Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways.
abstract: In dogs, only combined blockade of vasodilator pathways [via adenosine receptors, nitric oxide synthase (NOS) and ATP-sensitive K+ (KATP) channels] results in impairment of metabolic vasodilation, which suggests a redundancy design of coronary flow regulation. Conversely, in swine and humans, blocking KATP channels, adenosine receptors, or NOS each impairs coronary blood flow (CBF) at rest and during exercise. Consequently, we hypothesized that these vasodilators act in parallel rather than in redundancy to regulate CBF in swine. Swine exercised on a treadmill (0-5 km/h), during control and after blockade of KATP channels (with glibenclamide), adenosine receptors [with 8-phenyltheophylline (8-PT)], and/or NOS [with Nomega-nitro-l-arginine (l-NNA)]. l-NNA, 8-PT, and glibenclamide each reduced myocardial O2 delivery and coronary venous O2 tension. These effects of l-NNA, 8-PT, and glibenclamide were not modified by simultaneous blockade of the other vasodilators. Combined blockade of KATP channels and adenosine receptors with or without NOS inhibition was associated with increased H+ production and impaired myocardial function. However, despite an increase in O2 extraction to >90% during administration of l-NNA + 8-PT + glibenclamide, vasodilator reserve could still be recruited during exercise. Thus in awake swine, loss of KATP channels, adenosine, or NO is not compensated for by increased participation of the other two vasodilator mechanisms. These findings suggest a parallel rather than a redundancy design of CBF regulation in the porcine circulation.
authors.affiliation: Division of Experimental Cardiology, Thoraxcenter, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands. d.merkus@erasmusmc.nl
authors.forename: Daphne
authors.initials: D
authors.lastname: Merkus
authors.forename: David B
authors.initials: DB
authors.lastname: Haitsma
authors.forename: Tse-Yeung
authors.initials: TY
authors.lastname: Fung
authors.forename: Yvette J
authors.initials: YJ
authors.lastname: Assen
authors.forename: Pieter D
authors.initials: PD
authors.lastname: Verdouw
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000241:Adenosine / Q000502:physiology; D000818:Animals; D003326:Coronary Circulation / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D054086:KATP Channels; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D005082:Physical Exertion / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D012146:Rest / Q000502:physiology; D013552:Swine; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D054086:KATP Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D013806:Theophylline; C028322:8-phenyltheophylline; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D000241:Adenosine; D005905:Glyburide