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.

ATP-Binding Cassette Transporters, Adenosine/physiology, Animals, Coronary Circulation/*physiology, Enzyme Inhibitors/pharmacology, Exertion/*physiology, Female, Glyburide/pharmacology, Hemodynamic Processes/drug effects/physiology, Hypoglycemic Agents/pharmacology, In Vitro, Male, Myocardium/metabolism, Nitric Oxide Synthase Type III, Nitric Oxide Synthase/antagonists & inhibitors, Nitric Oxide/physiology, Oxygen Consumption/drug effects/physiology, Potassium Channel Blockers/pharmacology, Potassium Channels, Inwardly Rectifying, Potassium Channels/drug effects/physiology, Research Support, Non-U.S. Gov't, Rest/physiology, Swine, Theophylline/*analogs & derivatives/pharmacology, Vasodilation/*physiology, omega-N-Methylarginine/pharmacology
dx.doi.org/10.1152/ajpheart.00916.2002, hdl.handle.net/1765/13138
American Journal of Physiology - Heart and Circulatory Physiology
Erasmus MC: University Medical Center Rotterdam

Merkus, D, Haitsma, D.B, Fung, T.Y, Assen, Y.J, Verdouw, P.D, & Duncker, D.J.G.M. (2003). Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways. American Journal of Physiology - Heart and Circulatory Physiology, 424–433. doi:10.1152/ajpheart.00916.2002