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Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways

Division of Experimental Cardiology, Thoraxcenter, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands

Submitted 23 October 2002 ; accepted in final form 5 March 2003

In dogs, only combined blockade of vasodilator pathways [via adenosine receptors, nitric oxide synthase (NOS) and ATP-sensitive K⁺ (K_ATP) channels] results in impairment of metabolic vasodilation, which suggests a redundancy design of coronary flow regulation. Conversely, in swine and humans, blocking K_ATP 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 K_ATP channels (with glibenclamide), adenosine receptors [with 8-phenyltheophylline (8-PT)], and/or NOS [with N-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 K_ATP 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 K_ATP 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.

coronary circulation; vasoconstriction; dilation; nitric oxide; adenosine; ATP-sensitive K⁺ channel

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