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.

Coronary and muscle blood flow during physical exercise in humans; heterogenic alliance

“…Therefore, the authors [49] concluded 573 that the primary mechanism of the ATP-mediated vasodilation is 574 vascular hyperpolarization via activation of the K IR channels. 575 It should be stated, however, that some earlier studies question 576 the role of ATP as a factor controlling coronary blood flow during 577 exercise (in the absence of ischemia) [77,78]. Additionally, some 578 studies involving a single-leg knee-extensor exercise of submaxi-579 mal intensity as an exercise model have failed to demonstrate 580 significant changes in plasma ATP concentration despite signifi-581 cant alterations in blood O 2 content and limb blood flow in humans 582 [121,122].…”

Inadequate Myocardial Oxygen Supply/Demand in Experimental Pulmonary Hypertension

“…PO 2crit increases in most MCT rats, and correlates with the expression of HIF 1α in nuclei of cardiomyocytes. The upper value of PO 2crit is similar to coronary sinus PO 2 during maximum exercise, 20 hPa (swine: Merkus et al, 2003;dog: Tune et al, 2004). End capillary venous PO 2 in the RV myocardium of MCT rats is not known.…”

Meeting Report

“…Moreover, neither arterial, nor coronary venous plasma endothelin-levels are altered during exercise [75]. However, withdrawal of endothelininduced vasoconstriction contributes to recruitment of flow reserve in response to exercise [70,75] and preliminary data suggest that the responsiveness of the coronary vasculature to endothelin is reduced. This reduction in coronary responsiveness to endothelin is mediated through NO and prostacyclin [77], which are known to be able to induce post-translational modification of the endothelin receptors [78] and may therefore result in altered signal transduction.…”

“…Studies in vivo confirm a role for endothelin in exercise hyperemia (see also below), but do not show a change in the vasodilator influence of adenosine during exercise [74,75], while the role of H 2 O 2 still needs to be confirmed. Signals from the endothelium: The endothelium produces both vasodilators (NO and prostacyclin) and vasoconstrictors (endothelin).…”

“…The vasodilator effect of NO and prostacyclin on the coronary vasculature is not altered during exercise [76]. Moreover, neither arterial, nor coronary venous plasma endothelin-levels are altered during exercise [75]. However, withdrawal of endothelininduced vasoconstriction contributes to recruitment of flow reserve in response to exercise [70,75] and preliminary data suggest that the responsiveness of the coronary vasculature to endothelin is reduced.…”