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1 Department of Experimental Cardiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: d.merkus{at}erasmusmc.nl.
In dogs, blocking adenosine receptors and NO-synthase does not affect coronary blood flow at rest or during exercise. Conversely, K+ATP-channel blockade decreases coronary flow at rest, but does not alter the exercise-induced increase in flow. Only combined blockade of these vasodilator pathways results in an impairment of metabolic vasodilation, suggesting a redundancy design of coronary flow regulation. In contrast, in swine and humans, blocking K+ATP-channels, adenosine receptors or NO-synthase each impairs coronary blood flow (CBF) at rest and during exercise. Consequently, we tested the hypothesis that in swine, these vasodilator pathways act in parallel rather than in redundancy to regulate CBF. Swine were exercised on a treadmill at 0-5 km/h, during control and after blockade of K+ATP-channels (glibenclamide, 3 mg/kg IV), adenosine receptors (8-phenyltheophylline, 8PT, 5 mg/kg IV), and/or NO-synthase (N
-nitro-L-arginine, NLA, 20 mg/kg IV). NLA, 8PT and glibenclamide each reduced myocardial O2 delivery and coronary venous O2 tension. These effects of NLA, 8PT and glibenclamide were not modified by simultaneous blockade of the other vasodilator systems (i.e. the effects were additive), indicating a parallel design of CBF regulation. Combined blockade of K+ATP-channels and adenosine receptors with or without NO-synthase inhibition was associated with increased H+-production and impaired myocardial function. However, despite an increase in O2-extraction to over 90% during combined NLA+8PT+glibenclamide, vasodilator reserve could still be recruited during exercise to mediate the residual exercise-induced increase in CBF. Thus, in awake swine, loss of K+ATP channels, adenosine or NO vasodilator influence is not compensated by increased participation of the other two vasodilator mechanisms studied. These findings suggest a parallel rather than a redundancy design of CBF regulation in the porcine circulation.
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