Previous studies demonstrated a decreased flow reserve in the hypertrophied myocardium early after myocardial infarction (MI). Previously, we reported that exacerbation of hemodynamic abnormalities and neurohumoral activation during exercise caused slight impairment of myocardial O(2) supply in swine with a recent MI. We hypothesized that increased metabolic coronary vasodilation [via ATP-sensitive K(+) (K(ATP)(+)) channels and adenosine] may have partially compensated for the increased extravascular compressive forces and increased vasoconstrictor neurohormones, thereby preventing a more severe impairment of myocardial O(2) balance. Chronically instrumented swine were exercised on a treadmill up to 85% of maximum heart rate. Under resting conditions, adenosine receptor blockade [8-phenyltheophylline (8-PT), 5 mg/kg i.v.] and K(ATP)(+) channel blockade (glibenclamide, 3 mg/kg i.v.) produced similar decreases in myocardial O(2) supply in normal and MI swine. However, while glibenclamide's effect waned in normal swine during exercise (P < 0.05), it was maintained in MI swine. 8-PT's effect was maintained during exercise and was not different between normal and MI swine. Finally, in normal swine combined treatment with 8-PT and glibenclamide produced a vasoconstrictor response that equaled the sum of the responses to blockade of the individual pathways. In contrast, in MI swine the vasoconstrictor response to 8-PT and glibenclamide was similar to that produced by glibenclamide alone. In conclusion, despite significant hemodynamic abnormalities in swine with a recent MI, myocardial O(2) supply and O(2) consumption in remodeled myocardium are still closely matched during exercise. This close matching is supported by increased K(ATP)(+) channel-mediated coronary vasodilation. Although the net vasodilator influence of adenosine was unchanged in remodeled myocardium, it became exclusively dependent on K(ATP)(+) channel opening.
") . That the relatively small degree of perturbation in the oxygen balance was associated with myocardial metabolic distress was also reflected in the increased vasodilator influence through opening of K ATP channels , particularly during exercise ( Merkus et al . 2005b ) . Unexpectedly , we observed that despite increased circulating levels of noradrenalin , angiotensin II and endothelin - 1 , the coronary influences of α - adrenergic tone were not increased ( Duncker et al . 2005 ) , while the coronary vasoconstrictor influences of endogenous endo - thelin ( Merkus et al . 2005a ) and angiotensin II "
[Show abstract][Hide abstract] ABSTRACT: Since the completion of the Human Genome Project and the advent of the large scaled unbiased '-omics' techniques, the field of systems biology has emerged. Systems biology aims to move away from the traditional reductionist molecular approach, which focused on understanding the role of single genes or proteins, towards a more holistic approach by studying networks and interactions between individual components of networks. From a conceptual standpoint, systems biology elicits a 'back to the future' experience for any integrative physiologist. However, many of the new techniques and modalities employed by systems biologists yield tremendous potential for integrative physiologists to expand their tool arsenal to (quantitatively) study complex biological processes, such as cardiac remodelling and heart failure, in a truly holistic fashion. We therefore advocate that systems biology should not become/stay a separate discipline with '-omics' as its playing field, but should be integrated into physiology to create 'Integrative Physiology 2.0'.
The Journal of Physiology 02/2011; 589(Pt 5):1037-45. DOI:10.1113/jphysiol.2010.201533 · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Coronary blood flow is controlled via several vasoactive mediators that exert their effect on coronary resistance vessel tone through activation of K+ channels in vascular smooth muscle. Because Ca2+- activated K+ (KCa+ ) channels are the predominant K+ channels in the coronary vasculature, we hypothesized that KCa+ channel activation contributes to exercise-induced coronary vasodilation. In view of previous observations that ATPsensitive K+ (KATP+ ) channels contribute, in particular, to resting coronary resistance vessel tone, we additionally investigated the integrated control of coronary tone by KCa+ and KATP+ channels. For this purpose, the effect of KCa+ blockade with tetraethylammonium (TEA, 20 mg/kg iv) on coronary vasomotor tone was assessed in the absence and presence of KATP+ channel blockade with glibenclamide (3 mg/kg iv) in chronically instrumented swine at rest and during treadmill exercise. During exercise, myocardial O2 delivery increased commensurately with the increase in myocardial O2 consumption, so that myocardial O 2 extraction and coronary venous PO2 (PcvO2) were maintained constant. TEA (in a dose that had no effect on K ATP+ channels) had a small effect on the myocardial O 2 balance at rest and blunted the exercise-induced increase in myocardial O2 delivery, resulting in a progressive decrease of PcvO2 with increasing exercise intensity. Conversely, at rest glibenclamide caused a marked decrease in PcvO2 that waned at higher exercise levels. Combined KCa+ and KATP+ channel blockade resulted in coronary vasoconstriction at rest that was similar to that caused by glibenclamide alone and that was maintained during exercise, suggesting that KCa+ and K ATP+ channels act in a linear additive fashion. In conclusion, KCa+ channel activation contributes to the metabolic coronary vasodilation that occurs during exercise. Furthermore, in swine KCa+ and KATP+ channels contribute to coronary resistance vessel control in a linear additive fashion.
[Show abstract][Hide abstract] ABSTRACT: The ATP-sensitive potassium (K(ATP)) channel is a distinct type of potassium ion channel that is found in the vascular smooth muscle cells of a variety of mammalian species, including humans. The activity of K(ATP) channels is determined by many factors including cellular ATP and ADP levels, thus providing a link between cellular metabolism and vascular tone through its effects on membrane potential. Experimental studies using inhibitors of K(ATP) channels, such as the sulfonuylurea class of drugs, indicate that these channels modulate coronary vascular tone including the hyperaemia induced by increased myocardial metabolism. This review examines the evidence linking K(ATP) channels to the regulation of coronary vascular tone and the potential clinical implications of pharmacologic therapies that act on K(ATP) channels.
Trends in Cardiovascular Medicine 03/2007; 17(2):63-8. DOI:10.1016/j.tcm.2006.12.003 · 2.91 Impact Factor
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