Selective blockade of mitochondrial KATPchannels does not impair myocardial oxygen consumption

Opening of mitochondrial ATP-sensitive potassium (KATP) channels has been postulated to prevent inhibition of respiration resulting from matrix contraction during high rates of ATP synthesis. Glibenclamide, which blocks KATP channels on the sarcolemma of vascular smooth muscle cells and myocardial myocytes as well as on the inner mitochondrial membrane, results in a decrease of myocardial oxygen consumption (MV˙o 2) both at rest and during exercise. This study examined whether this represents a primary effect of blockade of mitochondrial KATP channels or occurs secondary to coronary resistance vessel constriction with a decrease of coronary blood flow (CBF) and myocardial oxygen availability. MV˙o 2 was measured at rest and during treadmill exercise in 10 dogs during control conditions, after selective mitochondrial KATP channel blockade with 5-hydroxydecanoate (5-HD), and after nonselective KATPchannel blockade with glibenclamide. During control conditions, exercise resulted in progressive increases of CBF and MV˙o 2. Glibenclamide (50 μg · kg−1 · min−1 ic) resulted in a 17 ± 6% decrease of resting CBF with a downward shift of CBF during exercise and a decrease of coronary venous Po 2, indicating increased myocardial oxygen extraction. In contrast with the effects of glibenclamide, 5-HD (0.7 mg · kg−1 · min−1 ic) had no effect on CBF, MV˙o 2, or myocardial oxygen extraction. These findings suggest that glibenclamide decreased MV˙o 2 by causing resistance vessel constriction with a decrease of CBF and oxygen available to the myocardium rather than to a primary reduction of mitochondrial respiration.

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Is Calcium a Coronary Vasoconstrictor In Vivo?

Anesthesiology ◽

10.1097/00000542-199803000-00025 ◽

1998 ◽

Vol 88 (3) ◽

pp. 735-743 ◽

Cited By ~ 3

Author(s):

George J. Crystal ◽

Xiping Zhou ◽

Ramez M. Salem

Keyword(s):

Blood Flow ◽

Oxygen Consumption ◽

Coronary Blood Flow ◽

Myocardial Oxygen Consumption ◽

Extraction Ratio ◽

Oxygen Extraction ◽

Oxygen Extraction Ratio ◽

Myocardial Oxygen Extraction ◽

Dose Dependent

Background Calcium produces constriction in isolated coronary vessels and in the coronary circulation of isolated hearts, but the importance of this mechanism in vivo remains controversial. Methods The left anterior descending coronary arteries of 20 anesthetized dogs whose chests had been opened were perfused at 80 mmHg. Myocardial segmental shortening was measured with ultrasonic crystals and coronary blood flow with a Doppler flow transducer. The coronary arteriovenous oxygen difference was determined and used to calculate myocardial oxygen consumption and the myocardial oxygen extraction ratio. The myocardial oxygen extraction ratio served as an index of effectiveness of metabolic vasodilation. Data were obtained during intracoronary infusions of CaCl2 (5, 10, and 15 mg/min) and compared with those during intracoronary infusions of dobutamine (2.5, 5.0, and 10.0 microg/min). Results CaCl2 caused dose-dependent increases in segmental shortening, accompanied by proportional increases in myocardial oxygen consumption. Although CaCl2 also increased coronary blood flow, these increases were less than proportional to those in myocardial oxygen consumption, and therefore the myocardial oxygen extraction ratio increased. Dobutamine caused dose-dependent increases in segmental shortening and myocardial oxygen consumption that were similar in magnitude to those caused by CaCl2. In contrast to CaCl2, however, the accompanying increases in coronary blood flow were proportional to the increases in myocardial oxygen consumption, with the result that the myocardial oxygen extraction ratio remained constant. Conclusions Calcium has a coronary vasoconstricting effect and a positive inotropic effect in vivo. This vasoconstricting effect impairs coupling of coronary blood flow to the augmented myocardial oxygen demand by metabolic vascular control mechanisms. Dobutamine is an inotropic agent with no apparent direct action on coronary resistance vessels in vivo.

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Both β1- and β2-adrenoceptors contribute to feedforward coronary resistance vessel dilation during exercise

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00135.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. H921-H929 ◽

Cited By ~ 28

Author(s):

Fen Gao ◽

Vincent J. de Beer ◽

Maaike Hoekstra ◽

Chuanshi Xiao ◽

Dirk J. Duncker ◽

...

Keyword(s):

Oxygen Consumption ◽

Myocardial Oxygen Consumption ◽

Oxygen Supply ◽

Left Ventricular ◽

Coronary Resistance ◽

Coronary Vasodilation ◽

Clockwise Rotation ◽

Resistance Vessel ◽

The Relationship ◽

Myocardial Oxygen Supply

During exercise, β-feedforward coronary vasodilation has been shown to contribute to the matching of myocardial oxygen supply with the demand of the myocardium. Since both β1- and β2-adrenoceptors are present in the coronary microvasculature, we investigated the relative contribution of these subtypes to β-feedforward coronary vasodilation during exercise as well as to infusion of the β1-agonist norepinephrine and the β1- and β2-agonist isoproterenol. Chronically instrumented swine were studied at rest and during graded treadmill exercise (1–5 km/h) under control conditions and after β1-blockade with metoprolol (0.5 mg/kg iv) and β1/β2-blockade with propranolol (0.5 mg/kg iv). The selectivity and degree of β-blockade of metoprolol and propranolol were confirmed using isoproterenol infusion (0.05–0.4 μg· kg−1·min−1) under resting conditions. Isoproterenol-induced coronary vasodilation was mediated through the β2-adrenoceptor, whereas norepinephrine-induced coronary vasodilation was principally mediated through the β1-adrenoceptor. Exercise resulted in a significant increase in left ventricular norepinephrine release and epinephrine uptake. β1-Adrenoceptor blockade with metoprolol had very little effect under resting conditions. However, during exercise, metoprolol attenuated the increase in myocardial oxygen supply in excess of the reduction in myocardial oxygen demand, as evidenced by a progressive decrease in coronary venous Po2. Consequently, metoprolol caused a clockwise rotation of the relationship between myocardial oxygen consumption and coronary venous Po2. Additional β2-adrenoceptor blockade with propranolol further inhibited myocardial oxygen supply during exercise, resulting in a further clockwise rotation of the relationship between myocardial oxygen consumption and coronary venous Po2. In conclusion, both β1- and β2-adrenoceptors contribute to the β-feedforward coronary resistance vessel dilation during exercise.

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The role of coronary flow and pressure as determinants of myocardial oxygen consumption in the presence or absence of vasomotor tone

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y77-067 ◽

1977 ◽

Vol 55 (3) ◽

pp. 471-477 ◽

Cited By ~ 5

Author(s):

D. T. Zborowska-Sluis ◽

R. R. Mildenberger ◽

G. A. Klassen

Keyword(s):

Oxygen Consumption ◽

Coronary Flow ◽

Myocardial Oxygen Consumption ◽

Important Determinant ◽

Significant Alteration ◽

Oxygen Extraction ◽

Vasomotor Tone ◽

Coronary Pressure

When coronary flow was kept constant and coronary pressure increased by angiotensin or decreased by dipyridamole, myocardial oxygen consumption (MVO2) remained unchanged. When vasomotor tone was abolished by dipyridamole or was intact, changing coronary flow resulted in a change in MVO2 in the same direction as flow; this change in MVO2 was in part the result of a significant alteration in coronary oxygen extraction. These results suggest that coronary flow, but not coronary pressure is an important determinant of MVO2 both in the presence or absence of vasomotor tone.

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The relationship between oxygen extraction and extravascular mean transit time in the canine heart

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y77-068 ◽

1977 ◽

Vol 55 (3) ◽

pp. 478-481 ◽

Cited By ~ 4

Author(s):

R. R. Mildenberger ◽

A. L'Abbate ◽

D. T. Zborowska-Sluis ◽

G. A. Klassen

Keyword(s):

Transit Time ◽

Myocardial Oxygen Consumption ◽

Mean Transit Time ◽

Time Dependent ◽

Oxygen Extraction ◽

Canine Heart ◽

Myocardial Oxygen Extraction ◽

The Relationship ◽

Mean Time ◽

Critical Link

A significant relationship was observed between myocardial oxygen extraction and the extravascular mean time transit time. This relationship implies that oxygen extraction by the myocardium is a time-dependent process, and emphasizes the critical link between blood flow and myocardial oxygen consumption.

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Nitric Oxide, Myocardial Oxygen Consumption, and ATP Synthesis

Circulation Research ◽

10.1161/01.res.83.10.1067 ◽

1998 ◽

Vol 83 (10) ◽

pp. 1067-1068 ◽

Cited By ~ 6

Author(s):

Joanne S. Ingwall ◽

Ralph A. Kelly

Keyword(s):

Nitric Oxide ◽

Oxygen Consumption ◽

Myocardial Oxygen Consumption ◽

Atp Synthesis

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Effect of pericoronary denervation on coronary hemodynamics

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1960.199.1.174 ◽

1960 ◽

Vol 199 (1) ◽

pp. 174-178 ◽

Cited By ~ 27

Author(s):

Norman Brachfeld ◽

R. Grier Monroe ◽

Richard Gorlin

Keyword(s):

Oxygen Consumption ◽

Coronary Flow ◽

Myocardial Oxygen Consumption ◽

Relative Increase ◽

Extraction Ratio ◽

Oxygen Extraction ◽

Concomitant Increase ◽

Oxygen Extraction Ratio ◽

Coronary Vasoconstriction

In a series of 15 dogs, the procedure of pericoronary neurectomy resulted in a relative increase in coronary flow and decrease in oxygen extraction. This was best illustrated by a decrease in coefficient of oxygen extraction (A-V)OO2/AOO2 and was suggested by an increase in coronary flow/oxygen extraction ratio relative to oxygen consumption. It is concluded that at rest the net result of neurogenic impulses (both sympathetic and parasympathetic) is some degree of coronary vasoconstriction. Following denervation, this constrictor tonus is lost and there is a concomitant increase in coronary flow for a given myocardial oxygen consumption.

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Myocardial Oxygen Consumption During Dobutamine and Exercise Stress: Is it Equivalent?

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(97)84825-5 ◽

1998 ◽

Vol 31 (2) ◽

pp. 257A

Author(s):

R Parmar

Keyword(s):

Oxygen Consumption ◽

Myocardial Oxygen Consumption ◽

Exercise Stress

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Clinical and Experimental Analysis of 201Thallium Uptake of the Heart

Nuklearmedizin ◽

10.1055/s-0037-1620682 ◽

1978 ◽

Vol 17 (04) ◽

pp. 142-148

Author(s):

U. Büll ◽

S. Bürger ◽

B. E. Strauer

Keyword(s):

Oxygen Consumption ◽

Left Ventricle ◽

Muscle Mass ◽

Myocardial Oxygen Consumption ◽

Animal Experiments ◽

Left Ventricular ◽

Left Ventricular Wall ◽

Ventricular Wall ◽

Flow Measurements ◽

Myocardial Flow

Studies were carried out in order to determine the factors influencing myocardial 201T1 uptake. A total of 158 patients was examined with regard to both 201T1 uptake and the assessment of left ventricular and coronary function (e. g. quantitative ventriculography, coronary arteriography, coronary blood flow measurements). Moreover, 42 animal experiments (closed chest cat) were performed. The results demonstrate that:1) 201T1 uptake in the normal and hypertrophied human heart is linearly correlated with the muscle mass of the left ventricle (LVMM);2) 201T1 uptake is enhanced in the inner (subendocardial) layer and is decreased in the outer (subepicardial) layer of the left ventricular wall. The 201T1 uptake of the right ventricle is 40% lower in comparison to the left ventricle;3) the basic correlation between 201T1 uptake and LVMM is influenced by alterations of both myocardial flow and myocardial oxygen consumption; and4) inotropic interventions (isoproterenol, calcium, norepinephrine) as well as coronary dilatation (dipyridamole) may considerably augment 201T1 uptake in accordance with changes in myocardial oxygen consumption and/or myocardial flow.It is concluded that myocardial 201T1 uptake is determined by multiple factors. The major determinants have been shown to include (i) muscle mass, (ii) myocardial flow and (iii) myocardial oxygen consumption. The clinical data obtained from patient groups with normal ventricular function, with coronary artery disease, with left ventricular wall motion abnormalities and with different degree of left ventricular hypertrophy are correlated with quantitated myocardial 201T1 uptake.

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