Metabolic Vasodilation Research Articles

Role of potassium as a coronary metabolic vasodilator

K+ release from the myocardium is associated with decreased coronary vascular resistance. Accumulation of extracellular K+ has been linked to mechanisms of vasodilation in the coronary circulation including activation of the electrogenic Na+-K+ pump in smooth muscle (Murray and Sparks, Circ. Res. 1977) and endothelial-mediated hyperpolarization via Kir2.1 channels (Zhao et al., PNAS 2020). Our objective was to examine K+ as a coronary metabolic vasodilator in vivo. Further, we addressed two potential shortcomings of previous studies: the short duration of the bolus K+ stimulus employed and the seemingly high concentrations required to produce vasodilation. We hypothesized that continuous, steady-state intracoronary infusions of K+ would produce sustained coronary vasodilation in a concentration-dependent manner. Our methods involved instrumenting anesthetized, open-chest Yorkshire swine (male and female, 60 kg) for measurements of coronary blood flow, as well as arterial and coronary venous blood sampling. The left anterior descending coronary artery was cannulated and perfused under the control of a pressure servo, allowing us to determine flow and infuse K+. Our results show small, but statistically significant (* represents p < 0.05), effects of K+ on coronary hemodynamics. The coronary venous K+ concentration was 4.0 ± 0.1 mM at baseline. Infusing K+ into the coronary artery at increasing rates increased coronary venous K+ to 4.9 ± 0.2*, 6.4 ± 0.2*, and 7.9 ± 0.2* mM. Higher K+ concentrations caused fatal arrhythmias. Coronary blood flow was 0.73 ± 0.14 ml/min/g at baseline. Infusing K+ into the coronary artery at increasing rates increased coronary blood flow to 0.78 ± 0.14*, 0.82 ± 0.15*, and 0.86 ± 0.16* ml/min/g. These small coronary blood flow changes were sustained during continuous K+ infusion. We conclude that K+ is a coronary vasodilator, as has been demonstrated previously. Importantly, however, we emphasize that the effects of K+ are extremely modest and the concentrations required to produce physiologically significant vasodilation are life-threatening. With the assumption that the venous K+ concentration is in equilibrium with that surrounding the smooth muscle and cardiac muscle of the working heart, we urge caution in interpreting isolated artery studies that routinely use 15-20 mM K+ to elicit hyperpolarization and vasodilation. Our data do not support the idea that K+ plays a major role in regulating coronary vascular resistance. This work was supported by National Institutes of Health grant R01 HL158723. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 120: Greater 24-hour Blood Pressure Variability Is Associated With Higher Retinal Microvascular Resistance And Smaller Lumen Diameter In Healthy Normotensive Adults

Introduction: Elevated blood pressure (BP) is associated with damage to high flow, low resistance target organs such as the retina. Recent evidence suggests that 24-hour BP variability (BPV) is a novel risk factor for cardiovascular disease, independent of 24-hour average BP. However, whether 24-hour BPV is related to concentric retinal arteriole remodeling in healthy adults is unknown. Thus, the purpose of our study was to determine the degree to which 24-hour BPV is associated with retinal lumen diameter and vascular resistance in healthy young/middle-aged adults, independent of 24-hour average BP. Methods: Healthy, normotensive adults aged 25 to 60 years (n=40; 50% female) underwent measurements of retinal arteriole diameter and flow using laser speckle flowgraphy. 24-hour brachial BP was determined using ambulatory BP monitoring. BPV was calculated as the standard deviation of all BP recordings for systolic and diastolic BP. Retinal vascular resistance was calculated as ocular perfusion pressure divided by mean retinal flow across 4 arterioles. Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV). Results: Higher 24-hour systolic and diastolic average BP were associated with smaller retinal lumen diameter and elevated vascular resistance (P<0.05). Although both systolic BPV (r=0.391, P=0.012) and diastolic BPV (r=0.315, P=0.048) were associated with higher retinal vascular resistance, only diastolic BPV was associated with smaller retinal arteriole lumen diameter (r=-0.393, P=0.012). The association of greater diastolic BPV with smaller retinal arteriole lumen diameter (β=-0.363, P=0.01) and higher retinal vascular resistance (β=0.395, P=0.007) remained after adjusting for age, body mass index, cfPWV, and 24-hour average diastolic BP. Conclusion: Higher diastolic BPV may contribute to adverse remodeling of retinal arterioles in healthy normotensive adults independent of arterial stiffness and traditional cardiovascular disease risk factors. Future studies could utilize local metabolic vasodilation via diffuse luminance flicker to examine whether retinal arteriole autoregulatory mechanisms are impaired in individuals with higher BPV.

Contribution of local metabolic control to coronary pressure-flow autoregulation

The coronary circulation has an innate ability to maintain constant blood flow over a wide range of perfusion pressures. This study interrogated the local metabolic hypothesis, which proposes that myocardial oxygen tension, indexed by coronary venous PO 2 (CvPO 2 ), determines the degree of coronary pressure-flow autoregulation by increasing the production of vasodilator metabolites as coronary perfusion pressure (CPP) is reduced. We tested this hypothesis by examining the extent to which dobutamine-induced increases in myocardial oxygen consumption (MVO 2 ) under both normoxic and hypoxemic conditions, influences coronary autoregulatory capability. Experiments were performed on open-chest anesthetized swine during 20 mmHg stepwise changes in coronary perfusion pressure (CPP) from 140 to 40 mmHg, via servo-controlled roller pump. Measurements were made in 3 conditions: a) normoxia (n = 7); b) normoxia with dobutamine (10 μg/kg/min, iv; n = 7); and c) hypoxemia (PaO 2 36-38 mmHg) plus dobutamine (n = 5). Under control-normoxic conditions, CvPO 2 decreased from 38 ± 2 to 22 ± 1 mmHg and coronary blood flow fell from 0.93 ± 0.15 to 0.32 ± 0.03 ml/min/g as CPP was reduced from 140 to 40 mmHg. Administration of dobutamine significantly increased heart rate (~60%; P < 0.001), but the combination of hypoxemia plus dobutamine did not further influence heart rate. Further, dobutamine with and without hypoxemia significantly increased MVO 2 (P < 0.001); however, CvPO 2 was reduced (P < 0.001) only in the presence of hypoxemia. Calculation of closed-loop autoregulatory gain (Gc) over a CPP range of 120 to 60 mmHg (value of 1 represents perfect autoregulation) was unaffected by dobutamine alone but tended to increase when dobutamine infusion was combined with reductions in PaO 2 ≤ 40 mmHg (P = 0.069). Additional analysis of the autoregulatory slope within this same CPP range revealed no differences between groups. However, there was a significant inverse association between Gc and CvPO 2 , measured at CPP of 100 mmHg, in the absence and presence of dobutamine-induced increases in MVO 2 ± hypoxemic conditions (P < 0.001, r = -0.722). The relationship of coronary resistance (CPP range of 120 to 60 mmHg) relative to respective CvPO 2 revealed that decreases in CvPO 2 were not associated with changes in coronary resistance until CvPO 2 fell below a relative threshold of ~ 25 mmHg (r = 0.88). These findings support the interpretation that the sensitivity of coronary autoregulatory behavior is directly coupled with the activation of local metabolic vasodilator pathways below a critical level of myocardial oxygenation. This work was supported by National Institutes of Health grant R01 HL158723. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mechanism of exercise intolerance in heart diseases predicted by a computer model of myocardial demand‐supply feedback system

Background and objectiveThe myocardial demand-supply feedback system plays an important role in augmenting blood supply in response to exercise-induced increased myocardial demand. During this feedback process, the myocardium and coronary blood flow interact bidirectionally at many different levels. MethodsTo investigate these interactions, a novel computational framework that considers the closed myocardial demand-supply feedback system was developed. In the framework coupling the systemic circulation of the left ventricle and coronary perfusion with regulation, myocardial work affects coronary perfusion via flow regulation mechanisms (e.g., metabolic regulation) and myocardial-vessel interactions, whereas coronary perfusion affects myocardial contractility in a closed feedback system. The framework was calibrated based on the measurements from healthy subjects under graded exercise conditions, and then was applied to simulate the effects of graded exercise on myocardial demand-supply under different physiological and pathological conditions. ResultsWe found that the framework can recapitulate key features found during exercise in clinical and animal studies. We showed that myocardial blood flow is increased but maximum hyperemia is reduced during exercise, which led to a reduction in coronary flow reserve. For coronary stenosis and myocardial inefficiency, the model predicts that an increase in heart rate is necessary to maintain the baseline cardiac output. Correspondingly, the resting coronary flow reserve is exhausted and the range of heart rate before exhaustion of coronary flow reserve is reduced. In the presence of metabolic regulation dysfunction, the model predicts that the metabolic vasodilator signal is higher at rest, saturates faster during exercise, and as a result, causes quicker exhaustion of coronary flow reserve. ConclusionsModel predictions showed that the coronary flow reserve deteriorates faster during graded exercise, which in turn, suggests a decrease in exercise tolerance for patients with stenosis, myocardial inefficiency and metabolic flow regulation dysfunction. The findings in this study may have clinical implications in diagnosing cardiovascular diseases.

Regulation of Coronary Blood Flow by the Carotid Body Chemoreceptors in Ovine Heart Failure.

Carotid bodies (CBs) are peripheral chemoreceptors, which are primary sensors of systemic hypoxia and their activation produces respiratory, autonomic, and cardiovascular adjustments critical for body homeostasis. We have previously shown that carotid chemoreceptor stimulation increases directly recorded cardiac sympathetic nerve activity (cardiac SNA) which increases coronary blood flow (CoBF) in conscious normal sheep. Previous studies have shown that chemoreflex sensitivity is augmented in heart failure (HF). We hypothesized that carotid chemoreceptor stimulation would increase CoBF to a greater extent in HF than control sheep. Experiments were conducted in conscious HF sheep and control sheep (n = 6/group) implanted with electrodes to record diaphragmatic electromyography (dEMG), flow probes to record CoBF as well as arterial pressure. There was a significant increase in mean arterial pressure (MAP), CoBF and coronary vascular conductance (CVC) in response to potassium cyanide (KCN) in both groups of sheep. To eliminate the effects of metabolic vasodilation, the KCN was repeated while the heart was paced at a constant level. In this paradigm, the increase in CoBF and CVC was augmented in the HF group compared to the control group. Pre-treatment with propranolol did not alter the CoBF or the CVC increase in the HF group indicating this was not mediated by an increase in cardiac sympathetic drive. The pressor response to CB activation was abolished by pre-treatment with intravenous atropine in both groups, but there was no change in the CoBF and vascular conductance responses. Our data suggest that in an ovine model of HF, carotid body (CB) mediated increases in CoBF and CVC are augmented compared to control animals. This increase in CoBF is mediated by an increase in cardiac SNA in the control group but not the HF group.

Effect of acute sympathetic activation on leg vasodilation before and after endurance exercise.

Vascular conductance (VC) regulation involves a continuous balance between metabolic vasodilation and sympathetic vasoconstriction. Endurance exercise challenges the sympathetic control on VC due to attenuated sympathetic receptor responsiveness and persistence of muscle vasodilation, especially in endurance athletes, predisposing them to blood pressure control dysfunctions. This study assessed whether acute handgrip-mediated sympathetic activation (SYMP) restrains sudden leg vasodilation before and after a half-marathon. Prior to, and within the 20 min following the race, 11 well-trained runners underwent two single passive leg movement (SPLM) tests to suddenly induce leg vasodilation, one without and the other during SYMP. Leg blood flow and mean arterial pressure were measured to assess changes in leg VC. Undertaking 60 sec of SYMP reduced the baseline leg VC both before (4.0 ± 1.0 vs. 3.3 ± 0.7 ml/min/mmHg; P=0.01; NO SYMP vs. SYMP, respectively) and after the race (4.6 ± 0.8 vs. 3.9 ± 0.8 ml/min/mmHg; P=0.01). However, SYMP did not reduce leg peak vasodilation immediately after the SPLM either before (11.5 ± 4.0 vs. 12.2 ± 3.8 ml/min/mmHg; P=0.35) or after the race (7.2 ± 2.0 vs. 7.3 ± 2.6 ml/min/mmHg; P=0.96). Furthermore, SYMP did not blunt the mean leg vasodilation over the 60 sec after the SPLM before (5.1 ± 1.7 vs. 5.9 ± 2.5 ml/min/mmHg; P=0.14) or after the race (4.8 ± 1.3 vs. 4.2 ± 1.5 ml/min/mmHg; P=0.26). This data suggest that the release of local vasoactive agents effectively opposes any preceding handgrip-mediated augmented vasoconstriction in endurance athletes before and after a half-marathon. Handgrip-mediated SYMP might improve normal vasoconstriction while athletes are still, but not necessarily while they move, as movements can induce a release of vasoactive molecules.

Adenosine Kinase Inhibition Augments Conducted Vasodilation and Prevents Left Ventricle Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is often manifested as impaired cardiovascular reserve. We sought to determine if conducted vasodilation, which coordinates microvascular resistance longitudinally to match tissue metabolic demand, becomes compromised in HFpEF. We hypothesized that the metabolic vasodilator adenosine facilitates and that inhibition of ADK (adenosine kinase) augments conducted vasodilation for a more efficient myocardial perfusion and improved left ventricle (LV) diastolic function in HFpEF. We assessed conducted vasodilation in obese ZSF1 rats that develop LV diastolic dysfunction and is used to model human HFpEF. Additionally, conducted vasodilation was measured in arterioles isolated from the right atrial appendages of patients with HFpEF. We found a markedly reduced conducted vasodilation both in obese ZSF1 rats and in patients with HFpEF. Impaired conducted vasodilation was accompanied by increased vascular ADK expression. Isolated rat and human arterioles incubated with adenosine (10 nmol/L) or ADK inhibitor ABT-702 (0.1 µmol/L) both displayed augmented conducted vasodilation. Treatment of obese ZSF1 rats with ABT-702 (1.5 mg/kg, IP for 8 weeks) prevented LV diastolic dysfunction, and in a crossover design augmented conducted vasodilation and improved LV diastolic function. ABT-702 treated obese ZSF1 rats exhibited reduced expression of myocardial carbonic anhydrase 9 and collagen, surrogate markers of myocardial hypoxia. Upregulation of vascular ADK mitigates adenosine-facilitated conducted vasodilation in obese ZSF1 rats and in patients with HFpEF. We propose that pharmacological inhibition of ADK could be beneficial for therapeutic augmentation of conducted vasodilation, thereby improving tissue perfusion and LV diastolic function in HFpEF.

The many faces of myocardial ischaemia and angina

Obstructive disease of the epicardial coronary arteries is the main cause of angina. However, a number of patients with anginal symptoms have normal coronaries or non-obstructive coronary artery disease (CAD) despite electrocardiographic evidence of ischaemia during stress testing. In addition to limited microvascular vasodilator capacity, the coronary microcirculation of these patients is particularly sensitive to vasoconstrictor stimuli, in a condition known as microvascular angina. This review briefly summarizes the determinants and control of coronary blood flow (CBF) and myocardial perfusion. It subsequently analyses the mechanisms responsible for transient myocardial ischaemia: obstructive CAD, coronary spasm and coronary microvascular dysfunction in the absence of epicardial coronary lesions, and variable combinations of structural anomalies, impaired endothelium-dependent and/or -independent vasodilation, and enhanced perception of pain. Lastly, we exemplify mechanism of angina during tachycardia. Distal to a coronary stenosis, coronary dilator reserve is already recruited and can be nearly exhausted at rest distal to a severe stenosis. Increased heart rate reduces the duration of diastole and thus CBF when metabolic vasodilation is no longer able to increase CBF. The increase in myocardial oxygen consumption and resulting metabolic vasodilation in adjacent myocardium without stenotic coronary arteries further acts to divert blood flow away from the post-stenotic coronary vascular bed through collaterals.

Capillary response to skeletal muscle contraction: evidence that redundancy between vasodilators is physiologically relevant during active hyperaemia.

The current theory behind matching blood flow to metabolic demand of skeletal muscle suggests redundant interactions between metabolic vasodilators. Capillaries play an important role in blood flow control given their ability to respond to muscle contraction by causing conducted vasodilatation in upstream arterioles that control their perfusion. We sought to determine whether redundancies occur between vasodilators at the level of the capillary by stimulating the capillaries with muscle contraction and vasodilators relevant to muscle contraction. We identified redundancies between potassium and both adenosine and nitric oxide, between nitric oxide and potassium, and between adenosine and both potassium and nitric oxide. During muscle contraction, we demonstrate redundancies between potassium and nitric oxide as well as between potassium and adenosine. Our data show that redundancy is physiologically relevant and involved in the coordination of the vasodilator response during muscle contraction at the level of the capillaries. We sought to determine if redundancy between vasodilators is physiologically relevant during active hyperaemia. As inhibitory interactions between vasodilators are indicative of redundancy, we tested whether vasodilators implicated in mediating active hyperaemia (potassium (K+ ), adenosine (ADO) and nitric oxide (NO)) inhibit one another's vasodilatory effects through direct application of pharmacological agents and during muscle contraction. Using the hamster cremaster muscle and intravital microscopy, we locally stimulated capillaries with one vasodilator in the absence and the presence of a second vasodilator (10-7 m S-nitroso-N-acetylpenicillamine (SNAP), 10-7 m ADO, 10mm KCl) applied sequentially and simultaneously, and observed the response in the associated upstream 4A arteriole controlling the perfusion of the stimulated capillary. We found that KCl significantly attenuated SNAP- and ADO-induced vasodilatations by ∼49.7% and ∼128.0% respectively and ADO significantly attenuated KCl- and SNAP-induced vasodilatations by ∼94.7% and ∼59.6%, respectively. NO significantly attenuated KCl vasodilatation by 93.8%. Further, during muscle contraction we found that inhibition of NO production using l-NG -nitroarginine methyl ester and inhibition of ADO receptors using xanthine amine congener was effective at inhibiting contraction-induced vasodilatation but only in the presence of K+ release channel inhibition. Thus, only when the inhibiting vasodilator K+ was blocked was the second vasodilator, NO or ADO, able to produce effective vasodilatation. Therefore, we show that there are inhibitory interactions between specific vasodilators at the level of the capillary. Further, these inhibitions can be observed during muscle contraction indicating that redundancies between vasodilators are physiologically relevant and influence vasodilatation during active hyperaemia.

Pathophysiology of Chronic Systolic Heart Failure. A View from the Periphery.

Heart failure is a common form of heart disease associated with progressive exercise intolerance and high risk of adverse clinical outcome events. The pathophysiology of chronic systolic heart failure is fundamentally determined by the failure of the circulatory system to deliver oxygen sufficient for metabolic needs, and it is best explained by a complex interplay between intrinsic abnormalities of ventricular pump function and extracardiac factors that limit oxygen use in metabolically active tissues. This brief review highlights the role of extracardiac factors (peripheral factors) that may impact exercise capacity in patients with chronic systolic heart failure. Reduced metabolic vasodilation limits delivery of available cardiac output reserve to skeletal muscle during exercise, and it is associated with reduced peak oxygen capacity. Abnormal substrate use in skeletal muscle due to reduced skeletal muscle mass, change in skeletal muscle fiber type, and mitochondrial dysfunction reduces work efficiency and submaximal exercise endurance capacity in patients with systolic heart failure. These extracardiac peripheral mechanisms of impaired exercise tolerance in chronic heart failure may be targets for novel therapeutic development in this patient population.

Skeletal muscle contraction-induced vasodilation in the microcirculation.

Maximal whole body exercise leads skeletal muscle blood flow to markedly increase to match metabolic demands, a phenomenon termed exercise hyperaemia that is accomplished by increasing vasodilation. However, local vasodilatory mechanisms in response to skeletal muscle contraction remain uncertain. This review highlights metabolic vasodilators released from contracting skeletal muscle, endothelium, or blood cells. As a considerable skeletal muscle vasodilation potentially results in hypotension, sympathetic nerve activity needs to be augmented to elevate cardiac output and blood pressure during dynamic exercise. However, since the enhanced sympathetic vasoconstriction restrains skeletal muscle blood flow, intramuscular arteries have an indispensable ability to blunt sympathetic activity for exercise hyperaemia. In addition, we discuss that mechanical compression of the intramuscular vasculature contributes to causing the initial phase of increasing vasodilation following a single muscle contraction. We have also chosen to focus on conducted (or ascending) electrical signals that evoke vasodilation of proximal feed arteries to elevate blood flow in the microcirculation of skeletal muscle. Endothelial hyperpolarization originating within distal arterioles ascends into the proximal feed arteries, thereby increasing total blood flow in contracting skeletal muscle. This brief review summarizes molecular mechanisms underlying the regulation of skeletal muscle blood flow to a single or sustained muscle contraction.

Muscle metaboreflex-induced vasoconstriction in the ischemic active muscle is exaggerated in heart failure.

When oxygen delivery to active muscle is insufficient to meet the metabolic demand during exercise, metabolites accumulate and stimulate skeletal muscle afferents, inducing a reflex increase in blood pressure, termed the muscle metaboreflex. In healthy individuals, muscle metaboreflex activation (MMA) during submaximal exercise increases arterial pressure primarily via an increase in cardiac output (CO), as little peripheral vasoconstriction occurs. This increase in CO partially restores blood flow to ischemic muscle. However, we recently demonstrated that MMA induces sympathetic vasoconstriction in ischemic active muscle, limiting the ability of the metaboreflex to restore blood flow. In heart failure (HF), increases in CO are limited, and metaboreflex-induced pressor responses occur predominantly via peripheral vasoconstriction. In the present study, we tested the hypothesis that vasoconstriction of ischemic active muscle is exaggerated in HF. Changes in hindlimb vascular resistance [femoral arterial pressure ÷ hindlimb blood flow (HLBF)] were observed during MMA (via graded reductions in HLBF) during mild exercise with and without α1-adrenergic blockade (prazosin, 50 µg/kg) before and after induction of HF. In normal animals, initial HLBF reductions caused metabolic vasodilation, while reductions below the metaboreflex threshold elicited reflex vasoconstriction, in ischemic active skeletal muscle, which was abolished after α1-adrenergic blockade. Metaboreflex-induced vasoconstriction of ischemic active muscle was exaggerated after induction of HF. This heightened vasoconstriction impairs the ability of the metaboreflex to restore blood flow to ischemic muscle in HF and may contribute to the exercise intolerance observed in these patients. We conclude that sympathetically mediated vasoconstriction of ischemic active muscle during MMA is exaggerated in HF. NEW & NOTEWORTHY We found that muscle metaboreflex-induced vasoconstriction of the ischemic active skeletal muscle from which the reflex originates is exaggerated in heart failure. This results in heightened metaboreflex activation, which further amplifies the reflex-induced vasoconstriction of the ischemic active skeletal muscle and contributes to exercise intolerance in patients.

Critical contribution of KV1 channels to the regulation of coronary blood flow.

Ion channels in smooth muscle control coronary vascular tone, but the identity of the potassium channels involved requires further investigation. The purpose of this study was to evaluate the functional role of KV1 channels on porcine coronary blood flow using the selective antagonist correolide. KV1 channel gene transcripts were found in porcine coronary arteries, with KCNA5 (encoding KV1.5) being most abundant (P<0.001). Immunohistochemical staining demonstrated KV1.5 protein in the vascular smooth muscle layer of both porcine and human coronary arteries, including microvessels. Whole-cell patch-clamp experiments demonstrated significant correolide-sensitive (1-10µM) current in coronary smooth muscle. In vivo studies included direct intracoronary infusion of vehicle or correolide into a pressure-clamped left anterior descending artery of healthy swine (n=5 in each group) with simultaneous measurement of coronary blood flow. Intracoronary correolide (~0.3-3µM targeted plasma concentration) had no effect on heart rate or systemic pressure, but reduced coronary blood flow in a dose-dependent manner (P<0.05). Dobutamine (0.3-10µg/kg/min) elicited coronary metabolic vasodilation and intracoronary correolide (3µM) significantly reduced coronary blood flow at any given level of myocardial oxygen consumption (P<0.001). Coronary artery occlusions (15s) elicited reactive hyperemia and correolide (3µM) reduced the flow volume repayment by approximately 30% (P<0.05). Taken together, these data support a major role for KV1 channels in modulating baseline coronary vascular tone and, perhaps, vasodilation in response to increased metabolism and transient ischemia.

Overexpressing superoxide dismutase 2 induces a supernormal cardiac function by enhancing redox-dependent mitochondrial function and metabolic dilation

During heightened cardiac work, O2 consumption by the heart benefits energy production via mitochondria. However, some electrons leak from the respiratory chain and yield superoxide, which is rapidly metabolized into H2O2 by SOD2. To understand the systemic effects of the metabolic dilator, H2O2, we studied mice with cardiac-specific SOD2 overexpression (SOD2-tg), which increases the H2O2 produced by cardiac mitochondria. Contrast echocardiography was employed to evaluate cardiac function, indicating that SOD2-tg had a significantly greater ejection fraction and a lower mean arterial pressure (MAP) that was partially normalized by intravenous injection of catalase. Norepinephrine-mediated myocardial blood flow (MBF) was significantly enhanced in SOD2-tg mice. Coupling of MBF to the double product (Heart Rate×MAP) was increased in SOD2-tg mice, indicating that the metabolic dilator, “spilled” over, inducing systemic vasodilation. The hypothesis that SOD2 overexpression effectively enhances mitochondrial function was further evaluated. Mitochondria of SOD2-tg mice had a decreased state 3 oxygen consumption rate, but maintained the same ATP production flux under the basal and L-NAME treatment conditions, indicating a higher bioenergetic efficiency. SOD2-tg mitochondria produced less superoxide, and had lower redox activity in converting cyclic hydroxylamine to stable nitroxide, and a lower GSSG concentration. EPR analysis of the isolated mitochondria showed a significant decrease in semiquinones at the SOD2-tg Qi site. These results support a more reductive physiological setting in the SOD2-tg murine heart. Cardiac mitochondria exhibited no significant differences in the respiratory control index between WT and SOD2-tg. We conclude that SOD2 overexpression in myocytes enhances mitochondrial function and metabolic vasodilation, leading to a phenotype of supernormal cardiac function.

Altered energy state reversibly controls smooth muscle contractile function in human saphenous vein during acute hypoxia–reoxygenation: Role of glycogen, AMP-activated protein kinase, and insulin-independent glucose uptake

Hypoxia is known to promote vasodilation of coronary vessels through several mediators including cardiac-derived adenosine and endothelium-derived prostanoids and nitric oxide. To date, the impact of endogenous glycogen depletion in vascular smooth muscle and the resultant alterations in cellular energy state (e.g., AMP-activated protein kinase, AMPK) on the contractile response to G protein-coupled receptor agonists (e.g., serotonin, 5-HT) has not yet been studied. In the present study, ex vivo exposure of endothelium-denuded human saphenous vein rings to hypoxic and glucose-deprived conditions during KCl-induced contractions for 30min resulted in a marked depletion of endogenous glycogen by ∼80% (from ∼1.78μmol/g under normoxia to ∼0.36μmol/g under hypoxia). Importantly, glycogen-depleted HSV rings, which were maintained under hypoxia/reoxygenation and glucose-deprived conditions, exhibited significant increases in basal AMPK phosphorylation (∼6-fold ↑) and 5-HT-induced AMPK phosphorylation (∼19-fold ↑) with an accompanying suppression of 5-HT-induced maximal contractile response (∼68% ↓), compared with respective controls. Exposure of glycogen-depleted HSV rings to exogenous D-glucose, but not the inactive glucose analogs, prevented the exaggerated increase in 5-HT-induced AMPK phosphorylation and restored 5-HT-induced maximal contractile response. In addition, the ability of exogenous D-glucose to rescue cellular stress and impaired contractile function occurred through GLUT1-mediated but insulin/GLUT4-independent mechanisms. Together, the present findings from clinically-relevant human saphenous vein suggest that the loss of endogenous glycogen in vascular smooth muscle and the resultant accentuation of AMPK phosphorylation by GPCR agonists may constitute a yet another mechanism of metabolic vasodilation of coronary vessels in ischemic heart disease.

'Fine-tuning' blood flow to the exercising muscle with advancing age: an update.

What is the topic of this review? This review focuses on age-related changes in the regulatory pathways that exist at the unique interface between the vascular smooth muscle and the endothelium of the skeletal muscle vasculature, and how these changes contribute to impairments in exercising skeletal muscle blood flow in the elderly. What advances does it highlight? Several recent in vivo human studies from our group and others are highlighted that have examined age-related changes in nitric oxide, endothelin-1, alpha adrenergic, and renin-angiotensin-aldosterone (RAAS) signaling. During dynamic exercise, oxygen demand from the exercising muscle is dramatically elevated, requiring a marked increase in skeletal muscle blood flow that is accomplished through a combination of systemic sympathoexcitation and local metabolic vasodilatation. With advancing age, the balance between these factors appears to be disrupted in favour of vasoconstriction, leading to an impairment in exercising skeletal muscle blood flow in the elderly. This 'hot topic' review aims to provide an update to our current knowledge of age-related changes in the neural and local mechanisms that contribute to this 'fine-tuning' of blood flow during exercise. The focus is on results from recent human studies that have adopted a reductionist approach to explore how age-related changes in both vasodilators (nitric oxide) and vasoconstrictors (endothelin-1, α-adrenergic agonists and angiotensinII) interact and how these changes impact blood flow to the exercising skeletal muscle with advancing age.

Breathing maneuvers as a metabolic coronary vasodilator for first-pass perfusion MR imaging

Methods We studied 24 healthy volunteers (37 ± 12 years; 62.5% men) in a clinical 3T MRI system. Each exam included three sets of first pass perfusion images, (1) at rest and, after 1 minute of hyperventilation during (2) a short breath-hold (SBH) or (3) a long breath-hold (LBH), performed in random order. A reader blinded to the maneuver applied, analyzed signal intensity upslope, upslope index and time between 20 and 80% of maximal signal. For inter-observer variability, a different, blinded, reader repeated the analysis in 4 volunteers.

Abstract 13035: Overexpressing Superoxide Dismutase 2 Induces Super-normal Cardiac Function by Enhancing Mitochondrial Function and Metabolic Dilation

During heightened cardiac work, O 2 consumption by the heart increases. This increase benefits energy production via mitochondrial e − transport, but some e − “leak” from respiratory chain and yields O 2 [[Unable to Display Character: &amp;#729;]] − , which is rapidly metabolized into H 2 O 2 by SOD2. To understand the potential systemic effects of the metabolic dilator, H 2 O 2 , we studied mice with cardiac specific SOD2 overexpression, which would increase H 2 O 2 produced by the cardiac mitochondria (by 1.9 fold vs WT). To determine if this enhanced production of H 2 O 2 enhances metabolic dilation, we first evaluated the effectiveness of SOD2 overexpression to effectively enhance mitochondrial function. Mitochondria of SOD2 transgenic mice had a decreased state 3 oxygen consumption rate, but maintained the same level of ATP production; thus indicating a higher P/O ratio and bioenergetics efficiency induced by overexpressing SOD2. Mitochondria of SOD2-tg (compared to WT) produced less • O 2 − , and had lower redox activity (by EPR) and lower GSSG concentration (decreased by 37.2±4.5%). EPR analysis of the isolated mitochondria showed significant decrease of semiquinone in the SOD2-tg at the Q i site (by 69.4±9.9%), and a diminished complex I-derived protein thiyl radical(s). These results support a more reductive physiological setting of the SOD2-tg heart. Cardiac mitochondria isolated from SOD2-tg exhibited no significant differences in the respiratory control index between WT and SOD2-tg. These results support that the SOD2 overexpression is effective and results in enhanced mitochondrial function. Contrast echocardiography was employed to evaluate hemodynamic effects. Mean arterial pressure (MAP) was lower in the SOD2-tg, but was normalized by intravenous injection of catalase suggesting “spill-over” of H 2 O 2 from the myocardium in sufficient amounts to produce a systemic effect. Increasing myocardial work (norepinephrine) caused a far greater increase myocardial blood flow (MBF) per level of work in SOD2-tg compared to WT. Echocardiography indicated SOD2-tg had a significant greater ejection fraction (90±1% vs 74±2%). In conclusion, SOD2 overexpression in myocytes enhances mitochondrial function and metabolic vasodilation, leading to phenotype of super-normal cardiac function.

English

The hypothesis that celiprolol, a i¢-1 adrenoceptor antagonist with the ancillary property of i¢-2 mediated vasodilation, would increase blood flow to active muscles during exercise and result in less impairment of exercise performance, compared with the i¢-1 antagonist atenolol was tested. After an initial 3 weeks washout phase, 11 untrained hypertensive men participated in a 6 week crossover study of the two drugs. Each treatment phase was followed by a 3 week placebo phase. Resting forearm and calf vascular resistance measured by venous occlusion plethysmography and submaximal and maximal bicycle ergometer exercise responses were evaluated at the end of each treatment and placebo phase. Celiprolol significantly decreased resting forearm and calf vascular resistance whereas atenolol had no significant effect. Neither i¢-blocker significantly affected submaximal exercise oxygen uptake, rate of perceived exertion, minute ventilation, or respiratory exchange ratio. Both i¢-blockers significantly and similarly decreased peak oxygen uptake; celiprolol 23.9 ±1.7, atenolol 24.9 ± 1.7, placebo 27.3 ± 1.3 ml/kg/min. These findings suggest that during exercise while on i¢-blockade, other factors such as sympathetic vasoconstriction or local metabolic vasodilation may override β-2-mediated vasodilation. Thus, the addition of β-2 agonist to β-1 antagonism decreases resting vascular resistance, but offers no advantage over conventional β-1 blockade therapy during exercise. Key words: Celiprolol, atenolol, oxygen uptake, venous occlusion plethysmography, bicycle ergometer, β-blocker, blood flow, vascular resistance.

Metabolic hyperemia requires ATP-sensitive K+ channels and H2O2 but not adenosine in isolated mouse hearts.

We have previously demonstrated that adenosine-mediated H2O2 production and opening of ATP-sensitive K(+) (KATP) channels contributes to coronary reactive hyperemia. The present study aimed to investigate the roles of adenosine, H2O2, and KATP channels in coronary metabolic hyperemia (MH). Experiments were conducted on isolated Langendorff-perfused mouse hearts using combined pharmacological approaches with adenosine receptor (AR) knockout mice. MH was induced by electrical pacing at graded frequencies. Coronary flow increased linearly from 14.4 ± 1.2 to 20.6 ± 1.2 ml·min(-1)·g(-1) with an increase in heart rate from 400 to 650 beats/min in wild-type mice. Neither non-selective blockade of ARs by 8-(p-sulfophenyl)theophylline (8-SPT; 50 μM) nor selective A2AAR blockade by SCH-58261 (1 μM) or deletion affected MH, although resting flow and left ventricular developed pressure were reduced. Combined A2AAR and A2BAR blockade or deletion showed similar effects as 8-SPT. Inhibition of nitric oxide synthesis by N-nitro-l-arginine methyl ester (100 μM) or combined 8-SPT administration failed to reduce MH, although resting flows were reduced (by ∼20%). However, glibenclamide (KATP channel blocker, 5 μM) decreased not only resting flow (by ∼45%) and left ventricular developed pressure (by ∼36%) but also markedly reduced MH by ∼94%, resulting in cardiac contractile dysfunction. Scavenging of H2O2 by catalase (2,500 U/min) also decreased resting flow (by ∼16%) and MH (by ∼24%) but to a lesser extent than glibenclamide. Our results suggest that while adenosine modulates coronary flow under both resting and ischemic conditions, it is not required for MH. However, H2O2 and KATP channels are important local control mechanisms responsible for both coronary ischemic and metabolic vasodilation.