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Browsing by Author "Baker, Hana E."
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Item Disentangling the Gordian knot of local metabolic control of coronary blood flow(American Physiological Society, 2020-01-01) Tune, Johnathan D.; Goodwill, Adam G.; Kiel, Alexander M.; Baker, Hana E.; Bender, Shawn B.; Merkus, Daphne; Duncker, Dirk J.; Cellular and Integrative Physiology, School of MedicineRecognition that coronary blood flow is tightly coupled with myocardial metabolism has been appreciated for well over half a century. However, exactly how coronary microvascular resistance is tightly coupled with myocardial oxygen consumption (MV̇o2) remains one of the most highly contested mysteries of the coronary circulation to this day. Understanding the mechanisms responsible for local metabolic control of coronary blood flow has been confounded by continued debate regarding both anticipated experimental outcomes and data interpretation. For a number of years, coronary venous Po2 has been generally accepted as a measure of myocardial tissue oxygenation and thus the classically proposed error signal for the generation of vasodilator metabolites in the heart. However, interpretation of changes in coronary venous Po2 relative to MV̇o2 are quite nuanced, inherently circular in nature, and subject to confounding influences that remain largely unaccounted for. The purpose of this review is to highlight difficulties in interpreting the complex interrelationship between key coronary outcome variables and the arguments that emerge from prior studies performed during exercise, hemodilution, hypoxemia, and alterations in perfusion pressure. Furthermore, potential paths forward are proposed to help to facilitate further dialogue and study to ultimately unravel what has become the Gordian knot of the coronary circulation.Item Distinct hemodynamic responses to (pyr)apelin-13 in large animal models(APS, 2020-04) Tune, Johnathan D.; Baker, Hana E.; Berwick, Zachary; Moberly, Steven P.; Casalini, Eli D.; Noblet, Jillian N.; Zhen, Eugene; Kowala, Mark C.; Christe, Michael E.; Goodwill, Adam; Cellular and Integrative Physiology, School of MedicineThis study tested the hypothesis that (pyr)apelin-13 dose-dependently augments myocardial contractility and coronary blood flow, irrespective of changes in systemic hemodynamics. Acute effects of intravenous (pyr)apelin-13 administration (10 to 1,000 nM) on blood pressure, heart rate, left ventricular pressure and volume, and coronary parameters were measured in dogs and pigs. Administration of (pyr)apelin-13 did not influence blood pressure (P = 0.59), dP/dtmax (P = 0.26), or dP/dtmin (P = 0.85) in dogs. However, heart rate dose-dependently increased > 70% (P < 0.01), which was accompanied by a significant increase in coronary blood flow (P < 0.05) and reductions in left ventricular end-diastolic volume and stroke volume (P < 0.001). In contrast, (pyr)apelin-13 did not significantly affect hemodynamics, coronary blood flow, or indexes of contractile function in pigs. Furthermore, swine studies found no effect of intracoronary (pyr)apelin-13 administration on coronary blood flow (P = 0.83) or vasorelaxation in isolated, endothelium-intact (P = 0.89) or denuded (P = 0.38) coronary artery rings. Examination of all data across (pyr)apelin-13 concentrations revealed an exponential increase in cardiac output as peripheral resistance decreased across pigs and dogs (P < 0.001; R2 = 0.78). Assessment of the Frank-Starling relationship demonstrated a significant linear relationship between left ventricular end-diastolic volume and stroke volume across species (P < 0.001; R2 = 0.70). Taken together, these findings demonstrate that (pyr)apelin-13 does not directly influence myocardial contractility or coronary blood flow in either dogs or pigs.Item Inhibition of sodium–glucose cotransporter-2 preserves cardiac function during regional myocardial ischemia independent of alterations in myocardial substrate utilization(Springer, 2019-04-19) Baker, Hana E.; Kiel, Alexander M.; Luebbe, Samuel T.; Simon, Blake R.; Earl, Conner C.; Regmi, Ajit; Roell, William C.; Mather, Kieren J.; Tune, Johnathan D.; Goodwill, Adam G.; Cellular and Integrative Physiology, School of MedicineThe goal of the present study was to evaluate the effects of SGLT2i on cardiac contractile function, substrate utilization, and efficiency before and during regional myocardial ischemia/reperfusion injury in normal, metabolically healthy swine. Lean swine received placebo or canagliflozin (300 mg PO) 24 h prior to and the morning of an invasive physiologic study protocol. Hemodynamic and cardiac function measurements were obtained at baseline, during a 30-min complete occlusion of the circumflex coronary artery, and during a 2-h reperfusion period. Blood pressure, heart rate, coronary flow, and myocardial oxygen consumption were unaffected by canagliflozin treatment. Ventricular volumes remained unchanged in controls throughout the protocol. At the onset of ischemia, canagliflozin produced acute large increases in left ventricular end-diastolic and systolic volumes which returned to baseline with reperfusion. Canagliflozin-mediated increases in end-diastolic volume were directly associated with increases in stroke volume and stroke work relative to controls during ischemia. Canagliflozin also increased cardiac work efficiency during ischemia relative to control swine. No differences in myocardial uptake of glucose, lactate, free fatty acids or ketones, were noted between treatment groups at any time. In separate experiments using a longer 60 min coronary occlusion followed by 2 h of reperfusion, canagliflozin increased end-diastolic volume and stroke volume and significantly diminished myocardial infarct size relative to control swine. These data demonstrate that SGLT2i with canagliflozin preserves cardiac contractile function and efficiency during regional myocardial ischemia and provides ischemia protection independent of alterations in myocardial substrate utilization.Item Local metabolic hypothesis is not sufficient to explain coronary autoregulatory behavior(Springer Nature, 2018-08-02) Kiel, Alexander M.; Goodwill, Adam G.; Baker, Hana E.; Dick, Gregory M.; Tune, Johnathan D.; Cellular and Integrative Physiology, School of MedicineThe local metabolic hypothesis proposes that myocardial oxygen tension determines the degree of autoregulation by increasing the production of vasodilator metabolites as perfusion pressure is reduced. Thus, normal physiologic levels of coronary venous PO2, an index of myocardial oxygenation, are proposed to be required for effective autoregulation. The present study challenged this hypothesis through determination of coronary responses to changes in coronary perfusion pressure (CPP 140-40 mmHg) in open-chest swine in the absence (n = 7) and presence of euvolemic hemodilution (~ 50% reduction in hematocrit), with (n = 5) and without (n = 6) infusion of dobutamine to augment MVO2. Coronary venous PO2 decreased over similar ranges (~ 28-15 mmHg) as CPP was lowered from 140 to 40 mmHg in each of the groups. However, coronary venous PO2 was not associated with changes in coronary blood flow (r = - 0.11; P = 0.29) or autoregulatory gain (r = - 0.29; P = 0.12). Coronary zero-flow pressure (Pzf) was measured in 20 mmHg increments and determined to be directly related to vascular resistance (r = 0.71; P < 0.001). Further analysis demonstrated that changes in coronary blood flow remained minimal at Pzf > 20 mmHg, but progressively increased as Pzf decreased below this threshold value (r = 0.68; P < 0.001). Coronary Pzf was also positively correlated with autoregulatory gain (r = 0.43; P = 0.001). These findings support that coronary autoregulatory behavior is predominantly dependent on an adequate degree of underlying vasomotor tone, independent of normal myocardial oxygen tension.Item Mineralocorticoid receptor blockade normalizes coronary resistance in obese swine independent of functional alterations in Kv channels(Springer, 2021-05-20) Goodwill, Adam G.; Baker, Hana E.; Dick, Gregory M.; McCallinhart, Patricia E.; Bailey, Chastidy A.; Brown, Scott M.; Man, Joshua J.; Tharp, Darla L.; Clark, Hannah E.; Blaettner, Bianca S.; Jaffe, Iris Z.; Bowles, Douglas K.; Trask, Aaron J.; Tune, Johnathan D.; Bender, Shawn B.; Anatomy, Cell Biology and Physiology, School of MedicineImpaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity, yet underlying mechanisms and potential therapeutic strategies remain poorly understood. Mineralocorticoid receptor (MR) antagonism improves coronary microvascular function in obese humans and animals. Whether MR blockade improves in vivo regulation of coronary flow, a process involving voltage-dependent K+ (Kv) channel activation, or reduces coronary structural remodeling in obesity is unclear. Thus, the goals of this investigation were to determine the effects of obesity on coronary responsiveness to reductions in arterial PO2 and potential involvement of Kv channels and whether the benefit of MR blockade involves improved coronary Kv function or altered passive structural properties of the coronary microcirculation. Hypoxemia increased coronary blood flow similarly in lean and obese swine; however, baseline coronary vascular resistance was significantly higher in obese swine. Inhibition of Kv channels reduced coronary blood flow and augmented coronary resistance under baseline conditions in lean but not obese swine and had no impact on hypoxemic coronary vasodilation. Chronic MR inhibition in obese swine normalized baseline coronary resistance, did not influence hypoxemic coronary vasodilation, and did not restore coronary Kv function (assessed in vivo, ex vivo, and via patch clamping). Lastly, MR blockade prevented obesity-associated coronary arteriolar stiffening independent of cardiac capillary density and changes in cardiac function. These data indicate that chronic MR inhibition prevents increased coronary resistance in obesity independent of Kv channel function and is associated with mitigation of obesity-mediated coronary arteriolar stiffening.