Browsing by Author "Casalini, Eli D."

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    Contribution of hydrogen sulfide to the control of coronary blood flow
    (Wiley, 2014-02) Casalini, Eli D.; Goodwill, Adam G.; Owen, Meredith K.; Moberly, Steven P.; Berwick, Zachary C.; Tune, Johnathan D.; Department of Cellular & Integrative Physiology, IU School of Medicine
    This study examined the mechanisms by which H2S modulates coronary microvascular resistance and myocardial perfusion at rest and in response to cardiac ischemia. Experiments were conducted in isolated coronary arteries and in open-chest anesthetized dogs. We found that the H2S substrate L-cysteine (1-10 mM) did not alter coronary tone of isolated arteries in vitro or coronary blood flow in vivo. In contrast, intracoronary (ic) H2S (0.1-3 mM) increased coronary flow from 0.49 ± 0.08 to 2.65 ± 0.13 ml/min/g (P□0.001). This increase in flow was unaffected by inhibition of Kv channels with 4-aminopyridine (P=0.127) but was attenuated (0.23 ± 0.02 to 1.13 ± 0.13 ml/min/g) by the KATP channel antagonist glibenclamide (P□0.001). Inhibition of NO synthesis (L-NAME) did not attenuate coronary responses to H2S. Immunohistochemistry revealed expression of cystathionine gamma-lyase (CSE), an endogenous H2S enzyme, in myocardium. Inhibition of CSE with β-cyano-L-alanine (10 µM) had no effect on baseline coronary flow or responses to a 15 sec coronary occlusion (P=0.82). These findings demonstrate that exogenous H2S induces potent, endothelial-independent dilation of the coronary microcirculation predominantly through the activation of KATP channels, however, our data do not support a functional role for endogenous H2S in the regulation of coronary microvascular resistance.
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    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 Medicine
    This 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.
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    Glucagon-like peptide-1 (7-36) but not (9-36) augments cardiac output during myocardial ischemia via a Frank-Starling mechanism
    (Springer, 2014) Goodwill, Adam G.; Tune, Johnathan D.; Noblet, Jillian N.; Conteh, Abass M.; Sassoon, Daniel; Casalini, Eli D.; Mather, Kieren J.; Department of Cellular & Integrative Physiology, IU School of Medicine
    This study examined the cardiovascular effects of GLP-1 (7-36) or (9-36) on myocardial oxygen consumption, function and systemic hemodynamics in vivo during normal perfusion and during acute, regional myocardial ischemia. Lean Ossabaw swine received systemic infusions of saline vehicle or GLP-1 (7-36 or 9-36) at 1.5, 3.0, and 10.0 pmol/kg/min in sequence for 30 min at each dose, followed by ligation of the left circumflex artery during continued infusion at 10.0 pmol/kg/min. Systemic GLP-1 (9-36) had no effect on coronary flow, blood pressure, heart rate or indices of cardiac function before or during regional myocardial ischemia. Systemic GLP-1 (7-36) exerted no cardiometabolic or hemodynamic effects prior to ischemia. During ischemia, GLP-1 (7-36) increased cardiac output by approximately 2 L/min relative to vehicle-controls (p = 0.003). This response was not diminished by treatment with the non-depolarizing ganglionic blocker hexamethonium. Left ventricular pressure-volume loops measured during steady-state conditions with graded occlusion of the inferior vena cava to assess load-independent contractility revealed that GLP-1 (7-36) produced marked increases in end-diastolic volume (74 ± 1 to 92 ± 5 ml; p = 0.03) and volume axis intercept (8 ± 2 to 26 ± 8; p = 0.05), without any change in the slope of the end-systolic pressure-volume relationship vs. vehicle during regional ischemia. GLP-1 (9-36) produced no changes in any of these parameters compared to vehicle. These findings indicate that short-term systemic treatment with GLP-1 (7-36) but not GLP-1 (9-36) significantly augments cardiac output during regional myocardial ischemia, via increases in ventricular preload without changes in cardiac inotropy.
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    KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine
    (American Physiological Society, 2016-03-15) Goodwill, Adam G.; Fu, Lijuan; Noblet, Jillian N.; Casalini, Eli D.; Sassoon, Daniel; Berwick, Zachary C.; Kassab, Ghassan S.; Tune, Johnathan D.; Dick, Gregory M.; Department of Cellular & Integrative Physiology, IU School of Medicine
    Hydrogen peroxide (H2O2) and voltage-dependent K(+) (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The KV channels responsible have not been identified, but KV7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that KV7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and KV7.4 protein (Western blot). Immunostaining demonstrated KV7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a KV7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a KV7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that KV7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular KV7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli.