Control of coronary blood flow during exercise.

Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195-7920, USA.
Exercise and sport sciences reviews (Impact Factor: 4.82). 08/2011; 40(1):37-42. DOI: 10.1097/JES.0b013e3182348cdd
Source: PubMed

ABSTRACT During exercise, coronary blood flow increases to match the augmented myocardial oxygen demand because of tachycardia. Coronary vasodilation during exercise is via a combination of feedforward and feedback control mechanisms. Feedforward control is mediated by sympathetic β-adrenoceptor vasodilation. Feedback vasodilator control is via a novel hypothesis where adenine nucleotides released from red blood cells act on endothelial purinergic receptors.

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    ABSTRACT: Endothelial dysfunction is associated with vascular risk factors such as dyslipidemia, hypertension, and diabetes, leading to coronary atherosclerosis. Sympathetic stress using cold-pressor testing (CPT) has been used to measure coronary endothelial function in humans with positron emission tomography (PET) myocardial blood flow (MBF) imaging, but is not practical in small animal models. This study characterized coronary vasomotor function in mice with [(11)C]acetate micro-PET measurements of nitric-oxide-mediated endothelial flow reserve (EFRNOM) (adrenergic-stress/rest MBF) and myocardial oxygen consumption (MVO2) using salbutamol β2-adrenergic-activation. [(11)C]acetate PET MBF was performed at rest + salbutamol (SB 0.2, 1.0 μg/kg/min) and norepinephrine (NE 3.2 μg/kg/min) stress to measure an index of MBF response. β-adrenergic specificity of NE was evaluated by pretreatment with α-adrenergic-antagonist phentolamine (PHE), and β2-selectivity was assessed using SB. Adjusting for changes in heart rate × systolic blood pressure product (RPP), the same stress/rest MBF ratio of 1.4 was measured using low-dose SB and NE in normal mice (equivalent to human CPT response). The MBF response was correlated with changes in MVO2 (p = 0.02). Nitric oxide synthase (NOS)-inhibited mice (N(g)-nitro-L-arginine methyl ester (L-NAME) pretreatment and endothelial nitric oxide synthase (eNOS) knockout) were used to assess the EFRNOM, in which the low-dose SB- and NE-stress MBF responses were completely blocked (p = 0.02). With high-dose SB-stress, the MBF ratio was reduced by 0.4 following NOS inhibition (p = 0.03). Low-dose salbutamol β2-adrenergic-stress [(11)C]acetate micro-PET imaging can be used to measure coronary-specific EFRNOM in mice and may be suitable for assessment of endothelial dysfunction in small animal models of disease and evaluation of new therapies.
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    Pharmacological reviews 01/2014; 66(1):102-192. DOI:10.1124/pr.113.008029 · 18.55 Impact Factor
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    ABSTRACT: Muscle metaboreflex activation during dynamic exercise induces a substantial increase in cardiac work and oxygen demand via a significant increase in heart rate, ventricular contractility and afterload. This increase in cardiac work should cause coronary metabolic vasodilation. However, little if any coronary vasodilation is observed due to concomitant sympathetically induced coronary vasoconstriction. In heart failure, cardiac output does not increase with MMA presumably due to impaired left ventricular contractility, and large decreases in coronary vascular conductance are observed. The purpose of this dissertation is to determine whether the muscle metaboreflex-induced restraint of coronary vasodilation functionally limits coronary blood flow and suppresses increases in left ventricular (LV) contractility in normal dogs and whether this coronary vasoconstriction could explain in part, the reduced ability to increase cardiac performance during heart failure conditions. We used chronically instrumented dogs (n=9, control and n=7, heart failure) and measured arterial pressure (MAP), cardiac output (CO), circumflex blood flow (CBF), and calculated coronary vascular conductance (CVC), maximal derivative of ventricular pressure (dp/dt), and preload recruitable stroke work (PRSW) at rest and during mild exercise (2mph) before and during activation of the muscle metaboreflex. Experiments were repeated after systemic alpha-1 adrenergic blockade (prazosin 50-100 μg/kg). In control studies during alpha-1 blockade we observed significantly greater increases in CVC, CBF and PRSW, as well as CO and dP/dtmax, with metaboreflex activation vs. those seen without alpha-1 blockade. In heart failure experiments during MMA, the increases in CBF, CVC, CO, and +dP/dtmax were significantly greater after alpha-1 adrenergic blockade. We conclude that the coronary vasoconstriction elicited by MMA limits the ability of muscle metaboreflex to increase left ventricular contractility in normal and heart failure conditions.


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