Control of coronary blood flow during exercise.
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.
SourceAvailable from: Etienne Croteau[Show abstract] [Hide abstract]
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.12/2014; 4(1):68. DOI:10.1186/s13550-014-0068-9
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ABSTRACT: Purinergic signaling plays important roles in control of vascular tone and remodeling. There is dual control of vascular tone by ATP released as a cotransmitter with noradrenaline from perivascular sympathetic nerves to cause vasoconstriction via P2X1 receptors, whereas ATP released from endothelial cells in response to changes in blood flow (producing shear stress) or hypoxia acts on P2X and P2Y receptors on endothelial cells to produce nitric oxide and endothelium-derived hyperpolarizing factor, which dilates vessels. ATP is also released from sensory-motor nerves during antidromic reflex activity to produce relaxation of some blood vessels. In this review, we stress the differences in neural and endothelial factors in purinergic control of different blood vessels. The long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides in promoting migration and proliferation of both vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis and vessel remodeling during restenosis after angioplasty are described. The pathophysiology of blood vessels and therapeutic potential of purinergic agents in diseases, including hypertension, atherosclerosis, ischemia, thrombosis and stroke, diabetes, and migraine, is discussed.Pharmacological reviews 01/2014; 66(1):102-192. DOI:10.1124/pr.113.008029 · 18.55 Impact Factor
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ABSTRACT: This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed. The actions of adenine nucleotides and nucleosides on cardiomyocytes, atrioventricular and sinoatrial nodes, cardiac fibroblasts, and coronary blood vessels are described. Cardiac release and degradation of ATP are also described. Finally, the involvement of purinergic signalling and its therapeutic potential in cardiac pathophysiology is reviewed, including acute and chronic heart failure, ischemia, infarction, arrhythmias, cardiomyopathy, syncope, hypertrophy, coronary artery disease, angina, diabetic cardiomyopathy, as well as heart transplantation and coronary bypass grafts.Purinergic Signalling 12/2014; 11(1). DOI:10.1007/s11302-014-9436-1 · 3.51 Impact Factor