Exercise is the most important physiological stimulus for increased myocardial oxygen demand. The requirement of exercising muscle for increased blood flow necessitates an increase in cardiac outpu...

Regulation of Coronary Blood Flow During Exercise

Adenosine is known to regulate myocardial and coronary circulatory functions. Adenosine not only dilates coronary vessels, but attenuates beta-adrenergic receptor-mediated increases in myocardial contractility and depresses both sinoatrial and atrioventricular node activities. The effects of adenosine are mediated by two distinct receptors (i.e., A1 and A2 receptors). A1 adenosine receptors, located in atrial and ventricular myocardium and sinoatrial/atrioventricular nodes, are responsible for inhibition of adenylyl cyclase activity. A2 adenosine receptors, located in coronary endothelial and smooth muscle cells, are responsible for stimulation of this enzyme activity. During increased myocardial oxygen demand due to rapid pacing and exercise, although both coronary blood flow and adenosine concentrations in the myocardium and coronary efflux increased, there is no clear consensus explaining its cause and effect relation at present. However, ischemia/reperfusion-induced coronary hyperemia is believed to be mostly attributed to released adenosine, and it has been proven that adenosine attenuates the severity of ischemia due to its coronary vasodilatory action. The beneficial effects of adenosine during ischemia/reperfusion processes do not seem simple. This is because myocardial ischemia and reperfusion injury is caused by 1) activated leukocytes and platelets, 2) ATP depletion and calcium overload of myocardium, and 3) catecholamine release from the presynaptic nerves as well as 4) the impaired coronary circulation. Intriguingly adenosine attenuates all of these deleterious actions and thereby attenuates ischemia/reperfusion injury. Indeed, adenosine attenuates the severity of contractile dysfunction (myocardial stunning) and limits the infarct size. Thus, administration of adenosine or potentiators of adenosine production in the ischemic myocardium may be beneficial for the attenuation of ischemic and reperfusion injuries, although further clinical investigations are necessary.

Adenosine, the heart, and coronary circulation.

The heart is uniquely responsible for providing its own blood supply through the coronary circulation. Regulation of coronary blood flow is quite complex and, after over 100 years of dedicated research, is understood to be dictated through multiple mechanisms that include extravascular compressive forces (tissue pressure), coronary perfusion pressure, myogenic, local metabolic, endothelial as well as neural and hormonal influences. While each of these determinants can have profound influence over myocardial perfusion, largely through effects on end-effector ion channels, these mechanisms collectively modulate coronary vascular resistance and act to ensure that the myocardial requirements for oxygen and substrates are adequately provided by the coronary circulation. The purpose of this series of Comprehensive Physiology is to highlight current knowledge regarding the physiologic regulation of coronary blood flow, with emphasis on functional anatomy and the interplay between the physical and biological determinants of myocardial oxygen delivery. © 2017 American Physiological Society. Compr Physiol 7:321-382, 2017.

Regulation of Coronary Blood Flow.

Ischemia has been traditionally defined as an insufficiency of oxygen delivery by the blood. Lately it has become clear that such a view is too restrictive. Hypoperfusion may be caused by both anatomic and functional impediments to either inflow to or outflow from an organ. Furthermore, the pathophysiologic consequences are likely to involve not only cellular hypoxia, but also a restricted supply of nutrients and other important molecules, and an abnormal elimination of physiologic wastes such as carbon dioxide. Acute mesenteric ischemia (AMI) is, therefore, a severe anatomic or functional limitation of the splanchnic circulation, resulting in a dual defect of intestinal hypoxia and cellular hypercarbia. It is a complex syndrome that includes three related processes: occlusive mesenteric ischemia, nonocclusive ischemia, and sepsis-induced splanchnic ischemia. Acute occlusive mesenteric ischemia is caused by a local impairment of splanchnic blood flow. Arterial occlusion is usually caused by embolism rather than thrombosis. Mesenteric vein thrombosis is responsible for 20% of acute occlusive mesenteric ischemia. This condition is termed primary when no predisposing factors can be identified. Secondary mesenteric vein thrombosis may occur in portal hypertension, intraabdominal infection, and carcinomatosis (particularly gastrointestinal and pancreatic). Nonocclusive mesenteric ischemia is caused by the nonobstructive reduction in oxygen delivery below the critical level where oxygen consumption becomes supply dependent and tissues resort to anaerobic metabolism. Nonocclusive mesenteric ischemia has been observed in shock syndromes, low-flow states, drug-induced vasoconstriction, hypotension complicating vasodilator therapy, and other conditions. Preexisting vascular disease such as diabetes with small vessel disease or arteriosclerosis will predispose to nonocclusive ischemia. Visceral hypoxia is characterized by a reduction in synthesis and an acceleration of the catabolism of adenosine triphosphate. Ischemia finally occurs because either oxygen consumption is reduced or oxygen demand is excessive, or a combination of both. Depressed mesenteric oxygen consumption generally develops because of diminished oxygen delivery. It may also be the consequence of severely reduced cellular oxygen uptake, or an abnormal oxygen utilization apparatus. Excessive acid is produced and buffered, thereby generating CO2 anaerobically. The increase in CO2 production, coupled with a reduction in CO2 removal due to a reduced or absent blood flow, forms the basis for cellular, tissue, and venous hypercarbia. Splanchnic flow is sensitive to numerous factors including the autonomic nervous system, hormones, endogenous mediators, and various drugs. Reperfusion injury is the secondary damage that occurs to ischemic tissues after the reestablishment of blood flow. It is characterized by intense vasospasm and ischemic injury of the intestinal mucosa. This may be due to oxygen-derived free-radical-mediated cellular damage. This secondary nonocclusive transformation of an occlusive ischemia provides a rationale for vasodilatory therapy of occlusive splanchnic ischemia. Sepsis is intricately associated with mesenteric ischemia. The evolution of primary AMI is almost always complicated by sepsis due to enteric organisms. Sepsis-induced gastrointestinal tract dysfunction appears due to visceral ischemia, probably caused by uncontrolled inflammation. When sepsis occurs in AMI, it usually marks the point at which the local disease process acquires a multisystemic dimension, heralding the syndrome of multisystem organ failure with its dismal prognosis. The difficulty of an early diagnosis is probably the most important cause of the high mortality, which varies from 60% to 90%. The diagnosis is particularly difficult in the elderly because of the lack of specificity and the paucity of symptoms. The diagnosis of AMI must be made on the basis of a high index of suspicion. Clinical clues include nausea, vomiting, and diffuse abdominal pain that is out of proportion to symptoms. The difficult diagnosis is compounded by the paucity of revealing laboratory data, which are often nonspecific and consist of a moderate leukocytosis, hyperamylasemia, and lactic acidosis. Rarely, a plain film of the abdomen may suggest the diagnosis. Angiography may demonstrate vasospasm, arterial occlusion, and venous obstruction. Other diagnostic modalities under investigation include mucosal tonometry, ultrasonic duplex scanning, flexible endoscopy, laparoscopy, surface oximetry, infrared photoplethysmography, and 31P magnetic resonance spectroscopy. Most cases of AMI are diagnosed long after the episode has started. The treatment of mesenteric ischemia has two major goals: the prevention of mesenteric infarction and the forestallment of sepsis and sepsis-induced multisystem organ failure. Management of established AMI involves treating the local intestinal injury as well as the systemic consequences, including sepsis. There are three types of care: resuscitative, operative, and nonoperative.

Acute mesenteric ischemia: pathophysiology, diagnosis, and treatment.

Under normal physiological conditions, coronary blood flow is closely matched with the rate of myocardial oxygen consumption. This matching of flow and metabolism is physiologically important due to the limited oxygen extraction reserve of the heart. Thus, when myocardial oxygen consumption is increased, as during exercise, coronary vasodilation and increased oxygen delivery are critical to preventing myocardial underperfusion and ischemia. Exercise coronary vasodilation is thought to be mediated primarily by the production of local metabolic vasodilators released from cardiomyocytes secondary to an increase in myocardial oxygen consumption. However, despite various investigations into this mechanism, the mediator(s) of metabolic coronary vasodilation remain unknown. As will be seen in this review, the adenosine, K(+)(ATP) channel and nitric oxide hypotheses have been found to be inadequate, either alone or in combination as multiple redundant compensatory mechanisms. Prostaglandins and potassium are also not important in steady-state coronary flow regulation. Other factors such as ATP and endothelium-derived hyperpolarizing factors have been proposed as potential local metabolic factors, but have not been examined during exercise coronary vasodilation. In contrast, norepinephrine released from sympathetic nerve endings mediates a feed-forward betaadrenoceptor coronary vasodilation that accounts for approximately 25% of coronary vasodilation observed during exercise. There is also a feed-forward alpha-adrenoceptor-mediated vasoconstriction that helps maintain blood flow to the vulnerable subendocardium when heart rate, myocardial contractility, and oxygen consumption are elevated during exercise. Control of coronary blood flow during pathophysiological conditions such as hypertension, diabetes mellitus, and heart failure is also addressed.

Control of coronary blood flow during exercise.

We determined the effect of alterations in coronary arterial PCO2 on coronary vascular resistance (CVR) at a constant coronary sinus (CS) PO2 and the effect of coronary arterial PO2 variation on CVR at a constant CS PCO2. A linear but opposing effect on CVR was found for both gases. The sensitivity of CVR to O2 change, represented as CVR/CS PO2, was approximately twice that of the ratio CVR/CS PCO2. (0.0852 +/- 0.006 vs. -0.0362 +/- 0.005). The entire range of CVR variation obtainable through CO2 variation was as great as that resulting from O2 variation. During randomized variation of O2 and CO2, CVR can be mathematically related in a multiple linear expression to CS PO2 and CS PCO2.

Relative effect of CO2 on canine coronary vascular resistance.

A micro-PCO2 electrode, with dimensions of 1 x 10 mm, and a 63% response time of 14 s was inserted into the left ventricular myocardium of the pentobarbital-anesthetized dog. Continuous recordings were made of myocardial PCO2 (PmCO2), arterial PCO2 (PaCO2), and coronary sinus PCO2 (CSPCO2) during variation of respiratory rate. PmCO2 and CSPCO2 were compared at varying coronary flow. PmCO2 was similar to and closely followed changes in CSPCO2. The difference between PmCO2 and CSPCO2 was -0.52 +/- 3.63 (SD) mmHg, and PmCO2 exceeded PaCO2 by 20.69 +/- 5.12 mmHg. After coronary occlusion, PmCO2, rose promptly, but CSPCO2 was only slightly elevated until the occlusion was released, when a CO2 efflux into the coronary sinus occurred. It is concluded that the electrode measures extracellular PCO2 and that extracellular and myocardial PCO2 are essentially equal. PmCO2 rises rapidly following coronary occlusion.

Measurement of myocardial PCO2 with a microelectrode: its relation to coronary sinus PCO2

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Relative effect of CO2 on canine coronary vascular resistance.

Measurement of myocardial PCO2 with a microelectrode: its relation to coronary sinus PCO2