Control of coronary blood flow during exercise

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.     

Feedforward sympathetic coronary vasodilation in exercising dogs.

The hypothesis that exercise-induced coronary vasodilation is a result of sympathetic activation of coronary smooth muscle beta-adrenoceptors was tested. Ten dogs were chronically instrumented with a flow transducer on the circumflex coronary artery and catheters in the aorta and coronary sinus. During treadmill exercise, coronary venous oxygen tension decreased with increasing myocardial oxygen consumption, indicating an imperfect match between myocardial blood flow and oxygen consumption. This match was improved after alpha-adrenoceptor blockade with phentolamine but was significantly worse than control after alpha + beta-adrenoceptor blockade with phentolamine plus propranolol. The response after alpha-adrenoceptor blockade included local metabolic vasodilation plus a beta-adrenoceptor vasodilator component, whereas the response after alpha + beta-adrenoceptor blockade contained only the local metabolic vasodilator component. The large difference in coronary venous oxygen tensions during exercise between alpha-adrenoceptor blockade and alpha + beta-adrenoceptor blockade indicates that there is significant feedforward beta-adrenoceptor coronary vasodilation in exercising dogs. Coronary venous and estimated myocardial interstitial adenosine concentrations did not increase during exercise before or after alpha + beta-adrenoceptor blockade, indicating that adenosine levels did not increase to compensate for the loss of feedforward beta-adrenoceptor-mediated coronary vasodilation. These results indicate a meaningful role for feedforward beta-receptor-mediated sympathetic coronary vasodilation during exercise.     

Adenosine is not responsible for local metabolic control of coronary blood flow in dogs during exercise

The purpose of this investigation was to quantitatively evaluate the role of adenosine in coronary exercise hyperemia. Dogs (n = 10) were chronically instrumented with catheters in the aorta and coronary sinus, and a flow probe on the circumflex coronary artery. Cardiac interstitial adenosine concentration was estimated from arterial and coronary venous plasma concentrations using a previously tested mathematical model. Coronary blood flow, myocardial oxygen consumption, heart rate, and aortic pressure were measured at rest and during graded treadmill exercise with and without adenosine receptor blockade with either 8-phenyltheophylline (8-PT) or 8-p-sulfophenyltheophylline (8-PST). In control vehicle dogs, exercise increased myocardial oxygen consumption 4.2-fold, coronary blood flow 3.8-fold, and heart rate 2.5-fold, whereas mean aortic pressure was unchanged. Coronary venous plasma adenosine concentration was little changed with exercise, and the estimated interstitial adenosine concentration remained well below the threshold for coronary vasodilation. Adenosine receptor blockade did not significantly alter myocardial oxygen consumption or coronary blood flow at rest or during exercise. Coronary venous and estimated interstitial adenosine concentration did not increase to overcome the receptor blockade with either 8-PT or 8-PST as would be predicted if adenosine were part of a high-gain, negative-feedback, local metabolic control mechanism. These results demonstrate that adenosine is not responsible for local metabolic control of coronary blood flow in dogs during exercise.     

Matching coronary blood flow to myocardial oxygen consumption.

At rest the myocardium extracts approximately 75% of the oxygen delivered by coronary blood flow. Thus there is little extraction reserve when myocardial oxygen consumption is augmented severalfold during exercise. There are local metabolic feedback and sympathetic feedforward control mechanisms that match coronary blood flow to myocardial oxygen consumption. Despite intensive research the local feedback control mechanism remains unknown. Physiological local metabolic control is not due to adenosine, ATP-dependent K(+) channels, nitric oxide, prostaglandins, or inhibition of endothelin. Adenosine and ATP-dependent K(+) channels are involved in pathophysiological ischemic or hypoxic coronary dilation and myocardial protection during ischemia. Sympathetic beta-adrenoceptor-mediated feedforward arteriolar vasodilation contributes approximately 25% of the increase in coronary blood flow during exercise. Sympathetic alpha-adrenoceptor-mediated vasoconstriction in medium and large coronary arteries during exercise helps maintain blood flow to the vulnerable subendocardium when cardiac contractility, heart rate, and myocardial oxygen consumption are high. In conclusion, several potential mediators of local metabolic control of the coronary circulation have been evaluated without success. More research is needed.     

Acute adaptations of the coronary circulation to exercise

Coronary blood flow is tightly coupled to myocardial oxygen consumption to maintain a consistently high level of myocardial oxygen extraction. This tight coupling has been proposed to depend on periarteriolar, oxygen tension, signals released from cardiomyocytes (adenosine acting on K _ATP ⁺ channels), and/or the endothelium (prostanoids, nitric oxide, endothelin [ET]) and autonomic influences (catecholamines), but the contribution of each of these regulatory pathways and their interactions are still incompletely understood. Until recently, experimental studies into the regulation of coronary blood flow during exercise were principally performed in the dog. We have performed several studies on the regulation of vasomotor tone in coronary resistance vessels in chronically instrumented exercising swine. These studies have shown that the coronary resistance vessels in swine lack significant α-adrenergic control, but that these vessels are subject to β-adrenergic feed-forward control during exercise, which is aided by a parasympathetic withdrawal. In addition, withdrawal of an ET-mediated vasoconstrictor influence also contributes to exercise-induced coronary vasodilation. Coronary blood flow regulation by endothelial and metabolic vasodilator pathways contributes to resting vasomotor tone regulation but does not appear to contribute to the exercise-induced coronary vasodilation. Furthermore, blockade of one vasodilator pathway is not compensated by an increased contribution of the other vasodilator mechanisms, suggesting that porcine coronary vasomotor control by endothelial and metabolic factors occurs in a linear additive rather than a nonlinear synergistic fashion.     

Role of nitric oxide in the control of coronary resistance in teleosts

In mammals, the in vivo coronary blood flow and myocardial oxygen consumption are closely related via changes in coronary resistance in response to the metabolic demands of the myocardium. A fine neurohumoral regulation of coronary resistance holds true also in fish, and particularly in teleosts, where several vasoconstrictive and vasodilative mechanisms have been described, with numerous putative effectors, including prostanoids, acetylcholine, adrenaline, serotonin, adenosine, steroid hormones. Here, a resume is reported of the available evidence on the involvement of nitric oxide (NO) in the control of coronary resistance in teleosts and particularly in salmonids. Most of the evidence reported is from a comprehensive study performed on a Langedorff-type preparation of the isolated trout heart. Using a physio-pharmacological approach, the experiments performed on this preparation have demonstrated that trout coronary resistance is reduced by l-arginine (NOS substrate), nitroprusside and SNAP (NO donors) and is increased by the NOS inhibitors l-NNA and l-NAME. The vasodilation induced by nitroprusside is blocked by the guanylate cyclase inhibitor methylene blue. l-arginine increases NO release in the perfusate, while l-NNA reduces the release. NO release is inversely related with the coronary resistance. l-NNA inhibits the vasodilatory effects of acetylcholine, serotonin and adenosine. The vasodilation induced by adenosine is accompanied by NO release and involves stretch receptors. Hypoxia induces vasodilation and both adenosine and NO release in the preparation; the NO release under hypoxia is blocked by theophylline. On the whole these data indicate that NO plays a central role in the control of coronary resistance in trout. In particular, a main role for NO as an amplifier of the adenosine-mediated vasodilation under hypoxia can be hypothesized.     

K(ATP)(+) channels, nitric oxide, and adenosine are not required for local metabolic coronary vasodilation

The role of ATP-sensitive K(+) (K(ATP)(+)) channels, nitric oxide, and adenosine in coronary exercise hyperemia was investigated. Dogs (n = 10) were chronically instrumented with catheters in the aorta and coronary sinus and instrumented with a flow transducer on the circumflex coronary artery. Cardiac interstitial adenosine concentration was estimated from arterial and coronary venous plasma concentrations using a previously tested mathematical model. Experiments were conducted at rest and during graded treadmill exercise with and without combined inhibition of K(ATP)(+) channels (glibenclamide, 1 mg/kg iv), nitric oxide synthesis (N(omega)-nitro-L-arginine, 35 mg/kg iv), and adenosine receptors (8-phenyltheophylline, 3 mg/kg iv). During control exercise, myocardial oxygen consumption increased ~2.9-fold, coronary blood flow increased ~2.6-fold, and coronary venous oxygen tension decreased from 19.9 +/- 0.4 to 13.7 +/- 0.6 mmHg. Triple blockade did not significantly change the myocardial oxygen consumption or coronary blood flow response during exercise but lowered the resting coronary venous oxygen tension to 10.0 +/- 0.4 mmHg and during exercise to 6.2 +/- 0.5 mmHg. Cardiac adenosine levels did not increase sufficiently to overcome the adenosine receptor blockade. These results indicate that combined inhibition of K(ATP)(+) channels, nitric oxide synthesis, and adenosine receptors lowers the balance between total oxygen supply and consumption at rest but that these factors are not required for local metabolic coronary vasodilation during exercise.     

Growth regulation of the vascular system: an emerging role for adenosine

The importance of metabolic factors in the regulation of angiogenesis is well understood. An increase in metabolic activity leads to a decrease in tissue oxygenation causing tissues to become hypoxic. The hypoxia initiates a variety of signals that stimulate angiogenesis, and the increase in vascularity that follows promotes oxygen delivery to the tissues. When the tissues receive adequate amounts of oxygen, the intermediate effectors return to normal levels, and angiogenesis ceases. An emerging concept is that adenosine released from hypoxic tissues has an important role in driving the angiogenesis. The following feedback control hypothesis is proposed: AMP is dephosphorylated by ecto-5'-nucleotidase, producing adenosine under hypoxic conditions in the extracellular space adjacent to a parenchymal cell (e.g., cardiomyocyte, skeletal muscle fiber, hepatocyte, etc.). Extracellular adenosine activates A(2) receptors, which stimulates the release of vascular endothelial growth factor (VEGF) from the parenchymal cell. VEGF binds to its receptor (VEGF receptor 2) on endothelial cells, stimulating their proliferation and migration. Adenosine can also stimulate endothelial cell proliferation independently of VEGF, which probably involves modulation of other proangiogenic and antiangiogenic growth factors and perhaps an intracellular mechanism. In addition, hemodynamic factors associated with adenosine-induced vasodilation may have a role in the development and remodeling of the vasculature. Once a new capillary network has been established, and the diffusion/perfusion capabilities of the vasculature are sufficient to supply the parenchymal cells with adequate amounts of oxygen, adenosine and VEGF as well as other proangiogenic and antiangiogenic growth factors return to near-normal levels, thus closing the negative feedback loop. The available data indicate that adenosine might be an essential mediator for up to 50-70% of the hypoxia-induced angiogenesis in some situations; however, additional studies in intact animals will be required to fully understand the quantitative importance of adenosine.     

Vasomotor control: functional hyperemia and beyond

Historically, functional hyperemia has been viewed largely as an interaction between a parenchymal cell and its associated microvasculature. Locally released metabolites have been thought to produce relaxation of the smooth muscle and a vasodilation that increases blood flow in proportion to metabolic need. This symposium report presents evidence from a variety of disciplines and a number of different types of biological preparations that demonstrates that functional hyperemia is a complex process involving several classes of microvessels including capillaries, arterioles, and small arteries. These vessels do not function independently but are coordinated by a complex set of interrelations involving at least three different modes of interaction between parenchymal cells and the various segments of the vascular bed. These are local metabolic effects, propagated effects extending over long segments of the vasculature, and flow-dependent vasodilation induced by local changes in blood flow. In addition to these acute responses to metabolic demand it appears that tissues may be capable of more long-term structural alterations of the arterial and arteriolar network in response to sustained changes in the relationship between supply and demand. The vascular bed appears to be able to adapt either by increasing the maximal anatomic diameter of the large arteries or by inserting new arterioles into the parenchyma. Thus, classical functional hyperemia appears to be but one manifestation of a multifaceted process leading to highly coordinated responses of many vascular elements, resulting finally in vascular patterns that are optimized to meet parenchymal cell demands.     

Plasma ATP during exercise: possible role in regulation of coronary blood flow

It was previously shown that red blood cells release ATP when blood oxygen tension decreases. ATP acts on microvascular endothelial cells to produce a retrograde conducted vasodilation (presumably via gap junctions) to the upstream arteriole. These observations form the basis for an ATP hypothesis of local metabolic control of coronary blood flow due to vasodilation in microvascular units where myocardial oxygen extraction is high. Dogs (n = 10) were instrumented with catheters in the aorta and coronary sinus, and a flow transducer was placed around the circumflex coronary artery. Arterial and coronary venous plasma ATP concentrations were measured at rest and during three levels of treadmill exercise by using a luciferin-luciferase assay. During exercise, myocardial oxygen consumption increased approximately 3.2-fold, coronary blood flow increased approximately 2.7-fold, and coronary venous oxygen tension decreased from 19 to 12.9 mmHg. Coronary venous plasma ATP concentration increased significantly from 31.1 to 51.2 nM (P < 0.01) during exercise. Coronary blood flow increased linearly with coronary venous ATP concentration (P < 0.01). Coronary venous-arterial plasma ATP concentration difference increased significantly during exercise (P < 0.05). The data support the hypothesis that ATP is one of the factors controlling coronary blood flow during exercise.     

Fetal pulmonary vasodilation and vasoreactivity during metabolic acidaemia

We studied the pulmonary vascular response to progressive metabolic acidaemia and to an abrupt increase in oxygen tension during metabolic acidaemia in 8 chronically-prepared fetal sheep. Left pulmonary artery blood flow was measured by electromagnetic flow transducer. Two and a half hour infusion of NH4Cl into the fetal inferior vena cava caused pH to fall to 6.94 +/- 0.01 from 7.37 +/- 0.01 (P less than 0.001). During this period of progressive metabolic acidaemia, left pulmonary artery blood flow increased from a baseline value of 60 +/- 8 to 105 +/- 14 ml.min-1 (P less than 0.002). Pulmonary artery pressure did not change significantly and calculated pulmonary vascular resistance fell indicating fetal pulmonary vasodilation. PO2 rose significantly (19.8 +/- 0.7 to 24.1 +/- 1.8 torr; P less than 0.03) and oxygen saturation fell (54.6 +/- 2.8% to 38.9 +/- 3.5%; P less than 0.001) confirming a rightward shift of the oxyhaemoglobin dissociation curve. During acidaemia, administration of 100% oxygen to the ewe further increased fetal PO2 to 37.9 +/- 2.3 torr within 10 min (P less than 0.001) and this increase in PO2 was accompanied by an increase in left pulmonary artery blood flow (P less than 0.001), a fall in pulmonary artery pressure (P less than 0.03) and a decrease in pulmonary vascular resistance (P less than 0.001) indicating further vasodilation. The response of the fetal pulmonary circulation to a 2-h period of increased oxygen tension was qualitatively similar in acidaemic and non-acidaemic fetuses. We conclude that the progressive metabolic acidaemia imposed by these experimental conditions increases pulmonary blood flow likely through an increase in fetal PO2 and that metabolic acidaemia does not block the normal vasodilatory response to an increase in oxygen tension.     

Alpha-adrenergic tone in the coronary circulation of the conscious dog

To examine the role of neural factors in the control of coronary vasoactivity in conscious animals, dogs were supplied with miniature pressure gauges in the aorta and left ventricle (to measure aortic and left ventricular pressures, respectively and with a flow probe on the left circumflex coronary artery (to measure coronary blood flow). The experiments were conducted several weeks after recovery from operation. Stimulation of the carotid chemoreceptor and pulmonary inflation elicited a biphasic reflex response. Initially, coronary vasodilation was observed; coronary blood flow tripled even after changes in metabolic factors were minimized by pretreatment with propranolol. A similar response occurred after a spontaneous deep breath. The coronary vasodilation could be blocked by alpha-adrenergic receptor blockade. The second phase of the response involved an increase in coronary vascular resistance, associated with elevated arterial pressure and an absolute reduction in coronary blood flow and coronary sinus oxygen content. The secondary coronary vasoconstriction was also abolished by alpha-adrenergic blockade. Paradoxically, alpha-adrenergic receptor blockade with phentolamine (at constant heart rate and after beta-adrenergic receptor blockade) did not increase coronary blood flow and reduced coronary vascular resistance only slightly. Selective alpha 1-adrenergic receptor blockade with prazosin and trimazosin on different days induced progressively greater reductions in coronary vascular resistance. Trimazosin was the only alpha-adrenergic receptor blocker to elevate coronary blood flow significantly. It is conceivable, but speculative, that withdrawal of alpha-adrenergic tone may involve activation of an intermediate agent, which is a potent coronary vasodilator. Alternatively, withdrawal of alpha-adrenergic tone may be an important mechanism for immediate control of the coronary circulation, but under more chronic conditions it plays a lesser role as a result of suppression by metabolic factors.     

Local control of skeletal muscle blood flow during exercise: influence of available oxygen

Reductions in oxygen availability (O(2)) by either reduced arterial O(2) content or reduced perfusion pressure can have profound influences on the circulation, including vasodilation in skeletal muscle vascular beds. The purpose of this review is to put into context the present evidence regarding mechanisms responsible for the local control of blood flow during acute systemic hypoxia and/or local hypoperfusion in contracting muscle. The combination of submaximal exercise and hypoxia produces a "compensatory" vasodilation and augmented blood flow in contracting muscles relative to the same level of exercise under normoxic conditions. A similar compensatory vasodilation is observed in response to local reductions in oxygen availability (i.e., hypoperfusion) during normoxic exercise. Available evidence suggests that nitric oxide (NO) contributes to the compensatory dilator response under each of these conditions, whereas adenosine appears to only play a role during hypoperfusion. During systemic hypoxia the NO-mediated component of the compensatory vasodilation is regulated through a β-adrenergic receptor mechanism at low-intensity exercise, while an additional (not yet identified) source of NO is likely to be engaged as exercise intensity increases during hypoxia. Potential candidates for stimulating and/or interacting with NO at higher exercise intensities include prostaglandins and/or ATP. Conversely, prostaglandins do not appear to play a role in the compensatory vasodilation during exercise with hypoperfusion. Taken together, the data for both hypoxia and hypoperfusion suggest NO is important in the compensatory vasodilation seen when oxygen availability is limited. This is important from a basic biological perspective and also has pathophysiological implications for diseases associated with either hypoxia or hypoperfusion.     

Effect of 2-(6-cyano-1-hexyn-1-yl)adenosine on ocular blood flow in rabbits

Previously, we reported that a relatively selective adenosine A(2A) receptor agonist 2-(6-cyano-1-hexyn-1-yl)adenosine (2-CN-Ado) elicited ocular hypotension in rabbits (Journal of Pharmacological Sciences 2005;97:501-509). In the present study, we investigated the effect of 2-CN-Ado on ocular blood flow in rabbit eyes. An intravitreal injection of 2-CN-Ado increased ocular blood flow, measured by a non-contact laser flowmeter. 2-CN-Ado-induced increase in ocular blood flow was accompanied with the retinal vasodilation. The increase in ocular blood flow was inhibited by an adenosine A(2A) receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine, but not by an adenosine A(2B) receptor antagonist alloxazine or an adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. The repetitive applications of topical 2-CN-Ado twice a day for 7 days produced a persistent increase in ocular blood flow with ocular hypotension. These results suggest that 2-CN-Ado increases the ocular blood flow mainly via adenosine A(2A) receptor, and that the topical application of 2-CN-Ado for several days not only increases the ocular blood flow but also prolong ocular hypotension, indicating that 2-CN-Ado may be a useful lead compound for the treatment of ischemic retinal diseases such as glaucoma.     

Coordination of kidney filtration and tubular reabsorption: considerations on the regulation of metabolic demand for tubular reabsorption

Kidney blood flow is highly regulated by a combination of myogenic autoregulation, multiple neurohormonal systems and the tubuloglomerular feedback system, the later of which specifically relates tubular reabsorption to the filtered load. Oxygen and substrate requirements of the kidney are dictated by both supply of oxygen and substrates and metabolic demands of the kidney. The tubuloglomerular feedback system utilizes mediators which are intimately linked to cellular metabolism, ATP and adenosine. This system based upon communication transfer between the macular densa and the afferent arteriole stabilizes kidney function and is not static but temporally adapts or resets to new external physiologic conditions. Such temporal adaptation occurs via modulators such as nitric oxide (NO), primarily derived from NOS-1, angiotensin II and COX-2 products. These hormonal influences also exert capacities to modulate cellular demands for oxygen, particularly NO which decreases oxygen consumption via multiple mechanisms. The several mechanisms whereby NO and other hormonal systems and transporter activity can regulate and produce changes in kidney metabolic demands are discussed. Modulators which influence temporal adaptation and resetting of TGF are also significant contributors to the regulation of cellular oxygen consumption in the kidney. These systems may act in concert to preserve the coordination of filtered load and tubular reabsorption and the metabolic demands of kidney function, thereby determining the ischemic threshold for kidney function.     

The use of 8-phenyltheophylline as a competitive antagonist of adenosine and an inhibitor of the intrinsic regulatory mechanism of the hepatic artery

Reduction of portal blood flow results in compensatory vasodilation of the hepatic artery, the hepatic arterial buffer response. The hypothesis tested is that the regulation of the buffer response is mediated by adenosine, where the local concentration of adenosine in the region of the hepatic arterial resistance vessels is regulated by washout of adenosine into portal venules that are in intimate contact with hepatic arterioles. In anesthetized cats, portal flow was reduced to zero by complete occlusion of all arterial supply to the guts. The resultant dilation of the hepatic artery compensated for 23.9 +/- 4.9% of the decrease in portal flow. Dose-response curves were obtained for the effect of intraportal adenosine infusion on hepatic arterial conductance in doses that did not lead to recirculation and secondary effects on the hepatic artery via altered portal blood flow. The dose to produce one-half maximal response for adenosine is 0.19 mg X kg-1 X min-1 (intraportal) and the estimated maximal dilation is equivalent to an increase in hepatic arterial conductance to 245% of the basal (100%) level. The adenosine antagonist, 8-phenyltheophylline, produced dose-related competitive antagonism of the dilator response to infused adenosine (but not to isoproterenol) and a similar, parallel antagonism of the hepatic arterial buffer response. If supramaximal blocking doses were used, the hepatic artery showed massive and prolonged constriction with blood flow decreasing to zero. The data strongly support the hypothesis that intrinsic hepatic arterial buffer response is mediated entirely by local adenosine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of adenosine in the isolatedRana ridibunda heart

Summary In an attempt to study the metabolic role of adenosine in the amphibian heart, we perfusedRana ridibunda hearts under conditions of decreased oxygen supply or increased oxygen demand and measured the rate of adenosine appearance as well as the concentrations of adenine nucleotides. Anoxia was associated with a significant increase in the myocardial and perfusate concentration of adenosine and its degradation products, inosine and hypoxanthine, while changes were also observed in the concentrations of adenine nucleotides and creatine phosphate. Furthermore, adenosine production inRana ridibunda hearts was enhanced under conditions of increased cardiac work induced by perfusion pressure elevation. Adenosine production was inversely proportional to the energy charge value calculated from the tissue content of adenine nucleotides under conditions of anoxia and increased heart work. The results are in accordance with the proposed role of adenosine as a physiological metabolic vasodilator in the coronary circulation of the mammalian heart and support the hypothesis that adenosine can be involved in regulating blood vessel resistance inRana ridibunda heart under conditions of low myocardial oxygen tension. Thus it appears that adenosine could act as a vasodilatory substance inRana ridibunda heart.     

Transmural difference in coronary arteriolar dilation to adenosine: effect of luminal pressure and K(ATP) channels

Coronary blood flow in the subendocardium is preferentially increased by adenosine but is redistributed to the subepicardium during ischemia in association with coronary pressure reduction. The mechanism for this flow redistribution remains unclear. Since adenosine is released during ischemia, it is possible that the coronary microcirculation exhibits a transmural difference in vasomotor responsiveness to adenosine at various intraluminal pressures. Although the ATP-sensitive K(+) (K(ATP)) channel has been shown to be involved in coronary arteriolar dilation to adenosine, its role in the transmural adenosine response remains elusive. To address these issues, pig subepicardial and subendocardial arterioles (60-120 micrometer) were isolated, cannulated, and pressurized to 20, 40, 60, or 80 cmH(2)O without flow for in vitro study. At each of these pressures, vessels developed basal tone and dilated concentration dependently to adenosine and the K(ATP) channel opener pinacidil. Subepicardial and subendocardial arterioles dilated equally to adenosine and pinacidil at 60 and 80 cmH(2)O luminal pressure. At lower luminal pressures (i.e., 20 and 40 cmH(2)O), vasodilation in both vessel types was enhanced. Enhanced vasodilatory responses were not affected by removal of endothelium but were abolished by the K(ATP) channel inhibitor glibenclamide. In a manner similar to reducing pressure, a subthreshold dose of pinacidil potentiated vasodilation to adenosine. In contrast to adenosine, dilation of coronary arterioles to sodium nitroprusside was independent of pressure changes. These results indicate that coronary microvascular dilation to adenosine is enhanced at lower intraluminal pressures by selective activation of smooth muscle K(ATP) channels. Since microvascular pressure has been shown to be consistently lower in the subendocardium than in the subepicardium, it is likely that the inherent pressure gradient in the coronary microcirculation across the ventricular wall may be an important determinant of transmural flow in vivo during resting conditions or under metabolic stress with adenosine release.     

Adenosine causes a biphasic response in the ovine fetal placental vasculature

We have reported in a previous study that adenosine infusion causes fetal placental vascular resistance to increase after 2 min. To determine whether this action is followed by a more prolonged vasodilation, we studied 7 mature fetal lambs. At surgery, catheters were inserted into the fetal hindlimb arteries and veins. After a five day recovery period, control blood flow measurements were made by radiolabeled microsphere technique immediately after an infusion of 0.9% NaCl, (vehicle, 1.03 ml.min-1) into a fetal vein for 2 min. Within 5 min of the control blood flow measurement, adenosine (10 mg/min) was infused for 2 min. Blood flow measurements were repeated 5, 10, 15, 20 and 30 min after the end of the infusion period. Fetal arterial blood pressure dropped from 50 +/- 1 to 34 +/- 5 mmHg immediately after the adenosine infusion and returned to the control value within 5 min after the infusion. No further blood pressure response was detected. However, placental vascular resistance fell from 0.334 +/- 0.040 to 0.269 +/- 0.027 (P less than 0.05) at the 15 min measurement, remained low through the 20 min measurement (P less than 0.001) and was not different from control levels 30 min after the adenosine infusion. We conclude that the fetal placental vasculature responds to systemic adenosine infusion in a biphasic manner. The immediate reaction to adenosine is a transient vasoconstriction in the fetal placental vasculature followed by vasodilation 15 to 20 min after the initial exposure to adenosine.     

Muscle pump does not enhance blood flow in exercising skeletal muscle.

The muscle pump theory holds that contraction aids muscle perfusion by emptying the venous circulation, which lowers venous pressure during relaxation and increases the pressure gradient across the muscle. We reasoned that the influence of a reduction in venous pressure could be determined after maximal pharmacological vasodilation, in which the changes in vascular tone would be minimized. Mongrel dogs (n = 7), instrumented for measurement of hindlimb blood flow, ran on a treadmill during continuous intra-arterial infusion of saline or adenosine (15-35 mg/min). Adenosine infusion was initiated at rest to achieve the highest blood flow possible. Peak hindlimb blood flow during exercise increased from baseline by 438 +/- 34 ml/min under saline conditions but decreased by 27 +/- 18 ml/min during adenosine infusion. The absence of an increase in blood flow in the vasodilated limb indicates that any change in venous pressure elicited by the muscle pump was not adequate to elevate hindlimb blood flow. The implication of this finding is that the hyperemic response to exercise is primarily attributable to vasodilation in the skeletal muscle vasculature.