Control Of Coronary Blood Flow Research Articles

Heart of the matter: coronary dysfunction in metabolic syndrome.

Metabolic syndrome (MetS) is a collection of risk factors including obesity, dyslipidemia, insulin resistance/impaired glucose tolerance, and/or hypertension. The incidence of obesity has reached pandemic levels, as ~20-30% of adults in most developed countries can be classified as having MetS. This increased prevalence of MetS is critical as it is associated with a two-fold elevated risk for cardiovascular disease. Although the pathophysiology underlying this increase in disease has not been clearly defined, recent evidence indicates that alterations in the control of coronary blood flow could play an important role. The purpose of this review is to highlight current understanding of the effects of MetS on regulation of coronary blood flow and to outline the potential mechanisms involved. In particular, the role of neurohumoral modulation via sympathetic α-adrenoceptors and the renin-angiotensin-aldosterone system (RAAS) are explored. Alterations in the contribution of end-effector K(+), Ca(2+), and transient receptor potential (TRP) channels are also addressed. Finally, future perspectives and potential therapeutic targeting of the microcirculation in MetS are discussed. This article is part of a Special Issue entitled "Coronary Blood Flow".

Contribution of voltage-dependent K+ channels to metabolic control of coronary blood flow

The purpose of this investigation was to test the hypothesis that K(V) channels contribute to metabolic control of coronary blood flow and that decreases in K(V) channel function and/or expression significantly attenuate myocardial oxygen supply-demand balance in the metabolic syndrome (MetS). Experiments were conducted in conscious, chronically instrumented Ossabaw swine fed either a normal maintenance diet or an excess calorie atherogenic diet that produces the clinical phenotype of early MetS. Data were obtained under resting conditions and during graded treadmill exercise before and after inhibition of K(V) channels with 4-aminopyridine (4-AP, 0.3mg/kg, iv). In lean-control swine, 4-AP reduced coronary blood flow ~15% at rest and ~20% during exercise. Inhibition of K(V) channels also increased aortic pressure (P<0.01) while reducing coronary venous PO(2) (P<0.01) at a given level of myocardial oxygen consumption (MVO(2)). Administration of 4-AP had no effect on coronary blood flow, aortic pressure, or coronary venous PO(2) in swine with MetS. The lack of response to 4-AP in MetS swine was associated with a ~20% reduction in coronary K(V) current (P<0.01) and decreased expression of K(V)1.5 channels in coronary arteries (P<0.01). Together, these data demonstrate that K(V) channels play an important role in balancing myocardial oxygen delivery with metabolism at rest and during exercise-induced increases in MVO(2). Our findings also indicate that decreases in K(V) channel current and expression contribute to impaired control of coronary blood flow in the MetS. This article is part of a Special Issue entitled "Coronary Blood Flow".

Contribution of IKCa channels to the control of coronary blood flow

The purpose of this investigation was to elucidate the contribution of intermediate conductance calcium-activated potassium channels (IK(Ca)) to the regulation of coronary blood flow in vivo. We hypothesized that IK(Ca) channels modulate coronary arteriolar resistance at rest and contribute to vasomotor responses to changes in coronary perfusion pressure and/or in response to cardiac ischemia. Experiments were conducted in open-chest anesthetized dogs in the absence and presence of IK(Ca) channel inhibitor, TRAM-34 (1 μg/min, intracoronary), and the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine-methyl ester (L-NAME) (150 μg/min, intracoronary). We found that administration of the potent SK(Ca) and IK(Ca) channel agonist NS309 dose-dependently increased coronary blood flow and that inhibition of IK(Ca) channels with TRAM-34 attenuated this response by ∼90%. The increase in coronary blood flow to NS309 was also decreased ∼100% by the inhibition of NO production with L-NAME. Multiple linear regression analysis demonstrated that TRAM-34 diminished the autoregulatory capability of the coronary circulation at coronary pressures ranging from 60 to 120 mmHg. However, inhibition of IK(Ca) channels did not affect coronary vasodilation in response to a transient 15 s coronary artery occlusion (i.e. reactive hyperemia). Our data reveal that IK(Ca) channels are functionally expressed in the coronary circulation and that activation of these channels produces marked coronary vasodilation in vivo, primarily via increases in endothelial NO production. In addition, IK(Ca) channels modestly contribute to changes in coronary vascular resistance in response to alterations in coronary perfusion pressure but do not contribute to the reactive hyperemic response following a brief coronary artery occlusion.

Integrated control of coronary blood flow in exercising swine by adenosine, nitric oxide and KATP channels

The mechanism of exercise‐induced coronary vasodilation remains incompletely understood. KATP channels in conjunction with nitric oxide (NO) and adenosine have been proposed to mediate exercise hyperemia in dogs but not in swine. Different results may have been due, in part, to different routes of administration of drugs to block these pathways. Hence, we studied the role of KATP channels together with NO and adenosine in exercise hyperemia in swine, using an identical drug dosing protocol and administration route that was previously shown to virtually abolish the exercise hyperemia in dogs. Swine exercised on a treadmill at 0–5 km/h, before and after blockade of KATP channels (glibenclamide, 50 μg/kg/min intracoronary (ic)), in the absence or presence of blockade of adenosine receptors (8‐phenyltheophylline, 8PT, 5 mg/kg iv) and NO‐synthase (nitro‐L‐arginine, NLA, 1.5 mg/kg, ic). Glibenclamide reduced myocardial O2 delivery and coronary venous O2 tension at rest and during exercise. Administration of 8PT + NLA reduced coronary venous O2 tension but did not enhance vasoconstriction to glibenclamide. Despite an increase in O2‐extraction to ~90% during combined NLA + 8PT + glibenclamide, exercise‐induced hyperemia was maintained. Thus, KATP channels, adenosine and NO do not appear to be critical for exercise coronary hyperemia, and act in a linear additive fashion, in swine.Supported by NHF Grant 2000T042

Contribution of IKCa Channels to the Control of Coronary Blood Flow

The purpose of this investigation was to determine the role of intermediate conductance calcium‐activated potassium channels (IKCa) in regulating coronary arteriolar resistance at rest, in response to changes in coronary perfusion pressure, and during cardiac ischemia. Experiments were conducted in open‐chest anesthetized dogs in the presence of IKCa channel inhibitor, TRAM‐34 (1 μg/min, ic), or the nitric oxide (NO) synthase inhibitor, L‐NAME (150 μg/min, ic). Administration of the SKCa and IKCa channel agonist NS309 dose‐dependently increased coronary blood flow and inhibition of IKCa channels with TRAM‐34 attenuated this response by ~ 90%. The increase in coronary blood flow with NS309 was also decreased ~100% by L‐NAME. In addition, TRAM‐34 diminished the autoregulatory capability of the coronary circulation at pressures ranging from 60 – 120 mmHg. However, inhibition of IKCa channels did not affect coronary reactive hyperemia. Our data reveal that IKCa channels are functionally expressed in the coronary vasculature and that activation of these channels produces marked coronary vasodilation in vivo, primarily via increases in endothelial NO production. In addition, IKCa channels modestly regulate vascular resistance in response to alterations in coronary perfusion pressure but do not modulate coronary vasodilation in response to cardiac ischemia. Support 10PRE4230035, HL092245

Adenine nucleotide control of coronary blood flow during exercise

The adenine nucleotide hypothesis postulates that the ATP released from red blood cells is broken down to ADP and AMP in coronary capillaries and that ATP, ADP, and AMP act on purinergic receptors on the surface of capillary endothelial cells. Purinergic receptor activation initiates a retrograde conducted vasodilator signal to the upstream arteriole that controls coronary blood flow in a negative feedback manner. A previous study (M. Farias 3rd, M. W. Gorman, M. V. Savage, and E. O. Feigl, Am J Physiol Heart Circ Physiol 288: H1586-H1590, 2005) demonstrated that coronary venous plasma ATP concentration increased during exercise and correlated with coronary blood flow. The present experiments test the adenine nucleotide hypothesis by examining the balance between oxygen delivery (via coronary blood flow) and myocardial oxygen consumption during exercise before and after purinergic receptor blockade. Dogs (n = 7) were chronically instrumented with catheters in the aorta and coronary sinus and a flow transducer around the circumflex coronary artery. During control treadmill exercise, myocardial oxygen consumption increased and the balance between oxygen delivery and myocardial oxygen consumption fell as indicated by a declining coronary venous oxygen tension. Blockade of P1 and P2Y(1) purinergic receptors combined with inhibition of nitric oxide synthesis significantly decreased the balance between oxygen delivery and myocardial oxygen consumption compared with control. The results support the hypothesis that ATP and its breakdown products ADP and AMP are part of a negative feedback control mechanism that matches coronary blood flow to myocardial oxygen consumption at rest and during exercise.

The muscle metaboreflex: reining in the heart?

the muscle metaboreflex, also known as the muscle chemoreflex, is one of the principal mediators of the cardiovascular exercise response. This reflex is thought to be triggered by metabolic by-products of ischemia that stimulate afferent nerve endings in skeletal muscle and leads to an increase in

Contribution of BKCa channels to local metabolic coronary vasodilation: effects of metabolic syndrome

This investigation was designed to examine the hypothesis that impaired function of coronary microvascular large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels in metabolic syndrome (MetS) significantly attenuates the balance between myocardial oxygen delivery and metabolism at rest and during exercise-induced increases in myocardial oxygen consumption (MVo(2)). Studies were conducted in conscious, chronically instrumented Ossabaw swine fed a normal maintenance diet (11% kcal from fat) or an excess calorie atherogenic diet (43% kcal from fat, 2% cholesterol, 20% kcal from fructose) that induces many common features of MetS. Data were collected under baseline/resting conditions and during graded treadmill exercise before and after selective blockade of BK(Ca) channels with penitrem A (10 microg/kg iv). We found that the exercise-induced increases in blood pressure were significantly elevated in MetS swine. No differences in baseline cardiac function or heart rate were noted. Induction of MetS produced a parallel downward shift in the relationship between coronary venous Po(2) and MVo(2) (P < 0.001) that was accompanied by a marked release of lactate (negative lactate uptake) as MVo(2) was increased with exercise (P < 0.005). Inhibition of BK(Ca) channels with penitrem A did not significantly affect blood pressure, heart rate, or the relationship between coronary venous Po(2) and MVo(2) in lean or MetS swine. These data indicate that BK(Ca) channels are not required for local metabolic control of coronary blood flow under physiological (lean) or pathophysiological (MetS) conditions. Therefore, diminished function of BK(Ca) channels does not contribute to the impairment of myocardial oxygen-supply demand balance in MetS.

Muscle Metaboreflex Control of Coronary Blood Flow and Ventricular Contractility During Dynamic Exercise in Heart Failure

Muscle metaboreflex activation (MMA) during dynamic exercise increases cardiac work and O2 demand via increases in heart rate, ventricular contractility and afterload. This increase in cardiac work should lead to metabolic coronary vasodilation. However, no change in coronary vascular conductance is seen, indicating that the increased sympathetic activity which increased contractility also caused 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. We tested whether this coronary vasoconstriction could explain in part, the reduced ability to increase cardiac performance during MMA. In conscious, chronically instrumented dogs after pacing induced heart failure, MMA responses during mild exercise were observed before and after α1 ‐ adrenergic blockade (prazosin 50‐100 μg/kg). During MMA, the increases in coronary blood flow, coronary vascular conductance, cardiac output, and +dP/dtmax were significantly greater after α1 ‐ adrenergic blockade. We conclude that during heart failure the coronary vasoconstriction limits the ability of muscle metaboreflex to increase left ventricular contractility. NIH HL 55473

Muscle Metaboreflex Control of Coronary Blood Flow and Ventricular Contractility During Dynamic Exercise

Muscle metaboreflex activation (MMA) 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 lead to coronary metabolic vasodilation. However, in this situation, little if any coronary vasodilation is observed. It is unclear if this lack of coronary vasodilation, which occurs as a result of increased coronary sympathetic stimulation due to MMA, suppresses any further increases in left ventricular contractility (LVC). The purpose of this study was to determine if this lack of coronary vasodilation leads to a buffered increase in LVC. Using chronically instrumented, conscious dogs we measured arterial pressure, cardiac output (CO), circumflex blood flow (CxBF), 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 after MMA. Experiments were repeated after alpha-1 adrenergic blockade (prazosin ∼50 ìg/kg). During prazosin we observed significantly greater increases in CVC, CxBF, CO, dP/dt, and PRSW, with MMA, over that of the control condition. We conclude that the lack of coronary vasodilation limits further improvement in LVC. NIH HL 55473

Adenosine Receptors and Angiogenesis

See related article, pages 1130–1138 As originally hypothesized by Berne,1 adenosine is formed in the heart during hypoxia or ischemia and serves as a negative feedback signal to maintain oxygen delivery within a normal physiological range. Adenosine is formed by the metabolism of ATP and transported into the extracellular space by various nucleoside transport proteins.2 In a more localized manner that provides the opportunity for coordinated signaling with the diverse P2 purinoreceptor family that recognizes ATP and ADP, adenosine is also formed from the extracellular metabolism of adenine nucleotides released from stored granules (sympathetic nerves, platelets, mast cells) or through hemichannels (neutrophils, endothelial cells, epithelial cells) by ecto-apyrases and ecto-nucleotidases.3–5 Adenosine signals through activation of widely distributed cell surface G protein–coupled receptors, of which 4 different subtypes have been identified designated A1, A2A, A2B, and A3.6 By activating A2A receptors that are abundantly expressed in coronary vascular smooth muscle, adenosine generated under hypoxic conditions produces potent vasodilation thereby increasing nutrient and oxygen delivery. Although less appreciated, adenosine also serves to maintain tissue oxygenation in response to chronic ischemic/hypoxic stress by increasing the formation of new blood vessels; that is, by stimulating angiogenesis.7,8 Using adenosine receptor agonists or modulators of adenosine metabolism, an important role for adenosine has been established in in vivo models of angiogenesis.7,8 In cell culture systems, adenosine stimulates endothelial cell migration, proliferation, and tube formation,7–11 actions required for the formation of new capillary networks. This action occurs at concentrations of adenosine that are …

Mechanisms of Coronary Dysfunction in Obesity and Insulin Resistance

The incidence of obesity and the metabolic syndrome has reached epidemic proportions and alterations in coronary microvascular function could contribute to the increased cardiovascular morbidity and mortality observed in these patients. This review highlights key mechanisms of impaired control of coronary blood flow in the metabolic syndrome. Specifically, coronary endothelial dysfunction, altered neurohumoral control, and the potential roles of smooth muscle ion channels are addressed. Recent studies indicate that alterations in endothelial-dependent vasodilation or endothelial-dependent vasoconstriction contribute little to obesity-induced impairments in coronary vascular control. In contrast, augmented vasoconstriction in response to neurohumoral mediators appears to play a significant role in coronary vascular dysfunction. The authors conclude that coronary dysfunction in the metabolic syndrome is characterized by an imbalance between coronary blood flow and myocardial metabolism that may be mediated by sensitization of vasoconstrictor pathways. Further, they suggest that alterations in smooth muscle ion channels, Ca(2+) handling, and cell signaling may be important mechanisms leading to coronary microvascular dysfunction. Importantly, however, more research is needed to clearly delineate specific mechanisms and identify potential therapeutic targets.

Sensitization of Coronary α ‐Adrenoceptor Vasoconstriction in the Prediabetic Metabolic Syndrome

This study tested whether alpha -adrenoceptor-mediated coronary vasoconstriction is augmented in the metabolic syndrome and is accompanied by the alteration of specific alpha(1)- and alpha(2)-coronary adrenoceptors. Studies were conducted in control and chronically high-fat-fed (6 weeks of 60% calories from fat) dogs with metabolic syndrome. Alterations in coronary alpha(1B)-, alpha(1D)-, and alpha(2A)-adrenoceptor mRNA and protein expression were examined by real-time PCR and Western analyses, respectively. Coronary blood flow and its response to intracoronary infusion of either the alpha1-adrenoceptor agonist methoxamine (0.1-3 mg) or the alpha(2)-adrenoceptor agonist BHT-933 (0.1-3 mg) were measured in anesthetized dogs. Basal plasma epinephrine and norepinephrine levels were higher in the high-fat-fed dogs compared to controls. Real-time PCR revealed no alterations of coronary artery or arteriole alpha1B-, alpha(1D)-, and alpha(2A)-adrenoceptor mRNA expression. However, Western blot analysis showed a significant decrease in alpha(2A)-adrenoceptor protein density with no change in alpha(1B)- or alpha(1D)-adrenoceptors. Methoxamine and BHT-933 produced dose-dependent decreases in coronary blood flow, but the decrease in coronary flow to methoxamine was significantly greater (approximately 20%) in dogs with the metabolic syndrome. No differences in the coronary flow response to BHT-933 were noted. These results indicate that the metabolic syndrome is associated with sensitization of alpha1- and alpha2-adrenoceptor signaling that could significantly limit control of coronary blood flow when the sympathetic nervous system is activated.

Hypoxia, coronary dilation, and the pentose phosphate pathway

hypoxic vasorelaxation of resistance arteries is an important feedback control mechanism to maintain adequate oxygenation of metabolically active tissues and is essential in tissues where oxygen extraction is nearly maximized, as it is in the heart. Although the physiological importance of this

Heterogeneous Kv1 function and expression in coronary myocytes from right and left ventricles in rats

Coronary blood flow control is not uniform along the vascular tree and particularly between the right coronary artery and the left anterior descending artery. Resting membrane potential that contributes largely to the vascular tone is mainly regulated by K(+) channels in coronary myocytes. In the present study, we hypothesized that right coronary artery (RCA) and left coronary artery (LCA) exhibited a cell-specific function of K(+) channels. The net outward current was markedly greater in RCA compared with LCA cells, and this difference was due to a larger 4-aminopyridine (4-AP)-sensitive voltage-gated potssium (Kv) current in RCA cells, whereas the iberiotoxin (IbTx)-sensitive, large conductance Ca(2+)-dependent potassium (BK(Ca)) current was smaller in RCA cells. To go further in the molecular identity of this Kv current, we used 50 nM correolide, which specifically blocked Kv1 family alpha-subunits. Outward currents generated by ramp depolarization protocols were highly sensitive to correolide in both RCA and LCA cells, suggesting that Kv1 contributed for a large part to the net outward current. 4-AP-induced contractions in isolated RCA, and LCA were greater than IbTx-induced contraction. Furthermore, the 4-AP-induced contraction in RCA was significantly greater than that in LCA, which is in agreement with the electrophysiological data. Finally, the Kv1.2 alpha-subunit but not the Kv1.5 was detected in both RCA and LCA using primary specific antibody in Western blotting and immunofluorescence assay, and expression of Kv1.2 alpha-subunit was markedly higher in RCA compared with LCA. In summary, we reported for the first time a heterogeneous function and expression of Kv1 alpha-subunits in rat coronary myocytes isolated from RCA or LCA.

Coronary arteriolar vasoconstriction to angiotensin II is augmented in prediabetic metabolic syndrome via activation of AT1 receptors

The metabolic syndrome is associated with activation of the renin-angiotensin system. However, whether the coronary vascular response to ANG II is altered under this condition is unknown. Experiments were conducted in control and chronically high-fat-fed dogs with the prediabetic metabolic syndrome both in vitro (isolated coronary arterioles, 60-110 microm) and in vivo (anesthetized and conscious). We found that plasma renin activity and ANG II levels are elevated in high-fat-fed dogs and that this increase in ANG II is associated with a significant increase in ANG II-mediated coronary vasoconstriction in isolated coronary arterioles and in anesthetized open-chest dogs. The vasoconstriction to ANG II is abolished by ANG II type 1 (AT1) receptor blockade. In conscious chronically instrumented dogs, AT1 receptor blockade with telmisartan improved the balance between coronary blood flow and myocardial oxygen consumption in the high-fat-fed dogs but not in normal control dogs, i.e., the relationship between coronary venous Po2 and myocardial oxygen consumption was shifted upward, toward normal control values. Quantitative assessment of coronary arteriolar AT1 and ANG II type 2 (AT2) receptor mRNA levels by real-time PCR revealed no significant difference between normal control and high-fat-fed dogs; however, Western blot analysis showed a significant increase in AT1 receptor protein level with no change in AT2 receptor protein density. These findings indicate that AT1 receptor-mediated coronary constriction is augmented in the prediabetic metabolic syndrome and contributes to impaired control of coronary blood flow via increases in circulating ANG II and/or coronary arteriolar AT1 receptor density.

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.

The Impact of ATP-Sensitive K+ Channel Subtype Selectivity of Insulin Secretagogues for the Coronary Vasculature and the Myocardium

Insulin secretagogues (sulfonylureas and glinides) increase insulin secretion by closing the ATP-sensitive K+ channel (KATP channel) in the pancreatic beta-cell membrane. KATP channels subserve important functions also in the heart. First, KATP channels in coronary myocytes contribute to the control of coronary blood flow at rest and in hypoxia. Second, KATP channels in the sarcolemma of cardiomyocytes (sarcKATP channels) are required for adaptation of the heart to stress. In addition, the opening of sarcKATP channels and of KATP channels in the inner membrane of mitochondria (mitoKATP channels) plays a central role in ischemic preconditioning. Opening of sarcKATP channels also underlies the ST-segment elevation of the electrocardiogram, the primary diagnostic tool for initiation of lysis therapy in acute myocardial infarction. Therefore, inhibition of cardiovascular KATP channels by insulin secretagogues is considered to increase cardiovascular risk. Electrophysiological experiments have shown that the secretagogues differ in their selectivity for the pancreatic over the cardiovascular KATP channels, being either highly selective (approximately 1,000x; short sulfonylureas such as nateglinide and mitiglinide), moderately selective (10-20x; long sulfonylureas such as glibenclamide [glyburide]), or essentially nonselective (<2x; repaglinide). New binding studies presented here give broadly similar results. In clinical studies, these differences are not yet taken into account. The hypothesis that the in vitro selectivity of the insulin secretagogues is of importance for the cardiovascular outcome of diabetic patients with coronary artery disease needs to be tested.

Altered muscle metaboreflex control of coronary blood flow and ventricular function in heart failure

We investigated the effect of muscle metaboreflex activation on left circumflex coronary blood flow (CBF), coronary vascular conductance (CVC), and regional left ventricular performance in conscious, chronically instrumented dogs during treadmill exercise before and after the induction of heart failure (HF). In control experiments, muscle metaboreflex activation during mild exercise elicited significant reflex increases in mean arterial pressure, heart rate, and cardiac output. CBF increased significantly, whereas no significant change in CVC occurred. There was no significant change in the minimal rate of myocardial shortening (-dl/dt(min)) with muscle metaboreflex activation during mild exercise (15.5 +/- 1.3 to 16.8 +/- 2.4 mm/s, P > 0.05); however, the maximal rate of myocardial relaxation (+dl/dt(max)) increased (from 26.3 +/- 4.0 to 33.7 +/- 5.7 mm/s, P < 0.05). Similar hemodynamic responses were observed with metaboreflex activation during moderate exercise, except there were significant changes in both -dl/dt(min) and dl/dt(max). In contrast, during mild exercise with metaboreflex activation during HF, no significant increase in cardiac output occurred, despite a significant increase in heart rate, inasmuch as a significant decrease in stroke volume occurred as well. The increases in mean arterial pressure and CBF were attenuated, and a significant reduction in CVC was observed (0.74 +/- 0.14 vs. 0.62 +/- 0.12 ml x min(-1) x mmHg(-1); P < 0.05). Similar results were observed during moderate exercise in HF. Muscle metaboreflex activation did not elicit significant changes in either -dl/dt(min) or +dl/dt(max) during mild exercise in HF. We conclude that during HF the elevated muscle metaboreflex-induced increases in sympathetic tone to the heart functionally vasoconstrict the coronary vasculature, which may limit increases in myocardial performance.

Berne's adenosine hypothesis of coronary blood flow control.

This essay looks at the historical significance of an APS classic paper that is freely available online: Berne RM. Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Physiol 204: 317–322, 1963 ( http://ajplegacy.physiology.org/cgi/reprint/204/2/317 ).