Coronary Pressure-flow Relations Research Articles

An intact animal model for the assessment of coronary blood flow regulation "Coronary blood flow regulation".

Coronary blood flow adapts to metabolic demand ("metabolic regulation") and remains relatively constant over a range of pressure changes ("autoregulation"). Coronary metabolic regulation and autoregulation are usually studied separately. We developed an intact animal experimental model to explore both regulatory mechanisms of coronary blood flow. Coronary pressure and flow‐velocities were measured in four anesthetized and closed‐chest pigs using an intracoronary Doppler wire. Metabolic regulation was assessed by coronary flow reserve defined as the ratio between the maximally vasodilated and the basal flow, with hyperemia achieved using intracoronary administration of adenosine (90 µg) or bradykinin (10–6 M) as endothelium‐independent and ‐dependent vasodilators respectively. For both vasodilators, we found a healthy coronary flow reserve ≥ 3.0 at baseline, which was maintained at 2.9 ± 0.2 after a 6‐hr period. Autoregulation was assessed by the lower breakpoint of coronary pressure‐flow relationships, with gradual decrease in coronary pressure through the inflation of an intracoronary balloon. We found a lower limit of autoregulation between 42 and 55 mmHg, which was stable during a 6‐hr period. We conclude that this intact animal model is adequate for the study of pharmacological interventions on the coronary circulation in health and disease, and as such suitable for preclinical drug studies.

Comparison between Diastolic Subendocardial Tissue Pressures Measured Directly or Calculated from Pressure-Flow Relations

Changes in intramyocardial tissue pressure modulate the relationship between coronary pressure and flow during the cardiac cycle. The present study compared the relation between measured and calculated diastolic subendocardial tissue pressure and coronary pressure at zero flow in anesthetized dogs after modulation of either coronary sinus (i.e. Fogarty catheter) or left ventricular intracavity (i.e. volume loading) pressure. Experiments were conducted in anesthetized, instrumented dogs; coronary pressure flow relations were constructed during pharmacologic vasodilatation and intramyocardial tissue pressure was measured using micromanometer pressure sensors. Elevated coronary sinus pressures did not affect subendocardial pressure-flow relations signifying that diastolic tissue pressure within this layer is the effective coronary back pressure. Higher left ventricular intracavity pressure did not affect either diastolic subendocardial tissue pressure or pressure flow relations within this layer. Results show a direct linear relation (y = 1.106x - 0.652; r2 = 0.59. P = 0.001) between measured and calculated diastolic subendocardial tissue pressure and coronary pressure at zero-flow over a wide range of pressures after either LV systemic or coronary sinus pressure modulation. Knowledge of back pressure in the subendocardium is useful for the evaluation of efficacy of cardiac interventions on myocardial perfusion particularly at the level of the microcirculation.

Coronary pressure-flow relations as basis for the understanding of coronary physiology

Recent technological advancements in the area of intracoronary physiology, as well as non-invasive contrast perfusion imaging, allow to make clinical decisions with respect to percutaneous coronary interventions and to identify microcirculatory coronary pathophysiology. The basic characteristics of coronary hemodynamics, as described by pressure-flow relations in the normal and diseased heart, need to be understood for a proper interpretation of these physiological measurements. Especially the hyperemic coronary pressure-flow relation, as well as the influence of cardiac function on it, bears great clinical significance. The interaction of a coronary stenosis with the coronary pressure-flow relation can be understood from the stenosis pressure drop-flow velocity relationship. Based on these relationships the clinically applied concepts of coronary flow velocity reserve, fractional flow reserve, stenosis resistance and microvascular resistance are discussed. Attention is further paid to the heterogeneous nature of myocardial perfusion, the vulnerability of the subendocardium and the role of collateral flow on hyperemic coronary pressure-flow relations. This article is part of a Special Issue entitled "Coronary Blood Flow".

Coronary microvascular dysfunction after myocardial infarction: increased coronary zero flow pressure both in the infarcted and in the remote myocardium is mainly related to left ventricular filling pressure

Objective:To investigate the underlying mechanisms of a decreased coronary flow reserve after myocardial infarction (MI) by analysing the characteristics of the diastolic hyperaemic coronary pressure–flow relationship.Design:Prospective study.Setting:Tertiary care hospital.Patients:68 patients...

Influence of Acute Renal Failure on Coronary Vasoregulation in Dogs

Impaired renal function is associated with an increased risk for cardiovascular events and death, but the pathophysiology is poorly defined. The hypothesis that coronary blood flow regulation and distribution of ventricular blood flow could be compromised during acute renal failure (ARF) was tested. In two separate groups (n = 14 each) of dogs with ARF, (1) coronary autoregulation (pressure-flow relations), vascular reserve (reactive hyperemia), and myocardial blood flow distribution (microspheres) and (2) coronary vessel responses to intracoronary infusion of select endothelium-dependent and -independent vasodilators were evaluated. In addition, coronary pressure-flow relations and vascular reserve after inhibition of nitric oxide and prostaglandin release were evaluated. Under resting conditions, myocardial oxygen consumption increased in dogs with ARF compared with no renal failure (NRF; 11.8 +/- 9.2 versus 5.0 +/- 1.5 ml O(2)/min per 100 g; P = 0.01), and the autoregulatory break point of the coronary pressure-flow relation was shifted to higher diastolic coronary pressures (60 +/- 17 versus 52 +/- 8 mmHg in NRF; P = 0.003); the latter was shifted further rightward after inhibition of both nitric oxide and prostaglandin release. The endocardial/epicardial blood flow ratio was comparable for both groups, suggesting preserved ventricular distribution of blood flow. In dogs with ARF, coronary vascular conductance also was reduced (P = 0.001 versus NRF), but coronary zero-flow pressure was unchanged. Vessel reactivity to each endothelium-dependent/independent compound also was blunted significantly. In conclusion, under resting conditions, coronary vascular tone, reserve, and vessel reactivity are markedly diminished with ARF, suggesting impaired vascular function. Consequently, during ARF, small increases in myocardial oxygen demand would induce subendocardial ischemia as a result of a limited capacity to increase oxygen supply and thereby contribute to higher risk for adverse coronary events and mortality.

Simultaneous digitization of intracoronary doppler and pressure to assess the influence of diastolic dysfunction on the hyperemic coronary pressure-flow relationship after myocardial infarction

Simultaneous digitization of intracoronary doppler and pressure to assess the influence of diastolic dysfunction on the hyperemic coronary pressure-flow relationship after myocardial infarction

Alterations of α-Adrenergic Modulations of Coronary Microvascular Tone in Dogs With Heart Failure

Background It remains unclear whether coronary microvascular response to α-adrenergic activation alters in chronic heart failure (CHF). Methods and Results We investigated the α-adrenergic receptor–mediated effects on coronary pressure-flow relationship (CPFR) in a tachycardia-induced canine heart failure model. The dogs studied were male (29 of 31) and the drugs were given intracoronary. The slope of CPFR during long diastole was evaluated as an index of coronary vascular resistance, during α 1- or α 2-adrenergic stimulation or inhibition under anesthesia in the baseline and failing state after 3 weeks of rapid ventricular pacing. Resting coronary blood flow and CPFR did not change in the failing state from the baseline state. Neither α 1 nor α 2 stimulation changed the slope of CPFR in the baseline state. However, in the failing state, α 1 stimulation decreased the slope of CPFR by 23 ± 5% ( P < .05), whereas α 2 stimulation increased it by 73 ± 10% ( P < .05), which was nearly abolished by pretreatment with N G-nitro- l-arginine methyl ester. Conclusion α 2-mediated vasodilatory action, presumably via endothelium-derived nitric oxide release, would be enhanced in the coronary microvascular bed, which may antagonize enhanced α 1-induced vasoconstriction in CHF.

Alterations of endothelium-dependent and -independent regulation of coronary blood flow during heart failure.

Conflicting data concerning the changes in basal coronary blood flow and nitric oxide (NO)-releasing capacity in chronic heart failure may be due to different phases or duration of heart failure. To investigate endothelium-dependent and -independent regulation of coronary blood flow in different phases of heart failure, coronary pressure-flow relationships during long diastole were obtained before and after rapid pacing of 3 and 5 wk at 240 beats/min in 12 or 6 dogs. Neither basal coronary blood flow nor the slope of coronary pressure-flow relationships changed; however, zero-flow pressure increased slightly after rapid pacing. Intracoronary injection of N(G)-nitro-L-arginine methyl ester decreased coronary blood flow at a perfusion pressure of 50 mmHg by approximately 20% at baseline, 55% after 3 wk of rapid pacing, and 20% after 5 wk of rapid pacing. Acetylcholine-induced increase in coronary blood flow was maintained for 3 wk but was finally attenuated after 5 wk of rapid pacing. In contrast, the coronary blood flow response to adenosine gradually decreased with time. These results suggest that basal coronary blood flow is maintained until the late stage of heart failure, presumably by an increases in NO production during the early stage and then by other vasodilatory substances during the late stage, and that endothelium-dependent vasodilation via exogenously administered acetylcholine in resistance vessels is not necessarily impaired in the early stage despite the gradual reduction of endothelium-independent vasodilation via adenosine in chronic heart failure.

Attenuation of angiotensin II-mediated coronary vasoconstriction and vasodilatory action of angiotensin-converting enzyme inhibitor in pacing-induced heart failure in dogs

OBJECTIVESWe investigated the changes in coronary vascular resistance caused by angiotensin II, angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 or 2 receptor (AT1R and AT2R, respectively) antagonists in chronic heart failure (CHF).BACKGROUNDAngiotensin II is an intense vasoconstrictor, and increased angiotensin II in CHF might exert significant vasoconstriction.METHODSEleven dogs were studied. Before and after three and five weeks of rapid pacing, coronary flow dynamics were evaluated by the coronary pressure–flow relationship (PFR) in long diastole, before and after intracoronary injection of angiotensin II, the ACE inhibitor enalaprilat, the AT1R antagonist L158,809 or the AT2R antagonist PD123319.RESULTSBefore rapid pacing, angiotensin II reduced the slope of PFR (1.16 ± 0.08 to 0.81 ± 0.07 ml/min/100 g left ventricular mass per mm Hg; p < 0.01) and increased the perfusion pressure at which coronary flow ceased (zero-flow pressure [Pf= 0]), whereas enalaprilat did not change either of them. After rapid pacing, angiotensin II did not change the slope or Pf= 0. In contrast, enalaprilat increased the slope (three weeks: 1.20 ± 0.05 to 1.50 ± 0.03; five weeks: 1.25 ± 0.19 to 1.37 ± 0.08; both p < 0.05) and decreased Pf= 0 after three weeks of pacing, but not after five weeks. Pretreatment with the bradykinin antagonist HOE-140 attenuated the enalaprilat-induced increase in coronary blood flow. L158,809 and PD123319 had no effect both before and after rapid pacing.CONCLUSIONSThis suggests that the coronary vasoconstrictive effect of angiotensin II would disappear and the vasodilatory effect of the ACE inhibitor, partly through bradykinin, would be enhanced in the early stage of CHF.

Determination of coronary zero flow pressure by analysis of the baseline pressure-flow relationship in humans.

The present study seeks to estimate the difference between coronary zero flow pressure (Pzf) by analysis of the baseline pressure-flow relationship and the Pzf calculated during a long diastole in humans. Although Pzf is likely to provide meaningful information about the characteristics of coronary circulation, there are no available data on Pzf in humans because Pzf is overestimated when it is calculated during normal cardiac cycles. Actual Pzf was determined in 15 subjects by analyzing the coronary pressure-flow relationship during a long cardiac cycle induced by an intracoronary adenosine triphosphate (ATP) infusion, and it was compared with the Pzf calculated during a normal cardiac cycle in order to estimate the difference. Pzf calculated during a normal cardiac cycle was 47 +/- 15 mmHg, which decreased to 36 +/- 9mmHg after intracoronary administration of ATP (0.05 mg) whereas actual Pzf was 21 +/- 7 mmHg. Pzf calculated in a pressure-flow relationship during a normal cardiac cycle under vasodilation correlated well with that during a long diastole (r = 0.75, p < 0.01), although it was 15 +/- 6 mmHg greater than the actual Pzf. It was concluded that Pzf during a normal cardiac cycle could be used to anticipate Pzf.

Effect of angiotensin inhibition on the coronary artery lower pressure limit in anesthetized dogs

The renin-angiotensin system plays a critical role in regulating vasoconstriction and vasodilatation that can influence myocardial blood flow and its transmural distribution. We tested the hypothesis that angiotensin inhibition can induce a leftward shift of the coronary autoregulatory pressure-flow relation and preserve distribution of myocardial blood flow at lower coronary perfusion pressures. We established circumflex artery pressure-flow relations under baseline conditions and after intracoronary enalaprilat or losartan potassium. Thereafter, transmural myocardial blood flow was measured at baseline and at the lower coronary pressure limit (LPL). With enalaprilat, the LPL was shifted leftward from 48 +/- 6 mmHg at baseline to 43 +/- 3 mmHg (P = 0.026); with losartan, the LPL was shifted leftward from 48 +/- 10 mmHg at baseline to 41 +/- 5 mmHg (P = 0.027). The leftward shift occurred while cardiac hemodynamics and MVO2 were maintained at control levels. These results indicate that angiotensin inhibition extends the range of coronary autoregulation to lower LPL while preserving myocardial blood flow distribution, a physiologic effect that might explain the lower incidence of coronary events in treated patients.

Augmented basal nitric oxide production contributes to maintenance of coronary blood flow in dogs with pacing-induced heart failure.

It remains controversial whether basal nitric oxide (NO) production in coronary resistance vessels in heart failure is enhanced or not. A transonic Doppler flow probe was placed around the left anterior descending coronary artery, and complete atrioventricular block was produced in fifteen dogs. The coronary pressure-flow relationships during long diastole were analyzed without and with pacing-induced heart failure. Three weeks after pacing at 240/min, plasma norepinephrine and renin activity significantly rose. Right atrial pressure and left ventricular end-diastolic pressure increased, and cardiac output and coronary perfusion pressure decreased; however, mean coronary blood flow did not change after pacing (55 +/- 5 to 52 +/- 5 ml/min/100 g, mean +/- SEM). The slope of the diastolic coronary pressure-flow relationship became steeper (1.22 +/- 0.13 to 1.62 +/- 0.09 ml/min/100 g/mmHg, p < 0.05) with a slight increase in the measured zero-flow pressure (29.5 +/- 1.1 to 32.8 +/- 1.5 mmHg, p < 0.05) after pacing. After pretreatment with indomethacin, administration of NG-nitro-L-arginine methyl ester caused an equal increase in the zero-flow pressure before (31.4 +/- 1.7 to 39.2 +/- 2.2 mmHg, p < 0.05) and after heart failure (33.9 +/- 2.5 to 41.6 +/- 2.2 mmHg, p < 0.05), and more decline of the slope of the coronary pressure-flow relationship in heart failure (1.86 +/- 0.22 to 1.20 +/- 0.05 ml/min/100 g/mmHg, p < 0.05) than before heart failure (1.11 +/- 0.12 to 1.05 +/- 0.11 ml/min/100 g/mmHg, N.S.). This indicates that in failing hearts the vasodilatory action of NO in small vessels predominates despite the presence of several vasoconstricting factors. These results suggest that coronary blood flow is maintained despite detrimental hemodynamic and activated neurohumoral factors in the initial stage of heart failure, and that increased basal NO production plays a central role in the maintenance of basal coronary blood flow.

Effects of cardiac contraction and increased coronary sinus pressure on the coronary arterial pressure-flow relationship.

Increased coronary sinus (CS) pressure and cardiac contraction impair coronary inflow independently. However, it has not been determined how the coronary pressure-flow relationship is strongly affected by changes in CS pressure in the beating heart compared to the non-beating heart. The purpose of this study was to evaluate the combined mechanical effects of cardiac contraction and increased CS pressure. Using isolated, perfused canine hearts, coronary perfusion pressure in the left anterior descending coronary artery (LAD) was gradually reduced in beating and non-beating conditions. Measurements were obtained with and without elevation of CS pressure to determine the mean LAD pressure-flow relationships. At normal and elevated CS pressures, the corresponding zero-flow pressures were not significantly different between the beating and non-beating hearts. A rightward shift of the mean coronary perfusion pressure-coronary flow curve for the beating heart compared to the non-beating heart was observed when CS pressure was not elevated. In contrast, the slopes for both beating and non-beating hearts were similar if the CS pressure was increased. There was a smaller increase in the mean intramyocardial pressure (IMP) at elevated CS pressures in the beating heart as compared to the non-beating heart. Moreover, the increase in diastolic IMP with increased CS pressures in the beating heart was significantly less than that in the non-beating heart. These results indicate that cardiac contraction attenuates the inhibitory effects of increased CS pressure on coronary inflow.

Left coronary pressure–flow relations of the beating and arrested rabbit heart at different ventricular volumes

To study the effect of cardiac contraction on left coronary artery pressure-flow relations at different vascular volumes and to compare these relations in the beating heart with those in the heart arrested in systole and diastole. Maximally vasodilated, Tyrode perfused, rabbit hearts (n = 6) with an intra-ventricular balloon were used. The left coronary artery was separately perfused via a cannula in the left main coronary artery. The slopes and the intercepts of left coronary pressure-flow relations were determined in the beating and arrested heart at different chamber volumes. A 3-factor design with repeated measures was used to compare the effect of three factors: phase of contraction (systole and diastole), chamber volume (V0 and V1, left ventricular end-diastolic pressure 1.4 and 20 mm Hg, respectively) and the type of contraction (beating and arrested; a measure of capacitive effects). The phase of contraction has a significant effect on the intercepts (> 40 mmHg, p = 0.00032) but not on the slopes of the pressure-flow relations. Chamber volume had a small effect on the intercepts (< 5 mm Hg, p = 0.037), but not on the slopes of the pressure-flow relations. The type of contraction has a significant effect on the slopes (approximately 10%, p = 0.00021) but not on the intercepts of the pressure-flow relations. In the isolated Tyrode perfused rabbit heart left coronary pressure-flow relations are mainly determined by contraction, while left ventricular chamber volume and capacitive effects contribute little.

Homogenization modeling for the mechanics of perfused myocardium.

Altered coronary perfusion can change the apparent diastolic stiffness of ventricular myocardium--the 'garden hose' effect. Our recent findings showed that myocardial strains are reduced during ventricular filling, primarily along the directions transverse to the coronary microvessels. In this article, we review hypotheses and theoretical models regarding the role that regional wall stress plays in the mechanical interaction between myocardium and coronary circulation. Various mechanisms have been used to explain the effects of the tissue stress on coronary flow, as well as the effect of coronary dynamics on myocardial mechanics. Many models of coronary pressure-flow relations using lumped parameter circuit analogs. Poroelasticity and swelling theories have been used to model the mechanics of perfused muscle. Here, we describe a new mathematical model of the mechanics of perfused myocardium derived using homogenization theory. In this model, perfused myocardium is treated as a nonlinear anisotropic elastic solid embedded with cylindrical vessels of known distensibility. The solid compartment is incompressible but the vascular compartment may change volume according to a simple relation between vessel diameter and perfusion pressure. The work done by the perfusion pressure in changing vascular volume contributes to the macroscopic strain energy and hence affects the stress and stiffness of the composite. Conversely, the stress in the tissue affects microvessel diameter and volume, since tractions transverse to the vessel axis oppose the internal blood pressure. Finite element simulations of passive filling show good agreement of model with experimental results.

Coronary microcirculation in health and disease. Summary of an NHLBI workshop.

This article summarizes a 2-day workshop on the coronary microcirculation held in Bethesda, Md, in September 1994 and sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health. The workshop explored a variety of topics pertaining to coronary microvascular physiology and pathophysiology. The latest methodologies that are being used to investigate the coronary microvasculature, including endoscopic microscopy of the intramural coronary microvasculature and micro-x-ray computerized tomography, were discussed. The most recent advances in the regulation of the coronary microcirculation-for example, myogenic and flow-dependent responses, KATP channels, and regional heterogeneity-were reported. The workshop touched on the relation of the microcirculation to clinically important conditions and offered recommendations for future research in this important area. Comparisons are made to recent advances in the peripheral circulation and current gaps in our knowledge concerning the coronary microcirculation. In recent years, research on the coronary microcirculation has made substantial advances, in part as a result of investigations in the peripheral microcirculation but also because of the application of unique methodologies. This research is providing new ways to investigate abnormalities of myocardial perfusion, an area of inquiry that until recently has been limited to examination of coronary pressure-flow relationships.

How cardiac contraction affects the coronary vasculature.

We modeled the influence of cardiac contraction on maximally dilated coronary blood vessels, whether single or in juxtaposition, taking into account the nonlinear material properties of both the vascular wall and the myocardium. We calculated pressure-area relations of single, embedded coronary blood vessels, and used these relations to calculate diastolic and systolic coronary pressure-flow relations in a model of the coronary vasculature. The model shows that the change in myocardial material properties during contraction can explain the decrease in coronary vessel area and coronary flow generally observed in experiments. The model also shows that arterioles can be protected from the compressive action of the cardiac muscle by the presence of accompanying venules, which is favorable for coronary blood flow.

Coronary back flow pressure is elevated in association with increased left ventricular end-diastolic pressure in humans.

To clarify the effect of left ventricular (LV) diastolic pressure on the coronary pressure-flow relation in humans, the instantaneous diastolic coronary pressure-Doppler flow velocity relation was analyzed at rest and during papaverine-induced maximal vasodilation in 15 patients with angiographically normal coronary arteries. The values for slope (alpha PF) and zero-flow pressure intercept (Pzf index) of the instantaneous diastolic coronary pressure-flow velocity relation were obtained by a linear regression analysis. Although alpha PF did not correlate with LV end-diastolic pressure (EDP), the Pzf index correlated positively with LVEDP both at rest and during maximal vasodilation (r = 0.64, P < 0.05 and r = 0.58, P < 0.05, respectively). Thus, the back pressure to coronary inflow, as indicated by the Pzf index, may be elevated in patients with increased LVEDP, resulting in the rightward shift of the maximally dilated coronary pressure-flow relation and decreased maximal coronary flow and reserve at any given perfusion pressure.

Minimal role of nitric oxide in basal coronary flow regulation and cardiac energetics of blood-perfused isolated canine heart.

1. The role of nitric oxide (NO) in the regulation of basal coronary perfusion and ventricular chamber energetics was studied in isovolumetrically contracting isolated blood-perfused canine hearts. Hearts were cross-perfused by a donor animal prior to isolation, and chamber volume controlled by a servo-pump. Coronary sinus flow and arterial-coronary sinus oxygen difference were measured to determine energetic efficiency. 2. NO synthase (NOS) was competitively inhibited by NG-monomethyl-L-arginine (L-NMMA; 0.5 mg kg-1, intracoronary), resulting in a reduction of acetylcholine (50 micrograms min-1)-induced flow augmentation from 143 to 62% (P < 0.001). 3. NOS inhibition had no significant effect on basal coronary flow. Coronary pressure-flow relationships were determined at a constant cardiac workload by varying mean perfusion pressure between 20 and 150 mmHg. Neither the shape of the relationship, nor the low-pressure value at which flow regulation was substantially diminished were altered by NOS inhibition. 4. Myocardial efficiency was assessed by the relationship between myocardial oxygen consumption and total pressure-volume area (PVA), with cavity volume altered to generate varying PVAs. This relative load-independent measure of energetic efficiency was minimally altered by NOS inhibition. 5. These results contrast with isolated crystalloid-perfused heart experiments and suggest that in hearts with highly controlled ventricular loading and whole-blood perfusion, effects of basal NO production on coronary perfusion and left ventricular energetics are minimal.

Role of K+ ATP channels and adenosine in the regulation of coronary blood flow during exercise with normal and restricted coronary blood flow.

Regulation of coronary vasomotor tone during exercise is incompletely understood. We investigated the contributions of K+ ATP channels and adenosine to the coronary vasodilation that occurs during exercise in the normal heart and in the presence of a coronary artery stenosis. Dogs that were chronically instrumented with a Doppler flow probe, hydraulic occluder, and indwelling catheter on the left anterior descending coronary artery were exercised on a treadmill to produce heart rates of approximately 200 beats/min. By graded inflation of the occluder to produce a wide range of coronary stenosis severities, we determined the coronary pressure-flow relation. K+ atp channel blockade with intracoronary glibenclamide (10-50 microgram/kg per min) decreased coronary blood flow during exercise at coronary pressures within and below the autoregulatory range, indicating that coronary K+ ATP channel activation is critical for producing coronary vasodilation with either normal arterial inflow or when flow is restricted by a coronary artery stenosis. Adenosine receptor blockade with intravenous 8-phenyltheophylline (5 mg/kg) had no effect on coronary flow at pressures within the autoregulatory range but decreased flow at pressures < 55 mmHg. In contrast, in the presence of K+ ATP channel blockade, the addition of adenosine receptor blockade further decreased coronary flow even at coronary pressures in the autoregulatory range, indicating increased importance of the vasodilator influence of endogenous adenosine during exercise when K+ atp channels are blocked. Intracoronary adenosine (50 microgram/kg per min) increased coronary flow at perfusion pressures both within and below the autoregulatory range. In contrast, selective K+ ATP channel activation with intracoronary pinacidil (0.2-5.0 microgram/kg per min) increased flow at normal but not at lower coronary pressures (< 55 mmHg). This finding demonstrates that not all K+ ATP channels are activated during exercise at pressures in the autoregulatory range, but that most K+ ATP channels are recruited as pressures approach the lower end of the autoregulatory plateau. Thus, K+ ATP channels and endogenous adenosine play a synergistic role in maintaining vasodilation during exercise in normal hearts and distal to a coronary artery stenosis that results in myocardial hypoperfusion during exercise.