Mechanical compression elicits NO-dependent increases in coronary flow

Our previous studies have demonstrated that a decrease in arteriolar diameter that causes endothelial deformation elicits the release of nitric oxide (NO). Thus we hypothesized that cardiac contraction, via deformation of coronary vessels, elicits the release of NO and increases in coronary flow. Coronary flow was measured at a constant perfusion pressure of 80 mmHg in Langendorff preparations of rat hearts. Hearts were placed in a sealed chamber surrounded with perfusion solution. The chamber pressure could be increased from 0 to 80 mmHg to generate extracardiac compression. To minimize the impact of metabolic vasodilatation and rhythmic changes in shear stress, nonbeating hearts, by perfusing the hearts with a solution containing 20 mM KCl, were used. After extracardiac compression for 10 or 20 s, coronary flow increased significantly, concurrent with an increased release of nitrite into the coronary effluent and increased phosphorylation of endothelial NO synthase in the hearts. Inhibition of NO synthesis eliminated the compression-induced increases in coronary flow. Shear stress-induced dilation could not account for this increased coronary flow. Furthermore, in isolated coronary arterioles, without intraluminal flow, the release of vascular compression elicited a NO-dependent dilation. Thus this study reveals a new mechanism that, via coronary vascular deformation, elicited by cardiac contraction, stimulates the endothelium to release NO, leading to increased coronary perfusion.     

A Simplified Technique for Postmortem Evaluation of Coronary Arteries

The growth of complex diagnostic and therapeutic technologies in the clinical management of cardiovascular diseases has mandated a more comprehensive and detailed analysis of cases which reach the pathology laboratory. This report describes in detail the relatively simple techniques and protocol which we have employed for postmortem evaluation of the coronary vascular bed and myocardium. The key elements include the use of a pigmented gelatin mass containing radiopaque material (Barosperse), proper injection technique with simultaneous filling of the main coronary vessels at identical pressures, postmortem arteriography, cardiac dissection, and histologic confirmation of coronary and myocardial lesions. Three cases with sharply differing cardiac diseases are presented to illustrate the kind of information which may be obtained with this approach. Our experience in terms of frequency and distribution of occlusive coronary vascular disease and the relationship to age and sex has been summarized. Significant disease (> 75% lumenal obstruction) was identified angiographically and confirmed by dissection in 46 of 57 cases of clinically suspected disease. None of six hearts from patients without clinical evidence for cardiovascular disease demonstrated actual or angiographically false-positive occlusive coronary disease. It is suggested that a more detailed analysis of the coronary vascular bed can be accomplished in the pathology laboratory with this relatively simple approach and that important information bearing on clinical management can be reliably obtained.     

Biphasic effects of platelet-activating factor on coronary blood flow in anesthetized dog

Platelet-activating factor (PAF), modulates vascular tone by influencing prostaglandin release and vascular permeability. To determine its coronary effects we administered RAF (0.3 to 10 ug) into the left main coronary artery of anesthetized dogs with patent left circumflex (LCx) and narrowed left anterior descending (LAD) coronary arteries. RAF produced an initial increase followed by a decrease in coronary blood flow (CBF). The CBF increase was greater in the patent LCx than in the narrowed LAD, but the decrease was similar in both. These effects of RAF on CBF were dose-dependent, and associated with an increase in prostacyclin and thromboxane A₂ metabolites. To examine the contribution of prostaglandin release in coronary effects of PAF, dogs were pretreated with indomethacin (5 mg/kg) followed by administration of PAF. In indomethacin-pretreated animals, the coronary effects of RAF were significantly attenuated. This study shows that RAF has biphasic effects on CBF in the normal coronary artery, but the major effect in the narrowed coronary is decrease in CBF. These effects of RAF can be attenuated by prior treatment of dogs with indomethacin.     

Simple physical model of coronary vasodilation

The coronary diastolic pressure-flow relationship was studied in two groups of dogs; in one group coronary circulation was characterized by normal tone of vascular smooth muscle, while in the other group, complete relaxation of smooth muscle fibres was produced by intravenous infusion of dipyridamole. The coronary flow (CF) was measured in both groups for several values of mean aortic blood pressure (ABP), the variations being obtained by means of a 10 s arterial haemorrhage. The measured CF versus ABP data were found to be well represented by best fit curves calculated by power regression methods. These curves were quite different in the presence and absence of dipyridamole infusion. A simple physical model is proposed for analysis of these curves; the model is based on the Poiseuille equation, modified to take into proper account the variations of the vessel radii under different ABP values during ventricular diastole. These variations are expressed by means of Laplace and Hooke's laws by equating wall tension due to APB, to the sum of tensions due to elastic and smooth muscle forces. Analysis of CF versus APB curves, performed on the basis of this model, shows that to account for the large change of coronary bed conductance observed under dipyridamole infusion one must assume not only that the smooth muscle tone is absent but also that some relevant variations occur in the whole coronary bed, thus pointing to possible recruitment of new blood vessel paths.     

Early changes in coronary artery wall structure detected by microcomputed tomography in experimental hypercholesterolemia

Changes in the structure of the artery wall commence shortly after exposure to cardiovascular risk factors, such as hypercholesterolemia (HC), but may be difficult to detect. The ability to study vascular wall structure could be helpful in evaluation of the factors that instigate atherosclerosis and its pathomechanisms. The present study tested the hypothesis that early morphological changes in coronary arteries of hypercholesterolemic (HC) pigs can be detected using the novel X-ray contrast agent OsO(4) and three-dimensional micro-computed tomography (CT). Two groups of pigs were studied after they were fed a normal or an HC (2% cholesterol) diet for 12 wk. Hearts were harvested, coronary arteries were injected with 1% OsO(4) solution, and cardiac samples (6-mum-thick) were scanned by micro-CT. Layers of the epicardial coronary artery wall, early lesions, and perivascular OsO(4) accumulation were determined. Leakage of OsO(4) from myocardial microvessels was used to assess vascular permeability, which was correlated with immunoreactivity of vascular endothelial growth factor in corresponding histological cross sections. OsO(4) enhanced the visualization of coronary artery wall layers and facilitated detection of early lesions in HC in longitudinal tomographic sections of vascular segments. Increased density of perivascular OsO(4) in HC was correlated with increased vascular endothelial growth factor expression and suggested increased microvascular permeability. The use of OsO(4) as a contrast agent in micro-CT allows three-dimensional visualization of coronary artery wall structure, early lesion formation, and changes in vascular permeability. Therefore, this technique can be a useful tool in atherosclerosis research.     

Anti-monocyte chemoattractant protein-1 gene therapy inhibits vascular remodeling in rats: blockade of MCP-1 activity after intramuscular transfer of a mutant gene inhibits vascular remodeling induced by chronic blockade of NO synthesis.

Monocyte chemoattractant protein-1 (MCP-1) may play an essential part in the formation of arteriosclerosis by recruiting monocytes into the arterial wall. Thus, we devised a new strategy for anti-MCP-1 gene therapy against arteriosclerosis by transfecting an amino-terminal deletion mutant (missing the amino-terminal amino acids 2 to 8) of the human MCP-1 gene into a remote organ (skeletal muscles). Intramuscular transduction with the mutant MCP-1 gene blocked monocyte recruitment induced by a subcutaneous injection of recombinant MCP-1. In a rat model in which the chronic inhibition of endothelial nitric oxide synthesis induces early vascular inflammation as well as subsequent coronary vascular remodeling, this strategy suppressed monocyte recruitment into the coronary vessels and the development of vascular medial thickening, but did not reduce perivascular fibrosis. Thus, MCP-1 is necessary for the development of medial thickening but not for fibrosis in this model. This new strategy may be a useful and feasible gene therapy against arteriosclerosis.     

Expansion and drug elution model of a coronary stent

The present study illustrates a possible methodology to investigate drug elution from an expanded coronary stent. Models based on finite element method have been built including the presence of the atherosclerotic plaque, the artery and the coronary stent. These models take into account the mechanical effects of the stent expansion as well as the effect of drug transport from the expanded stent into the arterial wall. Results allow to quantify the stress field in the vascular wall, the tissue prolapse within the stent struts, as well as the drug concentration at any location and time inside the arterial wall, together with several related quantities as the drug dose and the drug residence times.     

Expansion and drug elution model of a coronary stent

The present study illustrates a possible methodology to investigate drug elution from an expanded coronary stent. Models based on finite element method have been built including the presence of the atherosclerotic plaque, the artery and the coronary stent. These models take into account the mechanical effects of the stent expansion as well as the effect of drug transport from the expanded stent into the arterial wall. Results allow to quantify the stress field in the vascular wall, the tissue prolapse within the stent struts, as well as the drug concentration at any location and time inside the arterial wall, together with several related quantities as the drug dose and the drug residence times.     

Hyaluronidase treatment of coronary glycocalyx increases reactive hyperemia but not adenosine hyperemia in dog hearts

Because adenosine is commonly used for inducing maximal coronary hyperemia in the clinic, it is imperative that adenosine-induced hyperemia (AH) resembles coronary hyperemia that can be attained by endogenous stimuli. In the present study we hypothesized that coronary reactive hyperemia (RH) is limited compared with AH due to the presence of the glycocalyx and that the AH response is therefore unable to detect glycocalyx modifications. In anesthetized open-chest dogs, blood flow and pressure were measured in the left circumflex artery. RH after 15-s occlusion was compared with an intracoronary infusion of adenosine (650 microg; AH) during control conditions and after intracoronary treatment of the glycocalyx with hyaluronidase (20.000 U, 2 x 20 min; n = 6) or heat-inactivated hyaluronidase (n = 5). During control, coronary conductance during RH was 1.49 +/- 0.15 ml.mmHg(-1).min(-1) and 76 +/- 7% of coronary conductance during AH (P < 0.05). After hyaluronidase, RH conductance increased (P < 0.01) by 43 +/- 13% and became 93 +/- 4% of AH conductance (P = NS). Heat-inactivated hyaluronidase had no effect on RH and AH conductance. Our results demonstrate that adenosine-induced coronary hyperemia profoundly exceeds RH and that the difference is virtually abolished on selective removal of the glycocalyx. It is concluded that, compared with RH, adenosine-induced coronary hyperemia is not affected by modification of the glycocalyx. This glycocalyx insensitivity should be taken into account when using adenosine-induced coronary hyperemia as a marker for vasodilating capacity to an ischemic stimulus.     

Sensitivity and specificity of QTc dispersion for identification of risk of cardiac death in patients with peripheral vascular disease.

OBJECTIVE: To determine whether QTc dispersion, which is easily obtained from a standard electrocardiogram, can predict those patients with peripheral vascular disease who will subsequently suffer a cardiac death, despite having no cardiac symptoms or signs. DESIGN: Patients with peripheral vascular disease were followed up for five years after they had had coronary angiography, radionuclide ventriculography, and their QTc dispersion calculated from their 12 lead electrocardiogram. SUBJECTS: 49 such patients were then divided into three groups: survivors (34), cardiac death (12), and non-cardiac death (3). MAIN OUTCOME MEASURE: Survival. RESULTS: The mean (SD; range) ejection fractions were similar in all three groups: survivors 45.9 (11.0; 27.0-52.0), cardiac death 44.0 (7.90; 28.5-59.0), and non-cardiac death 45.3 (4.55; 39.0-50.0). QTc dispersion was significantly prolonged in the cardiac death group compared with in the survivors (86.3(23.9; 41.0-139) v 56.5 (25.4; 25.0-164); P = 0.002). A QTc dispersion > or = 60 ms had a 92% sensitivity and 81% specificity in predicting cardiac death, QTc dispersion in patients with diffuse coronary artery disease was significantly (P < 0.05) greater than in those with no disease or disease affecting one, two, or three vessels. CONCLUSIONS: There is a strong link between QTc dispersion and cardiac death in patients with peripheral vascular disease. QTc dispersion may therefore be a cheap and non-invasive way of assessing the risk of cardiac death in patients with peripheral vascular disease.     

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.     

In vivo measurement of coronary circulation angiotensin-converting enzyme activity in humans

Angiotensin-converting enzyme (ACE) is present on the luminal surface of the coronary vessels, mostly on capillary endothelium. ACE is also expressed on coronary smooth muscle cells and on plaque lipid-laden macrophages. Excessive coronary circulation (CC)-ACE activity might be linked to plaque progression. Here we used the biologically inactive ACE substrate (3)H-labeled benzoyl-Phe-Ala-Pro ([(3)H]BPAP) to quantify CC-ACE activity in 10 patients by means of the indicator-dilution technique. The results were compared with atherosclerotic burden determined by coronary angiography. There was a wide range of CC-ACE activity as revealed by percent [(3)H]BPAP hydrolysis (30-74%). The atherosclerotic extent scores ranged from 0.0 to 66.97, and the plaque area scores ranged from 0 to 80 mm(2). CC-ACE activity per unit extracellular space (V(max)/K(m)V(i)), an index of metabolically active vascular surface area, was correlated with myocardial blood flow (r = 0.738; P = 0.03) but not with measures of the atherosclerotic burden. These results show that CC-ACE activity can be safely measured in humans and that it is a good marker of the vascular area of the perfused myocardium. It does not, however, reflect epicardial atherosclerotic burden, suggesting that local tissue ACE may be more important in plaque development.     

Secretory phospholipase A2 activity in blood serum: The challenge to sense

Excess levels of secretory phospholipase A2 (sPLA2) is known to contribute to several inflammatory diseases including vascular inflammation correlating with coronary events in coronary artery disease. Thus a method to monitor sPLA2 activity in blood serum is urgently needed. Such method is still a challenge since existing fluorescent probes do not allow to monitor sPLA2 activity directly in blood serum. Here we analyze and overcome barriers in sPLA2 sensing methodology and report a fluorescent probe and a kinetic model of its hydrolysis by sPLA2. New probe is designed with a fluorophore and a quencher not interfering binding to the enzyme. At the same time phospholipid matrix bearing the probe promotes efficient initial quenching of the fluorophore. Kinetic model of probe hydrolysis takes into account signal change due to the side processes. The probe and the kinetic model applied together prove the concept that the activity of sPLA can be measured directly in blood serum.     

Effects of supplemental oxygen administration on coronary blood flow in patients undergoing cardiac catheterization

Patients with heart disease are frequently treated with supplemental oxygen. Although oxygen can exhibit vasoactive properties in many vascular beds, its effects on the coronary circulation have not been fully characterized. To examine whether supplemental oxygen administration affects coronary blood flow (CBF) in a clinical setting, we measured in 18 patients with stable coronary heart disease the effects of breathing 100% oxygen by face mask for 15 min on CBF (via coronary Doppler flow wire), conduit coronary diameter, CBF response to intracoronary infusion of the endothelium-dependent dilator ACh and to the endothelium-independent dilator adenosine, as well as arterial and coronary venous concentrations of the nitric oxide (NO) metabolites nitrotyrosine, NO(2)(-), and NO(3)(-). Relative to breathing room air, breathing of 100% oxygen increased coronary resistance by approximately 40%, decreased CBF by approximately 30%, increased the appearance of nitrotyrosine in coronary venous plasma, and significantly blunted the CBF response to ACh. Oxygen breathing elicited these changes without affecting the diameter of large-conduit coronary arteries, coronary venous concentrations of NO(2)(-) and NO(3)(-), or the coronary vasodilator response to adenosine. Administering supplemental oxygen to patients undergoing cardiac catheterization substantially increases coronary vascular resistance by a mechanism that may involve oxidative quenching of NO within the coronary microcirculation.     

Cardiac evaluation and risk reduction in patients undergoing major vascular operations.

Occult coronary artery disease often accompanies symptomatic peripheral vascular disease and has an important effect on survival. Most perioperative and late fatalities after peripheral vascular operations are due to cardiac causes. Noninvasive cardiac testing can identify patients at increased risk for postoperative cardiac complications, although controversy exists regarding the optimal preoperative evaluation. Risk reduction strategies for patients known to be at high risk are also controversial. Some authors advocate coronary revascularization with coronary artery bypass grafting or percutaneous transluminal coronary angioplasty before the vascular procedure. Others believe that the combined morbidity and mortality of 2 operations exceed those of a peripheral vascular operation performed with aggressive monitoring and medical therapy. Continuous electrocardiographic monitoring after an operation has identified silent myocardial ischemia as a powerful predictor of cardiac complications. Ongoing research is likely to provide insights into the pathogenesis of postoperative cardiac complications and may lead to specific therapeutic interventions. Few prospective studies have been done in this area, and the threshold for preoperative and postoperative intervention is unknown. I review the literature and present an algorithm to guide cardiac testing and risk reduction in patients undergoing elective vascular surgical procedures.     

Ventricular fibrillation following canine coronary artery reperfusion: different outcomes with pentobarbital and alpha-chloralose

We compared the incidence of ventricular fibrillation after release of a 20 min-proximal left anterior descending coronary artery ligation in dogs anesthetized with either pentobarbital (N = 26) or morphine sulfate plus alpha-chloralose (N = 26). Results were analyzed using the logistic risk regression model. In each group, outcome correlated with the amount of myocardium perfused by the ligated vessel (myocardium "at risk") as measured by postmortem coronary injection of monastral dyes. At any given myocardium at risk, animals anesthetized with alpha-chloralose were less likely to fibrillate after release than those anesthetized with pentobarbital (p less than 0.01). This difference in outcome can be described by the myocardium at risk at which half the animals are expected to fibrillate (MAR50). MAR50 was 20.9 g for the pentobarbital group and 30.7 g for the alpha-chloralose group. Myocardium at risk should be taken into account in intervention studies using this coronary reperfusion arrhythmia model. We chose the logistic risk regression model to correct for this variable because it allowed a good fit of the data and offered a concise standard format for expressing the results. Outcome in reperfusion studies may be influenced by the choice of anesthetic agent.     

Impact of age and hyperglycemia on the mechanical behavior of intact human coronary arteries: an ex vivo intravascular ultrasound study

Despite their advantages, percutaneous coronary interventional procedures are less effective in diabetic patients. Changes in the mechanical properties of vascular walls secondary to long-term hyperglycemia as well as other factors such as age may influence coronary distensibility. This investigation is aimed at deciphering the extent of these effects on distensibility of postmortem human coronary arteries in a controlled manner. Excised human left anterior descending (LAD) coronary arteries were obtained within 24 h postmortem. With the use of intravascular ultrasound, vascular deformation was analyzed at midregions of 51 moderate lesions. Intraluminal pressure was systematically altered using a computerized pressure pump system and monitored by a pressure-sensing guidewire. Distensibility, a normalized compliance term, was defined as the change in lumen area normalized by the initial reference area over a given pressure interval. With the use of multivariate analysis and repeated-measures ANOVA, coronary distensibility was independently influenced by hyperglycemia and age (P < 0.05) through the entire pressure range. Within physiological pressure range, distensibility was significantly reduced with age in nonhyperglycemic coronary specimens (10.55 +/- 4.41 vs. 6.99 +/- 2.45, x10(3) kPa(-1), P = 0.01), whereas the hyperglycemic vessels were stiff even in the younger group (7.90 +/- 5.82 vs. 7.20 +/- 3.36, x10(3) kPa(-1), P = 0.79). Similar results were observed with stiffness index and elastic modulus of the arteries. Hyperglycemia and age independently influenced the distensibility of moderately atherosclerotic LAD coronary arteries. The stiffening with age was overshadowed in the hyperglycemic group by as-yet-undetermined factors.     

A Comparison of Genome-Wide DNA Methylation Patterns between Different Vascular Tissues from Patients with Coronary Heart Disease

Epigenetic mechanisms of gene regulation in context of cardiovascular diseases are of considerable interest. So far, our current knowledge of the DNA methylation profiles for atherosclerosis affected and healthy human vascular tissues is still limited. Using the Illumina Infinium Human Methylation27 BeadChip, we performed a genome-wide analysis of DNA methylation in right coronary artery in the area of advanced atherosclerotic plaques, atherosclerotic-resistant internal mammary arteries, and great saphenous veins obtained from same patients with coronary heart disease. The resulting DNA methylation patterns were markedly different between all the vascular tissues. The genes hypomethylated in athero-prone arteries to compare with atherosclerotic-resistant arteries were predominately involved in regulation of inflammation and immune processes, as well as development. The great saphenous veins exhibited an increase of the DNA methylation age in comparison to the internal mammary arteries. Gene ontology analysis for genes harboring hypermethylated CpG-sites in veins revealed the enrichment for biological processes associated with the development. Four CpG-sites located within the MIR10B gene sequence and about 1 kb upstream of the HOXD4 gene were also confirmed as hypomethylated in the independent dataset of the right coronary arteries in the area of advanced atherosclerotic plaques in comparison with the other vascular tissues. The DNA methylation differences observed in vascular tissues of patients with coronary heart disease can provide new insights into the mechanisms underlying the development of pathology and explanation for the difference in graft patency after coronary artery bypass grafting surgery.     

Dynamics of flow, resistance, and intramural vascular volume in canine coronary circulation

Varying coronary volume will vary vascular resistance and thereby have an effect on coronary hemodynamics. Six ventricular septa were isolated from anesthetized dogs, dispersed in a biaxial stretch apparatus at diastolic stress, and perfused artificially with an oxygenated perfluorochemical emulsion at maximal vasodilation. Flow and thickness were measured continuously by an electromagnetic flow probe and sonomicrometer. Pressure was varied sinusoidally around 30, 50, and 70 mmHg with an amplitude of 7.5 mmHg; frequencies ranged between 0.015 and 7 Hz. Bode plots of admittance (flow/pressure) and capacitance (scaled thickness/pressure) were constructed. A two-compartment model was used in which the resistances vary with volume. Realistic values of microvascular compliance ( approximately 0.3 ml x mmHg(-1) x 100 g(-1)) were found. Values 10 times higher were then found when resistances were forced to be constant. We concluded that volume dependence of resistances have to be taken into account when dynamic or static pressure-flow relations are studied and conceal the effect of a large intramyocardial compliance on arterial hemodynamics.     

Quantitative analysis of feedforward sympathetic coronary vasodilation in exercising dogs.

Recent experiments demonstrate that feedforward sympathetic beta-adrenoceptor coronary vasodilation occurs during exercise. The present study quantitatively examined the contributions of epinephrine and norepinephrine to exercise coronary hyperemia and tested the hypothesis that circulating epinephrine causes feedforward beta-receptor-mediated coronary dilation. Dogs (n = 10) were chronically instrumented with a circumflex coronary artery flow transducer and catheters in the aorta and coronary sinus. During strenuous treadmill exercise, myocardial oxygen consumption increased by approximately 3.9-fold, coronary blood flow increased by approximately 3.6-fold, and arterial plasma epinephrine concentration increased by approximately 2.4-fold over resting levels. At arterial concentrations matching those during strenuous exercise, epinephrine infused at rest (n = 6) produced modest increases (18%) in flow and myocardial oxygen consumption but no evidence of direct beta-adrenoceptor-mediated coronary vasodilation. Arterial norepinephrine concentration increased by approximately 5. 4-fold during exercise, and coronary venous norepinephrine was always higher than arterial, indicating norepinephrine release from cardiac sympathetic nerves. With the use of a mathematical model of cardiac capillary norepinephrine transport, these norepinephrine concentrations predict an average interstitial norepinephrine concentration of approximately 12 nM during strenuous exercise. Published dose-response data indicate that this norepinephrine concentration increases isolated coronary arteriolar conductance by approximately 67%, which can account for approximately 25% of the increase in flow observed during exercise. It is concluded that a significant portion of coronary exercise hyperemia ( approximately 25%) can be accounted for by direct feedforward beta-adrenoceptor coronary vascular effects of norepinephrine, with little effect from circulating epinephrine.