Zero-flow pressures and pressure-flow relationships during single long diastoles in the canine coronary bed before and during maximum vasodilation. Limited influence of capacitive effects.

The proposal that diastolic coronary flow is regulated by an intramyocardial "back-pressure" that substantially exceeds coronary venous and ventricular diastolic pressures has been examined in an open-chest canine preparation in which instantaneous left circumflex pressure and flow could be followed to cessation of inflow during prolonged diastoles. Despite correlation coefficients consistently >0.90, pressure-flow data during individual diastoles were concave to the flow axis before and during pharmacologically induced maximum coronary vasodilation. Data were better fitted (P < 0.01) by second-order equations than by linear equations in >90% of cases. Second-order pressure-axis intercepts (P(f=0))(1) averaged 29+/-7 (SD) mm Hg before vasodilation and 15+/-2 mm Hg during vasodilation; left and right atrial pressures were always substantially lower (8+/-3 and 5+/-2 mm Hg before vasodilation and 8+/-2 and 4+/-1 mm Hg during dilation). Values of P(f=0) before vasodilation varied directly with levels of coronary inflow pressure. A modification of the experimental preparation in which diastolic circumflex pressure could be kept constant was used to evaluate the suggestion that P(f=0) measured during long diastoles are misleadingly high because of capacitive effects within the coronary circulation as inflow pressure decreases. Decreases in P(f=0) attributable to capacitive effects averaged only 5.9+/-3.0 mm Hg before vasodilation and were smaller during dilation. We conclude that P(f=0) is a quantitatively important determinant of coronary driving pressure and flow, resulting from both factors related to, and independent of, vasomotor tone. Adjustments of flow during changing physiological situations may involve significant changes in P(f=0) as well as in coronary resistance.

Differential 18F-2-deoxyglucose uptake in viable dysfunctional myocardium with normal resting perfusion: evidence for chronic stunning in pigs.

BACKGROUND: Viable, chronically dysfunctional myocardium can have normal or reduced resting flow. We previously produced hibernating myocardium with reduced resting flow in pigs with a chronic stenosis and hypothesized that hibernation is preceded by chronic stunning with normal resting perfusion. METHODS AND RESULTS: Pigs instrumented with a proximal left anterior descending coronary artery (LAD) stenosis were studied 1 or 2 months later in the closed-chest anesthetized state. Stenosis severity increased from 74+/-5% at 1 month to 83+/-6% at 2 months and was accompanied by anteroapical hypokinesis (wall motion score, 2.1+/-0.1 at 1 month and 1.5+/-0.3 at 2 months; normal=3). Resting perfusion was similar in normal and dysfunctional regions, but the deposition of 18F-2-deoxyglucose (FDG) varied. At 1 month, subendocardial FDG deposition by excised tissue counting was similar in each region (0. 034+/-0.006 mL. g-1. min-1 LAD region versus 0.032+/-0.004 mL. g-1. min-1 in normal regions, P=NS). At 2 months, subendocardial FDG deposition was increased (0.084+/-0.025 mL. g-1. min-1 LAD region versus 0.042+/-0.017 mL. g-1. min-1 in normal regions, P<0.05). Increases in FDG uptake were inversely related to LAD subendocardial flow reserve during adenosine (3.5+/-0.6 at 1 month versus 1.4+/-0.2 at 2 months, P<0.01). CONCLUSIONS: These data indicate a progression of physiological adaptations in pigs with viable, chronically dysfunctional myocardium. As coronary flow reserve decreases, fasting FDG uptake increases. Flow at rest remains normal, consistent with "chronic stunning," and contrasts with reduced flow and increased FDG characteristic of hibernating myocardium in similarly instrumented pigs after 3 months. This temporal progression of adaptations supports the hypothesis of a transition from a physiological phenotype of stunning to hibernation.

Temporal and spatial variations in structural protein expression during the progression from stunned to hibernating myocardium.

BACKGROUND: Dysfunctional and normally perfused remote regions show equal myolysis and glycogen accumulation in pig hibernating myocardium. We tested the hypothesis that these arose secondary to elevations in preload rather than ischemia. METHODS AND RESULTS: Expression of structural protein (desmin, desmoplakin, titin, cardiotin, alpha-smooth muscle actin, lamin-A/C, and lamin-B2) in viable dysfunctional myocardium was analyzed by immunohistochemistry. We performed blinded analysis of paired dysfunctional left anterior descending coronary artery and normal remote subendocardial samples from stunned (24 hours; n=6), and hibernating (2 weeks; n=6) myocardium versus sham controls pigs (n=7). Within 24 hours, cardiac myocytes globally reexpressed alpha-smooth muscle actin. In stunned myocardium, cardiotin was globally reduced, whereas reductions in desmin were restricted to the dysfunctional region. Alterations progressed with the transition to hibernating myocardium, in which desmin, cardiotin, and titin were globally reduced. A qualitatively similar reorganization of cytoskeletal proteins occurred 3 hours after transient elevation of left ventricular end-diastolic pressure to 33+/-3 mm Hg. CONCLUSIONS: Qualitative cardiomyocyte remodeling similar to that in humans with chronic hibernation occurs rapidly after a critical coronary stenosis is applied, as well as after transient elevations in left ventricular end-diastolic pressure in the absence of ischemia. Thus, reorganization of cytoskeletal proteins in patients with viable dysfunctional myocardium appears to reflect chronic and/or cyclical elevations in preload associated with episodes of spontaneous regional ischemia.

Stability of hibernating myocardium in pigs with a chronic left anterior descending coronary artery stenosis: absence of progressive fibrosis in the setting of stable reductions in flow, function and coronary flow reserve.

OBJECTIVES: This study was performed to determine whether hibernating myocardium is adaptive or is destined to undergo progressive irreversible injury. BACKGROUND: Previous studies have suggested that hibernating myocardium eventually results in progressive dysfunction. Since serial studies cannot be performed in humans, the temporal progression of physiologic and structural adaptations was evaluated in pigs with hibernating myocardium. METHODS: Pigs were instrumented with a left anterior descending coronary artery (LAD) stenosis (1.5 mm) and underwent physiologic studies three to five months later to quantify regional function, perfusion and 18F-2-deoxyglucose (FDG) uptake. Viability was confirmed by histology and contractile reserve. RESULTS: Hibernating myocardium was characterized by severe regional dysfunction (centerline score, -1.9+/-0.1), reduced resting subendocardial flow (LAD: 0.85+/-0.03 vs. normal: 1.02+/-0.03 ml/min/g, p < 0.01), critically reduced subendocardial flow reserve (adenosine flow: 1.04+/-0.09 ml/min/g, p = NS vs. rest; epinephrine flow: 0.88+/-0.07 ml/min/g, p = NS vs. rest) and increased FDG uptake (0.022+/-0.002 vs. 0.014+/-0.001 ml/g/min, p < 0.01). Physiologic parameters were not different among animals studied at three (93+/-1 days, n = 27), four (118+/-2 days, n = 26) or five months (150+/-6 days, n = 9). Pathology revealed a small increase in LAD connective tissue (6.4+/-0.4% vs. 4.0+/-0.2%, p < 0.001), with no change over this time frame. CONCLUSIONS: Thus, physiologic and structural features of hibernating myocardium remain constant for at least two months. The absence of functional deterioration or progressive fibrosis suggests that hibernation is adaptive rather than an unstable physiology destined to progress to irreversible injury. The stability of this model appears ideally suited for interventions targeted to improve flow and function in chronically dysfunctional myocardium.

Dissociation of diastolic pressure-segment length and pressure-wall thickness relations during vasodilation in the conscious dog.

The effects of pharmacologic vasodilation and reductions in circumflex coronary artery pressure on the ventricular diastolic pressure-segment length and pressure-wall thickness relations were studied in nine conscious dogs equipped with an inflatable cuff on the proximal circumflex artery, a micromanometer in the left ventricle and four sets of piezoelectric crystals to measure wall thickness and endocardial segment length in the left circumflex and left anterior descending artery territories. Adenosine infusion into the circumflex coronary artery increased endocardial and transmural blood flow to that territory (measured by microspheres) by 436% and 487%, respectively (both p less than 0.05), and shifted the left circumflex artery territory pressure-wall thickness curve upward (p less than 0.05) without affecting the circumflex pressure-segment length, the left anterior descending artery territory pressure-segment length or pressure-wall thickness curves significantly; papaverine also shifted the circumflex region pressure-wall thickness curve upward (p less than 0.05). Both with and without vasodilation, moderate reductions in circumflex artery perfusion pressure did not affect the position of the ventricular pressure-wall thickness or the pressure-segment length curve (although during adenosine infusion endocardial blood flow decreased from 436% to approximately 100% of control values). More severe reductions in perfusion pressure (less than 45 mm Hg under control conditions and less than 30 mm Hg during adenosine infusion) decreased coronary blood flow below control values and caused a marked downward shift of the circumflex region pressure-segment length curve without affecting the position of the pressure-wall thickness curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of coronary artery calcium to differentiate patients with early coronary atherosclerosis from luminally normal arteries.

Patients with angiographic evidence of early coronary atherosclerosis (<50% diameter stenosis) have a poorer prognosis than those with normal arteries and may benefit from more aggressive interventions targeted toward the primary prevention of cardiovascular disease. Using a calcium score of 5, fast computed tomography was able to identify 59% of patients with early atherosclerosis, while excluding 87% of patients with smooth, luminally normal coronary arteries.

Pulmonary arterial elasticity in awake dogs.

We measured the relationship between pulmonary arterial pressure (Ppa), diameter (D), and length of a segment of the main pulmonary artery (MPA) in chronically instrumented conscious dogs breathing spontaneously (CCC). There were no physiologically significant changes in Ppa or D in the CCC dogs postoperatively, and the cross-sectional MPA shape measured by fast computed tomography was nearly circular. These results suggest that the MPA was not distorted by chronic instrumentation. We compared measurements made in the CCC dogs with previous measurements in acutely instrumented anesthetized dogs with open chests (AAO). The elasticity of MPA in the CCC animals was frequency dependent between 1 and 14 Hz and was similar to that in the AAO dogs. Oscillations of D preceded Ppa at cardiac frequencies in the AAO animals, but the D and Ppa oscillations were in phase in the CCC animals. The oscillations of length relative to D were significantly less in the CCC than in the AAO dogs. We conclude that, with limitations, the hemodynamic properties of the MPA can be measured in the CCC subjects. We suggest that the discrepancies between the AAO and CCC dogs can be attributed to differences in extrinsic loading of the MPA.

Lessons from experimental models of hibernating myocardium.

Chronic animal models of viable dysfunctional myocardium are now available that recapitulate most if not all of the physiological findings in humans with hibernating myocardium. These include chronic reductions in resting perfusion and contractile function, critical limitations in coronary flow reserve and increased uptake of 18F-2-deoxyglucose. These changes occur in the absence of infarction or necrosis and are accompanied by regional reductions in sarcoplasmic reticulum calcium-handling proteins and myocyte loss that arise secondary to apoptosis. Longitudinal studies of viable dysfunctional myocardium indicate that a state of chronic stunning with normal resting flow precedes the development of hibernating myocardium but these are distinct entities within a continuum of chronic adaptations to ischemia. This indicates that reductions in resting flow are the result rather than cause of chronic contractile dysfunction. Thus, the original concept proposing an acute prolonged reduction in flow as the initial stimulus producing hibernating myocardium needs to be revised.

Modulation of coronary autoregulatory responses by endothelium-derived nitric oxide.

There is increasing evidence that endothelium-derived nitric oxide production is an important mechanism contributing to the regulation of myocardial perfusion during ischemia distal to a coronary stenosis. Studies in conscious chronically instrumented animals have extended observations in isolated arterioles to demonstrate that inhibiting nitric oxide synthase with L-arginine analogs increases the vulnerability of the myocardium to ischemia. The variable extent to which endothelium-dependent function is impaired in human atherosclerosis raises the possibility that abnormalities in resistance vessel control contribute to the functional significance of a fixed epicardial coronary stenosis. This may explain the wide variability between the physiological effects of a given coronary stenosis and its angiographic severity. Aggressive intervention to normalize endothelium-dependent vasodilation and local nitric oxide release may have beneficial effects on the functional significance of a coronary stenosis.

Adjustments in regional coronary perfusion accompanying reductions in regional coronary arterial pressure.

Regional flow per unit weight has been found to be reduced under basal conditions in areas of human myocardium which are supplied by severely stenotic coronary arteries or are entirely collateral-dependent. Coronary arterial pressure within these areas is presumably reduced substantially in relation to systemic arterial pressure. In experimental animals it has recently been demonstrated that reductions in local coronary arterial pressure can result in reductions in regional myocardial flow (in all transmural layers) before vasodilator reserve is exhausted. Although the functional and metabolic accompaniments of regional flow reductions occurring in the face of vasodilator reserve remain incompletely defined, a reduction in regional metabolic demand is among the possibilities deserving consideration.

Coronary pressure-function and steady-state pressure-flow relations during autoregulation in the unanesthetized dog.

The present study was intended to define the interrelation among endocardial flow, endocardial function, and coronary arterial pressure during spontaneous autoregulation in the left ventricle of chronically instrumented unanesthetized dogs. Steady-state sonomicrometric measurements of regional function and epicardial coronary artery pressure were used to determine the lower pressure limit of endocardial autoregulation while global indexes of myocardial demand remained constant. Transmural wall thickening in the circumflex bed remained unchanged (+/- 5% of control values) until coronary pressure fell below 39 +/- 5.6 (SD) mm Hg. Endocardial segment shortening was similarly constant until coronary pressure fell below 42 +/- 7.4 mm Hg. There was no significant change in endocardial flow as coronary pressure was reduced over the autoregulatory plateau from 84 to 49 mm Hg (1.05-0.99 ml/min/g, p = NS). Below the critical pressure limits, small additional reductions in pressure were associated with marked reductions in both endocardial flow and function. The coronary pressure-function relation was linear as well as steep in this range for both wall thickening (r = 0.94 +/- 0.05) and segment shortening (r = 0.96 +/- 0.03). Although the relation between endocardial flow and function showed more variability than pressure-function relations at low pressures, wall thickening reductions and endocardial flow reductions related on a nearly one-to-one basis. The present study establishes that the coronary pressure-function relation can be used to define the lower limit of endocardial autoregulation. It also indicates that the lower pressure limit of endocardial autoregulation is considerably less than in anesthetized animals (40 vs. 70 mm Hg) and that steady-state flow above this limit is controlled more tightly. Although these differences may relate to systemic hemodynamics, it seems likely that general anesthesia and/or acute surgical instrumentation alter coronary autoregulation under at least some experimental circumstances.

Reductions in regional myocardial function at rest in conscious dogs with chronically reduced regional coronary artery pressure.

We have examined the temporal response of regional subendocardial function in conscious chronically instrumented dogs following implantation of a circumflex ameroid occluder. Collateralization was limited by ligation of epicardial anastamoses between the circumflex and adjacent coronary arteries at the time of instrumentation. Sonomicrometrically measured regional function in the circumflex coronary artery became depressed relative to that in the left anterior descending coronary artery bed under resting conditions with the onset of an aortic-circumflex pressure gradient of 15 +/- 2.9 mm Hg (mean +/- SEM). At the time of total ameroid occlusion, the ratio of circumflex to left anterior descending coronary artery function fell to 68 +/- 8% of control, with mean circumflex coronary pressure decreasing to 60 +/- 1.6 mm Hg. Following ameroid occlusion, distal coronary pressure increased, and circumflex function recovered towards control but remained depressed relative to that in the left anterior descending coronary artery for 2-4 weeks. Measurements of regional subendocardial perfusion suggested a dissociation between subendocardial flow and function prior to but not following coronary occlusion by the ameroid. We conclude that this model results in reductions in regional function that are relatively prolonged and are not readily attributable to subendocardial infarction or a critical reduction in resting coronary flow. The data suggest that functional adaptations in response to gradually developing coronary occlusion are more complex than those associated with acute reductions in coronary artery pressure and flow.

A programmable pressure control system for coronary flow studies.

An electrohydraulic servo valve capable of reproducing phasic physiological pressure and flow waveforms has been designed and constructed. The device has been utilized successfully in canine coronary flow studies. By measuring coronary pressure directly it is possible to reproduce waveform frequency components as high as 50 Hz in the cannulated left circumflex coronary artery when operated in a negative feedback configuration. It may easily be adapted to operate in a pressure- or flow-controlled mode in any vascular bed. The closed-loop frequency response of the servo valve itself is flat to 100 Hz with a natural frequency of 170 Hz. When utilized in the cannulated bed the frequency response is dependent on perfusion circuit and catheter dynamics.

Nitric oxide mediates flow-dependent epicardial coronary vasodilation to changes in pulse frequency but not mean flow in conscious dogs.

BACKGROUND: Although epicardial coronary arteries dilate in response to changes in flow, the mechanisms responsible for this and the mechanical stimuli that are sensed by the endothelium are not completely defined. We performed the present study to determine the importance of nitric oxide in eliciting epicardial dilation to sustained changes in mean flow and pulse frequency in the coronary circulation of conscious dogs. METHODS AND RESULTS: Dogs were chronically instrumented with a circumflex coronary occluder, piezoelectric crystals to measure epicardial diameter, and a coronary artery catheter placed distal to the crystals for intracoronary drug infusion. Studies were conducted in dogs in the conscious state. We inhibited nitric oxide production by administering the arginine analog N omega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg IV), which attenuated the epicardial artery diameter changes to left atrial infusions of acetylcholine (10 micrograms/min) from 140 +/- 23 (+/- SEM) to 46 +/- 20 microns (P < .05). Epicardial dilation to sustained increases in mean coronary artery at a constant heart rate. Intracoronary adenosine increased mean flow to the same extent (180 +/- 21 versus 177 +/- 24 mL/min after L-NAME, P = NS), but inhibiting nitric oxide production had no effect on flow-mediated epicardial dilation, with coronary diameter increasing by 264 +/- 36 microns under control conditions and 294 +/- 67 microns after L-NAME (P = NS). In contrast, when pulse frequency was increased by pacing to a rate of 200 beats per minute, mean coronary flow increased to a similar level (78 +/- 9 versus 75 +/- 9 mL/min after L-NAME), but the epicardial diameter change to pacing was attenuated from 170 +/- 29 microns under control conditions to 54 +/- 23 microns after L-NAME (P < .01). CONCLUSIONS: These results demonstrate that in vivo, nitric oxide production is primarily responsible for eliciting epicardial coronary vasodilation to endothelium-dependent agonists and changes in coronary flow pulse frequency. The failure of L-NAME to affect epicardial vasodilation during sustained increases in mean flow when pulse frequency is held constant suggests that additional mechanisms are involved in flow-mediated vasodilation of epicardial coronary arteries.

Phasic volumetric coronary venous outflow patterns in conscious dogs.

We performed the present study to characterize phasic venous outflow patterns in conscious chronically instrumented dogs. An implantable ultrasonic transit-time flow probe capable of measuring volumetric venous outflow was placed on the coronary sinus (n = 9) and/or great cardiac vein (n = 5). Under resting conditions, great cardiac vein flow was predominantly systolic [systolic index 61 +/- 6%/beat (means +/- SD), diastolic index 39 +/- 6%/beat]. In contrast, coronary sinus volumetric flow was predominantly diastolic (systolic index 36 +/- 13%/beat, diastolic index 64 +/- 13%/beat). During adenosine vasodilation both great cardiac vein and coronary sinus flow patterns were predominantly systolic (systolic index 58 +/- 12%/beat for the coronary sinus and systolic index 75 +/- 6%/beat in great cardiac vein flow). In addition, the time at which peak venous flow occurred shifted from end systole to midsystole after vasodilation. The variation in coronary venous flow patterns with position suggests that outflow patterns are significantly influenced by a venous compliance between the great cardiac vein and distal coronary sinus. The lack of a predominantly systolic outflow pattern in the coronary sinus under resting conditions contrasts with previous findings in open-chest anesthetized animals and raises the possibility that cannulation of the coronary sinus and/or changes in vasomotor tone caused by anesthesia alter resting venous flow patterns.

Reduced regional myocardial perfusion in the presence of pharmacologic vasodilator reserve.

To determine whether reductions in regional myocardial perfusion at reduced coronary arterial pressures reliably indicate maximal vasodilation of the distal vasculature, coronary autoregulation was studied in open-chest dogs at heart rates of approximately 60 beats/min, a level at which metabolic demand, time-averaged systolic compressive forces, and transmural vasodilator reserve approximate those found under usual resting conditions. Circumflex pressure was controlled with a programmable pressure source. Regional circumflex inflow was 0.56 +/- 0.04(SEM) ml . min-1 . g-1 when circumflex pressure equaled spontaneous aortic pressure and fell to 0.34 +/- 0.02 ml . min-1 . g-1 when circumflex pressure was reduced to 35 mm Hg. Reductions were similar in each myocardial layer, with endocardial flow falling from 0.68 +/- 0.04 to 0.39 +/- 0.03 ml . min-1 . g-1. During adenosine-induced vasodilation at 35 mm Hg, full-thickness and endocardial flows rose to 0.92 +/- 0.08 and 1.07 +/- 0.10 ml . min-1 . g-1, respectively. When coronary pressure was reduced to 25 mm Hg and autoregulation was again operative, full-thickness and endocardial flows fell to 0.28 +/- 0.03 and 0.28 +/- 0.04 ml . min-1 . g-1. During adenosine vasodilation at 25 mm Hg endocardial flow did not increase significantly but epicardial reserve remained present. These results indicate that significant reductions in regional myocardial perfusion can occur before pharmacologic vasodilator reserve is exhausted. In the absence of tachycardia, endocardial vasodilator reserve can persist to coronary pressures less than 35 mm Hg, but is ordinarily exhausted before epicardial vasodilator reserve.

Effect of cardiac output on pulmonary hemodynamics.

The purpose of this study was to test the hypothesis that there is a direct relation between pulmonary arterial input resistance and compliance in seven anesthetized cats. Cardiac output was altered by varying the direction and flow through an arteriovenous fistula with a roller pump. Pulmonary arterial input impedance was calculated from the Fourier analysis of the pressure and flow waveforms. Input resistance, pulmonary arterial compliance and characteristic impedance were estimated from the impedance spectra with a lumped parameter model. We found that pulmonary arterial compliance increased with cardiac output (P less than 0.002) but characteristic impedance was independent of flow. The observed response has the effect of reducing the hydraulic power lost by the pulmonary vasculature due to wave reflection. In three additional cats we measured the diameter of the main pulmonary artery by sonomicrometry. We found a linear relation between mean pulmonary arterial pressure and pulmonary arterial diameter during alterations of cardiac output. This result suggests that the increase of pulmonary arterial compliance with cardiac output is due to geometric factors rather than changes in vascular elastic properties.

Chronic hibernation and chronic stunning: a continuum.

Identification of myocardial viability is of increasing clinical importance in managing patients with coronary artery disease and advanced left ventricular dysfunction. Although viable chronically dysfunctional myocardium is always the result of repetitive episodes of reversible ischemia, there may be multiple mechanisms responsible for the contractile dysfunction. Many patients have contractile dysfunction with normal resting perfusion, as determined by imaging, that is related to chronic myocardial stunning. Viability studies are generally unnecessary because normal resting perfusion would preclude significant fibrosis. The clinical problem arises in evaluating patients with depressed resting flow that can be due to hibernating myocardium or nontransmural infarction. In this circumstance viability studies are required to assess the likelihood of functional recovery after revascularization. Although hibernating myocardium was originally posited to develop in response to prolonged episodes of myocardial ischemia (experimentally termed "short-term hibernation"), subsequent studies have shown that this tenuous balance can only be maintained for a period of several hours before resulting in some degree of subendocardial infarction. More recent experimental studies have demonstrated that there is a progression from chronic stunning with normal flow to hibernating myocardium with reduced resting flow. This presumably arises from repetitive episodes of spontaneous ischemia that increase in frequency as the physiologic significance of a coronary stenosis progresses. Thus in this new paradigm reduced flow is a result, rather than the cause, of the contractile dysfunction. This review summarizes basic and clinical pathophysiologic studies supporting the claim that chronic stunning and hibernation are distinct entities that may represent opposite ends of a continuum of mechanisms in viable chronically dysfunctional myocardium.

Shear stress-induced vasodilation in porcine coronary conduit arteries is independent of nitric oxide release.

The present study was performed to determine the importance of nitric oxide in eliciting epicardial coronary artery dilation during sustained increases in shear stress in the absence of pulsatile flow. Isolated first-order porcine epicardial coronary conduit arteries (approximately 500 microm) were preconstricted (U-46619) and subjected to steady-state changes in flow in vitro. Nonpulsatile flow (shear stress range from 0 to approximately 100 dyn/cm2) produced a graded dilation of epicardial arteries. Inhibiting nitric oxide synthase with 10(-5) M N(omega)-nitro-L-arginine methyl ester (L-NAME) blocked bradykinin-induced vasodilation but did not affect the flow-diameter relation or the maximum change in diameter from static conditions (67 +/- 10 microm in control vs. 71 +/- 8 microm after L-NAME, P = not significant). The addition of indomethacin (10(-5) M) had no effect on flow-mediated vasodilation. Depolarizing vascular smooth muscle with KCl (60 mM) or removing the endothelium blocked bradykinin vasodilation and completely abolished flow-mediated responses. The K+ channel blocker tetraethylammonium chloride (TEA; 10(-4)M) attenuated flow-mediated vasodilation (maximum diameter change was 110 +/- 18 microm under control conditions vs. 58 +/- 10 microm after TEA, P < 0.001). These data indicate that epicardial coronary arteries dilate to steady-state changes in nonpulsatile flow via a mechanism that is independent of nitric oxide production. The ability to completely block this with KCl and attenuate it with TEA supports the hypothesis that epicardial coronary arteries dilate to steady levels of shear stress through hyperpolarization of vascular smooth muscle. This may be secondary to the release of an endothelium-dependent hyperpolarizing factor.

Adenosine-recruitable flow reserve is absent during myocardial ischemia in unanesthetized dogs studied in the basal state.

We conducted the present study to determine if pharmacologically recruitable flow reserve was present during ischemia in unanesthetized dogs studied in the absence of adrenergic activation. Microsphere measurements of regional perfusion at reduced coronary pressures in a distal circumflex region subjected to intracoronary adenosine infusion (0.265 mg/min IC) were compared with measurements in a proximal circumflex region where pressure was reduced but flow was being autoregulated normally. Ischemia began when coronary pressure was reduced below 40 mm Hg. At a coronary pressure of 28 +/- 1 (mean +/- SEM) mm Hg, subendocardial flow with autoregulation intact was 0.59 +/- 0.05 mL.min.g-1 and similar to that in the region receiving adenosine, which averaged 0.61 +/- 0.05 mL.min-1.g-1 (P = NS). Although adenosine increased subepicardial flow from 0.81 +/- 0.05 to 1.16 +/- 0.09 mL.min-1.g-1 (P < .001), the magnitude of the increase was minimal when coronary pressure fell to a level that caused subepicardial flow during autoregulation to be reduced below resting values. These results demonstrate that the substantially lower autoregulatory break point found in unanesthetized dogs studied in the basal state reflects the ability of intrinsic autoregulatory mechanisms to match local vasodilator reserve to that recruitable pharmacologically. This contrasts with the presence of pharmacologically recruitable subendocardial flow reserve in anesthetized animals and is most likely related to a low level of circulating catecholamines and lack of sympathetic activation in unanesthetized animals studied under basal conditions.