Reactive Hyperemic Response Research Articles

Direct In Vivo Observation of Subendocardial Arteriolar Response During Reactive Hyperemia

To study the vasodilatory capacity of subendocardial (ENDO) arterioles, we evaluated the reactive hyperemic responses of ENDO as well as subepicardial (EPI) arterioles in 40 dogs by our needle-probe intravital microscope. We also examined the individual and combined effects of an ATP-sensitive K+ channel blocker (glibenclamide, 200 micrograms/kg), an inhibitor of nitric oxide synthase (NG-monomethyl-L-arginine [L-NMMA], 2 mumol/min, 20 minutes), and an adenosine-receptor antagonist (8-phenyltheophylline [8PT], 0.75 mumol/min, 15 minutes). The percent increase in end-diastolic diameter of ENDO arterioles was larger (P < .01) than that of EPI arterioles during reactive hyperemia, especially for the arterioles larger than 120 microns (P < .01). The diastolic-to-systolic vascular pulsation amplitude at the peak flow was greater in ENDO than EPI arterioles (25% versus 6%, P < .05). Compared with control conditions, the presence of both glibenclamide and L-NMMA suppressed the vasodilation responses of ENDO arterioles (P < .01 for both) and EPI arterioles (P < .05 for both). The effect of L-NMMA was greater in ENDO arterioles (P < .01), but that of glibenclamide was not different between ENDO and EPI arterioles. 8PT influenced the hyperemic response, although statistical significance was found only in the flow response. The effect of combined infusion of L-NMMA and glibenclamide with or without 8PT was greater than that of individual infusions in both ENDO and EPI arterioles. Conclusions are as follows: (1) The vasodilatory response of ENDO arterioles was even larger than that of EPI arterioles. Thus, the smaller flow reserve of ENDO arterioles may be caused by other factors, including the greater effects of myocardial compression and nitric oxide on the ENDO arterioles. (2) The vascular responses of ENDO and EPI arterioles were modulated by both endothelium-independent and -dependent vasodilative factors, and the effect of each factor including adenosine was associated with the effects of others.

Cardiac hypertrophy impairs recovery from ischaemia because there is a reduced reactive hyperaemic response

The aim was to investigate whether impaired coronary flow reserve associated with cardiac hypertrophy could significantly limit the flow debt repayment following short periods of coronary occlusion and exacerbate or prolong episodes of myocardial ischaemia. Left ventricular hypertrophy was induced in guinea pigs by aortic constriction and the hearts were isolated six weeks later for Langendorff perfusion. Sham operated animals served as controls. The reactive hyperaemic response was studied following various lengths of occlusion of flow and the extent of aerobic and anaerobic metabolism was assessed in each group. Heart weight/body weight ratio was increased by approximately 25% (P < 0.001) with aortic constriction. The reactive hyperaemic flow response in isolated hearts was impaired by hypertrophy in both magnitude (P < 0.05) and duration. The repayment of flow debt was also significantly reduced, suggesting an inadequate recovery of the myocardium following the occlusion. The total amount of O2 consumed by the heart throughout the duration of hyperaemia was less in hypertrophy than in sham operated controls, suggesting a decrease in aerobic metabolism. Total lactate discharge expressed as a ratio of O2 consumed, which provides an estimation of the degree of anaerobic in relation to aerobic metabolism, was greater in hypertrophy than in sham operated controls. The hypertrophied heart is more vulnerable to brief periods of ischaemia because of an impaired reactive hyperaemic response which results in delayed metabolic recovery. These abnormalities may contribute to the increased morbidity associated with cardiac hypertrophy.

Cardiac hypertrophy impairs recovery from ischaemia because there is a reduced reactive hyperaemic response

Cardiac hypertrophy impairs recovery from ischaemia because there is a reduced reactive hyperaemic response

Effects of nitric oxide synthase inhibition on myocardial capillary permeability and reactive hyperaemic response

Effects of nitric oxide synthase inhibition on myocardial capillary permeability and reactive hyperaemic response

Effects of nitric oxide synthase inhibition on myocardial capillary permeability and reactive hyperaemic response

The aim was to examine the role of nitric oxide (NO) in the myocardial microcirculation. Open chest anaesthetised dogs received intracoronary infusion of NG-monomethyl-L-arginine (L-NMMA; 0.5 mg.kg-1 over 30 min). Myocardial microvascular extraction fraction of a small hydrophilic solute (technetium 99m labelled diethylenetriaminepenta-acetate [99mTc-DTPA]), and the regional myocardial plasma flow rate, were determined by the single injection, residue detection method, and the capillary permeability-surface area product was calculated. The tone in intramyocardial resistance vessels was assessed by the local 133Xe washout method during baseline conditions, in response to intracoronary acetylcholine, and during peak reactive hyperaemia after 10 s or 30 s of myocardial ischaemia, respectively. In eight open chest dogs, L-NMMA attenuated the increase in myocardial plasma flow rate in response to intracoronary acetylcholine by 32(SEM 7)%, but failed to alter baseline myocardial plasma flow rate significantly, as determined by the local 133Xe washout method. L-NMMA did not influence myocardial microvascular permeability to 99mTc-DTPA. However, intracoronary L-NMMA decreased the peak reactive hyperaemic myocardial plasma flow rate after 10 s, but not 30 s, of coronary occlusion. In open chest dogs, microvascular NO synthesis is not a major determinant of baseline myocardial plasma flow rate, and does not appear to influence myocardial microvascular permeability significantly. In this model, NO intervenes in the regulation of the peak reactive hyperaemic plasma flow rate following brief, but not more prolonged, periods of coronary occlusion.

Can Transcutaneous Oximetry Detect Nutritive Perfusion Disturbances in Patients with Lower Limb Ischemia?

Transcutaneous oximetry (Tc pO 2) performed at 37 and 44° on the dorsum of the foot and capillary microscopy of the nailfold of the big toe were applied to 85 patients with various (including asymptomatic) stages of lower limb ischemia to appreciate the relationship between (disturbances in) capillary perfusion and skin oxygen tension. In mildly diseased patients, capillary perfusion as measured by direct observation, was preserved. In critically ischemic patients in the supine position, red blood cell-perfused capillary density was reduced. Nutritive perfusion was severely reduced and showed an absent reactive hyperemia after a 1-min arterial occlusion. Also, postural vasoconstrictive activity was reduced, Tc pO 2 measured at 37° was very low already in mildly diseased patients, illustrating the poor oxygen diffusion toward the skin. At 44°, Tc pO 2 was severely reduced in critically ischemic patients. Reactive hyperemic response and postural vasoconstriction were suppressed, due to local heating of the skin. Measurement of the Tc pO 2 has limitations in the assessment of nutritive perfusion, as opposed to capillary microscopy, since it is an indirect measure of skin perfusion, not necessarily derived from capillaries only. The obligatory local skin heating impairs physiological studies as to hyperemic reserve capacity or postural constriction mechanisms. Thus, transcutaneous oximetry is a poor method of characterizing pathophysiological mechanisms occurring in skin nutritive microcirculation. However, capillary microscopy and transcutaneous oximetry can give additive information as to the severity of peripheral ischemia. Peak red blood cell velocity during reactive hyperemia using capillary microscopy and the resting Tc pO 2 at 44°, both measured in the supine position, appeared to be valuable microcirculatory parameters in detecting critical limb ischemia.

Assessment of working skeletal muscle oxygenation in patients with chronic heart failure

Patients with chronic heart failure (CHF) are frequently limited by muscle fatigue resulting from impaired skeletal muscle blood flow. Accordingly, we assessed working skeletal muscle oxygenation in such patients using near-infrared (NIR) spectroscopy. Nine normal subjects (mean age 52 years) and 12 patients with CHF (mean age 60 years) were studied. NIR spectroscopy was used to monitor relative changes in oxygenated hemoglobin (Hb) and myoglobin (Mb) (oxy Hb Mb ), deoxygenated Hb and Mb ( deoxy Hb Mb ), and total (oxy + deoxy) Hb and Mb (total Hb Mb ) contents in the vastus lateralis muscle at rest, during warm-up (0 W, 30 cycles/min to 3 min), incremental maximal supine bicycle exercise (ramp protocal, 15 W/min, 50 cycles/min), and recovery. At peak exercise the patients exhibited reduced heart rate, systolic blood pressure, peak exercise oxygen consumption (VO 2; 15 ± 3.0 ml/kg.min vs 32 ± 8.5 ml/kg/min), workload (99 ± 23.4 W vs 183 ± 68.4 W) as compared with the normal subjects. The respiratory quotient was comparable in both groups. In the normal subjects, oxy Hb Mb was increased from the warm-up period to the early phase of exercise, followed by a progressive decrease to peak exercise. In the recovery phase, oxy Hb Mb was increased abruptly. For these patients, change in oxy Hb Mb followed a pattern similar to that seen in normal subjects, and oxy Hb Mb was decreased earlier in contrast to that in the normal subjects. There was a significant difference in the change of oxy Hb Mb during warm-up, early phase exercise, and recovery between the two groups. Changes in deoxy Hb Mb and oxy Hb Mb were inversely proportionate in both groups. In the recovery phase, the change in totla Hb Mb was smaller than that in the normal subjects. These data suggest that oxygen delivery to working skeletal muscle is impaired throughout exercise and a reactive hyperemic response to strenuous exercise is blunted in patients with CHF.

Study of Dynamic Microcirculatory Problems in 'Blackfoot Disease' - Emphasizing Its Differences from Arteriosclerosis.

The cutaneous microcirculation can be divided into thermoregulatory shunt vessels and nutritive skin capillaries. Flux in nonnutritional shunt vessels dominates the signal recorded by the laser Doppler flowmeter. Computerized videophotometric capillaroscopy is a sensitive method for assessing cutaneous nutritive microcirculation. Using patients with blackfoot disease and arteriosclerosis as disease models, we evaluated the sensitivity and clinical usefulness of these relatively new techniques for peripheral vascular disorders. In blackfoot disease, blood flux measured by the laser Doppler flowmeter in the affected toe was lower than that in the nonaffected toe. In symptom-free fingers, blood flow was not significantly different between blackfoot disease and arteriosclerosis. However, blood flow in both diseases was lower than that of the control group. Patients who had the same status of thermoregulatory flow and eyeground arteriosclerotic classification underwent a 1-min arterial occlusion of the digits. The postocclusive reactive hyperemia response (PRH) of nailfold capillary loops was evaluated. All parameters for PRH for the cutaneous nutrient microcirculation including resting capillary blood cell velocity (rCBV), peak capillary blood cell velocity (pCBV) and time to pCBV were more significantly disturbed in the blackfoot disease group than in the arteriosclerotic group. On the basis of the results of this study, dynamic capillaroscopy provides a new approach for the early detection of circulatory disturbances resulting from different mechanisms. Copyright 1995 S. Karger AG, Basel

Impaired cholinergic peripheral vasodilation and its relationship to hyperemic calf blood flow response and exercise intolerance in patients with chronic heart failure

This study examined the peripheral endothelium-dependent vasodilatory response to acetylcholine and the endothelium-independent vasodilatory response to nitroprusside in 19 patients with chronic heart failure and eight controls. These peripheral blood flow responses were compared with hyperemic calf blood flow changes after maximum leg exercise and 5-min femoral occlusion. The peripheral blood flow response to forearm intra-arterial infusion of acetylcholine and sodium nitroprusside, and reactive hyperemic calf blood flow changes were measured by plethysmography. All peripheral blood flow responses were significantly reduced in patients with chronic heart failure ( P < 0.05). Reduction of acetylcholine-mediated changes in peripheral blood flow was correlated with exercise-induced calf blood flow response ( r = 0.51, P < 0.05), but not with occlusion-induced calf blood flow response ( r = 0.02, NS). Sodium nitroprusside-mediated changes were not correlated with any reactive hyperemic blood flow responses (exercise: r = 0.27, NS; occlusion: r = 0.11, NS). When the patients were divided into two subgroups based on the median exercise-induced calf blood flow change, the subgroup with the lower calf blood flow response showed a reduction in exercise capacity (anaerobic threshold: 11.8 ± 0.6 vs. 14.6 ± 1.0 ml/kg/min; P < 0.05). These findings suggest that endothelial dysfunction is related to a decrease in exercise-induced skeletal muscle blood flow and exercise capacity in patients with chronic heart failure.

1005-82 Myocardial and Coronary Vascular Protection After Coronary Occlusion and Reperfusion by Selective Sinoatrial Node Inhibition

Improved regional myocardial function and abnormal flow reserve resulting from myocardial ischemic injury has been observed with β-blockade. To determine if heart rate reduction alone would offer similar protection, anesthetized dogs were subjected to left anterior descending (LAD) occlusion and given a selective SA node inhibitor (ZD7288 0.5 mg/kg, n = 5 or buffer, n = 7). After 1 hour of occlusion they were reperfused. ZD7288 decreased heart rate by 28 ± 2% (153 ± 14 to 120 ± 11 bpm, p &lt; 0.05) at 1 hr after reperfusion. In buffer-treated dogs, peak reactive hyperemic (RH) response after 20 sec LAD occlusion, (index of coronary flow reserve), fell from 276 ± 22% to 135 ± 18% and LAD regional shortening fraction (SF, by ultrasonic crystals) decreased from 9.7 ± 1.5% to 0.6 ± 0.1% after reperfusion (both, p &lt; 0.001). In ZD7288-treated dogs, peak RH and SF after reperfusion (227 ± 19% and 4.2 ± 0.8%, respectively) were preserved (p &lt; 0.05) vs buffertreated dogs. Despite similar area of left ventricular (LV) at risk, infarct area (as % of LV). was also smaller in ZD7288-treated vs. buffer-treated dogs (14.0 ± 0.5 vs 23.0 ± 1.10%, P &lt; 0.05). Heart rate was maintained constant with atrial pacing in five other ZD7288-treated dogs and neither peak RH or SF were preserved compared with buffer-treated dogs. Thus, selective SA node inhibition alone, induced after coronary occlusion, results in myocardial and coronary vascular protection after reperfusion. Selective SA node inhibition may have clinical utility in acute myocardial patients who are not candidates for beta blockers.

Acute effects of glyburide on the regulation of peripheral blood flow in normal humans

Recent animal studies have demonstrated that selective blockade of ATP-sensitive K + (K ATP) channels of vascular smooth muscle results in a significant increase in peripheral vascular tone. The main aim of this study was to assess whether glyburide, a selective blocker of K ATP channels and commonly used antidiabetic agent, influences resting blood flow and reactive hyperemic response of peripheral tissues of normal subjects. Baseline calf blood flow was measured non-invasively in six normal subjects with femoral venous occlusive plethysmography. Calf blood flow was also serially measured every 30–60 s after the release of calf arterial occlusion (10 min duration). Reactive hyperemia was expressed in terms of peak post-occlusive flow, duration of hyperemia and reactive hyperemic volume. In each subject, baseline flow and reactive hyperemia were measured before (control) and every hour for 5 h after the oral ingestion of either 7.5 mg glyburide or a placebo on two separate days. Baseline calf flow declined by 30 and 42% of control values after 1 and 2 h of glyburide intake ( P < 0.05) with a return to control values by hours 3, 4 and 5. Peak post-occlusive flow after 1, 2 and 3 h of glyburide ingestion was lower than control values by 22, 30 and 28%, respectively ( P < 0.05). The duration of reactive hyperemia after 2 and 3 h of glyburide ingestion was significantly longer than control values ( P < 0.05), whereas reactive hyperemic volume remained unaffected by glyburide intake. Placebo elicited no significant changes in baseline flow or reactive hyperemia throughout the 5-h experimental period. These results indicate that a single dose of glyburide in the therapeutic range elicits significant alterations in the regulation of peripheral blood flow in normal subjects. We propose that these alterations are mediated through the blockade of vascular smooth muscle K ATP channels.

1014-92 Impaired Microcirculation in Chronic Heart Failure

The microcirculation plays a crucial role in the exchange of oxygen, energy rich substrates and metabolites. The effects on the microcirculation of impaired heart function and disturbed peripheral skin circulation in chronic heart failure (CHF) are unknown. Nailfold capillary morphology and dynamics in CHF were studied in relation to parameters of left ventricular (LV) structure and function. Twenty patients (13 male, 7 female, age 64 ± 2 years) with CHF NYHA class II underwent a capillaroscopic examination at the finger nailfold using a computerised videophotometric system (Capiflow) at rest and after 1 min arterial occlusion. Patients were treated with diuretics, ACE inhibitors and digoxin and mean duration of symptoms was 65 ± 9 months. Study parameters were number, length, and diameter of the capillaries as well as capillary blood velocity (CBV). Further experiments included echocardiography and determination of LV ejection fraction by Tc-scintigraphy. Nailfold capillaries in established CHF are enlarged (afferent diameter 6.6 ± 0.4 μm, efferent diameter 8.2 ± 0.4 μm, ref. resp. &lt;6 and &lt;8 μm) and CBV is dramatically decreased (351 ± 64 μ/s, ref. &gt;600 μm/s at 23°C). The reactive hyperemic response to one minute arterial occlusion is attenuated (peak CBV 879 ± 158 μm/s, ref &gt; 2000 μm/s). CBV correlates positively with LV ejection fraction (r = 0.61, p = 001) and inversely with LV end-diastolic (r = -0.56, P = 0.04) and end-systolic (r = -0.69, P = 0.01) diameters. The time-to-peak flow (35 ± 5 s, ref. 6–10 s) after one min arterial occlusion is positively related (r = 0.68, P &lt; 0.05) to the duration of CHF. Our data indicate that microcirculation in chronic heart failure deteriorates in function of the severity and duration of heart failure.

Protamine inhibits coronary collateral development in a canine model of repetitive coronary occlusion.

Protamine has been demonstrated to inhibit angiogenesis in vitro and in vivo; however, its effect on coronary collateral development has not been examined. The present investigation tested the hypothesis that subcutaneously administered protamine inhibits canine coronary collateral development in response to chronic myocardial ischemia. Dogs underwent daily, repetitive, 2-min, left anterior descending coronary artery (LAD) occlusions for 22 consecutive days. Regional myocardial blood flow (radioactive microspheres), LAD segment shortening, and coronary flow debt repayment were measured in saline-treated (n = 7) and protamine-treated (n = 6) dogs on days 1, 8, 15, and 22. Coronary collateral development in saline-treated dogs was demonstrated by time-dependent significant (P < 0.05) increases in collateral blood flow to ischemic myocardium [day 1 0.10 +/- 0.01 vs. day 22 0.88 +/- 0.05 (SE) ml.min-1.g-1], progressive normalization of myocardial contractile function during LAD occlusion, and successive reduction in flow debt repayment. In contrast, protamine treatment significantly attenuated, increases in collateral perfusion (day 1 0.13 +/- 0.02 vs. day 22 0.36 +/- 0.03 ml.min-1.g-1). Regional contractile dysfunction and postocclusive reactive hyperemic responses were sustained over time in protamine-treated compared with saline-treated dogs. The results demonstrate that protamine inhibits coronary collateral development in response to chronic myocardial ischemia.

A kinetic model of coronary reactive hyperemic response to transient ischemia

A kinetic model is proposed to delineate the factors that determine the coronary reactive hyperemic response (RHR) to transient ischemia. The model comprises of myocardial-interstitial (M) and vascular (V) compartments. Vasodilator metabolites (VM) are produced in the M compartment during the interval of coronary occlusion. The rate of VM production is dependent on the flow rate during the ischemic period, the ratio of excess flow above the control level (R) to the loss of flow during occlusion period (D), the amount of oxygen stored and the degree of vasodilation in the V compartment prior to occlusion. Following a complete release of occlusion, VM are transported from the M to V compartment and are washed out or degraded with time. The time course of RHR is determined by the coronary patency which is proportional to VM concentration in the V compartment. Based on a set of numerical constants, the model is tested by simulating RHR to the various occlusion manoeuvres: a pair of 10 sec occlusions separated by brief release, a 15 sec release followed by a second brief occlusion, a brief release of an occlusion followed by restricted inflow and a period of restricted inflow after occlusion. The simulated results fit the experimental R/D and RH durations data of canine hearts. Factors that determine the impairment of RH capacity in coronary stenosis are suggested in terms of the model scheme.

Aspects of coronary vasomotor regulation.

Matching the supply of blood and oxygen to the myocardial demand for oxygen is an essential function of the coronary regulatory system. The heart cannot tolerate a deficit of oxygen for more than a few seconds without harmful consequences, so that the regulatory system must respond rapidly to changes in oxygen demand or perfusion pressure. The matching of oxygen supply to myocardial oxygen demand can be examined in three main ways. One of them is to test autoregulation which may be defined as the response to a change in perfusion pressure when myocardial oxygen demand remains unchanged. To do this in the heart, the coronary artery must be cannulated so that changes in perfusion pressure have no or relatively little effect on myocardial oxygen demand. The second method is to examine the response during constant perfusion pressure to changed myocardial oxygen demand which may either be increased by pacing, increases in cardiac pressure or volume work, or infusion of metabolic stimulators like calcium or catecholamines, or may be decreased by decreasing cardiac pressure or volume work or by decreasing contractility. A subset of these experiments is to examine maximal flows induced by severe exercise or very rapid pacing. The third method is to examine the reactive hyperemic response; coronary flow is stopped for several seconds, and the hyperemic response after flow is restored is examined. It is possible that all these three methods are examining the same regulatory systems, except that reactive hyperemia only examines decreases in oxygen supply and definitely produces transient ischemia.KeywordsNitric OxideMyocardial Blood FlowAtrial Natriuretic PeptideCoronary FlowAdenosine DeaminaseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

A kinetic model of coronary reactive hyperemic response to transient ischemia

A kinetic model of coronary reactive hyperemic response to transient ischemia

Simultaneous assessment of muscle and skin blood fluxes with the laser-Doppler technique.

The laser-Doppler technique was used to assess local muscle and skin blood fluxes at the lower limb in 20 healthy volunteers. After puncturing the anterior tibial muscle with a steel cannula, a single-fibre probe with a diameter of 0.5 mm was inserted into the muscle. Simultaneously, the skin blood flux was measured at calf and foot. The muscle blood flux at rest was 3.5 to 4 times higher than the skin blood flux at calf or foot. The spatial variability of the muscle blood flux at three different sites of measurement was considerable and tended to be higher than in the skin of the calf. After an arterial occlusion lasting 3 min, peak flux was reached in the muscle after 18.7 +/- 9.8 s, in the skin of the calf after 16.8 +/- 9.3 s, and in the skin of the foot after 22.9 +/- 14.6 s (NS). The relative flux increase during reactive hyperaemia was significantly lower in the muscle (2.7 +/- 1.3) than in the skin of the calf (3.9 +/- 1.9; p<0.05) or the foot (5.1 +/- 3.5; p<0.005). The reproducibility of reactive hyperaemia response in muscle was excellent with unchanged probe position, but exhibited a marked variability on different days. The laser-Doppler technique provides the possibility for simultaneous measurement of flow dynamics in muscle and skin with a high temporal resolution. Methodological problems include differences in probe geometry of the single-fibre compared to standard probes and differences in optical properties of the tissues. Direct comparison of flux values may, therefore, be subject to criticism, but not the comparative analysis of relative flux changes. The influence of tissue trauma on muscle blood flux has to be considered for the analysis of flux data.

Blockade of Adenosine Triphosphate-sensitive Potassium Channels Eliminates Isoflurane-induced Coronary Artery Vasodilation

The mechanisms by which volatile anesthetics induce vasodilation are unknown. Recent studies of adenosine triphosphate-sensitive potassium channels (KATP channels) in the vascular smooth muscle of the coronary circulation suggest that these channels play a role in the coronary artery dilation produced by hypoxemia, the coronary blood flow (CBF) reactive hyperemic response, and in CBF auto regulation. We therefore conducted this study to determine the role of KATP channels in isoflurane-induced coronary vasodilation. Studies were conducted in six open-chest, anesthetized swine. The left anterior descending coronary artery was cannulated and perfused by blood passed through a membrane oxygenator. This preparation allowed us to administer drugs and volatile anesthetics regionally to the perfused myocardium, minimizing systemic effects. Regional CBF response to 1.5% and 3.0% isoflurane administered via the membrane oxygenator was measured before and after blockade of KATP channels, and was compared to the vasodilation produced by regional administration of several doses of sodium nitroprusside and adenosine. Blockade of KATP channels was achieved by regional intracoronary administration of glibenclamide (1-22 micrograms.kg-1.min-1), a specific blocker of these channels. Administration of 1.5 and 3.0 percent isoflurane increased regional CBF by 29 +/- 29% and by 62 +/- 28%, respectively. Under control conditions, blockade of KATP channels decreased mean CBF by 18%, but did not cause ischemia. KATP channel blockade totally eliminated the vasodilator response to both doses of isoflurane. During KATP channel blockade the response to 3% isoflurane was converted to net vasoconstriction: mean delta CBF = -5% +/- 6%, P = < 0.05 versus control. Negative inotropic effects of isoflurane were not eliminated by glibenclamide. Because KATP channel blockade was so effective in eliminating isoflurane-induced coronary vasodilation, the dose of glibenclamide was decreased in sequential experiments, but total blockade of isoflurane vasodilation was achieved even at the smallest dose of glibenclamide studied (1 microgram.kg-1.min-1). The vasodilator response to nitroprusside was not affected, and the vasodilator response to adenosine was partially inhibited (consistent with their known mechanisms of action). Blockade of KATP channels by glibenclamide completely inhibits isoflurane-induced coronary vasodilation in the regionally perfused swine myocardium. The response to sodium nitroprusside, a drug that induces vasodilation via a different mechanism, was unaffected. The response to adenosine, a drug whose vasodilation is partially mediated via KATP channels, was partially inhibited. These results suggest that in vivo isoflurane-induced coronary artery vasodilation is predominantly mediated by KATP channels.

Analysis of flow in coronary epicardial arterial tree and intramyocardial circulation

A mathematical model combining the coronary flow in the epicardial arterial tree and the intramyocardial circulation is presented. The epicardial arterial tree is represented by a resistive capacitive network based on its realistic anatomy. The intramyocardial flow is affected by the pump action of the contracting myocardium through the extravascular compressive pressure (ECP), which, in turn, affects the dynamic resistance and compliance changes based on the relationship between the transmural pressure and the cross-sectional area of a vessel. The model accounts for the autoregulatory mechanism of the intramyocardial compartments (arteriolar, microvascular and venular) and is structured according to the epicardial coronary anatomy. Realistic coronary epicardial arterial flow patterns are obtained, which compare well to experimentally measured data in six dogs under basal conditions and during reactive hyperemic response. Simulations of the average transmural flow in the three intramyocardial vascular compartments show that the flow in the arterial side is predominantly diastolic, with a systolic retrograde component, and is dominantly systolic antegrade flow in the venular side, consistent with experimental data. Interestingly, the transmurally average microcirculatory flow is continuous, with very small change throughout the cardiac cycle, and is practically insensitive to changes in the model parameters. The model presents a quantitative tool that describes the dynamic patterns of coronary flow in relationship to muscular and extravascular parameters.

Endothelial control of vascular and myocardial function in heart failure.

The effect of vascular endothelium, endocardium, and coronary endothelium on vascular tone and myocardial contraction-relaxation sequence in heart failure is discussed. Vascular endothelium affects underlying vascular smooth muscle through paracrine secretion of relaxing and constricting factors. In heart failure, systemic vasoconstriction results not only from neuroendocrine activation, but also from disturbed local endothelial control of vascular tone because of impaired endothelial-dependent vasodilation and because of increased plasma concentration of endothelin. Experimental evidence obtained in isolated cardiac muscle strips established the influence of endocardial endothelium on the duration of myocardial contraction and on the onset of myocardial relaxation. By analogy to vascular endothelium, both diffusible agents that abbreviate (endothelial-derived relaxation factor-like substance) and those that prolong (endocardin) myocardial contraction have been shown to be released from the endocardium. Similar agents are released from the coronary endothelium and, because of the close proximity of capillaries and myocytes, could exert a major effect on myocardial performance. Endothelial dysfunction and concomitant lack of release of myocardial relaxant factors could explain left ventricular relaxation abnormalities observed in the cardiac allograft or in arterial hypertension. Since endothelial-derived relaxation factor or nitric oxide mediates the coronary reactive hyperemic response, a negative inotropic action of nitric oxide could contribute to left ventricular failure when left ventricular wall stress is elevated, as occurs after myocardial infarction in the noninfarcted zone and during left ventricular volume or pressure overload in the absence of adequate hypertrophy.