Effect of coronary vasodilators and pacing upon regional oxygen balance of the ischaemic myocardium

In anaesthetized open-chest dogs, regional contractile force, epicardial tissue blood flow, and local NADH redox levels were recorded during graded ventricular pacing in the range 150-285 bpm. These parameters were measured before, and 30 min following LAD coronary artery occlusion. It was found that during pacing, blood supply to the untreated ischaemic region was reduced by 65.4 +/- 11% of control values at a rate of 150 bpm, and fell to -105 +/- 40.2% at a rate of 225 bpm. Hypopneic respiration prevented this pacing induced flow reduction. Pacing in the presence of nitroglycerin resulted in a marked increase in regional flow. Similarly, the vasodilator treatments prevented the marked elevation in NADH levels (77.5 +/- 15.6%) produced by pacing in the untreated ischaemic myocardium. The reduction in regional contractile force in the ischaemic region produced following pacing (-30.5%) was reversed during both vasodilator treatments (+47.2% during nitroglycerin and +23.4% during hypopnea). It was concluded that vasodilation improves regional ischaemic myocardial oxygen balance, thus expanding the functional reserve of the ischaemic muscle. Nitroglycerin is more active.     

Relation between myocardial substrate utilization, oxygen consumption and regional oxygen balance in the dog heart in vivo

The interaction between myocardial function, oxygen consumption and energy production was examined in the left ventricular myocardium during various physiological conditions. Myocardial function was measured by both LV dP/dTmax and by local contractile tension. Coronary blood flow was measured from the coronary sinus; regional coronary blood supply was recorded using a thermistor placed on the epicardial surface. Intracellular oxygen balance was estimated using NADH fluorescence. Myocardial oxygen consumption and utilization of glucose, pyruvate, lactate and free fatty acids were calculated from their concentrations in the arterial and coronary sinus blood. The effects of tachycardia at 180 and 240 bpm, noradrenaline infusion (25 micrograms kg-1 min-1), and increased coronary blood flow caused by hypopneic respiration were examined. During pacing, contractile force, coronary flow and NADH fluorescence increased. At 240 bpm, the lactate/pyruvate ratio increased from 5.98 +/- 0.92 to 8.76 +/- 1.41 and NADH fluorescence increased from 50 to 71.7 +/- 3.73 (as compared to control), indicating impairment of myocardial oxygenation. Hypopneic respiration produced a marked elevation of coronary blood flow. Both noradrenaline infusion and hypopnea produced a decrease in both NADH fluorescence and the lactate/pyruvate ratio. No significant difference was found between the FORCE/ATP, FORCE/MVO2 and ATP/MVO2 ratios during pacing and noradrenaline. However, during hypopnea, the amount of ATP apparently formed (as calculated by substrate utilization assuming the formation of 3 ATP molecules per oxygen) was disproportionately greater than contractile force and oxygen consumption. It is suggested that this discrepancy may be due to the uncoupling of oxidative phosphorylation.     

Myocardial contractile function during postischemic low-flow reperfusion: critical thresholds of NADH and O2 delivery

The degree of myocardial oxygen delivery (Do2) that is necessary to reestablish functional contractile activity after short-term global ischemia in heart is not known. To determine the relationship between Do2 and recovery of contractile and metabolic functions, we used tissue NADH fluorometric changes to characterize adequacy of reperfusion flow. Isolated perfused rat hearts were subjected to global ischemia and were reperfused at variable flow rates that ranged from 1 to 100% of baseline flow. Myocardial function and tissue NADH changes were continuously measured. NADH fluorescence rapidly increased and plateaued during ischemia. A strong inverse logarithmic correlation between NADH fluorescence and reperfusion Do2 was demonstrated (r = -0.952). Left ventricular function (rate-pressure product) was inversely related to NADH fluorescence at reperfusion flows from 25 to 100% of baseline (r = -0.922) but not at lower reperfusion flow levels. An apparent reperfusion threshold of 25% of baseline Do2 was necessary to resume contractile function. At very low reperfusion flows (1% of baseline), another threshold flow was identified at which NADH levels increased beyond that observed during global ischemia (3.4 +/- 3.0%, means +/- SE, n = 9), which suggests further reduction of the cellular redox state. This NADH increase at 1% of baseline reperfusion flow was blocked by removing glucose from the perfusate. NADH fluorescence is a sensitive indicator of myocardial cellular oxygen utilization over a wide range of reperfusion Do2 values. Although oxygen is utilized at very low flow rates, as indicated by changes in NADH, a critical threshold of approximately 25% of baseline Do2 is necessary to restore contractile function after short-term global ischemia.     

Variations in left and right ventricular oxygen balance produced by paired electrical stimulations

The possible differential effect of positive inotropic stimulation upon regional myocardial oxygen balance in the two ventricles was investigated during tachycardia and paired electrical stimulation. Isometric contractile force was measured by strain gauge arches; local coronary blood supply was measured by thermistor probes and intracellular NADH redox level was recorded using surface fluorometry. It was found that when contractility was increased by paired stimulation at a basic rate of 140 bpm, the inotropic response was more pronounced in the right ventricle (97.2 +/- 11.5%) than in the left (63.1 +/- 12.6%). Coronary blood supply to the left ventricle increased by 117.8 +/- 30.4% and the corresponding NADH redox level increased by 54.3 +/- 19.9%. When the contractile force was increased to the same extent (64.1 +/- 8.9%) by single stimulation at a rate of 210 bpm, the coronary flow to the left ventricle was increased by only 36.4 +/- 11.0% and the NADH state rose by 67.1 +/- 12.1%. It is concluded that paired stimulation reduced the mechanical limitation to flow during tachycardia, thus allowing coronary blood supply to increase in response to positive inotropic stimulation, thereby preserving a relatively improved oxygen state. It was also observed that the ratio contractile force/blood supply (contraction efficiency) was usually proportional to the NADH redox level (oxygen balance). Nevertheless, variations observed in the force/supply ratio for the left ventricle indicate that the NADH redox level cannot be predicted quantitatively by the force/supply ratio.     

Correlation of left phrenic arterial flow with regional diaphragmatic blood flow

Previous work has assumed that left phrenic arterial blood flow (Qpa) reflects diaphragmatic blood flow. We have tested this assumption in four anesthetized mechanically ventilated dogs by measuring Qpa with a Doppler flow probe and regional diaphragmatic blood flow with radiolabeled microspheres. Flows were examined during control 1 (diaphragm at rest), pacing (phrenic pacing: rate 20/min, duty cycle 0.33), control 2, hypotension (rest with mean arterial pressure reduced by 45% of the control 1 value), and hypotension and pacing. As a percent of the control 1 value, Qpa was 511 +/- 107% during pacing, 139 +/- 12% during control 2, 40 +/- 13% during hypotension, and finally 347 +/- 31% during hypotension and pacing. Similarly, percent left hemidiaphragmatic blood flow (Qlh) was 362 +/- 91% during pacing, 91 +/- 10% during control 2, 14 +/- 2% during hypotension, and finally 213 +/- 50% during hypotension and pacing. The changes in flow to the left costal and crural diaphragm were similar to those recorded for Qlh. We conclude that Qpa correlates with total and regional diaphragmatic blood flow (r = 0.77-0.81, P less than 0.001) under conditions of supramaximal phrenic nerve stimulation in which the metabolic demands of the region perfused by the phrenic artery are presumed to be similar to the metabolic demands of the rest of the diaphragm.     

The effects of changes in heart rate and aortic systolic pressure on left ventricular myocardial oxygen consumption in lambs

To determine whether changes in heart rate and aortic systolic pressure contribute equally to the determination of left ventricular myocardial oxygen consumption, we independently varied heart rate and pressure and compared the resultant oxygen consumption for similar rate-pressure products. In 6 young lambs which underwent atrioventricular node ablation, we varied heart rate by ventricular pacing at 250 beats/min, 300 beats/min, and 120 beats/min while aortic pressure remained stable and varied aortic systolic pressure by infusion of phenylephrine (to 132 +/- 15 mm Hg and 155 +/- 14 mm Hg) and by infusion of sodium nitroprusside (to 79 +/- 6 mm Hg) while heart rate was maintained stable at 200 beats/min. The 3 levels of change in aortic systolic pressure were chosen so that the ratepressure product during the pressure changes matched the rate-pressure product during the heart rate changes. We found that left ventricular myocardial oxygen consumption was the same at all 3 levels of the rate-pressure product whether heart rate was changed and pressure remained stable or pressure was changed and heart rate remained stable. Also, the correlation between oxygen consumption and the rate-pressure product was similar for both heart rate and pressure changes. During nitroprusside infusion at a fixed heart rate, oxygen extraction was significantly lower than during pacing at a heart rate of 120 beats/min when the rate-pressure product was comparable because of the direct vasodilatory effects of nitroprusside. We conclude that heart rate and aortic systolic pressure contribute equally to left ventricular myocardial oxygen consumption at the same rate-pressure product, even though there may be differences in myocardial blood flow and oxygen extraction.     

Coronary microcirculatory vasoconstriction is heterogeneously distributed in acutely ischemic myocardium

The classical model of coronary physiology implies the presence of maximal microcirculatory vasodilation during myocardial ischemia. However, Doppler monitoring of coronary blood flow (CBF) documented severe microcirculatory vasoconstriction during pacing-induced ischemia in patients with coronary artery disease. This study investigates the mechanisms that underlie this paradoxical behavior in nine patients with stable angina and single-vessel coronary disease who were candidates for stenting. While transstenotic pressures were continuously monitored, input CBF (in ml/min) to the poststenotic myocardium was measured by Doppler catheter and angiographic cross-sectional area. Simultaneously, specific myocardial blood flow (MBF, in ml.min(-1).g(-1)) was measured by 133Xe washout. Perfused tissue mass was calculated as CBF/MBF. Measurements were obtained at baseline, during pacing-induced ischemia, and after stenting. CBF and distal coronary pressure values were also measured during pacing with intracoronary adenosine administration. During pacing, CBF decreased to 64 +/- 24% of baseline and increased to 265 +/- 100% of ischemic flow after adenosine administration. In contrast, pacing increased MBF to 184 +/- 66% of baseline, measured as a function of the increased rate-pressure product (r = 0.69; P < 0.05). Thus, during pacing, perfused myocardial mass drastically decreased from 30 +/- 23 to 12 +/- 11 g (P < 0.01). Distal coronary pressure remained stable during pacing but decreased after adenosine administration. Stenting increased perfused myocardial mass to 39 +/- 23 g (P < 0.05 vs. baseline) as a function of the increase in distal coronary pressure (r = 0.71; P < 0.02). In conclusion, the vasoconstrictor response to pacing-induced ischemia is heterogeneously distributed and excludes a tissue fraction from perfusion. Within perfused tissue, the metabolic demand still controls the vasomotor tone.     

Restoration of impaired endothelium-dependent coronary vasodilation in failing heart: role of eNOS phosphorylation and CGMP/cGK-I signaling

In congestive heart failure (CHF), coronary vascular relaxation is associated with endothelial dysfunction and nitric oxide (NO) deficiency. This study explored the reversibility of this process in hearts recovering from CHF and its related mechanisms. Dogs were chronically instrumented to measure cardiac function and coronary blood flow (CBF). Heart failure was induced by right ventricular pacing at 240 beats/min for 3-4 wk, and cardiac recovery (CR) was allowed by the termination of cardiac pacing for 3-4 wk after the development of CHF, in which left ventricular contractile function was restored by 80-90%. The endothelium-dependent CBF response to bradykinin and acetylcholine was depressed in CHF and fully restored in CR. Myocardial NOx (nitrate/nitrite), endothelial NO synthase (eNOS) mRNA expression, total protein, and phosphorylated eNOS decreased significantly in failing hearts. However, myocardial NOx recovered to 78% of control and phosphorylated eNOS was fully restored in CR, despite the fact that eNOS mRNA expression and protein levels remained lower than control. Furthermore, the endothelium-independent CBF response to nitroglycerin did not change in CHF; however, it increased by 75% in CR, in conjunction with a near threefold increase in the phosphorylation of vasodilation-stimulated phosphoprotein (VASP) at Ser(239) in recovering hearts. Thus the complete restoration of endothelium-dependent coronary vascular relaxation during cardiac recovery from CHF was mediated by 1) a restoration of phosphorylated eNOS for partial recovery of the NO production and 2) an increase in cGMP/cGMP-dependent protein kinase-I pathway signaling activity for the enhancement of coronary vascular smooth muscle relaxation in response to NO.     

Changes in regional myocardial volume during the cardiac cycle: implications for transmural blood flow and cardiac structure

Although previous studies report a reduction in myocardial volume during systole, myocardial volume changes during the cardiac cycle have not been quantitatively analyzed with high spatiotemporal resolution. We studied the time course of myocardial volume in the anterior mid-left ventricular (LV) wall of normal canine heart in vivo (n = 14) during atrial or LV pacing using transmurally implanted markers and biplane cineradiography (8 ms/frame). During atrial pacing, there was a significant transmural gradient in maximum volume decrease (4.1, 6.8, and 10.3% at subepi, midwall, and subendo layer, respectively, P = 0.002). The rate of myocardial volume increase during diastole was 4.7 +/- 5.8, 6.8 +/- 6.1, and 10.8 +/- 7.7 ml.min(-1).g(-1), respectively, which is substantially larger than the average myocardial blood flow in the literature measured by the microsphere method (0.7-1.3 ml.min(-1).g(-1)). In the early activated region during LV pacing, myocardial volume began to decrease before the LV pressure upstroke. We conclude that the volume change is greater than would be estimated from the known average transmural blood flow. This implies the existence of blood-filled spaces within the myocardium, which could communicate with the ventricular lumen. Our data in the early activated region also suggest that myocardial volume change is caused not by the intramyocardial tissue pressure but by direct impingement of the contracting myocytes on the microvasculature.     

Mismatch between uniform increase in cardiac glucose uptake and regional contractile dysfunction in pacing-induced heart failure

Increased glucose utilization and regional differences in contractile function are well-known alterations of the failing heart and play an important pathophysiological role. We tested whether, similar to functional derangement, changes in glucose uptake develop following a regional pattern. Heart failure was induced in 13 chronically instrumented minipigs by pacing the left ventricular (LV) free wall at 180 beats/min for 3 wk. Regional changes in contractile function and stress were assessed by magnetic resonance imaging, whereas regional flow and glucose uptake were measured by positron emission tomography utilizing, respectively, the radiotracers [(13)N]ammonia and (18)F-deoxyglucose. In heart failure, LV end-diastolic pressure was 20 +/- 4 mmHg, and ejection fraction was 35 +/- 4% (all P < 0.05 vs. control). Sustained pacing-induced dyssynchronous LV activation caused a more pronounced decrease in LV systolic thickening (7.45 +/- 3.42 vs. 30.62 +/- 8.73%, P < 0.05) and circumferential shortening (-4.62 +/- 1.0 vs. -7.33 +/- 1.2%, P < 0.05) in the anterior/anterior-lateral region (pacing site) compared with the inferoseptal region (opposite site). Conversely, flow was reduced significantly by approximately 32% compared with control and was lower in the opposite site region. Despite these nonhomogeneous alterations, regional end-systolic wall stress was uniformly increased by 60% in the failing LV. Similar to wall stress, glucose uptake markedly increased vs. control (0.24 +/- 0.004 vs. 0.07 +/- 0.01 micromol x min(-1) x g(-1), P < 0.05), with no significant regional differences. In conclusion, high-frequency pacing of the LV free wall causes a dyssynchronous pattern of contraction that leads to progressive cardiac failure with a marked mismatch between increased glucose uptake and regional contractile dysfunction.     

Effect of blood pressure on vascular hemodynamics in acute tachycardia

Paroxysmal supraventricular tachycardia is accompanied by hypotension, which can affect vascular hemodynamics. Here, we hypothesized that a fall in blood flow as a result of hypotension has a larger effect on hemodynamics in medium-sized peripheral arteries compared with increased pulsatility in rapid pacing. To test this hypothesis, we experimentally and theoretically investigated hemodynamic changes in femoral, carotid, and subclavian arteries at heart rates of 95-170 beats/min after acute pacing. The arterial pressure, blood flow, and other hemodynamic parameters remained statistically unchanged for heart rates ≤ 135 beats/min. Systemic pressure and flow velocities, however, showed an abrupt decrease, resulting in larger alteration of hemodynamic parameters for heart rates ≥ 155 beats/min after pacing (initial period) and then recovered close to baseline after several minutes of pacing (recovery period). During the initial period, the pressure dropped from 88 mmHg (baseline) to 44 mmHg, and the flow velocity decreased to about one-third of baseline at heart rate of 170 beats/min. A hemodynamic analysis showed a velocity profile with a near-wall retrograde flow or a fully reversed flow during the initial period, which vanished at the recovery period. It was concluded that the initial fall of blood flow due to pressure drop led to transient flow reversal and negative wall shear stress because this phenomena was not observed at the recovery period. This study underscores the significant effects of hypotension on vascular hemodynamics, which may have relevance to physiology and chronic pathophysiology in paroxysmal supraventricular tachycardia.     

Cardiac output and muscle blood flow during rest-associated apneas of elephant seals

In order to evaluate hemodynamics and blood flow during rest-associated apnea in young elephant seals (Mirounga angustirostris), cardiac outputs (CO, thermodilution), heart rates (HR), and muscle blood flow (MBF, laser Doppler flowmetry) were measured. Mean apneic COs and HRs of three seals were 46% and 39% less than eupneic values, respectively (2.1+/-0.3 vs. 4.0+/-0.1 mL kg(-1) s(-1), and 54+/-6 vs. 89+/-14 beats min(-1)). The mean apneic stroke volume (SV) was not significantly different from the eupneic value (2.3+/-0.2 vs. 2.7+/-0.5 mL kg(-1)). Mean apneic MBF of three seals was 51% of the eupneic value. The decline in MBF during apnea was gradual, and variable in both rate and magnitude. In contrast to values previously documented in seals during forced submersions (FS), CO and SV during rest-associated apneas were maintained at levels characteristic of previously published values in similarly-sized terrestrial mammals at rest. Apneic COs of such magnitude and incomplete muscle ischemia during the apnea suggest that (1) most organs are not ischemic during rest-associated apneas, (2) the blood O(2) depletion rate is greater during rest-associated apneas than during FS, and (3) the blood O(2) store is not completely isolated from muscle during rest-associated apneas.     

Metabolic protection of the reperfused canine endocardium by the thromboxane synthetase inhibitor, dazoxiben

This study investigated whether dazoxiben, a thromboxane synthesis inhibitor, could reverse regional contractile dysfunction and protect against adenine nucleotide loss in the "stunned myocardium". Hearts from anesthetized dogs were "stunned" by 15 min of left anterior descending coronary artery occlusion followed by 3 hr of reperfusion. Left ventricular segment shortening (%SS) and regional myocardial blood flow (RMBF) were measured by sonomicrometry and the radioactive microsphere technique, respectively. Local coronary venous blood was withdrawn and thromboxane A2 and prostacyclin measured by radioimmunoassay. Transmural biopsies from the reperfused and nonischemic areas were taken at 3 hr following reperfusion for tissue metabolite analysis. During ischemia, %SS, RMBF and area at risk were decreased to similar levels in both control and dazoxiben-treated hearts indicating equivalent degrees of flow deprivation. During reperfusion, %SS recovered only partially and was not significantly improved by dazoxiben. Dazoxiben augmented peak prostacyclin production (123 +/- 31% vs. 292 +/- 49% of preocclusion values) following reperfusion, while it completely blocked thromboxane A2 production. Dazoxiben attenuated the decline in endocardial ATP (69 +/- 5% vs. 92 +/- 9% normalized to the nonischemic zone) and total adenine nucleotides. The results indicate that dazoxiben may elicit a cardioprotective effect on energy metabolism in the reperfused heart, but this is dissociated from any improvement in regional contractile function.     

Cardiac output distribution and regional blood flow during hypocarbia in monkeys

Cardiac output distribution and regional blood flow were studied during hypocarbia independent of changes in ventilatory parameters. Fifteen cynomolgus monkeys were anesthetized with methohexital sodium (8 mg/kg im) and hyperventilated through an endotracheal tube. Hypocarbia at two levels, 28 +/- 1.8 and 17 +/- 0.6 Torr, was achieved by a stepwise decreasing CO2 flow into the semiclosed system. Regional blood flow was determined with labeled microspheres. At each stage of experiments two sets of microspheres (9 and 15 microns diam) were used simultaneously. The use of two microsphere sizes allowed evaluation of the relationship between total (nutritive and nonnutritive) tissue blood flow, determined with 15-microns spheres, and nutritive blood flow, determined with 9-microns spheres. There was no change in cardiac output or arterial pressure during both degrees of studied hypocarbia. Hypocarbia was accompanied by a decrease in myocardial blood flow determined with 15-microns spheres and preservation of the flow determined with 9-microns spheres. Splenic blood flow was decreased, whereas hepatic arterial blood flow was increased during both levels of hypocarbia. Blood flow through the brain, renal cortex, and gut showed a biphasic response to hypocarbia: during hypocarbia at 28 +/- 1.8 Torr, blood flow determined with 15-microns spheres was unchanged (in the gut) or decreased (in the brain and kidneys), whereas blood flow determined with 9-microns spheres was decreased. During hypocarbia at 17 +/- 0.6 Torr, blood flow determined with 9-microns spheres had a tendency to restore to base-line values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional myocardial O2 consumption and coronary blood flow responses to acetylcholine in rabbit heart

The effect of acetylcholine on regional coronary blood flow and myocardial O2 consumption was determined in order to compare its direct vasodilatory effects with the metabolic vasoconstriction it induces. Experiments were conducted in seven untreated control anaesthetized open chest rabbits and seven rabbits which were infused with acetylcholine (1 microgram/kg/min). Myocardial blood flow was determined before and during acetylcholine infusion using radioactive microspheres. Regional arterial and venous O2 saturation was analyzed microspectrophotometrically. Acetylcholine reduced heart rate by 30% and significantly depressed the arterial systolic and diastolic blood pressure. The mean O2 consumption was significantly reduced with acetylcholine from 9.6 +/- 2.0 to 6.1 +/- 3.6 ml O2/min/100 g. Coronary blood flow decreased uniformly across the left ventricular wall by about 50% and resistance to flow increased by 42% despite potential direct cholinergic vasodilation. O2 extraction was not affected by acetylcholine infusion. It is concluded that the acetylcholine infusion directly decreased myocardial O2 consumption, which in turn lowered the coronary blood flow and increased the resistance. The decreased flow was related to a reduced metabolic demand rather than a direct result of lowered blood pressure. Unaffected myocardial O2 extraction also suggested that blood flow and metabolism were matched. This indicates that direct cholinergic vasodilation of the coronary vasculature does not allow a greater reduction in metabolism than flow in the anaesthetized open chest rabbit heart during acetylcholine infusion.     

Mitochondrial NAD(P)H, ADP, oxidative phosphorylation, and contraction in isolated heart cells

To examine the relationship between mitochondrial NADH (NADH(m)) and cardiac work output, NADH(m) and the amplitude and frequency of the contractile response of electrically paced rat heart cells were measured at 25 degrees C. With 5.4 mM glucose plus 2 mM beta-hydroxybutyrate, NADH(m) was reversibly decreased by 23%, and the amplitude of contraction was reversibly decreased by 27% during 4-Hz pacing. With glucose plus 2 mM pyruvate or with 10 mM 2-deoxy-D-glucose, NADH(m) was maintained during rapid pacing, and the contractile amplitude remained high. Phosphocreatine levels decreased with 2-deoxy-D-glucose administration but not with rapid pacing. Respiration increased to meet the increased ATP demand at 30 degrees C. The data suggest that 1) when NADH(m) is decreased during rapid pacing with defined substrates, the amplitude of contraction is decreased; 2) the amplitude of contraction during electrical pacing does not change with rate of pacing when both the ATP and NADH(m) levels are continuously replenished; and 3) the replenishment of NADH(m) during pacing with physiological substrates may be rate-limited by substrate supply to mitochondrial dehydrogenases. During activation of mitochondrial dehydrogenases, or a significant increase in free ADP induced by 2-deoxy-D-glucose, this rate limitation is bypassed or overcome.     

Acetaminophen and myocardial infarction in dogs

The hypothesis that acetaminophen can reduce necrosis during myocardial infarction was tested in male dogs. Two groups were studied: vehicle- (n=10) and acetaminophen-treated (n=10) dogs. All dogs were obtained from the same vendor, and there were no significant differences in their ages (18 +/- 2 mo), weights (24 +/- 1 kg), or housing conditions. Selected physiological data, e.g., coronary blood flow, nonspecific collateral flow, epicardial temperature, heart rate, systemic mean arterial pressure, left ventricular developed pressure, the maximal first derivative of left ventricular developed pressure, blood gases, and pH, were collected at baseline and during regional myocardial ischemia and reperfusion. There were no significant differences in coronary blood flow, nonspecific collateral flow, epicardial temperature, heart rate, systemic mean arterial pressure, or blood gases and pH between the two groups at any of the three time intervals, even though there was a trend toward improved function in the presence of acetaminophen. Infarct size, the main objective of the investigation, was markedly and significantly reduced by acetaminophen. For example, when expressed as a percentage of ventricular wet weight, infarct size was 8 +/- 1 versus 3 +/- 1%(P <0.05) in vehicle- and acetaminophen-treated hearts, respectively. When infarct size was expressed as percentage of the area at risk, it was 35 +/- 3 versus 13 +/- 2% (P <0.05) in vehicle- and acetaminophen-treated groups, respectively. When area at risk was expressed as percentage of total ventricular mass, there were no differences in the two groups. Results reveal that the recently reported cardioprotective properties of acetaminophen in vitro can now be extended to the in vivo arena. They suggest that it is necessary to add acetaminophen to the growing list of pharmaceuticals that possess cardioprotective efficacy in mammals.     

Effect of saline infusion on body temperature and endurance during heavy exercise

We tested the hypothesis that volume infusion during strenuous exercise, by expanding blood volume, would allow better skin blood flow and better temperature homeostasis and thereby improve endurance time. Nine males exercised to exhaustion at 84.0 +/- 3.14% (SE) of maximum O2 consumption on a cycle ergometer in a double-blind randomized protocol with either no infusion (control) or an infusion of 0.9% NaCl (mean vol 1,280.3 +/- 107.3 ml). Blood samples and expired gases (breath-by-breath), as well as core and skin temperatures, were analyzed. Plasma volume decreased less during exercise with the infusion at 15 min (-13.7 +/- 1.4% control vs. -5.3 +/- 1.7% infusion, P less than 0.05) and at exhaustion (-13.6 +/- 1.2% vs. -1.3 +/- 2.2%, P less than 0.01). The improved fluid homeostasis was associated with a lower core temperature during exercise (39.0 +/- 0.2 degrees C for control and 38.5 +/- 0.2 degrees C for infusion at exhaustion, P less than 0.01) and lower heart rate (194.1 +/- 3.9 beats/min for control and 186.0 +/- 5.1 beats/min for infusion at exhaustion, P less than 0.05). However, endurance time did not differ between control and infusion (21.96 +/- 3.56 and 20.82 +/- 2.63 min, respectively), and neither did [H+], peak O2 uptake, and CO2 production, end-tidal partial pressure of CO2, blood lactate, or blood pressure. In conclusion, saline infusion increases heat dissipation and lowers core temperature during strenuous exercise but does not influence endurance time.     

High resolution mechanical function in the intact porcine heart: mechanical effects of pacemaker location

The necessity to quantify the mechanical function with high spatial resolution stemmed from the advancement of myocardial salvaging techniques. Since these therapies are localized interventions, a whole field technique with high spatial resolution was needed to differentiate the normal, diseased, and treated myocardium. We developed a phase correlation algorithm for measuring myocardial displacement at high spatial resolution and to determine the regional mechanical function in the intact heart. Porcine hearts were exposed and high contrast microparticles were placed on the myocardium. A pressure transducer, inserted into the left ventricle, synchronized the pressure (LVP) with image acquisition using a charge-coupled device camera. The deformation of the myocardium was measured with a resolution of 0.58+/-0.04 mm. Within the region of interest (ROI), regional stroke work (RSW), defined as the integral of LVP with respect to regional area, was determined on average at 21 locations with a resolution of 27.1+/-2.7 mm2. To alter regional mechanical function, the heart was paced at three different locations around the ROI. Independent of the pacemaker location, RSW decreased in the ROI. In addition, a gradient of increasing RSW in the outward direction radiating from the pacemaker was observed in all pacing protocols. These data demonstrated the ability to determine regional whole field mechanical function with high spatial resolution, and the significant alterations induced by electrical pacing.     

Distribution of blood flow during exercise after blood volume expansion in swine

To study the distribution of blood flow after blood volume expansion, seven miniature swine ran at high speed (17.6-20 km/h, estimated to require 115% of maximal O2 uptake) on a motor-driven treadmill on two occasions: once during normovolemia and once after an acute 15% blood volume expansion (homologous whole blood). O2 uptake, cardiac output, heart rate, mean arterial pressure, and distribution of blood flow (with radiolabeled microspheres) were measured at the same time during each of the exercise bouts. Maximal heart rate was identical between conditions (mean 266); mean arterial pressure was elevated during the hypovolemic exercise (149 +/- 5 vs. 137 +/- 6 mmHg). Although cardiac output was higher and arterial O2 saturation was maintained during the hypervolemic condition (10.5 +/- 0.7 vs. 9.3 +/- 0.6 l/min), O2 uptake was not different (1.74 +/- 0.08 vs. 1.74 +/- 0.09 l/min). Mean blood flows to cardiac (+12.9%), locomotory (+9.8%), and respiratory (+7.5%) muscles were all elevated during hypervolemic exercise, while visceral and brain blood flows were unchanged. Calculated resistances to flow in skeletal and cardiac muscle were not different between conditions. Under the experimental conditions of this study, O2 uptake in the miniature swine was limited at the level of the muscles during hypervolemic exercise. The results also indicate that neither intrinsic contractile properties of the heart nor coronary blood flow limits myocardial performance during normovolemic exercise, because both the pumping capacity of the heart and the coronary blood flow were elevated in the hypervolemic condition.