Preload Recruitable Work Area Research Articles

The p38 MAPK Inhibitor SB203580 Blocks Adenosine A1 Receptor-Induced Attenuation of In Vivo Myocardial Stunning

There is considerable evidence implicating a key role for p38 mitogen-activated protein kinase (MAPK) in ischemic and pharmacological preconditioning against myocardial infarction. However, there have been few, if any, studies examining the role of p38 MAPK in the protection of stunned myocardium. The purpose of this study was to determine whether p38 MAPK plays a role in the adenosine A(1) receptor anti-stunning effect in in vivo porcine myocardium. Regional myocardial stunning in anesthetized, open-chest pigs was induced by 15 min of left anterior descending coronary artery (LAD) occlusion and 3 h of reperfusion (RP). Animals were treated with either vehicle (n = 5), AMP579 (70 microg/kg i.v.; 25 microg/kg bolus + 1.5 microg/kg/min for 30 min prior to ischemia, n = 5), the p38 MAPK inhibitor SB203580 (0.25 mg/kg i.v. bolus, n = 4) or a combination of SB203580 plus AMP579 (n = 5). Regional ventricular function was monitored by measurements of segment shortening and load insensitive parameters including preload recruitable stroke work (PRSW) and PRSW area (PRSWA). The ischemic area at risk was similar in all groups and there was no necrosis in any heart. Treatment with AMP579 significantly improved reperfusion regional PRSW and PRSWA compared to vehicle controls. The p38 inhibitor SB203580 alone did not alter the extent of myocardial stunning, but it abolished the beneficial effect of AMP579 pretreatment. These results provide the first evidence that p38 MAPK activation may play an important role in the mechanism by which adenosine agonists attenuate myocardial stunning.

Calcitonin gene–related peptide enhances the recovery of contractile function in stunned myocardium

Introduction: Calcitonin gene-related peptide, a potent vasodilating inotropic agent, increases coronary artery perfusion when administered exogenously and reduces ischemic injury in nonmyocardial tissue. However, it is unclear whether this agent improves recovery of myocardial performance after reversible myocardial ischemia. Methods: Nine dogs underwent complete occlusion of the left anterior descending coronary artery for 15 minutes and were monitored during 24 hours of reperfusion. Calcitonin gene–related peptide (0.07 μg · kg –1 · min –1), nitroglycerin (65 μg · kg –1 · min –1), or saline solution placebo was infused intravenously during initial reperfusion. Ischemia/reperfusion was repeated in concurrent 24-hour periods until all animals received infusions in random order. Micromanometry and sonomicrometry determined left ventricular pressure and myocardial segment length. Myocardial performance, based on the linear relationship between stroke work and end-diastolic segment length, was estimated with the preload recruitable work area.Results were analyzed as percent control and compared statistically with the use of repeated measures analysis of variance. Results: Recovery of myocardial performance was augmented during reperfusion with calcitonin gene–related peptide infusion relative to placebo ( P = .005; mean preload recruitable work area ± SE after calcitonin gene–related peptide infusion, 2484 ± 705 mm Hg at 90 minutes of reperfusion versus 1473 ± 300 mm Hg for placebo. Recovery of performance after nitroglycerin infusion was similar to recovery after placebo. Conclusions: Calcitonin gene–related peptide infusion improves recovery of contractile function in stunned myocardium. Unlike inotropic agents that impair recovery from reversible ischemia, calcitonin gene–related peptide may confer cardioprotective effects on ischemic myocardium. (J Thorac Cardiovasc Surg 2000;119:1246-54)

Early postoperative changes in regional systolic and diastolic left ventricular function after transmyocardial laser revascularization: A comparison of holmium:YAG and CO2 lasers

OBJECTIVESThe purpose of this study was to determine the short-term effects of transmyocardial laser revascularization (TMR) on regional left ventricular systolic and diastolic function, myocardial blood flow (MBF) and myocardial water content (MWC).BACKGROUNDClinical studies of TMR have noted a significant incidence of cardiac complications in the early postoperative period. However, the early post-treatment effects of laser therapy on the myocardium and their potential contribution to postoperative cardiac morbidity are unknown.METHODSSwine underwent holmium:yttrium-aluminum-garnet (holmium:YAG) (n = 12) or carbon dioxide (CO2) (n = 12) laser TMR. Regional systolic function for the lased and nonlased regions was quantitated using preload recruitable work area (PRWA) and regional diastolic function with the ventricular stiffness constant alpha.RESULTSPreload recruitable work area was significantly decreased in the lased regions both 1 (59.8 ± 13.0% of baseline, p = 0.02) and 6 h (64.2 ± 9.4% of baseline, p = 0.02) after holmium:YAG TMR. This decreased PRWA was associated with a significant reduction in MBF to the lased regions (13.2% reduction at 1 h, p = 0.02; 18.4% decrease at 6 h post-TMR, p = 0.01). These changes were not seen after CO2 laser TMR. A significant increase in MWC (1.4 ± 0.3% increase with holmium:YAG, p = 0.004; 1 ± 0.2% increase with CO2, p = 0.002) and alpha (217.4 ± 44.2% of baseline 6 h post-holmium:YAG TMR, p = 0.05; 206 ± 36.7% of baseline 6 h post-CO2 TMR, p = 0.03) was seen after TMR with both lasers.CONCLUSIONSIn the early postoperative setting, impaired regional systolic function in association with regional ischemia is seen after TMR with a holmium:YAG laser. Both holmium:YAG and CO2 lasers are associated with increased MWC and impaired diastolic relaxation in the lased regions. These changes may explain the significant incidence of early postoperative cardiac morbidity. The impact of these findings on anginal relief and long-term outcome are not known.

A comparison of the effects of fentanyl and propofol on left ventricular contractility during myocardial stunning

The intravenous anaesthetic propofol has been shown to possess free radical scavenging activity and calcium channel blocking effects in a number of in vitro models. We decided to compare the effects of propofol with those of fentanyl on myocardial contractility during and after ischaemia to determine whether propofol could protect the heart and improve recovery of ventricular contractile function in open-chested dogs. Twenty adult beagles were acutely instrumented, under halothane anaesthesia, to measure ECG; aortic, left ventricular pressures; cardiac output; coronary flow; and segmental lengths in the regions perfused by the left anterior and left circumflex coronary arteries. After surgery and a stabilisation period halothane anaesthesia was terminated and fentanyl (100 microg x kg[-1] bolus followed by 2 microg x kg[-1] x min[-1] infusion; n=10) or propofol (5 mg x kg[-1] bolus followed by 0.3 mg x kg[-1] x min[-1] infusion; n=10) anaesthesia commenced. After a stabilisation period the LAD coronary artery was occluded for 10 min and then reperfused for 3 h. Measurements were taken throughout the protocol. We found no significant difference in recovery of contractile function between propofol and fentanyl as assessed by normalised preload recruitable work area (50+/-10 vs 47+/-16%), normalised systolic shortening (36+/-12 vs 48+/-14%) and peak left ventricular dP/dt (1665+/-276 vs 1846+/-151 mmHg x s[-1]) at the end of reperfusion. We conclude that at the concentration used in this study propofol shows no improvement in contractility during "stunning" when compared to fentanyl.

Beneficial effect of concomitant administration of isoflurane and nicorandil

In common with halogenated anaesthetics, nicorandil, a new KATP channel opener, has been shown to have cardioprotective and vasodilator effects. Recent studies have also suggested that the vasodilator and protective effects of halogenated anaesthetics are mediated partly via KATP channel opening. This study examined the effects of concurrent administration of nicorandil and isoflurane on haemodynamic state and ventricular function before, during and after 15 min of ischaemia. We studied left ventricular function in 40 anaesthetized rabbits using ultrasonomicrometry. Measurements were obtained before, during and after 15 min of regional ischaemia. Regional ventricular function was assessed in terms of systolic shortening (SS%) and preload recruitable work area (PRWA, the area beneath the regional stroke work vs end-diastolic length relationship) during reperfusion. Four groups were studied: group F (n = 10) received a bolus dose of fentanyl 100 micrograms kg-1 and then 400 micrograms kg-1 h-1 throughout; group 1 (n = 10) received 2.05% end-tidal concentration of isoflurane (1 MAC); group FN (n = 10) received fentanyl, a bolus does of nicorandil 100 micrograms kg-1 and then 25 micrograms kg-1 min-1, 15 min before occlusion; and group IN (n = 10) received isoflurane and nicorandil. Isoflurane decreased left ventricular systolic pressure and ventricular contractility (+dP/dtmax, slope of preload recruitable stroke work, and SS%). Nicorandil increased -dP/dtmax in group FN. Post-ischaemic regional left ventricular contractility in group I did not differ from that in group F, however, groups receiving nicorandil recovered to a greater extent. Group IN showed better recovery compared with all other groups when ventricular contractility was assessed by PRWA normalized to pre-occlusion values (mean 99.3 (SEM 10.5)% vs 73.4 (7.5)%, 50.2 (5.8)% and 52.4 (3.7)% at 120 min reperfusion in groups FN, I and F, respectively). Tissue ATP and lactate contents did not differ between groups. We conclude that concurrent administration of nicorandil and isoflurane enhanced post-ischaemic recovery compared with isoflurane anaesthesia or nicorandil and fentanyl administration.

Minimally invasive mitral valve replacement: Port-access technique, feasibility, and myocardial functional preservation

Objective: This experiment examined the feasibility of minimally invasive port-access mitral valve replacement via a 2.5 cm incision. Methods: The study evaluated valvular performance and myocardial functional recovery in six mongrel dogs after port-access mitral valve replacement with a St. Jude Medical prosthesis (St. Jude Medical, Inc., St. Paul, Minn.). Femoro-femoral cardiopulmonary bypass and a balloon catheter system for myocardial protection with cardioplegic arrest (Heartport, Inc., Redwood City, Calif.) were used. The mitral valve was replaced through a 2.5 cm port in the left side of the chest, and the animals were weaned from bypass. Cardiac function was measured before and at 30 and 60 minutes after bypass. Left ventricular pressure and electrical conductance volume were used to calculate changes in load-independent indexes of ventricular function. Results: Each procedure was successfully completed. Recovery of left ventricular function was excellent at 30 and 60 minutes after bypass compared with the prebypass values for elastance (30 minutes = 4.04 ± 0.97 and 60 minutes = 4.27 ± 0.57 vs prebypass = 4.45 ± 0.96; p = 0.51) and for preload recruitable stroke work (30 minutes = 76.23 ± 4.80 and 60 minutes = 71.21 ± 2.99 vs prebypass = 71.23 ± 3.75; p = 0.45). Preload recruitable work area remained at 96% and 85% of baseline at 30 and 60 minutes ( p = not significant). In addition, transesophageal echocardiography demonstrated normal prosthetic valve function, as well as normal regional and global ventricular wall motion. Autopsy revealed secure annular-sewing apposition and normal leaflet motion. Conclusions: These results suggest that minimally invasive mitral valve replacement using percutaneous cardiopulmonary bypass with cardioplegic arrest is technically reproducible, achieves normal valve placement, and results in complete cardiac functional recovery. Minimally invasive mitral valve replacement is now feasible, and clinical trials are indicated. (J Thorac Cardiovasc Surg 1997; 113:1022-31)

Diminished myocardial function precedes tissue acidosis during coronary hypoperfusion.

The current study sought to elucidate the relationship between myocardial pH and function during a significant but not absolute reduction in coronary flow. In a canine model, a partial coronary arterial stenosis was created, with the left anterior descending coronary artery (LAD) flow reduced by 50% compared to prestenosis levels, and maintained at that level for the duration of the study. During the experiment, interstitial myocardial pH and regional myocardial function, as assessed by the regional preload recruitable work area (PRWA), were measured. PRWA was depressed to 60% of baseline values, on average, for the entire period of reduced LAD flow. In contrast to the pattern observed with myocardial blood flow and systolic function, metabolic evidence of myocardial ischemia, that is, reduced myocardial pH did not become significantly different from baseline levels until after LAD flow had been reduced for 15 min. Thus, measurable changes in myocardial pH appeared slowly over time despite the fact that regional myocardial blood flow was decreased immediately. Therefore, myocardial pH cannot be used to anticipate alterations in myocardial contractile function.

Glyburide, a KATP Channel Antagonist, Attenuates the Cardioprotective Effects of Isoflurane in Stunned Myocardium

This investigation examined the role of myocardial adenosine triphosphate-regulated potassium (KATP) channels in isoflurane-induced enhancement of myocardial function after reversible tissue injury produced by a 15-min left anterior descending coronary artery occlusion (LAD) and reperfusion. Dogs (n = 14) were chronically instrumented for measurement of left ventricular (LV) and aortic blood pressure, cardiac output, coronary blood flow velocity, and subendocardial segment length. Regional myocardial contractility was evaluated with preload recruitable work area (PRWA). Isovolumic relaxation was assessed with a time constant (tau). Hemodynamic variables and LV function were measured in the conscious state, during 2% isoflurane anesthesia for 45 min before and during a 15-min LAD occlusion, and at several intervals after reperfusion in dogs pretreated with glyburide (0.3 mg/kg, intravenously) or drug vehicle. LAD occlusion caused regional dyskinesia and increases in tau. Vehicle-pretreated dogs demonstrated full recovery of segment shortening by 5 h postreperfusion and recovery of PRWA and tau by 30 min postreperfusion. In contrast, dogs pretreated with glyburide demonstrated sustained systolic and diastolic dysfunction. Segment shortening recovered to only 70% +/- 5%, PRWA remained depressed at 48% +/- 10% and tau was prolonged to 116% +/- 5% of control values at 5 h postreperfusion. The results indicate that isoflurane enhances recovery of myocardial contractile function by 5 h postreperfusion, in comparison to previous findings in conscious dogs. These effects are partially blocked by glyburide pretreatment, indicating that KATP channel activation by isoflurance may mediate these cardioprotective effects.

Glyburide, a KATP Channel Antagonist, Attenuates the Cardioprotective Effects of Isoflurane in Stunned Myocardium

This investigation examined the role of myocardial adenosine triphosphate-regulated potassium (KATP) channels in isoflurane-induced enhancement of myocardial function after reversible tissue injury produced by a 15-min left anterior descending coronary artery occlusion (LAD) and reperfusion. Dogs (n = 14) were chronically instrumented for measurement of left ventricular (LV) and aortic blood pressure, cardiac output, coronary blood flow velocity, and subendocardial segment length. Regional myocardial contractility was evaluated with preload recruitable work area (PRWA). Isovolumic relaxation was assessed with a time constant (tau). Hemodynamic variables and LV function were measured in the conscious state, during 2% isoflurane anesthesia for 45 min before and during a 15-min LAD occlusion, and at several intervals after reperfusion in dogs pretreated with glyburide (0.3 mg/kg, intravenously) or drug vehicle. LAD occlusion caused regional dyskinesia and increases in tau. Vehicle-pretreated dogs demonstrated full recovery of segment shortening by 5 h postreperfusion and recovery of PRWA and tau by 30 min postreperfusion. In contrast, dogs pretreated with glyburide demonstrated sustained systolic and diastolic dysfunction. Segment shortening recovered to only 70% +/- 5%, PRWA remained depressed at 48% +/- 10%, and tau was prolonged to 116% +/- 5% of control values at 5 h postreperfusion. The results indicate that isoflurane enhances recovery of myocardial contractile function by 5 h postreperfusion, in comparison to previous findings in conscious dogs. These effects are partially blocked by glyburide pretreatment, indicating that KATP channel activation by isoflurane may mediate these cardioprotective effects. (Anesth Analg 1996;83:27-33)

Minimally invasive cardiopulmonary bypass with cardioplegic arrest: A closed chest technique with equivalent myocardial protection

Thoracoscopic cardiac surgery is presently under intense investigation. This study examined the feasibility and efficacy of closed chest cardiopulmonary bypass and cardioplegic arrest in comparison with standard open chest methods in a dog model. The minimally invasive closed chest group (n = 6) underwent percutaneous cardiopulmonary bypass and cardiac venting, as well as antegrade cardioplegic arrest through use of a specially designed percutaneous endovascular aortic occluder and cardioplegic solution delivery system. The control group (n = 6) underwent standard sternotomy and conventional open chest cardiopulmonary bypass, aortic crossclamping, and antegrade cardioplegia. Ischemic arrest time was 1 hour in each group. Ventricular pressures and sonomicrometer segment lengths were recorded before bypass and at 30 and 60 minutes after bypass. Left ventricular function did not differ significantly between the two groups, as demonstrated by measurements of elastance and end-diastolic stroke work. Also, the preload recruitable work area was 69% and 60% of baseline at 30 and 60 minutes after bypass in the minimally invasive group versus 65% and 62% in the conventional control group (p = not significant); the stroke work end-diastolic length relationship was 78% and 71% of baseline in the minimally invasive group at these intervals versus 77% and 74% in the conventional control group (p = not significant). Myocardial temperatures were similar throughout bypass in the two groups, and ultrastructural examination of prebypass and postbypass biopsy specimens showed no differences between groups. These results demonstrate that minimally invasive cardiopulmonary bypass with cardioplegic arrest is as feasible, safe, and effective as conventional open chest cardiopulmonary bypass. Thus current technology may allow wider clinical application of closed chest cardiac surgery. (J T horac C ardiovasc S urg 1996;111:556-66)

706-5 Calcitonin Gene-related Peptide Improves Recovery from Reversible Myocardial Ischemia

Calcitonin gene-related peptide (CGRP) has been found to have inotropic properties and a short half-life. CGRP has been demonstrated to reduce ischemic injury in tissue flaps as well as to increase coronary artery flow, while other available inotropes have been shown to impair recovery from myocardial ischemia. Yet, a therapeutic role for CGRP in myocardial ischemia has not been defined. Therefore, CGRP was compared to placebo in nine chronically instrumented conscious dogs who underwent two 15 minute left anterior descending coronary artery occlusions separated by at least 24 hours of reperfusion. Left ventricular transmural pressure and myocardial segment length were measured at control and during reperfusion. Either CGRP (0.07 μg/kg/min) or saline placebo was randomly chosen and continuously infused from 45 to 105 minutes of reperfusion. The alternative infusion was given during the second study. Regional function was assessed using preload recruitable work area (PRWA), a load-insensitive measure of regional myocardial performance. PRWA was calculated as the area beneath the linear stroke work vs. end-diastolic length relationship. Data are mean PRWA (% of control) ± SEM for the 9 dogs. 90 Min 3 Hours 8 Hours 24 Hours Placebo 89 ± 7 82 ± 8 94 ± 10 79 ± 7 CGRP * 155 ± 22 * 115 ± 9 * 118 ± 12 * 108 ± 15 * p < 0.05 vs. placebo Despite a short half-life of less than 30 minutes, CGRP caused a significantly more rapid return of cardiac function from ischemia than placebo throughout the entire 24 hours of reperfusion. These results suggest that CGRP may improve recovery from reversible myocardial ischemia and may have unique properties as an intravenous inotrope in an intensive care unit setting because it does not appear to impair recovery from acute myocardial ischemia.

Decreasing myocardial pH reflects ischemia during continuous warm retrograde cardioplegic arrest

Warm continuous retrograde cardioplegia is thought to prevent myocardial ischemia. We tested this hypothesis by subjecting canine hearts to 2 hours of either antegrade or retrograde perfusion with normothermic blood cardioplegia. Ischemie alterations were evaluated through the measurement of myocardial pH, tissue levels of adenosine triphosphate and lactate, and the preservation of left ventricular contractility. Antegrade perfusion resulted in uniformly positive changes in the myocardial pH in both ventricles, preserved levels of adenosine triphosphate, and small increases in the myocardial lactate levels. In contrast, retrograde perfusion caused the myocardial pH to decrease, especially in the right ventricle. Tissue lactate levels rose to a significantly greater extent during retrograde perfusion and adenosine triphosphate levels declined, although not to a statistically significant degree. Finally, myocardial function, as assessed by the preload recruitable work area, was preserved (103% ± 20% of baseline) in the antegrade group but was markedly diminished (33% ± 6%) in retrogradely perfused left ventricles 35 minutes after the aortic cross-clamp was removed. These data suggest that ischemie metabolism and the subsequent alteration of myocardial function take place despite continuous retrograde perfusion with normothermic blood cardioplegia.

Changes in left ventricular performance after global ischemia: Assessing LV pressure-volume relationship

To determine the effect of ischemia and reperfusion on left ventricular systolic function, we studied the ischemia-induced rightward shift of the ventricular pressure-volume relationship. Eight mongrel dogs were intubated, and their hearts were exposed through a thoracotomy. A conductance catheter and micromanometer were used to obtain instantaneous left ventricular pressure-volume data. The dogs were subjected to 20 minutes of normothermic global myocardial ischemia, followed by 80 minutes of reperfusion under total cardiopulmonary bypass. Data were acquired during transient (10- to 12-second) periods of acute volume loading before ischemia and at 20-minute intervals during reperfusion as bypass was continued. The relationship between stroke work and end-diastolic volume (ie, preioad recruitable stroke work [PRSW]) and the end-systolic pressure-volume relationship were highly linear throughout the study (mean r = 0.954 to 0.983 for PRSW; mean r = 0.954 to 0.984 for end-systolic pressure-volume relationship). Ischemia produced changes in the PRSW; (1) the slope decreased significantly at 20 minutes and 40 minutes of reperfusion then returned to preischemic levels at 60 minutes and 80 minutes, and (2) the x-intercept increased significantly up to 60 minutes. The preload recruitable work area (the area under the linear regression line of PRSW) reflected changes in both slope and x-intercept of PRSW and was significantly decreased throughout the 80 minutes of reperfusion despite gradual recovery. The slope and the x-intercept of the endsystolic pressure-volume relationship did not change after ischemia. These results indicate that systolic dysfunction, defined as preload recruitable work area, is related to the rightward shift of the ventricular pressure-volume relationship and that systolic dysfunction may be present, even when the slopes of both PRSW and the end-systolic pressure-volume relationship have recovered.

The Effects of Local Ventricular Pacing on Recovery from Regional Myocardial Ischemia

After surgical revascularization of ischemic myocardium, temporary ventricular pacing is often used, yet no data exist to indicate whether pacing ischemic versus nonischemic myocardium affects myocardial recovery. Therefore, chronically instrumented conscious dogs were studied with segment length transducers in the left anterior descending (LAD) distribution, left ventricular and pericardial micromanometers, pneumatic occluders on the LAD and venae cavae, and bipolar ventricular pacing wires, one pair in the LAD zone and one pair in the nonischemic (LCX) zone. Six dogs underwent a total of twelve 15-min LAD occlusions, each followed by 48 hr of reperfusion. Just after reperfusion, either the LAD or LCX zone was paced at 150 bpm for 45 min. LAD versus LCX pacing decreased regional stroke work (6 ± 5 versus 19 ± 5 kerg · cm -2) and produced contractile asynchrony. Myocardial contractile function was assessed using preload recruitable work area (PRWA), the area under the regional stroke work versus end-diastolic length relationship. Relative to LCX pacing, LAD pacing significantly delayed the recovery of PRWA after 4 hr of reperfusion (54 ± 9 versus 83 ± 9% control PRWA, P < 0.05). Perhaps by increased contractile asynchrony despite the decreased regional stroke work, ventricular pacing of ischemically injured myocardium delays functional recovery and should be avoided in clinical settings where the ventricular pacing site may be chosen.

Recovery of myocardial function after repetitive episodes of reversible ischemia.

The question of whether recovery of regional myocardial function after repetitive, reversible ischemia differs from recovery after a single episode of myocardial ischemia remains controversial. Therefore, eight conscious dogs were instrumented with ultrasonic dimension transducers and left ventricular micromanometers. Each animal underwent (in random sequence, 72 h apart) a single 15-min left anterior descending coronary arterial (LAD) occlusion and two 15-min LAD occlusions separated by 1 h of reperfusion. The preload recruitable work area (PRWA; the area beneath the regional stroke work vs. end-diastolic length relationship) quantified regional myocardial performance. Repetitive ischemia significantly delayed recovery of PRWA over the first 24 h (P < 0.05). Although postischemic myocardial creep resolved rapidly after single occlusion, double occlusion prevented recovery of creep during the first 4 h of reperfusion. The recovery time course of PRWA paralleled the resolution of myocardial creep, suggesting that creep contributed significantly to delayed functional recovery and that myocardial "stunning" after repetitive ischemia may result in part from interaction between postischemic diastolic properties and systolic dysfunction.

Cocaine Depresses Myocardial Contractility and Prolongs Isovolumetric Relaxation in Conscious Dogs with Partial Autonomic Nervous System Blockade

The direct effects of cocaine on myocardial contractility and isovolumetric relaxation were investigated in conscious dogs (n = 8) chronically instrumented for measurement of hemodynamics, including left ventricular pressure (LVP) and subendocardial segment length. Experiments were performed in the presence of pharmacologic blockade of beta-adrenergic, cholinergic, and ganglionic receptors because cocaine indirectly produces significant alterations in systemic hemodynamics through central and peripheral sympathomimetic actions. Myocardial contractility was quantitated using the preload recruitable stroke work (PRSW) versus end-diastolic segment length (EDL) relationship. LVP-segment length loops were generated in the unsedated control state and after cocaine administration with use of preload reduction by abrupt inferior vena caval constriction, and PRSW versus EDL slope (Mw) and length intercept (Lw) were calculated. In addition, regional preload recruitable work area (PRWA) and stroke work at constant EDL (SWEDL) were also determined. Ventricular relaxation was assessed using a time constant of isovolumetric relaxation assuming a nonzero asymptote of LVP decay. Systemic hemodynamics, myocardial contractility, and isovolumetric relaxation were recorded and calculated before and 1, 3, 5, and 10 min after cocaine administration (2 mg/kg intravenously, i.v.). Mw was significantly (p less than 0.05) reduced by cocaine (63 +/- 8 during control to 45 +/- 8 mm Hg at 1 min after drug administration). PRWA also reflected significant decreases in myocardial contractility after cocaine administration (1,800 +/- 260 during control to 1,200 +/- 220 mm Hg.mm2 at 1 min after drug administration). Similar results were observed with SWEDL (469 +/- 60 during control to 317 +/- 52 mm Hg.mm at 1 min after cocaine administration). All three indexes of contractile state demonstrated complete recovery of contractile function by 10 min after cocaine administration. The time constant of isovolumetric relaxation was prolonged by cocaine (35 +/- 2 during control to 46 +/- 3 ms at 3 min after drug administration), indicating impairment of diastolic function. Ventricular relaxation returned to control levels within 5 min after cocaine administration. No cocaine-induced alterations in coronary blood flow (CBF) or changes in calculated pressure work index (PWI, an indicator of myocardial O2 consumption) were observed. The present results suggest that cocaine produces direct negative inotropic and lusitropic effects independent of changes in myocardial O2 supply and demand and autonomic nervous system activity in conscious chronically instrumented dogs.

The Effects of Dopamine on Myocardial Functional Recovery After Reversible Ischemic Injury

Dopamine frequently is used to improve cardiac performance after acute myocardial ischemia. Inotropic agents, however, increase myocardial oxygen demand and could potentially delay recovery from ischemic injury. To evaluate this problem, we studied eight chronically instrumented dogs in the conscious state and performed two 15-minute coronary occlusions 48 hours apart. After one of the occlusions, either dopamine (15 μg/kg/min) or saline placebo was administered intravenously from 1.0 to 1.5 hours of reperfusion. The alternative infusion was given during the second study. Preload recruitable work area, the area beneath the stroke work versus end-diastolic length relationship, was used to assess intrinsic myocardial performance. Ischemia decreased preload recruitable work area to 13% of control after both occlusions. After reperfusion, a 30-minute dopamine infusion acutely increased myocardial function nearly threefold as compared with placebo. Myocardial performance after dopamine administration, however, was significantly depressed compared with placebo throughout the remaining 24 hours of reperfusion (p

The Effects of Dopamine on Myocardial Functional Recovery After Reversible Ischemic Injury

Dopamine frequently is used to improve cardiac performance after acute myocardial ischemia. Inotropic agents, however, increase myocardial oxygen demand and could potentially delay recovery from ischemic injury. To evaluate this problem, we studied eight chronically instrumented dogs in the conscious state and performed two 15-minute coronary occlusions 48 hours apart. After one of the occlusions, either dopamine (15 micrograms/kg/min) or saline placebo was administered intravenously from 1.0 to 1.5 hours of reperfusion. The alternative infusion was given during the second study. Preload recruitable work area, the area beneath the stroke work versus end-diastolic length relationship, was used to assess intrinsic myocardial performance. Ischemia decreased preload recruitable work area to 13% of control after both occlusions. After reperfusion, a 30-minute dopamine infusion acutely increased myocardial function nearly threefold as compared with placebo. Myocardial performance after dopamine administration, however, was significantly depressed compared with placebo throughout the remaining 24 hours of reperfusion (p less than 0.01). These data indicate that dopamine may impair functional recovery after ischemic myocardial injury and suggest that inotropic interventions should be used in this setting only when absolutely indicated.

Ketamine depresses myocardial contractility as evaluated by the preload recruitable stroke work relationship in chronically instrumented dogs with autonomic nervous system blockade.

Previous investigations examining the direct actions of ketamine on myocardial contractility in vivo suggest that ketamine may produce depression of contractile function under certain circumstances. Such studies have had significant limitations in that reliable, easily quantified, load-independent indices of contractility were not used, and ketamine produces dramatic sympathomimetic pressor effects mediated via an intact autonomic nervous system. In the present investigation, eight experiments were performed using dogs chronically instrumented for measurement of aortic and left ventricular pressure; rate of increase of left ventricular pressure (dP/dt), subendocardial segment length, and cardiac output. Contractility was evaluated using the linear relationship between preload recruitable stroke work and end-diastolic segment length. The slope (Mw) and length intercept of this relationship, and two derived variables, preload recruitable work area (PRWA) and stroke work at constant end-diastolic length (SWEDL), were used as indices of contractility. Pharmacologic blockade of the autonomic nervous system was instituted in all experiments since a portion of the systemic hemodynamic actions of ketamine are secondary to stimulation of the autonomic nervous system. Systemic hemodynamics and indices of contractile function were recorded and evaluated in the conscious state and after a 20-min equilibration at 25-, 50-, and 100-mg.kg-1.h-1 infusions of ketamine. A significant (P less than 0.05) and dose-dependent decrease in Mw (68 +/- 7 during control to 41 +/- 2 mmHg at 100 mg.kg-1.h-1) was observed, demonstrating depression of myocardial contractility.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of dopamine on myocardial functional recovery after reversible ischemic injury

Dopamine frequently is used to improve cardiac performance after acute myocardial ischemia. Inotropic agents, however, increase myocardial oxygen demand and could potentially delay recovery from ischemic injury. To evaluate this problem, we studied eight chronically instrumented dogs in the conscious state and performed two 15-minute coronary occlusions 48 hours apart. After one of the occlusions, either dopamine (15 micrograms/kg/min) or saline placebo was administered intravenously from 1.0 to 1.5 hours of reperfusion. The alternative infusion was given during the second study. Preload recruitable work area, the area beneath the stroke work versus end-diastolic length relationship, was used to assess intrinsic myocardial performance. Ischemia decreased preload recruitable work area to 13% of control after both occlusions. After reperfusion, a 30-minute dopamine infusion acutely increased myocardial function nearly threefold as compared with placebo. Myocardial performance after dopamine administration, however, was significantly depressed compared with placebo throughout the remaining 24 hours of reperfusion (p less than 0.01). These data indicate that dopamine may impair functional recovery after ischemic myocardial injury and suggest that inotropic interventions should be used in this setting only when absolutely indicated.