Dermot Lowe

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)

Levosimendan Enhances Left Ventricular Systolic and Diastolic Function in Conscious Dogs with Pacing-induced Cardiomyopathy

We examined the left ventricular (LV) mechanical actions of levosimendan (LSM) before and after the development of pacing-induced cardiomyopathy in conscious dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dt, subendocardial segment length, and cardiac output (CO). The slope (Mw) of the regional preload recruitable stroke work relation was used to assess myocardial contractility. Diastolic function was evaluated with a time constant of isovolumic relaxation (tau), the maximal rate of segment-lengthening velocity (dL/dt), and a regional chamber-stiffness constant (Kp). On different experimental days, dogs were assigned to receive LSM (12- or 24-microgram/kg loading dose and 0.2 or 0.4 microgram/kg/min infusion) before rapid ventricular pacing was initiated. Dogs were then paced at 240 beats/min for 22 +/- 2 days, and the low and high doses of LSM were repeated on separate days. LSM increased Mw and +dP/dt in dogs before the initiation of pacing, consistent with enhanced myocardial contractility. LSM also improved indices of LV diastolic function (decreases in tau and Kp and increases in dL/dt) in dogs before pacing. Rapid ventricular pacing over a 3-week period increased LV end-diastolic pressure and produced systolic (decreases in Mw and +dP/dt) and diastolic (increases in tau and Kp and decreases in dL/dt) dysfunction. LSM significantly (p < 0.05) increased Mw (54 +/- 3 to 98 +/- 6 mm Hg) +dP/dt and dL/dt (57 +/- 13 to 72 +/- 13 mm/s) and decreased tau (66 +/- 4 to 52 +/- 3 ms) and Kp (1.14 +/- 0.14 to 0.71 +/- 0.03 mm-1) in the presence of LV dysfunction. In contrast to the findings in normal dogs, however, LSM did not alter heart rate and calculated indices of myocardial oxygen consumption in dogs after pacing. The findings indicate that LSM produces favorable alterations in hemodynamics and positive inotropic and lusitropic effects in conscious dogs with left ventricular dysfunction.

Influence of volatile anesthetics on left ventricular afterload in vivo : Differences between desflurane and sevoflurane

Background This investigation examined the effects of desflurane and sevoflurane on quantitative indices of left ventricular afterload derived from aortic input impedance (Zin) interpreted using a three-element Windkessel model. Methods After Animal Care Committee approval, dogs (n = 8) were chronically instrumented for measurement of systemic hemodynamics including aortic blood pressure and flow. On separate days, aortic pressure and flow waveforms were recorded under steady-state conditions in the conscious state and after equilibration for 30 min at 1.1, 1.3, 1.5, and 1.7 minimum alveolar concentration of desflurane or sevoflurane. Aortic input impedance spectra were obtained via power spectral analysis of aortic pressure and flow waveforms. Characteristic aortic impedance (Z sub c) and total arterial resistance were calculated as the mean of the magnitude of Zin between 2 and 15 Hz and the difference between Zin at zero frequency and Zc, respectively. Total arterial compliance (C) was calculated from aortic pressure and flow waveforms using the Windkessel model. Results Desflurane and sevoflurane increased heart rate and decreased systolic, diastolic, and mean arterial pressure, left ventricular systolic pressure, left ventricular peak positive rate of increase in left ventricular pressure, percent segment shortening, and stroke volume. Sevoflurane, but not desflurane, decreased cardiac output. Desflurane, but not sevoflurane, decreased systemic vascular resistance. Desflurane decreased R (3,170+/-188 during control to 2441 +/-220 dynes *symbol* second *symbol* centimeter sup -5 at 1.7 minimum alveolar concentration) and did not alter C and Zc. In contrast, sevoflurane increased C (0.57+/-0.05 during control to 0.79+/-0.05 ml/mmHg at 1.7 minimum alveolar concentration) and Z sub c (139+/-10 during control to 194+/-14 dynes *symbol* second *symbol* centimeter sup -5 at 1.7 minimum alveolar concentration) but did not change R. Conclusions The results indicate that desflurane and sevoflurane produce substantially different effects on left ventricular afterload in chronically instrumented dogs. Desflurane-induced decreases in systemic vascular resistance occur primarily because of effects on arteriolar resistance vessels. In contrast, sevoflurane increased C and Zc concomitant with pressure-dependent reductions in aortic diameter, suggesting that this anesthetic may alter left ventricular afterload by affecting the mechanical properties of the aorta.

Desflurane and Isoflurane Exert Modest Beneficial Actions on Left Ventricular Diastolic Function during Myocardial Ischemia in Dogs

Background Volatile anesthetics exert cardioprotective effects during myocardial ischemia. This investigation examined the regional systolic and diastolic mechanical responses to brief left anterior descending coronary artery (LAD) occlusion in the central ischemic zone and in remote normal myocardium in the conscious state and during desflurane and isoflurane anesthesia.

Propofol alters left ventricular afterload as evaluated by aortic input impedance in dogs

Background Systemic vascular resistance incompletely describes left ventricular afterload because of the phasic nature of arterial pressure and blood flow. Aortic input impedance is an experimental description of left ventricular afterload that incorporates the frequency-dependent characteristics and viscoelastic properties of the arterial system. The effects of propofol on aortic input impedance were examined using three variables derived from the three-element Windkessel model: characteristic aortic impedance, total arterial compliance, and total arterial resistance. Methods Eight dogs were chronically instrumented for measurement of aortic pressure, left ventricular pressure, +dP/dt, subendocardial segment length, and aortic blood flow. Systemic hemodynamics and aortic blood pressure and flow waveforms were recorded in the conscious state and after a bolus of 5 mg *symbol* kg sup -1 propofol and infusion for 15 min at 25, 50, and 100 mg *symbol* kg sup -1 *symbol* h sup -1. Aortic input impedance spectra were generated using power spectral analysis of aortic pressure and flow waveforms corrected for the phase responses of the pressure and flow transducers. Characteristic aortic impedance, total arterial resistance, and total arterial compliance were calculated from the aortic input impedance spectrum and the aortic pressure waveform. Parameters describing the net site and magnitude or arterial wave reflection were determined from aortic impedance. Results Propofol decreased total arterial resistance (3.05 +/-0.20 during control to 2.29+/-0.18 dynes *symbol* s *symbol* cm sup -5 *symbol* 103 at the high dose) and increased total arterial compliance (0.53+/-0.04 during control to 1.15 +/-0.17 ml *symbol* mmHg sup -1 at the high dose) in a dose-related manner. Propofol increased characteristic aortic impedance (1.49+/-0.15 during control to 2.20+/-0.20 dynes *symbol* s *symbol* cm sup -5 *symbol* 102 at the high dose). The net site and the magnitude of arterial wave reflection were unchanged by propofol. Conclusions In chronically instrumented dogs, propofol decreased total arterial resistance, a property of arteriolar resistance vessels, consistent with the known actions of this drug on systemic vascular resistance. Propofol also increased total arterial compliance and characteristic aortic impedance, indicating that this anesthetic affects the mechanical properties of the aorta. Propofol had no effect on arterial wave reflection patterns. The results indicate that propofol reduces left ventricular afterload via decreases in peripheral resistance and increases in arterial compliance.

cardiovascular Effects of Propofol in Dogs with Dilated Cardiomyopathy

Background The authors tested the hypothesis that propofol improves left ventricular diastolic function in dogs with dilated cardiomyopathy by reducing left ventricular preload and afterload. Methods Seven dogs were instrumented for left ventricular and aortic pressures, aortic blood flow, and subendocardial segment length. Left ventricular afterload and contractility were quantified with aortic input impedance and preload recruitable stroke work, respectively. Diastolic function was evaluated with a time constant of left ventricular relaxation (tau); segment‐lengthening velocities and time‐velocity integrals during early left ventricular filling (dL/dtE and TVI‐E, respectively) and atrial systole (dL/dtA and TVI‐A, respectively); and a regional chamber stiffness constant (K). Dogs were paced at 240 beats/min for 18 +/‐ 3 days, and hemodynamics were recorded in sinus rhythm in the conscious state. Anesthesia was induced with propofol (5 mg/kg) and maintained with propofol infusions at 25, 50, and 100 mg [center dot] kg sup ‐1 [center dot] h sup ‐1, and hemodynamics were recorded after 15 min of equilibration at each dose. Results Propofol decreased mean arterial pressure, left ventricular end‐diastolic pressure, and K but did not change heart rate. Propofol reduced total arterial resistance and increased total arterial compliance derived from aortic input impedance. Propofol also reduced preload recruitable stroke work. The lowest dose of propofol decreased tau. Propofol decreased dL/dtE and TVI‐E and reduced the dL/dt‐E/A and TVI‐E/A ratios. Conclusions Propofol reduces left ventricular preload, afterload, and regional chamber stiffness, causes direct negative inotropic effects, and impairs early‐diastolic left ventricular filling in dogs with dilated cardiomyopathy.

Isoflurane, but Not Halothane, Improves Indices of Diastolic Performance in Dogs with Rapid Ventricular, Pacing-induced Cardiomyopathy

Background The left ventricular (LV) mechanical effects of isoflurane and halothane were examined in dogs with rapid LV pacing-induced cardiomyopathy. These experiments tested the hypothesis that isoflurane and halothane differentially enhance indices of diastolic performance in dogs with moderate LV dysfunction. Methods Eight dogs were chronically instrumented for measurement of LV and aortic pressures, subendocardial segment length, and cardiac output. Contractility was quantified by preload recruitable stroke work (Mw). Diastolic function was evaluated with a time constant of isovolumic relaxation (tau), segment lengthening velocities and time-velocity integrals during early filling (dL/dtE and TVI-E) and atrial systole (dL/dtA and TVI-A), and a regional chamber stiffness constant (Kp). Hemodynamics and LV function were recorded in the conscious state before pacing. The left ventricles of the dogs were then continuously paced at ventricular rates between 220 and 240 beats *symbol* min sup -1 for 10 plus/minus 1 days and monitored on a daily basis. After the development of moderate LV dysfunction, pacing was temporarily discontinued, and dogs were studied in sinus rhythm in the conscious state and after 20 min equilibration at 1.1, 1.4, and 1.7 minimum alveolar concentration isoflurane and halothane on separate days. Results Chronic rapid pacing increased baseline (sinus rhythm) heart rate, LV end-diastolic pressure, and end-diastolic segment length and decreased mean arterial pressure, LV systolic pressure, and cardiac output. Mw decreased and tau and Kp increased, consistent with LV systolic and diastolic dysfunction. Reductions in dL/dtE /dL/dt sub A and TVI-E/A occurred, which indicated that LV filling was more dependent on atrial systole. In dogs with cardiomyopathy, isoflurane and halothane increased heart rate and decreased mean arterial pressure, LV systolic pressure, LV end-diastolic pressure, cardiac output, Mw, and Kp. Decreases in LV end-diastolic pressure were more pronounced in dogs anesthetized with 1.1 minimum alveolar concentration isoflurane compared with halothane. Halothane-induced decreases Mw were greater than those observed with equi-minimum alveolar concentration isoflurane. A reduction in tau and increases in TVI-E/TVI-A and the ratio of early to total LV filling were observed with isoflurane. In contrast, halothane caused dose-related reductions in dL/dtE, dL/dt sub A, TVI-E, and TVI-A, and did not improve the ratios of these variables. Conclusions Isoflurane, but not halothane, improved several indices of diastolic performance in dogs with pacing-induced LV dysfunction, despite producing simultaneous negative inotropic effects. These findings can probably be attributed to favorable reductions in LV preload and not to direct lusitropic effects. Improvement of filling dynamics may partially offset the decrement in LV systolic function by isoflurane in the setting of LV dysfunction.

Effects of Levosimendan on Left Ventricular Function: Correlation With Plasma Concentrations in Conscious Dogs

OBJECTIVES To test the hypothesis that the hemodynamic and left ventricular functional actions of levosimendan (Orion Pharmaceutica, Espoo, Finland), a new myofilament calcium sensitizer with phosphodiesterase-inhibiting properties, in conscious dogs are correlated with plasma concentrations of the drug measured with reverse-phase, high-performance liquid chromatography. DESIGN Prospective investigation. SETTING Research laboratory. PARTICIPANTS Fifteen chronically instrumented dogs. INTERVENTIONS On different experimental days, dogs were assigned to receive intravenous levosimendan (12 or 24 micrograms/kg loading dose and 0.2 or 0.4 microgram/kg/min infusion, respectively). MEASUREMENTS AND MAIN RESULTS Systemic and coronary hemodynamics, left ventricular function, and plasma concentrations were determined at scheduled intervals during and after levosimendan infusions. Levosimendan increased heart rate and cardiac output and decreased left ventricular end-diastolic pressure and systemic vascular resistance. Levosimendan caused dose-related enhancement of left ventricular systolic (increases in regional preload recruitable stroke work slope and +dP/dtmax) and diastolic functions (decreases in the time constant of isovolumic relaxation and regional chamber stiffness). The elimination half-life of levosimendan was 0.76 +/- 0.04 hours. CONCLUSIONS The hemodynamic actions and left ventricular functional effects of levosimendan correlated closely with plasma concentrations and returned to baseline values within 3 hours after discontinuation of the drug.

Levosimendan potentiates the inotropic actions of dopamine in conscious dogs

We examined the hemodynamic and left ventricular (LV) functional actions of dopamine with and without levosimendan in dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dtmax, subendocardial segment length, and cardiac output (CO). On different experimental days, dogs were randomly assigned to receive dopamine (2.5, 5.0, and 10.0 micrograms kg-1 min-1) in the absence and presence of levosimendan (0.125, 0.25, and 0.5 microgram kg-1 min-1) or levosimendan alone. Dopamine increased heart rate (HR), CO, stroke volume (SV), and pressure-work index (PWI) and decreased systemic vascular resistance (SVR). Dopamine also increased LV systolic and end-diastolic pressures (LVSP and LVEDP) and mean arterial pressure (MAP). Dopamine caused dose-related positive inotropic [increases in preload recruitable stroke work (Mw) and + dP/ dtmax] and lusitropic effects [decreases in the time constant of isovolumic relaxation (tau) and increases in maximum segment-lengthening velocity (dL/dtmax)]. Dopamine also increased the regional chamber thickness constant (Kp) concomitant with increases in LVEDP. In the presence of levosimendan, dopamine-induced increases in HR, PWI, CO, and SV and decreases in SVR were enhanced. Increases in MAP, LVSP, and LVEDP observed with dopamine alone were attenuated by the addition of levosimendan. Dopamine-induced increases in Mw and +dP/dtmax were enhanced by levosimendan. Reductions in tau and increases in dL/dtmax produced by dopamine were similar with and without levosimendan. However, levosimendan abolished increases in Kp caused by dopamine alone. Levosimendan alone caused dose-related improvements in indices of LV systolic and diastolic function. The results indicate that levosimendan potentiates the positive inotropic effects of dopamine in conscious, unsedated dogs, while attenuating the deleterious action of dopamine on chamber compliance.

The effects of Isoflurane and halothane on left ventricular afterload in dogs with dilated cardiomyopathy

The effects of volatile anesthetics, including isoflurane (ISO) and halothane (HAL), on determinants of left ventricular (LV) afterload have not been comprehensively described in experimental models of, or patients with, heart failure.We tested the hypothesis that ISO and HAL produce beneficial alterations in LV afterload when evaluated with aortic input impedance and interpreted using a three-element Windkessel model in dogs before and after development of pacing-induced cardiomyopathy. Hemodynamics and aortic pressure and blood flow waveforms were recorded in the conscious state and during 1.1- and 1.5-minimum alveolar anesthetic concentration (MAC) ISO and HAL anesthesia on separate days in chronically instrumented dogs (n = 6). Dogs were then paced at 220-240 bpm for 20 +/- 3 days (mean = SEM) to develop cardiomyopathy, and the experiments were repeated after pacing had been temporarily discontinued. ISO decreased mean arterial pressure (MAP), mean aortic blood flow (MAQ), and total arterial resistance (R) and increased total arterial compliance (C) and characteristic aortic impedance (Zc) in dogs before pacing. HAL decreased MAP and MAQ and increased C but did not alter R and Zc. Chronic rapid LV pacing increased HR and LV end-diastolic pressure and decreased MAP, LV systolic pressure, and the peak rate of increase of LV pressure. MAQ, C, R, and Zc were unchanged. ISO and HAL decreased arterial pressure but did not affect C and Zc in the presence of LV dysfunction. HAL, but not ISO, increased R at 1.1 MAC, which indicates that this drug increases resistance to LV ejection. In contrast to findings in normal dogs, these results indicate that neither ISO nor HAL reduce arterial hydraulic resistance to LV ejection or favorably improve the rectifying properties of the aorta in dogs with pacing-induced cardiomyopathy. Implications: Isoflurane and halothane produce favorable alterations in the determinants of left ventricular afterload before, but not after, the production of experimental left ventricular dysfunction by sustained, rapid cardiac pacing in chronically instrumented dogs. (Anesth Analg 1997;85:979-86)