Dexmedetomidine produces similar alterations in the determinants of left ventricular afterload in conscious dogs before and after the development of pacing-induced cardiomyopathy

BACKGROUND: The authors tested the hypothesis that intravenous dexmedetomidine produces alterations in left ventricular (LV) afterload that are deleterious to cardiac performance in conscious dogs with pacing-induced cardiomyopathy. METHODS: Dogs (n = 8) were fitted with instruments for long-term measurement of LV and aortic blood pressure, aortic blood flow, and subendocardial segment length and received dexmedetomidine (1.25, 2.5, and 5 microg/kg) in a cumulative manner before and after 19+/-3 (mean +/- SEM) days of rapid LV pacing. LV afterload was measured with aortic input impedance [Zin(omega)] and quantified with a three-element Windkessel model. Hemodynamics and Zin(omega)) were assessed under control conditions and 5 and 60 min after administration of each dose. RESULTS: Dexmedetomidine caused early and late decreases in heart rate, the maximum rate of increase of LV pressure, mean aortic blood flow, and stroke volume in dogs before and after pacing. Dexmedetomidine caused similar early increases in total arterial resistance and decreases in total arterial compliance in dogs before and after pacing. Early dexmedetomidine-induced increases in resistance and decreases in compliance caused similar reductions in mean aortic blood flow in cardiomyopathic compared with healthy dogs. Resistance and compliance returned to control values, and characteristic aortic impedance decreased late after dexmedetomidine in healthy dogs. In contrast, resistance remained elevated late after dexmedetomidine in dogs with dilated cardiomyopathy. CONCLUSIONS: Dexmedetomidine causes similar alterations in hemodynamics and LV afterload in conscious dogs with and without pacing-induced cardiomyopathy.     

Altered ventricular and myocyte response to angiotensin II in pacing-induced heart failure

Alterations in the cardiac response to angiotensin II (Ang II) may contribute to the functional impairment in tachycardia-induced heart failure (congestive heart failure [CHF]). Accordingly, we studied the response to Ang II in eight conscious instrumented dogs before and after inducing CHF. Left ventricular (LV) performance was assessed by measuring LV pressure and LV volume. Isolated myocyte function was evaluated using computer-assessed videomicroscopy. In conscious animals before CHF, Ang II produced a load-dependent slowing of the time constant of LV relaxation (tau) and did not depress intact LV contractile function. After CHF, although Ang II produced a similar increase in LV systolic pressure, the increases in LV diastolic pressure and time constant tau were much greater, and contractile performance was depressed. These changes persisted when the elevation of end-systolic pressure was prevented by nitroprusside. Similar changes were also present after autonomic blockade. In isolated myocytes, before CHF, Ang II (10(-6) mol/L) produced a slight positive inotropic effect. In contrast, after CHF, Ang II produced a negative inotropic effect and slowed the rate of relengthening. The effects in the intact LV and myocytes were reversed by an Ang II AT1 receptor blocker (losartan). We conclude that pacing-induced CHF alters the LV and myocyte response to Ang II, so that Ang II produces direct depressions in intact LV contraction, relaxation, and filling and exacerbates myocyte contractile dysfunction. These effects are mediated through the activation of AT1 receptors.     

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. METHODS: Eighteen experiments were performed in nine dogs chronically instrumented for measurement of aortic and left ventricular pressure, cardiac output, LAD coronary blood flow velocity, and LAD and left circumflex coronary artery subendocardial segment length. Regional myocardial contractility was evaluated with the slope of the preload recruitable stroke work relationship determined from a series of left ventricular pressure-segment length diagrams in the LAD and left circumflex coronary artery zones. Diastolic function was assessed with a time constant of isovolumic relaxation (tau), maximum segment lengthening velocity in LAD and left circumflex coronary artery regions, and regional chamber stiffness constants derived using monoexponential and three-element exponential curve fitting in each zone. On separate experimental days, hemodynamics and indices of regional functional were obtained in the conscious state and during 1.1 and 1.6 minimum alveolar concentration end-tidal desflurane or isoflurane before and during LAD occlusion. RESULTS: In conscious dogs, LAD occlusion abolished regional stroke work, increased chamber stiffness (monoexponential: 0.39 +/- 0.04 during control to 1.34 +/- 0.39 mm-1 during LAD occlusion), and decreased the rate of early ventricular filling in the ischemic zone. These changes were accompanied by increased contractility (slope: 103 +/- 8 during control to 112 +/- 7 mmHg during LAD occlusion), rapid filling rate (maximum segment lengthening velocity: 46 +/- 5 during control to 55 +/- 7 mm.s-1 during LAD occlusion), and chamber stiffness (monoexponential: 0.43 +/- 0.05 during control to 1.14 +/- 0.25 mm-1 during LAD occlusion) in the normal region. Increases in tau were also observed in the conscious state during the period of myocardial ischemia. Desflurane and isoflurane increased tau and decreased the slope and maximum segment lengthening velocity in a dose-related manner. Monoexponential and three-element element exponential curve fitting were unchanged by the volatile anesthetics in the absence of ischemia. Myocardial contractility and rapid filling rate were enhanced in the nonischemic region during LAD occlusion in the presence of desflurane and isoflurane. In contrast to the findings in the conscious state, ischemia-induced increases in tau and chamber stiffness in the ischemic and normal zones were attenuated during anesthesia induced by desflurane and isoflurane. CONCLUSIONS: The results indicate that increases in contractility of remote myocardium during brief regional ischemia were preserved in the presence of desflurane and isoflurane anesthesia. In addition, desflurane and isoflurane blunted ischemia-induced increases in tau and regional chamber stiffness in both the ischemic and nonischemic zones. These results demonstrate that the volatile anesthetics may exert important beneficial actions on left ventricular mechanics in the presence of severe abnormalities in systolic and diastolic function during ischemia.     

Effects of load manipulations, heart rate, and contractility on left ventricular apical rotation. An experimental study in anesthetized dogs

BACKGROUND: Left ventricular twist or torsion has been defined as the counterclockwise rotation of the ventricular apex with respect to the base during systole. We have recently shown that since base rotation is minimal, measurement of apex rotation reflects the dynamics of left ventricular (LV) twist. Since the mechanisms by which load and contractility affect twist are controversial, we aimed to determine the relation between apex rotation and volume, contractility, and heart rate under conditions in which dimensions and pressures were accurately measured. METHODS AND RESULTS: Using our optical device coupled to the LV apex, apex rotation was recorded simultaneously with LV pressure, ECG, LV segment length, and minor-axis diameters (sonomicrometry) in 12 open-chest dogs. Using vena caval occlusion and volume loading, a linear end-diastolic (ED) relation between apex rotation and LV area index was obtained (slope, 0.61 +/- 0.06 degrees/percent change; intercept, -60.1 +/- 6.2 degrees; n = 10) that differed from the end-systolic (ES) relation (slope, 1.36 +/- 0.27 degree/percent change; intercept, -132.5 +/- 24.9 degrees; P < .005). With changes in contractility, afterload, or heart rate, for both ED and ES the apex rotation-volume points fell within the range of the relations established by changing preload, suggesting that volume is the major determinant of twist. Vena caval occlusion (preload and afterload decrease) caused an increase in amplitude of apex rotation, with maximal apex rotation occurring earlier in ejection. In contrast, acute volume loading (predominant preload increase) caused a small decrease in the amplitude of apex rotation, and twist relaxation was delayed into the isovolumic relaxation period. Likewise, with single-beat aortic occlusion (increased afterload), there was a slight decrease in the amplitude of apex rotation, and maximal apex rotation was delayed into the isovolumic relaxation period. Paired pacing (increased contractility) increased the total amplitude of apex rotation by 42% and caused a delay in untwisting until the end of the isovolumic relaxation period. An increase in heart rate over 150 beats per minute resulted in a significant decrease in the amplitude of apex rotation with a similar delay of twist relaxation into the isovolumic relaxation period. CONCLUSIONS: The effects of load, contractility, and heart rate manipulations on LV twist as measured throughout the cardiac cycle by the optical apex rotation method are manifested by changes in both the amplitude and dynamics of torsion. LV twist at ED and ES is primarily a function of volume; this relation appears to be unaltered by heart rate, afterload, and contractility. Whereas decreased load caused early untwisting, increases in preload, afterload, heart rate, and contractility caused a consistent pattern of delay in twist relaxation.     

Desflurane, sevoflurane, and isoflurane impair canine left ventricular-arterial coupling and mechanical efficiency

BACKGROUND: The effects of desflurane, sevoflurane, and isoflurane on left ventricular-arterial coupling and mechanical efficiency were examined and compared in acutely instrumented dogs. METHODS: Twenty-four open-chest, barbiturate-anesthetized dogs were instrumented for measurement of aortic and left ventricular (LV) pressure (micromanometer-tipped catheter), dP/dtmax, and LV volume (conductance catheter). Myocardial contractility was assessed with the end-systolic pressure-volume relation (Ees) and preload recruitable stroke work (Msw) generated from a series of LV pressure-volume diagrams. Left ventricular-arterial coupling and mechanical efficiency were determined by the ratio of Ees to effective arterial elastance (Ea; the ratio of end-systolic arterial pressure to stroke volume) and the ratio of stroke work (SW) to pressure-volume area (PVA), respectively. RESULTS: Desflurane, sevoflurane, and isoflurane reduced heart rate, mean arterial pressure, and left ventricular systolic pressure. All three anesthetics caused similar decreases in myocardial contractility and left ventricular afterload, as indicated by reductions in Ees, Msw, and dP/dtmax and Ea, respectively. Despite causing simultaneous declines in Ees and Ea, desflurane decreased Ees/Ea (1.02 +/- 0.16 during control to 0.62 +/- 0.14 at 1.2 minimum alveolar concentration) and SW/PVA (0.51 +/- 0.04 during control to 0.43 +/- 0.05 at 1.2 minimum alveolar concentration). Similar results were observed with sevoflurane and isoflurane. CONCLUSIONS: The present findings indicate that volatile anesthetics preserve optimum left ventricular-arterial coupling and efficiency at low anesthetic concentrations (< 0.9 minimum alveolar concentration); however, mechanical matching of energy transfer from the left ventricle to the arterial circulation degenerates at higher end-tidal concentrations. These detrimental alterations in left ventricular-arterial coupling produced by desflurane, sevoflurane, and isoflurane contribute to reductions in overall cardiac performance observed with these agents in vivo.     

Loading sequence plays an important role in enhanced load sensitivity of left ventricular relaxation in conscious dogs with tachycardia-induced cardiomyopathy

BACKGROUND: Left ventricular relaxation rate in the failing heart depends more on the systolic load than in the normal heart. To elucidate the mechanisms for the enhanced load sensitivity of left ventricular relaxation in heart failure, we examined the relative contributions of changes in end-systolic volume and loading sequence to the left ventricular relaxation rate. METHODS AND RESULTS: In seven conscious dogs, the time constant (Td) of left ventricular pressure decay, end-systolic volume, systolic circumferential force, and time to peak force during caval occlusion were compared before and after development of tachycardia-induced heart failure. Rapid ventricular pacing decreased the slope of the end-systolic pressure-volume relation from 4.5 to 2.8 mm Hg/mL (P < .01) and prolonged Td from 33 to 49 ms (P < .01). In normal conditions, caval occlusion reduced end-systolic force (-580 g, P < .01) and end-systolic volume (-7 mL, P < .01) but did not change Td or time to peak force. In heart failure, however, caval occlusion shortened Td (-11 ms, P < .01), with a concomitant decrease in the time to peak force (-30 ms, P < .01), while end-systolic volume and force declined slightly. Consequently, for a comparable reduction in end-systolic force, Td decreased more in heart failure than in normal hearts, suggesting enhanced load sensitivity. Moreover, changes in Td correlated well with those in the time to peak force (r = .79, P < .01) but not with those in end-systolic volume. CONCLUSIONS: Loading sequence rather than elastic recoil seems to play the predominant role in the enhanced load sensitivity of left ventricular relaxation in heart failure.     

Effects of felodipine on left ventricular systolic and diastolic performance in congestive heart failure

We studied the effects of a dihydropyridine calcium blocker, felodipine, on left ventricular (LV) contractile performance and diastolic filling dynamics in conscious dogs with pacing-induced congestive heart failure (CHF) before and after autonomic blockade. Eleven conscious dogs were instrumented to measure micromanometer LV and left atrial (LA) pressure (P) and to determine LV volume (V) from three dimensions. CHF was induced by 4 to 5 weeks of right ventricular pacing. After CHF, the mean LV end-diastolic (ED) P increased (9.7 +/- 2.9 vs. 27.9 +/- 6.8 mm Hg, P < .05), LVEDV and end-systolic (ES) V increased and stroke volume (SV) decreased (15.3 +/- 2.4 vs. 9.6 +/- 3.0 ml, P < .05). The time constant of LV relaxation (T) (25.9 +/- 2.9 vs. 37.9 +/- 5.1 msec, P < .05) and LVES wall stress (WS) (63.4 +/- 21.0 vs. 74.6 +/- 23.7 g/cm2, P < .05) also increased. After CHF, felodipine (25 nmol/kg i.v., plasma concentrations 17.4 +/- 3.2 nmol/L) produced significant decreases in LVESP (119 +/- 12 vs. 96 +/- 11 mm Hg, P < .05), arterial elastance, total systolic resistance (TSR) (0.11 +/- 0.04 vs. 0.07 +/- 0.03 mm Hg/ml/min, P < .05) and LVESWS (74.6 +/- 23.7 vs. 60.2 +/- 17.3 g/cm2, P < .05). Felodipine increased the slopes of the ESP-V relation (5.6 +/- 1.5 vs. 7.8 +/- 0.7 mm Hg/ml, P < .05), the dP/dtmax-EDV relation (51.4 +/- 6.1 vs. 85.3 +/- 10.1 mm Hg/ml sec, P < .05) and the stroke work-EDV relation (69.8 +/- 7.1 vs. 78.9 +/- 7.1 mm Hg, P < .05) and shifted all three relations to the left, indicating enhanced contractile performance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of left ventricular early diastolic performance by color tissue Doppler imaging of the mitral annulus

A noninvasive assessment of left ventricular (LV) diastolic performance by tissue Doppler imaging was performed in 56 patients (8 patients with atypical chest pain, 42 with coronary artery disease with a previous myocardial infarction, and 6 without a previous myocardial infarction) who underwent cardiac catheterization. Mitral annular velocity (MAV) during early ventricular diastole was obtained by M-mode color tissue Doppler imaging at the posterior corner of the mitral annulus. In each patient, the negative peak of the first derivative of LV pressure decay (peak -dP/dt) and a time constant of LV relaxation (tau) were calculated from the LV pressure waves obtained by a catheter-tip micromanometer. LV end-systolic volume index was measured from contrast left ventriculography. MAV during early diastole was significantly correlated with tau (r = -0.73, p <0.001), peak -dP/dt (r = 0.58, p <0.001), and LV end-systolic volume index (r = -0.63, p <0.001). On multivariate regression analysis with MAV during early diastole, tau and LV end-systolic volume index were selected as prime determinants (r = 0.80, p <0.001). These findings suggest that MAV during early diastole has a direct relation to LV elastic recoil as well as to LV relaxation. MAV during early diastole gives important information regarding LV behavior in late systole to early diastole where LV early diastolic performance is determined.     

Tension-frequency relationships in normal and cardiomyopathic dog and hamster myocardium

The objective of this study was to evaluate the tension-frequency relationship in normal and cardiomyopathic myocardium from one species with a negative or biphasic relationship, the hamster, and one with a positive relationship, the dog. Left ventricular papillary muscles from 100-day-old normal Syrian and cardiomyopathic (CHF-147) hamsters and right ventricular papillary muscles or trabeculae from normal mongrel dogs and dog with pacing-induced heart failure were used for the study. Stimulation frequency was varied from 1 to 90/min and isometric contractions recorded at each frequency prior to and after the addition of phenylephrine 10 microM. A tension-frequency relationship at varying extracellular calcium concentrations (1.25, 2.5 and 5.0 mM) was also constructed in normal hamster myocardium. Ryanodine 1.2 microM was added to a bath with normal hamster muscles and a force-frequency relationship constructed prior to and after adding phenylephrine 10 microM. A calcium dose-response curve in normal and cardiomyopathic dog myocardium was also constructed. Normal and cardiomyopathic hamster myocardium had a biphasic tension-frequency relationship with the increase in tension during the second phase being greater in normal v cardiomyopathic hamster myocardium (0.66 +/- 0.19 v 0.12 +/- 0.03 g/mm2, P < 0.05). The initial decrease in tension in response to increasing stimulation frequency was markedly attenuated in normal hamster myocardium by increasing extracellular calcium concentration. Developed tension was eliminated at lower stimulation rates by ryanodine such that when developed tension did occur, it increased with increasing stimulation rates. The addition of phenylephrine to hamster myocardium modified the tension-frequency relationship of both normal and cardiomyopathic dog myocardium and their response to phenylephrine were similar. In each case, tension increased progressively with increasing stimulation rate. Although the absolute increase in tension caused by increasing extracellular calcium was less in cardiomyopathic dog myocardium, the percent increase in tension and shortening was greater. We conclude that the tension-frequency relationship of normal and cardiomyopathic hamster myocardium are biphasic, with the initial negative phase being the result of limitations of sarcoplasmic reticulum calcium handling. Phenylephrine modifies this relationship to a uniphasic positive one, likely by its effects on both the sarcolemma and the sarcoplasmic reticulum. Also, the tension-frequency relationship of normal and cardiomyopathic dog myocardium are similar and unmodified by phenylephrine.     

Patterns of grief reaction after pregnancy loss

BACKGROUND: Different regions within the left ventricle are preferentially supplied by the left or right sympathetic system. In order to characterize different influences of left vs right sympathetic lateralization on LV function, haemodynamic effects of right and left stellate ganglion stimulations (RSGS and LSGS) as well as a right sympathetic block (RSB) were compared. METHODS: Seven alpha-chloralose anaesthetized open chest dogs were instrumented for measurement of LV pressure (tip manometers) and regional LV wall thickness (WT, sonomicrometry) in the antero-apical wall (AW, innervated by right stellate ganglion) and postero-basal wall (PW, left stellate ganglion). Timing of regional myocadial wall motion was evaluated by the phase of the first Fourier transform of the WT signals, LV asynchrony by the phase difference (phi) between both regions, and LV diastolic function by the time constant of isovolumic relaxation (tau). Measurements were performed before and after RSB (5 ml of lidocaine 1%); in 6 dogs of this group, RSGS and LSGS (4 V, 0.2 ms, 20 Hz) were performed before RSB. In order to investigate a regional inotropic stimulation without systemic effect, 6 additional dogs received intracoronary noradrenaline injections (NIC, 0.25 microgram) into the left circumflex artery perfused myocardium. RESULTS: LSGS and NIC led to an earlier PW-motion within the cardiac cycle (phase reduction by 40.0 +/- 15.0 degree (SEM) and 55.5 +/- 11.2 degrees) and RSGS induced an earlier AW-motion (by 33.7 +/- 15.2 degrees). After RSB, AW-motion was delayed (38.1 +/- 9.2 degrees). The consequence was an asynchronous wall motion pattern after all interventions (change in phi: LSGS-64.7 +/- 18.7 degrees, RSGS 41.1 +/- 15.7 degrees, NIC -74.5 +/- 17.4 degrees, RSB -52.6 +/- 14.6 degrees), and a prolonged relaxation (tau increase: RSGS 9.4 +/- 1.9, NIC 8.3 +/- 1.5, RSB 3.7 +/- 0.8 ms). CONCLUSION: Unilateral increases as well as decreases of sympathetic tone to the heart result in an asynchronous wall motion pattern and an impaired LV relaxation.     

Effects of partial left ventriculectomy on left ventricular performance in patients with nonischemic dilated cardiomyopathy

OBJECTIVES: This study sought to assess the effects of partial left ventriculectomy (PLV) on left ventricular (LV) performance in a series of consecutive patients with nonischemic dilated cardiomyopathy. BACKGROUND: Reduction of LV systolic function in patients with heart failure is associated with an increase of LV volume and alteration of its shape. Recently, PLV, a novel surgical procedure, was proposed as a treatment option to alter this process in patients with dilated cardiomyopathy. METHODS: We studied 19 patients with severely symptomatic nonischemic dilated cardiomyopathy, before and 13+/-3 days after surgery, and 12 controls. Single-plane left ventriculography with simultaneous measurements of femoral artery pressure was performed during right heart pacing. RESULTS: The LV end-diastolic and end-systolic volume indexes decreased after PLV (from 169 to 102 ml/m2, and from 127 to 60 ml/m2, respectively, p < 0.0001 for both). Despite a decrease in LV mass index (from 162 to 137 g/m2, p < 0.0001), there was a significant decrease in LV circumferential end-systolic and end-diastolic stresses (from 277 to 159 g/cm2, p < 0.0001 and from 79 to 39 g/cm2, p = 0.0014, respectively). Ejection fraction improved (from 24% to 41%, p < 0.0001); the stroke work index remained unchanged. CONCLUSIONS: The PLV improves LV performance by a dramatic reduction of ventricular end-systolic and end-diastolic stresses. Further studies are needed to assess whether this effect is sustained during long-term follow-up and to define the role of PLV in the treatment of patients with dilated cardiomyopathy.     

Development of decompensated dilated cardiomyopathy is associated with decreased gene expression and activity of the milrinone-sensitive cAMP phosphodiesterase PDE3A

BACKGROUND: Phosphodiesterase III (PDE3) inhibitors are inotropic agents used to treat congestive heart failure (CHF) and are less effective in patients with severe CHF. Little is known about relative changes in PDE3 activity or gene expression during the evolution of cardiomyopathy. METHODS AND RESULTS: In the present study, we evaluated temporal changes in PDE3A gene expression before and after pacing-induced CHF in nine mongrel dogs. Three weeks of left ventricular (LV) pacing produced LV end-diastolic pressures of 15+/-1.7 mm Hg, whereas overt CHF at 4 to 5 weeks was associated with LV end-diastolic pressures of 24+/-1.7 mm Hg; prepacing values were 6.6+/-0.6 mm Hg. Total RNA isolated from LV tissues was analyzed on Northern blots; 10 unpaced normal hearts served as tissue controls. Signals for PDE3A mRNAs (7, 8, and 10 kb) or PDE4D (7.6 kb) were normalized against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or ribosomal 18S RNA. Before the onset of CHF, PDE3A/GAPDH ratios were not different between the control and 3-week paced groups. In contrast, all PDE3A/GAPDH ratios were selectively reduced by 52%, and PDE3A/18S was reduced by 70% (P<.05) in CHF; PDE4D/GAPDH (or 18S) was unchanged. LV tissues from four control and four CHF dogs were also processed to isolate cytosolic and microsomal membrane protein for cAMP PDE3 activity assays. CHF was associated with a significant 54% reduction (P<.05) in microsomal but not cytosolic PDE3 activity. CONCLUSIONS: Selective downregulation of PDE3A may account in part for the ineffectiveness of milrinone in the treatment of severe CHF.     

Roles of Rho-associated kinase in cytokinesis; mutations in Rho-associated kinase phosphorylation sites impair cytokinetic segregation of glial filaments

The effects of sevoflurane on myocardial contraction and relaxation are poorly understood. Therefore, we studied the effects of equianaesthetic concentrations (0.5, 1, 1.5, 2 and 2.5 MAC) of sevoflurane, isoflurane and halothane on inotropic and lusitropic (myocardial relaxation) variables, and post-rest potentiation in rat left ventricular papillary muscles in vitro. Sevoflurane and isoflurane caused comparable concentration-dependent negative inotropic effects which were significantly lower than those induced by halothane (P < 0.05). Sevoflurane and isoflurane did not modify lusitropic variables under low or high load, whereas halothane showed a negative lusitropic effect at high concentrations. Halothane suppressed post-rest potentiation, whereas isoflurane and sevoflurane did not. Post-rest recovery was unaffected by halothane, isoflurane or sevoflurane at any concentration. Thus in rat myocardium, sevoflurane and isoflurane caused comparable negative inotropic effects, had no significant lusitropic effects and did not alter post-rest potentiation, suggesting that they did not significantly modify the functions of the sarcoplasmic reticulum.     

Preoperative assessment of esophageal pathology

Sodium pentobarbital (PB), 30 mg/kg, iv, was administered to 30 conscious dogs instrumented for measurement of cardiac output and regional blood flow distribution, left ventricular (LV) diameter, LV pressure, dP/dt, and dD/dt, i.e., velocity of myocardial fiber shortening. Ventilation was controlled during anesthesia to maintain arterial blood gases at control values for conscious dogs. The anesthetic produced an initial transient, peripheral vasodilation but the steady state effects 15-30 minutes later were characterized by slight reductions in mesenteric flow and cardiac output and increases in mesenteric and systemic resistances, whereas iliac and renal resistances were not significantly different from control. When heart rate rose, PB increased end-systolic diameter and decreased coronary resistance, LV end-diastolic diameter, dP/dt/P (42%), and shortening velocity (36%). When heart rate was controlled, PB still increased end-systolic diameter and decreased shortening velocity and dP/dt/P, as occurred during spontaneous rhythm, but end-diastolic diameter rose instead of falling and coronary resistance did not change. After recovery from bilateral cervical section of both carotid sinus and aortic nerves, PB failed to elicit tachycardia. Thus, PB affects systemic and regional hemodynamics only slightly, but depresses the myocardium markedly. The tachycardia associated with PB anesthesia in intact, trained dogs appears not to be only vagolytic, as previously thought, but is predominantly mediated through the arterial baroreceptor reflex.     

Cardiac sympathetic stimulation increases cardiac contractility but decreases contractile efficiency in canine hearts in vivo

The effect of cardiac sympathetic stimulation on cardiac contractile efficiency was studied in dogs. In 19 anesthetized and open-chest dogs, left ventricular (LV) pressure, LV volume, coronary blood flow and coronary venous oxygen saturation were measured simultaneously. The LV end-systolic pressure volume relations (ESPVR) and the relation between myocardial oxygen consumption (VO2)-pressure volume area (PVA) were obtained during a transient occlusion of the inferior vena cava before and after sympathetic stimulation (9V, 6 Hz, 40 sec) both with and without 50 mg/kg of 2,3-butanedione monoxime (BDM). Without BDM, sympathetic stimulation increased the slope of ESPVR by 62% (p<0.05), the slope of the VO2-PVA line by 19% (p<0.05) and the y-axis intercept of the VO2-PVA by 65% (p<0.05). With BDM, the increase in the slope of the VO2-PVA line became insignificant although other responses were similarly preserved. These data imply that cardiac sympathetic stimulation decreases cardiac contractile efficiency through mechanisms by which norepinephrine-induced beta-adrenergic activation enhances myosin ATPase-operating ATP hydrolysis in crossbridge formation.     

A comparison of cathepsin B processing and distribution during neuronal death in rats following global ischemia or decapitation necrosis

OBJECTIVE: The relationship between the left ventricular (LV) relaxation time constant and early diastolic filling is not fully defined. This study provides additional evidence that LV isovolumic pressure fall in the normal intact heart in response to certain interventions is not adequately described by a model of monoexponential decay and that its relationship to filling is complex. METHODS AND RESULTS: To gain further insight into the relationship between LV relaxation and early rapid filling we measured LV isovolumic relaxation rate, peak early filling velocity (E), LV volumes, and transmitral pressures at baseline and in the first postextrasystolic beat after a short-coupled extrasystole in 9 anesthetized dogs. Postextrasystolic isovolumic relaxation rate was slowed as measured by 3 commonly used time constants, while E was increased 32%. LV contractility and peak pressure were also increased, while LV end-systolic volume was decreased. LV minimum pressure was deceased, while the early diastolic transmitral pressure gradient was increased. Although all relaxation time constants measured over the entire isovolumic relaxation phase indicated slowed relaxation, direct measurement of isovolumic relaxation time indicated no change in relaxation rate. Calculation of the time constants and direct measurement of isovolumic relaxation time during early isovolumic pressure decay indicated slowed postextrasystolic pressure decay rate compared with baseline, while calculation of time constants and direct measurement of isovolumic relaxation time during late isovolumic relaxation indicated augmented postextrasystolic pressure decay rate versus baseline. CONCLUSIONS: This non-exponential behavior of LV isovolumic pressure decay in postextrasystolic beats after short-coupled extrasystoles provides further evidence that the relationship that exists between ventricular relaxation and early filling is not simple. The results are interpreted in terms of current theoretical formulations that attribute control of myocardial relaxation to the interaction between inactivation-dependent and load-dependent mechanisms.     

Effects of intrapleural pressure changes on canine left ventricular function

Left ventricular diameter, pressure, and dP/dt, as well as aortic and intrapleural pressures, were recorded simultaneously from 10 acute anethetized mongrel dogs. Normal inspiration produced a significant decrease in end-diastolic diameter (46.9 +/- 1.2 to 43.1 +/- 1.0 mm) and end-systolic diameter (35.5 +/- 1.4 to 34.2 +/- 1.7 mm), reducing stroke diameter 2.5 mm. Airway occlusion (greater than or equal to 60%) produced a reduction in the decrease of end-diastolic diameter seen with normal inspiration and, to a lesser degree, in end-systolic diameter. Because only acute airway occlusion greater than or equal to 80% produced a significant increase in left ventricular afterload, the authors conclude that normal spontaneous inspiration results in a decrease in left ventricular preload due to pooling of blood in the pulmonary vasculature. The data suggest that this decrease in left ventricular preload is the predominant mechanism responsible for the inspiratory decrease in left ventricular stroke volume.     

Clinical comparison of isoflurance and halothane anesthetics

Isoflurane and halothane were compared in two similar groups of 100 patients each. Isoflurane compared favorably with halothane in producing adequate anesthesia in all our patients. Induction period was a little stormy when there was direct induction with isoflurane. Maintenance was excellent and recovery was good. Mean concentration necessary to induce anesthesia was 3.07% with isoflurane and 2.56% with halothane. Mean maintenance with isoflurane was 1.39%, compared to 1.40% with halothane. Less curare was required for relaxation when used with isoflurane than with halothane. This difference was not seen with pancuronium (Pavulon). Patient recovery was faster with isoflurane than with halothane. Incidence of delirium and shivering in the recovery period was similar for both agents. Incidence of nausea and vomiting was greater with isoflurane. Other clinical and biochemical postoperative comparisons did not show any significant differences between the two agents.     

Enflurane and isoflurane, but not halothane, protect against myocardial reperfusion injury after cardioplegic arrest with HTK solution in the isolated rat heart

To investigate the effects of halothane, enflurane, and isoflurane on myocardial reperfusion injury after ischemic protection by cardioplegic arrest, isolated perfused rat hearts were arrested by infusion of cold HTK cardioplegic solution containing 0.015 mmol/L Ca2+ and underwent 30 min of ischemia and a subsequent 60 min of reperfusion. Left ventricular (LV) developed pressure and creatine kinase (CK) release were measured as variables of myocardial function and cellular injury, respectively. In the treatment groups (each n = 9), anesthetics were given during the first 30 min of reperfusion in a concentration equivalent to 1.5 minimum alveolar anesthetic concentration of the rat. Nine hearts underwent the protocol without anesthetics (controls). Seven hearts underwent ischemia and reperfusion without cardioplegia and anesthetics. In a second series of experiments, halothane was tested after cardioplegic arrest with a modified HTK solution containing 0.15 mmol/L Ca2+ to investigate the influence of calcium content on protective actions against reperfusion injury by halothane. LV developed pressure recovered to 59%+/-5% of baseline in controls. In the experiments with HTK solution, isoflurane and enflurane further improved functional recovery to 84% of baseline (P < 0.05), whereas halothane-treated hearts showed a functional recovery similar to that of controls. CK release was significantly reduced during early reperfusion by isoflurane and enflurane, but not by halothane. After cardioplegic arrest with the Ca2+-adjusted HTK solution, halothane significantly reduced CK release but did not further improve myocardial function. Isoflurane and enflurane given during the early reperfusion period after ischemic protection by cardioplegia offer additional protection against myocardial reperfusion injury. The protective actions of halothane depended on the calcium content of the cardioplegic solution. IMPLICATIONS: Enflurane and isoflurane administered in concentrations equivalent to 1.5 minimum alveolar anesthetic concentration in rats during early reperfusion offer additional protection against myocardial reperfusion injury even after prior cardioplegic protection. Protective effects of halothane solely against cellular injury were observed only when cardioplegia contained a higher calcium concentration.     

Verification of a free vascularized nerve graft model in the rat with application to the peripheral nerve allograft

The effects of moderate systemic hypotension with halothane (HALO) and isoflurane (ISO) on regional myocardial function and perfusion were studied in dogs with chronic coronary artery occlusion. Vasodilator reserve in collateral-dependent (CD) myocardium was quantified in conscious animals by using a dipyridamole challenge test. Blood flow was distributed homogeneously to the normal (Nl) and CD myocardium at rest, but subendocardial perfusion increased only in the Nl area after dipyridamole. HALO and ISO were administered at doses that reduced diastolic arterial pressure to 50 mm Hg. End-tidal concentrations were 1.3 +/- 0.2 vol% for HALO (1.5 minimum alveolar anesthetic concentration) and 1.8 +/- 0.2 vol% for ISO (1.4 minimum alveolar anesthetic concentration), respectively. Global and regional hemodynamic depression were more pronounced with HALO. Systolic wall-thickening fraction decreased both in the Nl (-37%) and CD area (-27%). Myocardial blood flow to Nl and CD myocardium decreased to a comparable extent. ISO predominantly decreased systemic vascular resistance and, when compared to HALO, decreased systolic wall-thickening fraction less in both the Nl (-19%) and CD area (-18%). In addition, regional myocardial perfusion to both Nl and CD myocardium remained virtually unaltered from conscious control conditions. Despite reductions of diastolic blood pressure to 50 mm Hg, neither HALO nor ISO induced ischemic dysfunction in myocardium with diminished vasodilator reserve. Both anesthetics preserved intercoronary as well as transmural blood flow distribution. During HALO, myocardial perfusion was less both in Nl and CD myocardium due to a more pronounced metabolic depression. We conclude that moderate hypotensive doses of ISO and HALO preserve regional myocardial function of collateral-dependent myocardium in dogs with single vessel occlusion and enhanced collateral circulation.