Biomedical subjects

F G Spinale

Publications and source records attributed to F G Spinale.

At least 91 records · Page 5Linked to original sources

PubMed1997

Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure: I. Effects on left ventricular performance and neurohormonal systems.

BACKGROUND: The goal of this study was to determine the effects of ACE inhibition (ACEI) alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade on LV function, systemic hemodynamics, and neurohormonal system activity in a model of congestive heart failure (CHF). METHODS AND RESULTS: Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) ACEI (benazeprilat, 0.187 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (3) AT1 Ang II receptor blockade (valsartan, 3 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (4) ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg x kg(-1) d(-1)) and rapid pacing (n=9), and (5) sham controls (n=10). In the pacing group, LV fractional shortening (LVFS) fell (13.4+/-1.4% versus 39.1+/-1.0%) and end-diastolic dimension (LVEDD) increased (5.61+/-0.11 versus 3.45+/-0.07 cm) compared with control (P<.05). With AT1 Ang II blockade and rapid pacing, LVEDD and LVFS were unchanged from pacing-only values. ACEI reduced LVEDD (4.95+/-0.11 cm) and increased LVFS (20.9+/-1.9%) from pacing-only values (P<.05). ACEI and AT1 Ang II blockade reduced LVEDD (4.68+/-0.07 cm) and increased LVFS (25.2+/-0.9%) from pacing only (P<.05). Plasma norepinephrine and endothelin increased by more than fivefold with chronic pacing and remained elevated with AT1 Ang II blockade. Plasma norepinephrine was reduced from pacing-only values by more than twofold in the ACEI group and the combination group. ACEI and AT1 Ang II receptor blockade reduced plasma endothelin levels by >50% from rapid-pacing values. CONCLUSIONS: These findings suggest that the effects of ACEI in the setting of CHF are not solely due to modulation of Ang II levels but rather to alternative enzymatic pathways and that combined ACEI and AT1 Ang II receptor blockade may provide unique benefits for LV pump function and neurohormonal systems in the setting of CHF.

Aldosterone↗

PubMed1997

Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure: II. Effects on myocyte contractile processes.

BACKGROUND: The goal of this study was to determine the effects of ACE inhibition alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade in a model of congestive heart failure (CHF) on isolated LV myocyte function and fundamental components of the excitation-contraction coupling process. METHODS AND RESULTS: Pigs were randomly assigned to one of five groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant ACEI (benazeprilat, 0.187 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (3) concomitant AT1 Ang II receptor blockade (valsartan, 3 mg/kg/d) and rapid pacing (n=9), (4) concomitant ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg x kg(-1) x d(-1)) and rapid pacing (n=9), and (5) sham controls (n=10). LV myocyte shortening velocity was reduced with chronic rapid pacing compared with control (27.2+/-0.6 versus 58.6+/-1.2 microm/s, P<.05) and remained reduced with AT1 Ang II receptor blockade and rapid pacing (28.0+/-0.5 microm/s, P<.05). Myocyte shortening velocity increased with ACEI or combination treatment compared with rapid pacing only (36.9+/-0.7 and 42.3+/-0.8 microm/s, respectively, P<.05). Myocyte beta-adrenergic response was reduced by >50% in both the rapid pacing group and the AT1 Ang II blockade group and improved by 25% with ACEI and increased by 54% with combined treatment. Both L-type Ca2+ channel density and the relative abundance of sarcoplasmic reticulum Ca2+ ATPase density were reduced with rapid pacing and returned to control levels in the combined ACEI and AT1 Ang II blockade group. CONCLUSIONS: The unique findings of this study were twofold. First, basic defects in specific components of the myocyte excitation-contraction coupling process that occur with CHF are reversible. Second, combined ACEI and AT1 Ang II blockade may provide unique benefits on myocyte contractile processes in the setting of CHF.

Analysis of Variance↗

PubMed1997

Fate of gelatin-resorcinol-formaldehyde/glutaraldeyde adhesive on femoral vessel morphology.

Several clinical reports have demonstrated that gelatin-resorcinol-formaldehyde/glutaraldehyde (GRFG) glue can be useful in the repair of acute aortic dissection; however, the cellular and extracellular events that follow GRFG application, as well as the mechanisms responsible for the long-term strength and adhesive properties of GRFG, remain unclear. Accordingly, the present study examined the long-term effects of GRFG adhesive application on femoral vessel extracellular structure and composition. The left and right femoral artery and vein were sterilely exposed in adult rats, and GRFG (2 mL) was applied between and around one pair of vessels. An equivalent amount of sterile saline was applied to the contralateral vessels to serve as an intrinsic control. At either 1 (n = 6) or 2 (n = 6) months postoperatively, the lower extremities were perfusion fixed and harvested to preserve the native anatomy and cytoarchitecture of the femoral region. Gross examination of the specimens revealed no evidence of necrosis or wound breakdown. Tissue blocks (4 microm) were then sectioned perpendicular to the treated vessel region and subjected to histomorphometric analysis using computer-assisted microscopy. The perivascular capsule area, relative content of fibrillar collagen, and number of nucleated cells within the interstitial space were computed. At 1 and 2 months following the application of GRFG adhesive, perivascular capsular size increased by 42 and 221%, respectively. Perivascular interstitial collagen content increased by 21% at 1 month and by 50% at 2 months. The nucleated cell number increased by 107% at 1 month and by 166% at 2 months. This cellular infiltrate appeared to be of fibroblastic morphology. Thus, a potential contributory mechanism to the long-term strength and adhesive capacities of GRFG adhesive may be extracellular remodeling and not the intrinsic properties of GRFG glue itself.

Animals↗

PubMed1997

Concomitant endothelin receptor subtype-A blockade during the progression of pacing-induced congestive heart failure in rabbits. Beneficial effects on left ventricular and myocyte function.

BACKGROUND: Plasma levels of endothelin-1 (ET-1) are increased in patients and animals with severe congestive heart failure (CHF). It remains unknown, however, whether ET-1 plays a direct and contributory role in the progression of CHF. Accordingly, the present project tested the hypothesis that chronic blockade of the ETA receptor would have direct and beneficial effects on left ventricular (LV) and myocyte function in a model of CHF. METHODS AND RESULTS: Global LV and isolated myocyte function were examined in rabbits in the following groups (12 per group): chronic rapid ventricular pacing (RVP; 400 bpm, 3 weeks), RVP and concomitant administration of the selective ETA receptor antagonist (PD 156707 24 mg/d), and sham controls. LV fractional shortening decreased after RVP (17 +/- 5 versus 42 +/- 3%) and end-diastolic dimension increased (2.36 +/- 0.44 versus 1.24 +/- 0.18 cm) compared with controls (P < .05). With RVP plus ETA blockade, LV fractional shortening was increased (33 +/- 6%) and end-diastolic dimension decreased (2.02 +/- 0.30 cm) compared with RVP-only values (P < .05). Plasma norepinephrine and endothelin increased twofold in the RVP group. In the RVP plus ETA blockade group, plasma endothelin increased threefold compared with RVP values. Isolated myocyte shortening velocity declined after RVP (42 +/- 13 versus 72 +/- 10 microns/s, P < .05) compared with controls but was normalized with RVP plus ETA blockade (77 +/- 16 microns/s). Myocyte inotropic response to extracellular Ca2+, beta-receptor stimulation, and ET-1 was reduced in the RVP group and returned to control levels with RVP and concomitant ETA receptor blockade. CONCLUSIONS: The results from this study suggest that chronically elevated ET-1 levels and subsequent activation of the ETA receptor play a direct and contributory role in the progression of the CHF process. Thus, specific ETA receptor blockade may provide a new and useful therapeutic modality in the setting of CHF.

Animals↗

PubMed1997

Effects of chronic angiotensin-converting enzyme inhibition on left ventricular and myocyte structure and function during recovery from chronic rapid pacing.

LV and myocyte function and angiotensin converting enzyme (ACE) activity with ACE inhibitor (ACEI) treatment were examined in four groups of dogs (n = 6 each): (1) control; (2) with 4 weeks of recovery from chronic rapid pacing (REC: 216 beats/min), (3) ACEI for the first 14 days of REC (ACEI--14), and (4) ACEI for 28 days of REC (ACEI--28). Three additional control dogs were administered ACEI for 28 days. LV mass increased with REC compared to control (146 +/- 6 v 92 +/- 3 g, P < 0.05), was unaffected with ACEI--14, and was decreased with ACEI--28 compared to REC (111 +/- 8 g, P < 0.05). Myocyte function was decreased in REC compared to controls (43 +/- 3 v 63 +/- 3 microns/s, P < 0.05) and was similarly reduced with ACEI--14. However, with ACEI--28, myocyte shortening velocity was increased compared to REC (56 +/- 1 microns/s, P < 0.05). Myocyte beta-adrenergic response was decreased with REC and ACEI--14 compared to controls (53 +/- 9 and 57 +/- 14, respectively v 127 +/- 14 microns/s, P < 0.05). ACEI--28 resulted in a normalization of myocyte beta-adrenergic responsiveness (108 +/- 3 microns/s). LV myocardial ACE activity increased in REC compared to control (5.82 +/- 0.21 v 3.51 +/- 0.15 nmol/mg/min, P < 0.05). With ACEI--14 or ACEI--28, myocardial ACE activity was decreased compared to REC (4.16 +/- 0.06 and 4.08 +/- 0.23 nmol/mg/min; P < 0.05). In control dogs administered ACEI, there were no differences in any of these parameters compared to controls. The unique findings in this study were: (1) effects of ACEI treatment in this model of LV hypertrophy were time dependent with respect to LV mass and LV and myocyte function; and (2) the effect of ACEI treatment on the degree of LV hypertrophy appears to not be solely due modulation of myocardial ACE activity.

Adrenergic beta-Agonists↗

PubMed1997

Left ventricular regional myocyte contractility in normal and heart failure states.

Fundamental determinants of left ventricular (LV) pump performance are preload, afterload and myocyte contractility. Regional variability in LV end systolic wall stress, an important index of LV afterload, has been well defined in both control and congestive heart failure (CHF) states. The goal of this study was to examine end systolic wall stress and myocyte contractile function in three circumferential regions of the LV in both control and CHF states. Accordingly, LV end systolic wall stress and myocyte velocity of shortening were measured from the basal, mid and apical regions in control pigs (n=5) and following the induction of pacing-induced CHF (3 weeks, 240 beats/min, n=5). LV mid wall, circumferential, end systolic wall stress decreased from base to apex in both control (35+/-7 v 16+/-4 g/cm2, P<0.05) and CHF (155+/-23 v 92+/-24 g/cm2, P<0.05) states. In the CHF group, LV end systolic wall stress was elevated by 300% compared to control values in all regions. LV myocyte velocity of shortening was equivalent in the basal and mid regions of control myocytes (52+/-2 v 57+/-2 m/s), and was higher in the apical region (63+/-3 microm/s, P<0.05). In the CHF group, LV myocyte velocity of shortening was reduced by 45% compared to controls with no regional variation. beta-adrenergic stimulation increased myocyte velocity in both the control and CHF groups, however, regional variation was observed only in the CHF group. These unique results demonstrated that minimal regional variations in myocyte contractile function exist in both control and congestive heart failure states, and does not necessarily parallel patterns of regional LV end systolic wall stress.

Animals↗

PubMed1997

Myocardial electrophysiological properties in the presence of an AT1 angiotensin II receptor antagonist.

INTRODUCTION: Blockade of the AT1 angiotensin II (Ang II) receptor has been shown to provide anti-hypertensive effects. However, whether AT1 Ang II receptor antagonists influence myocardial electrophysiological properties remains unclear. METHODS AND RESULTS: Accordingly, atrial and ventricular myocardial electrophysiological properties were examined in adult rat (n = 13) and guinea pig (n = 9) myocardial preparations in the presence of the specific AT1 Ang II receptor antagonist, valsartan (CGP 48933; 0.5, 5, or 500 mumol/L). These concentrations reflect up to 100 fold higher drug concentrations than those observed in clinical trials. Transmembrane potential data were recorded using standard microelectrode techniques at baseline and following superfusion with valsartan. The lower concentrations of valsartan (0.5 and 5 mumol/L) had minimal effects on myocardial electrophysiology. In the presence of 500 mumol/L of valsartan, resting membrane potential increased from baseline in both rat (-82.3 +/- 4.1 vs -76.8 +/- 5.8 mV, p < 0.05) and guinea pig (-81.6 +/- 2.9 vs -76.9 +/- 2.0 mV, p < 0.05) atrial myocardium. Action potential duration at 90% repolarization was increased in guinea pig atrial (91.7 +/- 1.4 vs 80.0 +/- 5.6 ms, p < 0.05) and ventricular (131.1 +/- 8.1 vs 118.7 +/- 8.3 ms, p < 0.05) myocardium following exposure to 500 mumol/L of valsartan. In a separate series of experiments, Ang II (1.0 mumol/L) had no effect on atrial or ventricular action potential characteristics in either species. CONCLUSION: Thus, the effects of valsartan, which were observed only at concentrations 100 fold higher than those reported in clinical trials, may be due to non-specific drug interactions with the myocyte sarcolemma.

Angiotensin Receptor Antagonists↗

PubMed1997

The relation between changes in myocyte orientation and contractile function with electrical field stimulation.

The cardiac myocyte is the fundamental contractile unit of the heart, and therefore recent studies have examined myocyte function through electrical field stimulation. However, the relation between changes in electrical field orientation and myocyte contractile function remains unclear. Accordingly, the goal of the present study was to measure myocyte contractile function with known changes in myocyte orientation with respect to the electrodes. Isolated left ventricular porcine myocytes (n = 32) were field stimulated (0.5 - 1.5 Hz, 5 ms, double contraction threshold) in a thermostatically controlled chamber. Myocyte velocity of shortening was measured by high speed video microscopy. Myocyte position was altered and quantified with respect to the electrodes. When myocyte position approached alignment with the electrodes, contractile activity ceased. Contractile activity resumed when the myocyte moved greater than 25 degrees from the parallel position. When contractions could be successfully elicited, the velocity of shortening was 48+/-15 microm/s and did not differ at any orientation. These results suggest that angular orientation should be carefully considered when evaluating the contractile performance of electrically stimulated myocytes.

Animals↗

PubMed1997

Protective effects of adenosine on myocyte contractility during cardioplegic arrest.

BACKGROUND: Adenosine delivery to the left ventricular myocardium has been demonstrated to provide protective effects in the setting of ischemia and reperfusion. However, whether adenosine has direct protective effects on isolated myocytes in the setting of cardioplegic arrest was unclear. METHODS: Isolated porcine left ventricular myocytes were assigned to one of the following treatment groups: (1) cardioplegia: 24 mEq/L K+, 4 degrees C for 2 hours followed by rewarming (cell media, 37 degrees C; n = 29); (2) cardioplegia augmented with adenosine (1 to 200 micromol/L) followed by rewarming (n = 98); and (3) normothermic control (cell media, 37 degrees C, 2 hours; n = 175). Myocyte contractility was measured by computer-aided videomicroscopy. RESULTS: Cardioplegic arrest and rewarming reduced myocyte shortening velocity compared with normothermic control (25.3 +/- 2.5 microm/s versus 50.9 +/- 1.4 microm/s, p < 0.05). Adenosine-augmented cardioplegic arrest improved myocyte contractility with rewarming in a concentration-dependent fashion. For example, cardioplegia augmented with 10 micromol/L adenosine improved myocyte shortening velocity by 33% (33.6 +/- 3.0 microm/s versus 25.3 +/- 2.5 microm/s, p < 0.05), whereas 200 micromol/L adenosine improved shortening velocity by 97% (49.9 +/- 3.4 microm/s vs 25.3 +/- 2.5 microm/s, p < 0.05) compared with conventional cardioplegia. CONCLUSIONS: This study demonstrated concentration-dependent protective effects of adenosine-augmented cardioplegia on myocyte contractile function with subsequent reperfusion and rewarming. These results suggest that stimulation of putative myocyte adenosine receptors may provide enhanced protective effects on myocyte contractile processes during cardioplegic arrest.

Adenosine↗

PubMed1997

Protein kinase C activation before cardioplegic arrest: beneficial effects on myocyte contractility.

OBJECTIVE: A potential intracellular mechanism for the protective effects of myocardial preconditioning is the activation of protein kinase C. The present study tested the hypothesis that a brief period of protein kinase C activation before cardioplegic arrest would provide protective effects on myocyte contractility with subsequent reperfusion and rewarming. METHODS: Left ventricular porcine myocytes were assigned to the following treatments: (1) Protein kinase C/cardioplegia: Protein kinase C activation in myocytes (n = 39) for 3 minutes with a phorbol ester (10(-9) mol/L of phorbol 12-myristate 13-acetate) in oxygenated, normothermic (37 degrees C) cell media. Protein kinase C activation was followed by 2 hours of cardioplegic arrest (K+, 24 mEq/L; HCO3-, 30 mEq/L; 4 degrees C) and a 5-minute reperfusion period (37 degrees C media). (2) Cardioplegia: Myocytes (n = 31), 2 hours of cardioplegic arrest, and a 5-minute reperfusion and rewarming period. Myocyte contractility was measured by means of high-speed videomicroscopy. For comparison purposes, contractile function was examined in myocytes (n = 70) under normothermic control conditions. RESULTS: Myocyte shortening velocity was reduced after cardioplegic arrest when compared with normothermic values (22.3 +/- 1.6 vs 48.8 +/- 2.0 microm/sec, p < 0.0001). Protein kinase C activation before cardioplegic arrest normalized myocyte shortening velocity (48.8 +/- 2.5 microm/sec). Co-incubation with phorbol 12-myristate 13-acetate and chelerythrine (10(-6) mol/L), an inhibitor of protein kinase C, before cardioplegic arrest abolished the protective effects of phorbol 12-myristate 13-acetate pretreatment. CONCLUSION: These results suggest that an endogenous means of providing improved myocardial protection during prolonged cardioplegic arrest can be achieved through a brief period of protein kinase C activation.

Animals↗

PubMed1997

Differential effects of novel protamine variants on myocyte contractile function with left ventricular failure.

BACKGROUND: Protamine administration can cause left ventricular (LV) dysfunction, which may have clinical significance in the setting of congestive heart failure (CHF). Protamine variants have recently been constructed with heparin reversal capacity similar to protamine. The purpose of this study was to examine the potential differential effects of these protamine variants on isolated myocyte contractile function in normal myocytes and in myocytes after the development of CHF. METHODS: Contractile function was measured by means of computer-aided videomicroscopy in myocytes from five normal pigs and five pigs with CHF induced by rapid pacing (240 beats/min for 3 weeks). Myocyte contractility was examined in the presence of 40 micrograms/ml native protamine or one of three protamine variants: (1) reduced charge (+18) and lysine substituted for arginine; (2) lysine-substituted variant with glutamic acid substituted for the initial proline; or (3) arginine-rich peptide with a terminal arginine-glycine-aspartic acid (RGD) amino acid sequence. RESULTS: In the presence of native protamine, myocyte percent shortening fell from baseline in both the normal (2.86 +/- 0.15 versus 4.58 +/- 0.08, p < 0.05) and the CHF groups (1.01 +/- 0.06 versus 2.07 +/- 0.05, p < 0.05). With both of the lysine-substituted protamine variants, percent shortening fell from baseline in the normal group (3.42 +/- 0.20 for arginine and 3.74 +/- 0.20 for glutamic acid versus 4.58 +/- 0.08, p < 0.05), and was unchanged in the CHF group (1.94 +/- 0.13 versus 2.07 +/- 0.05, p = 0.34 for arginine; and 1.96 +/- 0.10 versus 2.07 +/- 0.05, p = 0.31, for glutamic acid). However, with the arginine/RGD variant, percent shortening fell from baseline in both the normal (2.86 +/- 0.23 versus 4.58 +/- 0.08, p < 0.05) and the CHF groups (1.32 +/- 0.10 versus 2.07 +/- 0.05, p < 0.05). CONCLUSIONS: Specific changes in the primary and secondary structures of protamine had different effects on myocyte contractile function. Furthermore, the negative effects of lysine-substituted protamine variants on myocyte contractility were less pronounced in both CHF and normal myocytes. Thus protamine variants may be of clinical use, particularly in the setting of preexisting LV dysfunction.

Animals↗

PubMed1997

Pulmonary hemodynamics and endothelin levels in pacing-induced heart failure: during rest and exercise.

Elevated plasma levels of endothelin (ET) have been reported to accompany the development of heart failure (HF), and therefore, this potent vasoconstrictive peptide has been postulated to contribute to the altered pulmonary hemodynamics that occur in this disease process. The overall goal of this study was to examine more carefully the relationship between ET levels in the pulmonary system and pulmonary hemodynamics in the normal and HF states, during both rest and exercise. This study used a porcine model of chronic rapid pacing that has been shown in previous studies to produce left ventricular dysfunction and neurohormonal system activation consistent with the syndrome of HF. Pigs (n = 10) were chronically instrumented to measure pulmonary and systemic hemodynamics, parenchymal flow, and ET content and to obtain blood samples from the pulmonary circuit in the conscious state. Measurements were performed in the normal control state and again following the development of pacing-induced HF (240 beats/min per 21 days), both at rest and during treadmill exercise (3 mph, 15 degrees incline, 12 minutes). With HF, under ambient resting conditions, a threefold increase in pulmonary plasma ET occurred and was accompanied by a fivefold increase in pulmonary vascular resistance. During treadmill exercise, pulmonary plasma ET and pulmonary vascular resistance remained elevated in the HF group when compared with the normal state and were associated with a sixfold decrease in pulmonary parenchymal flow. Pulmonary parenchymal ET content was increased with HF when compared with values for normal control subjects (8.5 +/- 0.6 vs 5.6 +/- 0.8 fmol ET/mg protein, P < .05). Thus, the findings of this study suggest that in this model of HF, increased ET within the pulmonary circuit contributed to abnormalities in resistive properties and parenchymal flow.

Animals↗

PubMed1997

Negative and selective effects of propofol on isolated swine myocyte contractile function in pacing-induced congestive heart failure.

BACKGROUND: Although propofol (2-6 di-isopropylphenol) is commonly used to induce and maintain anesthesia and sedation for surgery, systematic hypotension and reduced cardiac output can occur in patients with or without intrinsic cardiac disease. The effect of propofol on myocyte contractility after the development of congestive heart failure (CHF) remains unknown. This study tested the hypothesis that propofol would have direct effects on myocyte contractile function in both healthy and CHF cardiac myocyte preparations. METHODS: Isolated left ventricular (LV) myocyte contractile function (shortening velocity, micron/s) was examined in myocytes from five control pigs and in five pigs with pacing-induced CHF (240 beats/min, for 3 weeks) in the presence of propofol concentrations ranging from 1-6 micrograms/ml. In addition, myocyte contractility in response to beta-adrenergic receptor stimulation (isoproterenol, 10-50 nM) in the presence of propofol (3 micrograms/ml) was examined. RESULTS: Three weeks of pacing caused LV dysfunction consistent with CHF as evidenced by increased LV end-diastolic diameter (control 3.3 +/- 0.1 cm vs. CHF 5.6 +/- 0.2 cm; P < 0.05) and reduced LV fractional shortening (control 34 +/- 3% vs. CHF 12 +/- 2%, P < 0.05). Propofol (6 micrograms/ml) caused a concentration-dependent negative effect on velocity of shortening from baseline in both control (67 +/- 2 microns/s vs. 27 +/- 3 microns/s; P < 0.05) and CHF myocytes (29 +/- 1 microns/s vs. 15 +/- 1 microns/s; P < 0.05). Importantly, CHF myocytes were more sensitive than control myocytes to the negative effects of propofol on velocity of shortening at the lower concentration (1 microgram/ml). beta-adrenergic responsiveness was reduced by propofol (3 micrograms/ml) in control myocytes only. CONCLUSIONS: Propofol has a direct and negative effect on basal myocyte contractile processes in the setting of CHF, which is more pronounced than that on healthy myocytes at reduced propofol concentrations.

Adrenergic beta-Agonists↗

PubMed1997

Angiotensin II subtype-1 receptor blockade during the development of left ventricular hypertrophy in dogs: effects on ventricular and myocyte function.

Inhibition of the angiotensin-converting enzyme (ACE) in developing left ventricular (LV) hypertrophy has been demonstrated to have inhibitory effects on myocardial growth. An important mechanism of action of ACE inhibition is modulation of myocardial AT1 Ang II-receptor activity. However, whether and to what extent AT1 Ang II-receptor blockade may influence LV and myocyte function during the hypertrophic process remains unclear. Accordingly, our project examined the relation between changes in LV and myocyte function during the LV hypertrophic process that occurs after recovery from long-term rapid pacing. Dogs were randomly assigned to the following treatment groups: (a) Pace and Recovery, long-term rapid pacing (4 weeks; 216 +/- 2 beats/min) followed by a 4-week recovery period (n = 6); (b) Recovery/AT1 Block, concomitant AT1 Ang II-receptor blockade [irbesartan (SR 47436; BMS-186295) 30 mg/kg b.i.d.] administered during the 4-week recovery period (n = 5); and (c) Control, sham controls (n = 6). There was no difference in mean arterial pressure in any of the three groups. With pacing and recovery, LV end-diastolic volume and mass were increased by >50% from control values. The significant LV remodeling that occurred with recovery from long-term rapid pacing was associated with a decline in LV ejection fraction (59 +/- 3% vs. 68 +/- 4%) and myocyte velocity of shortening (43 +/- 3 microm/s vs. 63 +/- 3 microm/s) when compared with controls (p < 0.05). With recovery from long-term rapid pacing, LV myocyte length (176 +/- 6 microm vs. 150 +/- 1 microm) and cross-sectional area were increased (292 +/- 7 microm2 vs. 227 +/- 6 microm2) compared with controls (p < 0.05). With AT1 Ang II block during recovery from rapid pacing, LV end-diastolic volume was similar to untreated recovery values, but LV mass was normalized. LV ejection fraction was not different from control values with AT1 Ang II-receptor block. Steady-state myocyte velocity of shortening with AT1 Ang II block was similar to control values (55 +/- 5 microm/s), but percentage shortening remained reduced from control (3.55 +/- 0.37% vs. 4.71 +/- 0.12%, respectively, p < 0.05) and was similar to untreated recovery (3.59 +/- 0.23%). With AT1 Ang II block, myocyte length was similar to untreated recovery values, but cross-sectional area was reduced (260 +/- 5 microm2, p < 0.05). Thus AT1 Ang II-receptor blockade instituted in this model of developing LV hypertrophy, significantly reduced LV mass but did not reduce the degree of LV dilation. The cellular basis for these effects of AT1 Ang II-receptor blockade included persistent abnormalities in LV myocyte geometry. AT1 Ang II-receptor blockade improved certain indices of myocyte contractile function from untreated hypertrophy values. These findings suggest that in this pacing-recovery model, the development of LV hypertrophy and myocyte contractile dysfunction may be caused, at least in part, by AT1 Ang II-receptor activation.

Angiotensin Receptor Antagonists↗

PubMed1997

Myosin heavy chain synthesis is increased in a rabbit model of heart failure.

Chronic ventricular tachycardia (chronic VT) causes left ventricular (LV) dysfunction and is associated with increased LV wall stress and neurohormonal activation, but no LV hypertrophy. The mechanisms responsible for the lack of myocardial growth with chronic VT are unknown. Accordingly, this study examined contractile protein [myosin heavy chain (MHC)] synthesis in a rabbit model of chronic VT. MHC mRNA levels, protein concentration, and synthesis rates were examined in control rabbits (n = 18) and in rabbits with chronic VT (400 beats/min, 3 wk, n = 18). With chronic VT, LV end-diastolic volume increased (8.2 +/- 0.8 vs. 5.3 +/- 0.6 ml, P < 0.05), ejection fraction decreased (12 +/- 3 vs. 38 +/- 4%, P < 0.05) and peak systolic wall stress increased (963 +/- 93 vs. 262 +/- 42 g/cm2, P < 0.05). Plasma catecholamine and endothelin levels also increased threefold, and renin activity increased twofold. Despite these stimuli for hypertrophy, LV mass-to-body weight ratio was unchanged (1.15 +/- 0.07 vs. 1.25 +/- 0.05 g/kg). At the myocyte level, chronic VT caused myocyte lengthening (159.6 +/- 1.8 vs. 121.6 +/- 1.4 microm, P < 0.05), but a reduction in myocyte cross-sectional area (199 +/- 6 vs. 249 +/- 7 microm2, P < 0.0001), as well as a reduced velocity of shortening (42.6 +/- 1.6 vs. 74.1 +/- 2.8 microm/s, P < 0.05). Chronic VT resulted in a significant increase in the rate of MHC synthesis, but paradoxically, there was no change in LV MHC content. Despite increased MHC synthesis, relative levels of MHC mRNA were not increased in chronic VT (2.79 +/- 0.23 vs. 2.44 +/- 0.20 AU, relative to glyceraldehyde-3-phosphate dehydrogenase), suggesting an increase in MHC translational efficiency. These unique findings suggest accelerated degradative processes must contribute to the failure of myocardial growth in this model of LV dysfunction in which increased LV wall stress, neurohormonal activation, and increased protein synthesis occurred.

Animals↗

PubMed1997

Relationship between external load and isolated myocyte contractile function with CHF in pigs.

Past studies have demonstrated that the negative relationship between afterload and contractile performance of papillary muscles is shifted downward and to the left with the development of hypertrophy. However, it remained unclear whether a similar load-contractility relationship could be constructed for isolated myocytes, particularly with the development of congestive heart failure (CHF). Accordingly, the effect of incrementally increased external loads on the contractile performance of left ventricular (LV) myocytes isolated from pigs in the normal state (n = 5) and after the development of chronic supraventricular tachycardia (SVT)-induced CHF (SVT-CHF; 240 beats/min, 3 wk; n = 5) was examined. This study used precalibrated microspheres to impose a quantifiable load on isolated myocytes, and myocyte contractility was assessed by videomicroscopy. Steady-state unloaded extent of shortening was 5.4 +/- 0.2 microns in control myocytes (n = 80) and was significantly reduced in the myocytes with the development of SVT-CHF (4.4 +/- 0.2 microns, n = 93; P < 0.05). Inverse relationships between relative resistive load and myocyte contractile function were observed at both normal and CHF states (r2 > 0.85). For myocyte velocity of shortening, the slope of this relationship was significantly reduced in the SVT-CHF state compared with controls (-46.3 x 10(-6) and -34.6 x 10(-6) microns3.microN-1.s-1, respectively; P < 0.05). At higher relative resistive loads (> 0.18 x 10(-6) microN/microns2), the reduction in myocyte shortening extent under an equivalent relative resistive load was significantly greater in the SVT-CHF myocytes compared with controls (62.8 +/- 3.9 vs. 45.6 +/- 4.7%, respectively, P < 0.05). The present study demonstrated for the first time that a load-dependent relationship can be derived for intact isolated LV myocytes in both normal and CHF states. The defect in the capacity of SVT-CHF myocytes to respond to an increased relative resistive load is a likely contributory mechanism for the LV pump dysfunction that occurs in this model of CHF.

Animals↗

PubMed1997

Angiotensin-converting enzyme inhibition and angiotensin II subtype-1 receptor blockade during the progression of left ventricular dysfunction: differential effects on myocyte contractile processes.

Inhibition of the angiotensin-converting enzyme (ACE) in the setting of chronic left ventricular (LV) dysfunction has been demonstrated to have beneficial effects on survival and symptoms. However, whether ACE inhibition has direct effects on myocyte contractile processes and if these effects are mediated primarily through the AT1 angiotensin-II receptor subtype remains unclear. The present project examined the relationship between changes in LV and myocyte function and beta adrenergic receptor transduction in four groups of six dogs each: (1) Rapid Pace: LV failure induced by chronic rapid pacing (4 weeks; 216 +/- 2 bpm); (2) Rapid Pace/ACEI: concomitant ACE inhibition (ACEI: fosinopril 30 mg/kg b.i.d.) with chronic pacing; (3) Rapid Pace/AT1 Block: concomitant AT1 Ang-II receptor blockade [Irbesartan: SR 47436(BMS-186295) 30 mg/kg b.i.d.] with chronic pacing; and (4) CONTROL: sham controls. With Rapid Pace, the LV end-diastolic volume increased by 62% and the ejection fraction decreased by 53% from control. With Rapid Pace/ACEI, the LV end-diastolic volume was reduced by 24% and the ejection fraction increased by 26% from Rapid Pace only values. Rapid Pace/AT1 Block did not improve LV geometry or function from Rapid Pace values. Myocyte contractile function decreased by 40% with Rapid Pace and increased from this value by 32% with Rapid Pace/ACEI. Rapid Pace/AT1 Block had no effect on myocyte function when compared with Rapid Pace values. With Rapid Pace/ACEI, beta receptor density and cyclic AMP production were normalized and associated with an improvement in myocyte beta adrenergic response compared with Rapid Pace only. Although Rapid Pace/AT1 also normalized beta receptor density, cyclic AMP production was unchanged and myocyte beta adrenergic response was reduced by 15% compared with Rapid Pace only. ACE inhibition with chronic rapid pacing improved LV and myocyte geometry and function, and normalized beta receptor density and cyclic AMP production. However, AT1 Ang-II receptor blockade with chronic rapid pacing failed to provide similar protective effects on LV and myocyte geometry and function. These unique findings suggest that the effects of ACE inhibition on LV geometry and myocyte contractile processes in the setting of developing LV failure are not primarily caused by modulation of AT1 Ang-II receptor activation.

Angiotensin Receptor Antagonists↗

PubMed1996

Contributory mechanisms for the beneficial effects of myocyte preconditioning during cardioplegic arrest.

BACKGROUND: Preconditioning protects the myocardium from ischemia and may be a potent means of endogenous cardioprotection during cardioplegic arrest and rewarming. However, fundamental mechanisms that potentially contribute to the beneficial effects of preconditioning during cardioplegic arrest and rewarming remain unclear. Accordingly, the overall goal of the present study was to examine the potential mechanisms by which preconditioning protects myocyte contractile function during simulated cardioplegic arrest and rewarming. METHODS AND RESULTS: Left ventricular isolated porcine myocyte contractile function was examined with the use of videomicroscopy under three conditions: (1) normothermia, maintained in cell medium (37 degrees C) for 2 hours; (2) simulated cardioplegic arrest and rewarming, incubated in crystalloid cardioplegic solution (24 mEq/L K+, 4 degrees C) for 2 hours followed by normothermic reperfusion; and (3) preconditioning/cardioplegic arrest and rewarming, hypoxia (20 minutes) and reoxygenation (20 minutes) followed by simulated cardioplegic arrest and rewarming. Cardioplegic arrest and rewarming caused a decline in steady-state myocyte shortening velocity compared with normothermic controls (22.0 +/- 1.6 versus 57.2 +/- 2.6 microns/s, respectively, P < .05), which was significantly improved with preconditioning (36.1 1.7 microns/s, P < .05). In the next series of experiments, the influence of nonmyocyte cell populations with respect to preconditioning and cardioplegic arrest was examined. Endothelial or smooth muscle cell cultures were subjected to a period of hypoxia (20 minutes) and reoxygenation (20 minutes) and the eluent incubated with naive myocytes, which were then subjected to simulated cardioplegic arrest and rewarming. Pretreatment with the eluent from endothelial cultures followed by cardioplegic arrest and rewarming improved myocyte function compared with cardioplegia-alone values (31.7 +/- 2.2 versus 24.7 +/- 1.6 microns/s, respectively, P < .05), whereas smooth muscle culture eluent pretreatment resulted in no change (23.7 +/- 4.0 microns/s, P = .81). Molecular mechanisms for the protective effects of preconditioning on myocyte contractile processes with cardioplegic arrest and rewarming were examined in a final series of experiments. Adenosine-mediated pathways or ATP-sensitive potassium channels were activated by augmenting cardioplegic solutions with adenosine (200 mumol/L) or the potassium channel opener aprikalim (100 mumol/L), respectively. Both adenosine and aprikalim augmentation significantly improved myocyte function compared with cardioplegia-alone values (53.5 +/- 1.7, 57.6 +/- 2.0 versus 25.7 +/- 1.4 microns/s, respectively, P < .05). CONCLUSIONS: The unique findings from the present study demonstrated that preconditioning provides protective effects on myocyte contractile processes independent of nonmyocyte cell populations and that these effects are mediated in part through the activation of adenosine pathways or ATP-sensitive potassium channels. Thus, preconditioning adjuvant to cardioplegia may provide a novel means of protecting myocardial function after cardioplegic arrest and rewarming.

Adenosine↗