Intrapericardial paclitaxel delivery inhibits neointimal proliferation and promotes arterial enlargement after porcine coronary overstretch.

BACKGROUND: Catheter-based intrapericardial (IPC) delivery of therapeutic agents has recently been demonstrated. Paclitaxel is known to inhibit vascular smooth muscle cell proliferation. This study examined the effect of IPC instillation of paclitaxel on neointimal proliferation after balloon overstretch of porcine coronary arteries. METHODS AND RESULTS: Overstretch injury of coronary arteries was followed by IPC administration of micellar paclitaxel at low dose (LD, 10 mg; n=6) or high dose (HD, 50 mg; n=7) or of control micelles (50 mg, n=5). Animals were euthanized 28 days after balloon dilation. Arterial injury indices were no different among the groups. The neointimal area, maximal intimal thickness, and adventitial thickness were significantly reduced in both LD (0.47+/-0.04 mm(2), 0.43+/-0.03 mm, and 0.35+/-0.02 mm, respectively) and HD (0.51+/-0.06 mm(2), 0.42+/-0.03 mm, and 0. 38+/-0.03 mm, respectively) paclitaxel groups compared with the control group (0.79+/-0.07 mm(2), 0.56+/-0.02 mm, and 0.47+/-0.02 mm, respectively; P:<0.001). Meanwhile, the vessel circumference measured at the external elastic lamina of paclitaxel-treated vessels was significantly larger than the control circumference. Apoptotic cells were found in the neointima. The apoptotic cell percentage was not different between the control (1.72%) and LD (2. 31%) groups but was higher in the HD group (7.07%, P:<0.0001 versus control and LD groups). Immunostaining for matrix metalloproteinase-2 revealed concurrent reduction in the HD group compared with the control and LD groups. CONCLUSIONS: IPC space delivery of a single dose of paclitaxel significantly reduces vessel narrowing in this balloon-overstretch model. This effect is mediated by reduction of neointimal mass as well as positive vascular remodeling.

Evaluation of ventricular contractility indexes in the dog with left ventricular dysfunction induced by rapid atrial pacing.

Eight dogs were studied by simultaneous invasive hemodynamic and two-dimensional echocardiographic methods to determine whether left ventricular contractility is altered by 2 weeks of rapid atrial pacing. Additionally, this study evaluated the response of three ventricular contractility indexes to both the pacing intervention and acute load alteration. The indexes compared were ejection fraction, peak systolic pressure to end-systolic volume index ratio (SBP/ESVI) and end-systolic wall stress to end-systolic volume index ratio (ESWS/ESVI). After 2 weeks of pacing at 265 +/- 20 min-1 (mean +/- SD), cardiac index and ejection fraction were reduced to 73 +/- 38 ml/kg per min and 22 +/- 6%, respectively, from 161 +/- 22 and 46 +/- 7 before pacing (both p less than 0.001). Concomitantly, SBP/ESVI and ESWS/ESVI were reduced to 34 +/- 10 mm Hg/ml per kg and 54 +/- 19 g/cm2 per ml per kg, respectively, from 84 +/- 29 and 121 +/- 36 before pacing (both p less than 0.005). There were high correlations for the changes in SBP/ESVI and ejection fraction (r = 0.94, p less than 0.001) and ESWS/ESVI and ejection fraction (r = 0.89, p less than 0.003). Acute afterload alteration with phenylephrine depressed ejection fraction but not SBP/ESVI or ESWS/ESVI. Therefore, this study demonstrates 1) that left ventricular contractility is markedly depressed in the dog by 2 weeks of rapid atrial pacing, and 2) that SBP/ESVI and ESWS/ESVI are superior to ejection fraction as ventricular contractility indexes because these ratios accurately measure contractility changes but are influenced less by after-load conditions.

Alteration of antioxidant status in diabetic rats by chronic exposure to psychological stressors.

Antioxidant status was measured in heart, liver, kidney, lung, and erythrocytes of 2-week streptozotocin-diabetic male Wistar rats exposed to chronic intermittent psychological stress consisting of 1 h of restraint twice daily for 14 days. Diabetes reduced erythrocyte and heart and liver susceptibility to hydrogen peroxide-induced glutathione depletion. Susceptibility to peroxide-induced thiobarbituric acid reactive substance (TBARS) formation increased in erythrocytes, liver, kidney, and lung but decreased in heart. Significant changes also occurred in glutathione levels (increased in heart and decreased in liver) and in the activities of catalase (reduced in liver and kidney), glutathione reductase (elevated in heart and liver), and glutathione peroxidase (decreased in liver and lung), but not Cu,Zn-superoxide dismutase. Stress potentiated diabetes-associated hyperglycemia and attenuated diabetes-induced hyperlipidemia. In addition, the reduction in peroxide-induced glutathione depletion in heart and liver and the increased TBARS formation in kidney and lung were reversed. Similarly, the diabetes-induced induced increase in liver glutathione reductase and decreases in liver and lung glutathione peroxidase activities were abolished by stress. Thus, the relative resistance of antioxidant systems to stress can be modified under pathologic conditions in which antioxidant alterations are present.

Myocardial protection during ischemia in the isolated perfused rabbit heart.

Although many studies of the protective effects of cardioplegic solutions using hypothermia have been conducted, it is also necessary to examine their protective effects under normothermia as regional increases in myocardial temperature during hypothermic arrest are often reported. For this purpose myocardial protection was investigated in the isolated perfused rabbit heart exposed to 60 minutes of normothermic global ischemia during which Krebs-Henseleit, blood with heparin, Tyers', and St. Thomas' Hospital solutions were infused at 0.2 mL/min. Percent functional recovery dP/dtmax (mm hg/sec) at 5 minutes relative to pre-ischemic values using Tyers' (12 +/- 5)% was significantly less (p less than 0.05) than recovery using Krebs-Henseleit (57 +/- 13)% and St. Thomas' Hospital solution (47 +/- 5)%. Recovery using blood (79 +/- 7)% was significantly better than all other solutions. Following 25 minutes reperfusion, 4/6 hearts perfused with Tyers' experienced left ventricular fibrillation, while recovery of developed pressure with Krebs-Henseleit (74 +/- 5.8)%, St. Thomas' Hospital (66 +/- 3.4)% and blood (98 +/- 2.9)% was again significantly improved relative to Tyers', (p less than 0.05). Time to develop 5 mm contracture during the ischemic period was significantly shorter using Tyers' than with the other solutions. Using these indices of function, whereas Tyers' solution provided poor protection, blood provided excellent protection in rabbit hearts under normothermic conditions.

Improved functional recovery of the atherosclerotic rabbit heart subjected to normothermic global ischemia.

Contractile function before, during and after a period of ischemia was evaluated in perfused hearts from rabbits fed either 2% cholesterol or a control diet for two months. Rabbits were sacrificed and the hearts were perfused by the Langendorff normothermic perfusion technique. After a 30-min baseline period, the hearts were subjected to a 60-min period of low flow ischemia (0.2 mL/min) with Krebs-Henseleit solution containing either 2.5 mM (normocalcemic) or 0.5 mM (hypocalcemic) calcium. Subsequently the hearts were reperfused for 30 mins. No significant differences in baseline contractile function (expressed by developed pressure and dP/dtmax) were observed between hearts from cholesterol-fed and control rabbits. Although, initially the degree of contracture, as measured by an increase in end diastolic pressure from baseline, was less in cholesterol-fed rabbit hearts, this difference did not persist beyond 40 mins of ischemic perfusion. Hypocalcemic ischemic perfusion was associated with a delay in development of contracture relative to normocalcemic perfusion in the hearts from cholesterol-fed rabbits. These results suggest an early resistance to ischemia by hearts from cholesterol-fed rabbits. Upon reperfusion, the hearts from control rabbits exhibited a sudden increase in contracture following ischemic perfusion with 0.5 mM calcium which was not observed in the hearts from rabbits fed a cholesterol diet. There was improved functional recovery and less contracture development post reperfusion in the hearts from cholesterol-fed rabbits, independent of the concentration of calcium used during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial functional preservation during ischemia: influence of beta blocking agents.

To determine whether prior acute Beta blockade protects the heart against the deleterious effects of normothermic low flow global ischemia on myocardial function, aortic pressure, developed pressure, dP/dtmax and end diastolic pressure were monitored in isolated perfused rabbit hearts prior to, during and following 30 and 60 min ischemia, during which either Krebs-Henseleit (control) or Beta blocking agents. Bevantolol (cardioselective) or Propranolol (non-selective) were perfused through the heart. Control hearts made ischemic for 30 min and then reperfused had significantly elevated end diastolic (p < .01) and aortic pressures (p < .01) and reduced developed pressure relative to baseline (p < .05). Hearts treated with Bevantolol or Propranolol (3 x 10(-5) m/l) 5 min prior to and during 30 min ischemia recovered preischemic developed pressure and dP/dtmax (p > 0.05), while end diastolic pressure was elevated (p < .01, p < .05 respectively). Aortic pressure was unchanged relative to baseline (p > .05). Comparison of indices from hearts under Beta blockade with controls showed that following 30 min ischemia and recovery, the Bevantolol treated group had reduced aortic pressure (p < .01) and end diastolic pressure (p < .05) and increased percent developed pressure and percent dP/dtmax (p < .001) relative to control. In the propranolol treated group, end diastolic pressure was reduced and percent developed pressure (p < .01) and percent dP/dtmax (p < .001) were increased relative to unblocked hearts. Following 60 min ischemia and 30 min reperfusion, reduction in all functional indices occurred, however dP/dtmax was unchanged from baseline in the Propranolol and Bevantolol treated groups. Comparison between groups showed that the Bevantolol treated group had significantly better dP/dtmax and developed pressure (p < .05), whereas the Propranolol group shows no significant difference from baseline (p > .05) (K-H). We conclude that following short periods of ischemia, Beta blockade protects the heart from deleterious function effects of ischemia but that the protective effect is diminished in Bevantolol relative to Propranolol treatments following prolonged ischemia. The data indicates that the beneficial effects of Beta blockade in reducing ischemic induced damage occurs early during conditions of ischemia such as would be present in the setting of acute myocardial infarction.

Alteration of antioxidant status following sympathectomy: differential effects of modified plasma levels of adrenaline and noradrenaline.

The influence of altered levels of endogenous catecholamines following adrenalectomy or 6-hydroxydopamine (6-OH) treatment (alone or in combination) on enzymatic (glutathione reductase, catalase, glutathione peroxidase and Cu, Zn superoxide dismutase) and non-enzymatic (glutathione) antioxidant components of heart, liver, kidney, lung and erythrocytes in male Wistar rats was investigated. Functional antioxidant status was assessed in terms of susceptibility to t-butylhydroperoxide-induced sulfhydryl group oxidation (an indirect measure of glutathione depletion) and lipid peroxidation, as measured by thiobarbituric acid-reactive substance (TBARS) formation. Reduced levels of adrenaline and noradrenaline resulted from adrenalectomy and 6-OH treatment, respectively, while a combination of these treatments led to a reduction in the levels of both catecholamines. Adrenalectomy was associated with alterations in glutathione reductase activity in the heart and liver (increased). 6-OH treatment alone produced an elevation in glutathione reductase activity only in the heart. In adrenalectomized animals, 6-OH treatment produced no further increases in glutathione reductase activities of heart or liver. In lung, however, the combination of adrenalectomy and 6-OH treatment caused an elevation in both glutathione peroxidase and glutathione reductase activities. Glutathione levels of liver alone were elevated following adrenalectomy, while those of erythrocytes and liver (but not other tissues investigated) were increased by the combination of adrenalectomy and 6-OH treatment. The kidney was relatively resistant to the effects of sympathectomy and showed no changes in any of the antioxidant components measured. Adrenalectomy alone or in combination with 6-OH produced an increased in susceptibility to peroxide-induced sulfhydryl group oxidation only in the heart. 6-OH treatment caused a reduction in peroxide-induced TBARS formation only in the kidney. Both adrenalectomy and the combination of adrenalectomy and 6-OH treatment were associated with reduced TBARS formation in the liver, lung and kidney, but not heart. Results from this study demonstrate that the effects of sympathectomy on antioxidant status vary among tissues. Differences between adrenalectomy and 6-OH treatment on antioxidant components are suggestive of differential actions of adrenaline and noradrenaline on tissue antioxidant status which may have important implications under conditions associated with elevations in levels of these catecholamines including chronic stress and myocardial infarction.