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The conundrum of restenosis remains the most significant challenge in revascularization techniques. This article reviews the current understanding of restenosis based upon laboratory investigations, clinical experience, and the efficacy of mechanical and pharmacologic interventions that have been attempted to prevent and/or reduce its occurrence. However, terminology really comes into play because restenosis is really the mechanism by which the body heals and is not a rapid deposition of atherosclerotic plaque.

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We investigated the effect of long-term oral pretreatment with the beta-adrenergic antagonist, propranolol (Inderal LA, 160 mg daily for 8 days) on the functional recovery of myocardium after 15-minute coronary artery occlusion followed by 3 hours of reperfusion in barbital-anesthetized dogs. Propranolol-pretreated dogs (N = 9) displayed a significantly lower left ventricular peak-positive rise in ventricular pressure (dP/dt), heart rate, and rate-pressure product throughout the experiment compared with the control group (N = 15). Subendocardial percent segment shortening as measured by sonomicrometry recovered to 65.4 +/- 7.2% of the preocclusion level after pretreatment with propranolol, whereas the control group recovered to only 11.1% +/- 10.2% after 3 hours of reperfusion. To ascertain the beneficial role of a lower heart rate on the recovery of regional contractile function, a third group of dogs (N = 6) was pretreated with propranolol, but heart rate was maintained at control levels by atrial pacing. The beneficial effects of pretreatment with propranolol were abolished in this group. There were no differences between groups in myocardial perfusion in the normal region as measured by the radioactive microsphere technique. However, in postischemic, reperfused myocardium, there was a significantly higher blood flow to subepicardium, mid-myocardium, and subendocardium after reperfusion in the propranolol-pretreated, unpaced group. Thus long-term oral pretreatment with propranolol enhances the contractile recovery of postischemic, reperfused myocardium. This protective effect of beta-adrenergic blockade is primarily related to the reduction in heart rate and enhanced perfusion in the postischemic region.

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Under sterile conditions, dogs were instrumented for continuous measurement of hemodynamics, and an Ameroid constrictor was positioned around the left carotid artery to produce slowly progressive narrowing of the vessel. In the awake, unsedated state, carotid cyclical blood flow reduction abruptly appeared on day 5.1 +/- 0.6 (mean +/- S.E.M.) at a frequency of 6.7 +/- 0.6 cycles per 30 minutes and usually remained present for only 1 day. The vessel was totally occluded on day 7.9 +/- 0.8. No focal neurologic deficit was observed. Following administration of the new thromboxane receptor antagonist, BM 13.505 (4-[2-(4-chlorobenzene-sulfonamide)-ethy]-benzene acetic acid), 50 and 100 micrograms/kg intravenously, the cyclical reduction in carotid blood flow was abolished for 30 +/- 5 and 45 +/- 15 minutes, respectively. No changes in systemic hemodynamics were observed over the course of the experiment. It is concluded that slowly progressive constriction of the carotid artery may provide an in vivo model for the study of perfusion deficits present in transient ischemic attacks. In addition, the results support the hypothesis that platelet aggregation plays a major role in cyclical carotid flow reduction, and the phenomenon can be eliminated by treatment with a new thromboxane receptor antagonist, BM 13.505.

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Following brief periods (5-15 min) of total coronary artery occlusion and subsequent reperfusion, despite an absence of tissue necrosis, a decrement in contractile function of the postischemic myocardium may nevertheless be present for prolonged periods. This has been termed "stunned" myocardium to differentiate the condition from ischemia or infarction. Because the influence of volatile anesthetics on the recovery of postischemic, reperfused myocardium has yet to be studied, the purpose of this investigation was to compare the effects of halothane and isoflurane on systemic and regional hemodynamics following a brief coronary artery occlusion and reperfusion. Nine groups comprising 79 experiments were completed in 42 chronically instrumented dogs. In awake, unsedated dogs a 15-min coronary artery occlusion resulted in paradoxical systolic lengthening in the ischemic zone. Following reperfusion active systolic shortening slowly returned toward control levels but remained approximately 50% depressed from control at 5 h. In contrast, dogs anesthetized with halothane or isoflurane (2% inspired concentration) demonstrated complete recovery of function 3-5 h following reperfusion. Because the anesthetics directly depressed contractile function, additional experiments were conducted in which a 15-minute coronary artery occlusion was produced during volatile anesthesia; however, each animal was allowed to emerge from the anesthetized state at the onset of reperfusion. Similar results were obtained in these experiments, demonstrating total recovery of contractile function within 3-5 h following reperfusion. Thus, despite comparable degrees of contractile dysfunction during coronary artery occlusion in awake and anesthetized dogs, the present results demonstrate that halothane and isoflurane produce marked improvement in the recovery of segment function following a transient ischemic episode. Therefore, volatile anesthetics may attenuate postischemic left ventricular dysfunction occurring intraoperatively and enhance recovery of regional wall motion abnormalities during reperfusion.

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The influence of volatile anesthetics on ventricular repolarization in vivo (QT interval) has not been studied in a systematic fashion. The purpose of this investigation was to characterize the electrocardiographic and hemodynamic actions of the volatile anesthetics halothane, isoflurane, and enflurane in chronically instrumented dogs. Because autonomic nervous system tone may influence ECG findings, experiments were completed with and without concomitant pharmacologic autonomic nervous system blockade. In six groups comprising 50 experiments with 21 instrumented dogs, anesthesia was mask-induced with nitrous oxide, oxygen, and one of the volatile anesthetics and maintained with the volatile anesthetic in 100% oxygen for 2 hours. Changes in the ECG and in hemodynamics were compared to the conscious state. In the absence of autonomic nervous system blockade, halothane and isoflurane significantly prolonged the QT interval (0.24 +/- 0.01 to 0.30 +/- 0.01 second and 0.22 +/- 0.01 to 0.28 +/- 0.01 second, respectively), whereas enflurane produced no change in ventricular repolarization (0.24 +/- 0.01 to 0.26 +/- 0.01 second). All of the volatile anesthetics increased the QT interval corrected for changes in basal heart rate (QTc), and all agents decreased intravascular pressure and dP/dt. Following autonomic nervous system blockade, halothane, isoflurane, and enflurane significantly increased the QT interval and QTc. The results demonstrate that ventricular repolarization is directly altered by the volatile anesthetics independent of changes in autonomic nervous tone. Whether or not such effects are additive with other congenital or acquired forms of QTc prolongation has yet to be examined. The present results indicate that caution should be used during the administration of volatile anesthetics to patients with abnormalities of the QT interval.

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Under sterile conditions, dogs were instrumented for continuous measurement of hemodynamics, and an Ameroid constrictor was positioned around either the left carotid, left femoral, or left anterior descending coronary artery to produce slowly progressive narrowing of the vessel. Cyclic flow reduction (CFR) developed in the carotid artery in seven of nine dogs on day 5.1 +/- 0.8 (mean +/- S.E.M.) at a frequency of 6.7 +/- 0.6 cycles per 30 min. This phenomenon was abolished for 30 +/- 5 and 45 +/- 15 min with intravenous administration of 50 and 100 micrograms/kg, respectively of the thromboxane receptor antagonist, BM 13.505, 4-[2-(4-chloro-benzene-sulfonamide)-ethyl]-benzene acetic acid. Total carotid artery occlusion occurred on day 7.9 +/- 0.8. CFR developed in the femoral artery in one of three dogs on day 4 at a frequency of 7 cycles per 30 min and was abolished for 82 min after BM 13.505 (50 micrograms/kg i.v.). The vessel became totally occluded on day 7. Finally, CFR developed in the left anterior descending coronary artery in three of five dogs on day 9.3 +/- 4.9 at a frequency of 6.2 +/- 0.9 cycles per 30 min. CFR was abolished for 37 min after BM 13.505 (50 micrograms/kg i.v.) and for several hours after an oral dose of aspirin (650 mg). Total coronary occlusion was observed on day 17.4 +/- 2.6. The present results demonstrate that CFR can be induced in various arteries in conscious, chronically instrumented dogs by slowly progressive narrowing via Ameroid constrictors. This phenomenon may serve as a model for transient ischemic attack, claudication, and unstable angina. Because the conscious state is maintained, drug interactions with anesthetics are avoided. The usefulness of inhibitors of platelet aggregation in this model documents the potential benefit of such compounds in various vascular disease states.

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The hemodynamic actions of a new inotropic agent, MCI-154, were compared to dopamine, ouabain and milrinone in conscious, chronically instrumented dogs. MCI-154 and milrinone produced similar hemodynamic changes: increases in heart rate, diastolic coronary blood flow velocity and peak positive dP/dt. Neither agent had significant effects on arterial pressure while both drugs reduced left ventricular end-diastolic pressure in a dose-related fashion and myocardial segment length, indicating a decrease in diastolic left-ventricular size. MCI-154 was found to be approximately twice as potent as milrinone. In contrast, dopamine and ouabain produced little change in left ventricular end-diastolic pressure or myocardial segment length during diastole, while both drugs produced increases in arterial and left ventricular systolic pressures. An increase in left ventricular afterload was not observed with either MCI-154 or milrinone, highlighting an important advantage of the latter compounds.

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Effects of the intracellular calcium antagonist, KT-362, on systemic and coronary hemodynamics and the electrocardiogram were evaluated in chronically instrumented, awake dogs during intravenous infusion or bolus administration. Both methods of administration resulted in systemic hypotension, tachycardia and decreases in left ventricular pressure and peak positive left ventricular dP/dt. KT-362 produced a transient increase in mean coronary blood flow velocity only during bolus injection, while subendocardial segment shortening was depressed only by drug infusion. Prolongation of QRS duration and the QT interval (corrected for change in heart rate, QTc) also occurred during drug infusion. The results suggest that the hemodynamic effects of intracellular calcium antagonism by KT-362 are qualitatively similar to those of other calcium channel blocking agents which inhibit extracellular calcium influx. In contrast, the actions of KT-362 on cardiac conduction may be different from those of other slow channel calcium blocking agents.

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