Coronary Occlusion In Dogs Research Articles

Endothelium-dependent hyperpolarization-mediated vasodilatation compensates nitric oxide-mediated endothelial dysfunction during ischemia in diabetes-induced canine coronary collateral microcirculation in vivo.

It has been previously demonstrated that endothelial caveolin-1 plays crucial roles to produce an endothelium-derived hyperpolarizing factor in mouse mesenteric arteries. We examined whether this mechanism is involved in the endothelium-dependent hyperpolarization-mediated responses to compensate reduced NO-mediated responses in diabetes mellitus during coronary occlusion in dogs in vivo. Canine subepicardial collateral coronary small arteries (≥100μm) and arterioles (<100μm) were observed by an intravital microscope. Experiments were performed during occlusion of the left anterior descending coronary artery (90minutes) under the following conditions (n=6 each); (i) control, (ii) diabetes mellitus, and (iii) diabetes mellitus+L-NMMA+KCa channel blockade. Vascular and myocardial levels of caveolin-1, eNOS, and caspase-3 were measured by ELISA. Caveolin-1 levels in the ischemic area were greater in coronary microvessels than in conduit arteries in the control group. NO-mediated coronary vasodilatations of small arteries to bradykinin did not increase in diabetes mellitus associated with decreased eNOS phosphorylation at Ser1177 compared with baseline of controls and were restored by compensation of endothelium-dependent hyperpolarization and were suppressed by KCa channel blockade. NO-mediated vasodilatations of small coronary arteries during coronary occlusion are impaired in diabetes mellitus and are compensated by endothelium-dependent hyperpolarization of arterioles in dogs in vivo.

Quantitative Three-Dimensional Wall Motion Analysis Predicts Ischemic Region Size and Location

Stress echocardiography is an important screening test for coronary artery disease. Currently, cardiologists rely on visual analysis of left ventricular (LV) wall motion abnormalities, which is subjective and qualitative. We previously used finite-element models of the regionally ischemic left ventricle to develop a wall motion measure, 3DFS, for predicting ischemic region size and location from real-time 3D echocardiography (RT3DE). The purpose of this study was to validate these methods against regional blood flow measurements during regional ischemia and to compare the accuracy of our methods to the current state of the art, visual scoring by trained cardiologists. We acquired RT3DE images during 20 brief (<2 min) coronary occlusions in dogs and determined ischemic region size and location by microsphere-based measurement of regional perfusion. We identified regions of abnormal wall motion using 3DFS and by blinded visual scoring. 3DFS predicted ischemic region size well (correlation r (2) = 0.64 against microspheres, p < 0.0001), reducing error by more than half compared to visual scoring (8 +/- 9% vs. 19 +/- 14%, p < 0.05), while localizing the ischemic region with equal accuracy. We conclude that 3DFS is an objective, quantitative measure of wall motion that localizes acutely ischemic regions as accurately as wall motion scoring while providing superior quantification of ischemic region size.

Superoxygen Therapy

In North America, every 25 seconds someone will have a coronary event and every minute someone will die of one.1 ST elevation myocardial infarction (STEMI) is the most dramatic manifestation of coronary artery disease and remains as one of the most important causes of mortality in the industrialized world. Prompt and successful reperfusion therapy (either pharmacologically with use of fibrinolytic therapy or mechanically with primary percutaneous coronary intervention [PCI]) is currently the cornerstone of acute management of STEMI to salvage ischemic myocardium and limit infarct size. Although undoubtedly beneficial, reperfusion of an occluded artery represents “a double-edge sword,”2 because restoration of epicardial coronary flow initiates a series of complex biochemical and molecular phenomena, which will ultimately mitigate myocardial healing. Thus, with reperfusion comes reperfusion injury.3 Article see p 366 Although the concept of cardioprotection (myocardial salvage) was first suggested by Braunwald,4 it was the seminal works of Reimer et al who crystallized the fact that there exists a window of opportunity to act to limit myocardial injury. They postulated that a “wavefront phenomenon” of cardiac necrosis, if left unchecked, would extend the infarct from the subendocardial region to the subepicardial region by using canine models of transiently or permanently occluded coronary arteries.5 Thereafter, over the course of 3 decades, mixed and disappointing results have plagued both experimental and clinical attempts to limit the deleterious effects of early reperfusion through either pharmacological (adenosine, calcium channel blockers, Na+/H+ exchange inhibitors, KATP channel openers, and glucose-insulin-potassium infusion) or nonpharmacological (therapeutic hypothermia) means.3,6 The reasons for such inconsistent findings in cardioprotection are multifold. First, reperfusion injury encompasses numerous, overlapping mediators of cardiomyocyte death from oxidative stress and Ca2+ overload to alterations in cellular pH, as well as an inflammatory process with a central …

Duration of Symptoms Is Not Always the Key Modulator of the Choice of Reperfusion for ST-Elevation Myocardial Infarction

Fibrinolytic therapy (FT) and primary percutaneous coronary intervention (PCI) are both well-accepted reperfusion therapies in ST-segment elevation myocardial infarction (STEMI). The evidence of randomized clinical trials indicates a relatively modest difference in 30-day mortality (≈1%) in favor of primary PCI over fibrin-specific FT and was based on very timely primary PCI (ie, a primary PCI–related delay of 40 minutes [door-to-balloon less door-to-needle time]).1 Longer delays to primary PCI, which are far more frequent in clinical practice,2 are associated with attenuated benefit or no benefit at all, particularly when compared with fibrin-specific FT.3,4 The benefit of timely primary PCI over FT is likely to especially apply to higher-risk patients.5,6 Irrespective of the method of reperfusion, the potential for myocardial salvage and better clinical outcome is inversely proportional to ischemic time or its only available clinical surrogate, symptom duration.7–12 These considerations underpin the notion expressed in the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of STEMI that timely reperfusion therapy is likely more important in determining outcome than whether FT or primary PCI is the chosen reperfusion method.13 Response by Armstrong et al p 1310 The ACC/AHA STEMI guidelines highlight the time point of 3 hours of symptom duration in guiding the choice of reperfusion therapy. They state that if symptom duration is <3 hours, no preference exists between FT and primary PCI provided that treatment is timely (for FT, door-to-needle time <30 minutes; for primary PCI, door-to-balloon time <90 minutes and ≤60 minutes between estimated needle time and estimated balloon time). However, if symptom duration exceeds 3 hours, these guidelines favor primary PCI over FT, again provided that primary PCI can be performed in a timely fashion.13 This article reexamines the evidence that may or may not be the basis …

Intramyocardial delivery of basic fibroblast growth factor-impregnated gelatin hydrogel microspheres enhances collateral circulation to infarcted canine myocardium.

The present study examined whether basic fibroblast growth factor (bFGF)-impregnated acidic gelatin hydrogel microspheres (AGHM) would enhance collateral development to the infarct area in dogs with coronary occlusion. Studies were conducted in 28 dogs with a 2-week occlusion of the proximal left anterior descending coronary artery (LAD). The dogs were divided into 3 groups according to treatment: Group A treated with bFGF-impregnated AGHM in the infarct area; Group B with free-form bFGF; Group C with AGHM alone. Coronary angiography (n=15; Group A, 7 dogs; Group B, 5 dogs; Group C, 3 dogs) and a regional myocardial blood flow study (n=13; Group A, 6 dogs; Group B, 4 dogs; Group C, 3 dogs) were repeated at a 2-week interval. Coronary angiography revealed that in Group A, antegrade flow in the LAD distal to the occlusion, which was assessed by Thrombolysis in Myocardial Infarction (TIMI) grade, was significantly increased after treatment. In contrast, in Groups B and C, the treatment did not change the flow grade in the LAD. In Group A, the regional myocardial blood flow in the collateral dependent area was significantly increased after treatment, and the regional myocardial blood flow reserve after adenosine injection was also significantly increased. These measurements remained after treatment in Groups B and C. The immunohistochemical study with factor VIII-related antigen revealed an increase of vascular density in the ischemic region in Group A. Intramyocardial delivery of bFGF-impregnated AGHM, but not free-form bFGF, improves the collateral circulation to the infarct area of a coronary occlusion in dogs.

Effects of Thoracic Epidural Anesthesia on Systemic and Myocardial Oxygen Supply/Demand Balance during Coronary Occlusion in Dogs

Effects of Thoracic Epidural Anesthesia on Systemic and Myocardial Oxygen Supply/Demand Balance during Coronary Occlusion in Dogs

The renin-angiotensin system and ACE inhibitors in the peri-operative period

Anaesthetists will encounter more patients in the peri-operative period on angiotensin-converting enzyme (ACE) inhibitor therapy because of their efficacy in the treatment of hypertension and cardiac failure. Pre-operative therapy with ACE inhibitors has been associated with severe hypotension after the induction of and during anaesthesia. While ACE inhibitors have not been found especially useful in managing the haemodynamic consequences of laryngoscopy and intubation, they may have a role when induced hypotension is required to minimize blood loss. It is now apparent that the renin-angiotensin system (RAS) plays a critical role in the defence of blood loss, and thus ACE inhibitors may have a deterimental effect in the peri-operative period in this respect. High thoracic epidural anaesthesia may not only have its well-known sympatholytic effect, but may also inhibit activation of the RAS system. However, on the positive side, ACE inhibitors have been shown to diminish the activation of cardiovascular mediators in cardiac surgical patients, are probably renoprotective during aortic surgery and have been shown to reduce myocardial infarct size after coronary occlusion in dogs, suggesting a possible myocardial protective effect. Thus further studies will be required to determine the exact role of ACE inhibitors in the peri-operative period.

Thoracic Epidural Anesthesia and the Patient with Heart Disease

Thoracic Epidural Anesthesia and the Patient with Heart Disease

966-39 Hypertension and Left Ventricular Hypertrophy Further Impair Utilization of the Reduced Coronary Reserve in Patients with Coronary Artery Stenosis

Left ventricular hypertrophy (LVH) predisposes to an increased infarct size after coronary occlusion in dog. Aim of the study was to investigate the impact of the coexistence of LVH secondary to hypertension and coronary stenosis on the coronary vasodilator capacity in man. Coronary flow velocity in left anterior descending artery (LAD) was monitored by Transesophageal-Doppler at baseline and during low- and high-dose of iv. Dipyridamole (0.56 mg/Kg/4 min followed after 2 min by 0.28 mg/Kg/2 min) in 56 patients, divided as follows: 19 normal controls (N Group), 21 pts with hypertension, LVH and no CAD (LVH Group), and 16 pts with moderate LAD artery stenosis (≤ 75%) [10 without LVH (LAD Group) and 6 with LVH secondary to hypertension (LAD + LVH Group)]. All pts had Dipyridamole Echo test negative for left ventricular asynergy. Blood pressure and left ventricular mass were similar in N vs LAD pts, and in LVH vs LAD + LVH. Mean total coronary flow velocity was measured from Doppler recordings. Coronary reserve was computed as the ratio of high-dose Dipyridamole to Basal flow velocity. Minimum coronary resistance and the percent of coronary reserve recruited after low-dose Dipyridamole were also computed. Baseline coronary flow velocity was 29 ± 6 cm/sec in N, and significantly higher in LVH and CAD (39 ± 11 and 41 ± 11, respectively, p &lt; 0.01). Coronary flow velocity after high-dose Dipyridamole was 92 ± 18 in N, and significantly lower only in LAD + LVH (68 ± 16, p &lt; 0.05). Coronary reserve was 3.3 ± 0.7 in N, and significantly reduced in all pts subgroups (2.4 ± 0.4, 2.2 ± 0.6, 2.3 ± 0.4 in LVH, LAD, LAD + LVH; P &lt; 0.01 vs N). Percent of coronary reserve recruited after low-dose Dipyridamole was 94 ± 8% in N, 91 ± 11% in LAD, and lower in LVH (79 ± 11%, P &lt; 0.01 vs N) and in LAD + LVH (69 ± 10%, P &lt; 0.05 vs LVH). Compared to N, minimum coronary resistance was significantly higher in LVH (p &lt; 0.05) and LAD + LVH (p &lt; 0.01) (0.94 ± 0.2 vs 1.20 ± 0.3 and 1.40 ± 0.4 mmHg/ml/min, respectively); it was also higher in LAD + LVH than in LAD alone (1.07 ± 0.2 mmHg/ml/min, p &lt; 0.05). Coronary reserve is similarly reduced in pts with LVH secondary to hypertension, LAD stenosis alone, or LVH + LAD stenosis. Coexistence of hypertensive LVH with LAD stenosis is associated. compared to LAD stenosis alone, with significantly higher minimum coronary resistance and a hindered utilization of the reduced coronary reserve.

Monophosphoryl lipid A preserves myocardial contractile function following multiple, brief periods of coronary occlusion in dogs.

The effects of a 1- or 24-hour pretreatment regimen with monophosphoryl lipid A (MLA, 35 micrograms/kg i.v.) on myocardial stunning produced by repetitive coronary occlusions were studied in barbital-anesthetized dogs. Regional segment function (%SS) and myocardial blood flow were measured by sonomicrometry and the radioactive microsphere technique, respectively. In controls, six 5-min periods of coronary occlusion interpersed with 10-min periods of reperfusion and ultimately followed by 2 h of reperfusion produced regional segment dysfunction. Pretreatment with MLA for 1 h prior to the first occlusion period had no effect on %SS, however, pretreatment with MLA 24 h prior to the first occlusion period resulted in a significant (p < 0.05) improvement in the recovery of %SS at all reperfusion periods as compared to the control group. In addition, segment dysfunction during each occlusion period was significantly less severe in animals receiving a 24-hour pretreatment with MLA as compared to the controls. These results are the first to demonstrate that MLA, a lipid A derivative of endotoxin, preserves contractile function of ischemic myocardium in an in vivo canine model and that its cardio-protection is time dependent.

Preservation of high regional blood flow at epicardial rim after coronary occlusion in dogs.

A thin myocardial layer adjacent to the epicardium (epicardial rim) often survives after transmural myocardial infarction. Regional myocardial blood flow (Qm) at this rim may be high enough to maintain myocardial viability during coronary occlusion. To test this hypothesis, we measured Qm in 12 anesthetized dogs during left anterior descending coronary artery occlusion using nonradioactive colored microspheres. Myocardium in the region supplied by the occluded artery was sliced into sections approximately 0.5 mm thick from the epicardial surface to the endocardium, and the Qm in each section was determined. During occlusion, the Qm of myocardium within 0.5 mm of the epicardial surface remained at 74.8 +/- 8.8% of the preocclusion level. Maintenance of this high Qm during occlusion was abolished when an epicardial incision approximately 1 mm deep was made around the occluded area. These findings suggest that Qm is maintained at a surprisingly high level at the epicardial rim after coronary occlusion through epicardial arterial communications, which may be sufficient to maintain myocardial viability.

Angiotensin and angiotensin-converting enzyme inhibitors

The advent of the increasing use of different angiotensin-converting enzyme (ACE) inhibitors for the treatment of hypertension and cardiac failure has resulted in intense interest in the renin-angiotensin system (RAS) and its manipulation for therapeutic gain, and thus more patients will present for surgical anaesthesia while on maintenance therapy with these agents. The RAS is increasingly described in terms of systemic and tissue components. The systemic component is important in maintaining cardiovascular and body fluid homoeostasis, and is activated through renin release by the juxtaglomerular cells of the kidney in response to signs of disequilibrium. Angiotensin I is formed from renin substrate and is converted by ACE to angiotensin II, the major mediator of this system, which in turn stimulates aldosterone release from the adrenal cortex. In addition, aldosterone can be released independently in response to changes in plasma potassium concentration. The release of these hormones is regulated through various feedback mechanisms. The role of the tissue RAS is not clear but has been found to be present in many organ systems and is increasingly seen as the major site of action of ACE inhibitor drugs. The first oral ACE inhibitor, captopril, introduced in 1977, was followed by enalapril (which can also be administered intravenously) and lisinopril. These agents inhibit the conversion of angiotensin I to angiotensin II. ACE inhibitors also inhibit the inactivation of bradykinin, a vasodilator, which in turn enhances vasodilatory prostaglandin formation. ACE inhibitors have been found increasingly useful in the therapy of hypertension and cardiac failure, and new indications for their use are under investigation. The effect of anaesthesia on the RAS has undergone limited study. Indications are that neither the RAS nor ACE are directly affected by anaesthetics. Preoperative therapy with ACE inhibitors has been associated with severe hypotension after induction of and during anaesthesia. In addition, the critical role of the RAS in the defence of blood loss is becoming apparent in patients receiving ACE inhibitors. In aortic surgery, however, ACE inhibition may be renoprotective, and experimentally these drugs have been shown to reduce myocardial infarct size after coronary occlusion in dogs. Thus, further studies are required to determine the exact role of ACE inhibitors in the perioperative period.

Preservation of high coronary flow at the epicardial rim during coronary occlusion in dogs

Preservation of high coronary flow at the epicardial rim during coronary occlusion in dogs

Ventricular arrhythmias, sudden death, and silent myocardial ischemia

T HE ASSOCIATION between acute ischemia and ventricular arrhythmia in experimental animals is well established. Kaplinsky et al’ found two periods of early ventricular arrhythmia within 30 minutes of coronary occlusion in dogs. Janse et al* described two mechanisms of ventricular arrhythmia during acute experimental ischemia. At the normal side of the ischemic border they found a focal mechanism, induced possibly by injury currents in the normal Purkinje fibers, whereas in the ischemic myocardium they found macroand microreentry ventricular arrhythmia. Coronary occlusion in cats3 caused increased conduction time through the myocardium and epicardial regions, asynchronous depolarization and shortening of the refractory period, accompanied by ventricular arrhythmias. Kabell et al4 demonstrated that ischemia induced by reduction of collateral flow to an infarcted area in experimental animals, induced fractionation and delay of the electrogram in the infarcted zone and a higher frequency of pacing-induced ventricular tachycardia (VT). The effect of repeated 5-minute periods of ischemia followed by reperfusion on ventricular arrhythmia was assessed by Shiki and Hearse5 in rats; during reperfusion all animals exhibited VT and 83% of them exhibited ventricular fibrillation (VF). After conversion to sinus rhythm and following recovery, they were again subjected to 5-minute periods of ischemia and reperfusion. Following a short recovery period from the initial bout of ischemia only 8% to 17% of the experimental animals developed VT and none had VF, whereas longer recovery periods were associated with a progressive return of vulnerability. Thus, a very short period of ischemia and reperfusion “preconditioned” and protected the myocardium from reperfusion arrhythmias, but for only a short period of time. Recent evidence suggests that platelet activation may contribute to arrhythmogenesis during myocardial ischemia. Flores et al6 found that in ischemic myocardium platelets increased conduction time and reduced action potential duration. Further support for the role of platelets in inducing life-threatening arrhythmias was provided by Davies et al7 who described platelet aggregation as a frequent finding in patients with unstable angina suffering sudden ischemic cardiac death. The association between catecholamines, ischemia, and arrhythmia is a complex one. Within 10 minutes of ischemia the noradrenaline concentration in the myocardium is increased.8l” The accumulation of catecholamines in the extracellular space during ischemia in viable myocardium can cause malignant arrhythmia and acceleration of cell damage.‘O High doses of epinephrine decrease the resting membrane potential and action potential amplitude, slow conduction, and produce undirectional block; all these alterations predispose to reentrant arrhythmias. Epinephrine can also induce triggered activity, the underlying cause of automatic arrhythmias. i1,12 The importance of the sympathetic system during ischemia-induced arrhythmias is further substantiated by the protective effects of beta blockers both against myocardial ischemia and necrosisi3s14 and cardiac arrhythmias. 15.1h In human hearts no enhanced cardiac release of noradrenaline during coronary angioplastyinduced ischemia could be detected by sampling of coronary sinus blood.17 An association between ischemia and arrhythmias in humans was demonstrated by Garan et al’s in 17 patients with multivessel disease who survived out-ofhospital cardiac arrest. Before bypass surgery all developed VT during pacing-induced ischemia; after surgery VT or VF could not be induced in 10 patients, suggesting that ischemia was a major contributing factor for arrhythmia in these patients. Morady et al’” performed electrophysiological stimulation in 15 survivors

Analysis of factors affecting platelet function in coronary venous blood after coronary occlusion in dogs

Analysis of factors affecting platelet function in coronary venous blood after coronary occlusion in dogs

Decreased regional lactate production and output due to intracoronary continuous infusion of esmolol during acute coronary occlusion in dogs

This study was designed to test the hypothesis that intracoronary administration of esmolol can confer metabolic protection during coronary constriction or occlusion, without affecting hemodynamic parameters, in a canine model. Seventeen anesthetized open-chest dogs underwent direct cannulation of the left anterior descending coronary artery (LADa), its companion vein (LADv), and the distal circumflex vein (CFXv). LADa flow was measured with an electromagnetic flowmeter. Using a micrometer-driven snare around the LADa, flow was reduced by 50%, 75%, and 100% for 15 minutes, with 1 hour of normal flow before each constriction. In 7 dogs (group 1) chosen randomly, esmolol, 15 to 20 μg/kg/min, was infused continuously into the LADa; the rate was adjusted to maintain baseline hemodynamic values. The second group (10 dogs) was not treated with esmolol. Heart rate (HR), electrocardiogram (ECG), LADa flow, LV dP/dt, and aorta (Ao), pulmonary artery (PA), LADa, and left ventricular (LV) pressures were recorded continuously. Cardiac output (CO) (thermodilution) was measured and blood was sampled from all catheters before and after constrictions for analysis of glucose, lactate, sodium, potassium, and blood gases. Flow and pressure in the LADa in both groups decreased similarly during each corresponding constriction. Systolic LV pressure, LV dP/dt, and LV stroke work index were affected in both groups only during 100% constriction. HR, Ao, and PA pressures, and total and peripheral pulmonary resistances were affected similarly in both groups during each constriction. Myocardial lactate extraction and consumption were less negative (negative = net production and output) in the LAD perfusion bed during corresponding constrictions with esmolol than without it. Electrolyte and glucose concentrations and extraction and arteriovenous oxygen content differences in the ischemic and nonischemic areas during constriction were affected similarly in both groups. The ratio of oxygen delivery to oxygen consumption in the ischemic zone was higher with esmolol than without it before constriction (75% and 100%) and during constriction (50%). This study indicates that the intracoronary use of esmolol during moderate-to-severe coronary hypoperfusion can protect ischemic myocardium.

Alpha‐adrenoceptor subtypes and regional myocardial blood flow distribution during coronary occlusion in dogs

The involvement of postsynaptic alpha-adrenoceptors in the distribution of regional myocardial blood flows (RMBFs, microsphere technique) within the left ventricle has been investigated during intermittent coronary artery occlusion in open-chest anesthetized dogs. Two types of RMBFs distribution were assessed: (1) between endocardial (endo) and epicardial (epi) layers (endo/epi ratio) and (2) between nonischemic (NIZ) and ischemic zones (IZ) (IZ/NIZ ratio). Equipressor does of selective alpha 1-(cirazoline after rauwolscine) and alpha 2-(UK-14,304 after prazosin) adrenoceptor agonists were infused in dogs previously submitted to ganglionic and muscarinic blockade. In a control group, aortic pressure was mechanically raised by aortic stenosis to levels similar to those reached with both alpha-adrenoceptor agonists. Cirazoline and aortic stenosis increased RMBFs in IZ and NIZ but did not alter the calculated coronary resistance in NIZ and did not affect endo/epi and IZ/NIZ ratios. In contrast, UK-14,304 preferentially augmented coronary resistance in NIZ, increased IZ/NIZ ratio (both P less than 0.05) but did not affect endo/epi ratio in IZ and NIZ. Thus, we conclude that if transmural distribution of RMBFs (endo/epi ratio) is not preferentially controlled by any alpha-adrenoceptor subtype, postsynaptic alpha 2-adrenoceptors are of importance during coronary occlusion in promoting a favorable redistribution of RMBFs from NIZ towards IZ by inducing a selective NIZ coronary vasoconstriction (ie a "reverse coronary steal").

Influence of angiotensin-converting enzyme inhibition on cardiac function in myocardial infarction

Cardiac function in myocardial infarction (MI) depends on the extent of damage in ischemic myocardium and the compensatory response of residual myocardium. Because thrombolytic therapy is performed in many patients, reperfusion of ischemic myocardium may take place at various stages of progression of the ischemic insult. If perfusion is reestablished before necrosis occurs, myocardium may recover immediately or after hours to weeks (“stunned myocardium”). If coronary occlusion persists, necrosis develops in the subendocardium, propagates transmurally and forms a scar after the healing phase. Residual myocardium responds to loss of contractile tissue and material properties of the ischemic zone by hypertrophy and dilatation. This study shows that left ventricular dilatation is accompanied by an increase in stroke volume from 4 days to 4 weeks; however, left ventricular dilatation progresses while stroke volume remains constant from 4 weeks to 6 months, suggestive of non-compensatory left ventricular dilatation. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce lactate production after 60 seconds, and infarct size after 6 hours of coronary occlusion in dogs. Stunned myocardium recovers faster in animal experiments and pacing-induced myocardial ischemia may be prevented by ACE inhibitors. Left ventricular dilatation and mortality is reduced by ACE inhibitors in rats after MI. Several potential mechanisms are discussed to establish a favorable action of ACE inhibitors at various stages of MI. Clinical evidence is still pending; however, large studies are ongoing to clarify potential indications of ACE inhibitors in ischemic heart disease in humans.

Effects of the Partial β1-Adrenergic Agonist, Xamoterol, on Hemodynamics and Regional Myocardial Function During Acute Coronary Occlusion in Dogs

Xamoterol is a partial beta 1-adrenergic agonist that has combined beta 1-stimulating and beta 1-blocking actions. We studied the effects of xamoterol on hemodynamics and regional left ventricular (LV) function after circumflex coronary artery occlusion in eight anesthetized dogs. Left ventricular systolic wall thickening (%WT: sonomicrometry) was measured in nonischemic, marginal, and ischemic zones. Xamoterol (350 micrograms/kg i.v.) increased the maximum LV pressure (dP/dt) by 62% and aortic flow (AOF) by 52% and decreased LV end-diastolic pressure (EDP) but did not change heart rate (HR) and peak LV pressure (LVP). Xamoterol increased %WT in nonischemic (23.6 +/- 2.3 to 35.1 +/- 2.6%, p less than 0.05) and marginal (5.0 +/- 0.6 to 12.0 +/- 1.5%, p less than 0.05), but not in the ischemic region [-5.7 +/- 0.7 to -2.7 +/- 0.3%, not significant (NS)]. The beta 1-blocking action of xamoterol was evaluated. Xamoterol significantly attenuated the increase in HR and maximum dP/dt caused by isoproterenol (0.1 microgram/kg/min). %WT in each region was maintained at the level caused by xamoterol after isoproterenol. Thus, xamoterol improved cardiac function, yet prevented excessive stimulation by catecholamine in the presence of acute myocardial ischemia.

A possible involvement of oxygen free radicals in the development of myocardial acidosis during coronary occlusion in dogs.

The present study was designed to examine whether free radical scavengers attenuate myocardial acidosis induced by partial occlusion of the coronary artery in dogs. The myocardial pH was determined by a micro glass pH electrode inserted in the endocardial layers of the left ventricular wall perfused by the left anterior descending coronary artery. The left anterior descending coronary artery was occluded for 90 min incompletely so that the flow would be 1/2-1/3 the original flow. The myocardial pH before partial occlusion was 7.54-7.55. Partial occlusion decreased the flow in the left anterior descending coronary artery by 49.3-64.9% and the myocardial pH by 0.71-0.76, and increased the ST segment (surface electrocardiogram) by 6.3-9.3 mV. Saline (0.5 ml/kg), recombinant human superoxide dismutase (70,000 or 210,000 U/kg), or catalase (55,000 or 165,000 U/kg) was injected intravenously 30 min after partial occlusion. The injection of recombinant human superoxide dismutase or catalase alone did not restore the myocardial pH that had been decreased by coronary occlusion. The combined injection of recombinant human superoxide dismutase (70,000 U/kg) + catalase (55,000 U/kg), however, restored the myocardial pH without restoration of ST segment. In conclusion, recombinant human superoxide dismutase + catalase attenuated myocardial acidosis during ischaemia, suggesting a possible involvement of oxygen free radicals in the development of myocardial acidosis (especially in the endocardial layers) during ischaemia.