E. Hexeberg

Carvedilol improves function and reduces infarct size in the feline myocardium by protecting against lethal reperfusion injury

This study examined the effect of carvedilol, a vasodilating beta-adrenoceptor antagonist and antioxidant, on lethal reperfusion injury in feline hearts subjected to 40 min of regional ischemia and 180 min of reperfusion. 30 open chest anaesthetized cats were randomized into three groups. A control (n = 10) was compared with a group given carvedilol before coronary artery occlusions (n = 10) and a group given carvedilol immediately before and during early reperfusion (n = 10). Regional myocardial function was measured by sonomicrometry. Infarct size was determined by staining the left ventricle with triphenyl tetrazolium chloride. Myocardial blood flow was measured by radiolabeled microspheres. Tissue levels of glutathione were measured after reperfusion. Infarct size was significantly reduced compared to control both when carvedilol was given before ischemia (0.2 +/- 0.1 vs. 17.6 +/- 3.6%, P < 0.05). and when given immediately before reperfusion (3.7 +/- 1.3 vs. 17.6 +/- 3.6%, P < 0.05). Regional shortening improved significantly and the incidence of ventricular fibrillation during early reperfusion was reduced in both groups treated with carvedilol compared to control. Oxidized glutathione did not differ between groups in the post-ischaemic myocardium. This study supports that lethal reperfusion injury is a significant phenomenon. Furthermore, carvedilol reduces infarct size and reperfusion arrhythmias, and improves post-ischaemic regional myocardial function by protecting against both ischaemic and lethal reperfusion injury. The present study does not answer whether it is the non-selective beta- or alpha 1-receptor antagonism, the antiarrhythmic or the antioxidant actions of carvedilol that is responsible for the protective effect.

A study on lipid metabolism in heart and liver of cholesterol- and pectin-fed rats

Pectin is known as a cholesterol-reducing dietary fibre, and in the present study we addressed the question whether pectin affected the quantity of lipid in droplets in the myocardial cells and of lipid in the liver cells. Male Wistar rats received either a diet containing cholesterol or a standard diet without cholesterol with 0, 50 or 100 g pectin/kg incorporated for 10 d. The fractional volume of lipid droplets in the myocardial cells decreased as a function of pectin dose in both the standard-fed and the cholesterol-fed rats. Serum cholesterol was significantly reduced in both groups after addition of 100 g pectin/kg diet. The cholesterol diet increased the liver cholesterol level, and 100 g pectin/kg diet resulted in a lower concentration of liver cholesterol in the cholesterol-fed animals, but the influence on standard-fed rats was modest. Hydroxymethylglutaryl-CoA reductase (EC 1.1.1.88; HMG-CoA reductase) activity increased when pectin was given in the standard diet. Liver triacylglycerol level increased after cholesterol and pectin feeding. Mitochondrial fatty acid oxidation and phosphatidate phosphohydrolase (EC 3.1.3.4) activity tended to decrease, whereas the peroxisomal fatty acid oxidation and acyl-CoA oxidase activity were unchanged. Increased hepatic triacylglycerol content by cholesterol and pectin treatment may be due to inhibited mitochondrial fatty acid oxidation along with increased availability of fatty acid for esterification and triacylglycerol synthesis. The presence of pectin in the diets of cholesterol-fed rats resulted in increased hepatic concentration of triacylglycerols and increased mitochondrial fatty acid oxidation. In this case the hepatic accumulation of triacylglycerol may be mediated by a reduced efflux of triacylglycerols from the liver.

Endogenous Adenosine Attenuates Myocardial Stunning by Antiadrenergic Effects Exerted During Ischemia and Not During Reperfusion

Summary The effect of adenosine receptor blockade and adrenergic blockade on myocardial stunning [left anterior descending coronary artery (LAD) occluded for 10 min and reperfused for 180 min] was studied in 38 open-chest cats. A control group (Control) was compared with two other groups in which adenosine receptors were blocked by 8-phenyltheophylline (7.5 mg/kg) before reperfusion (8-PT-R) or before ischemia (8-PT-I). Group A, in which adrenergic receptors were blocked (doxazosin 200 μg/kg + propranolol I mg/kg), was compared with group A + 8-PT-I, in which both adenosine and adrenergic receptors were blocked before coronary artery occlusion. Regional systolic function assessed by sonomicrometry in the LAD perfused area recovered less in 8-PT-I (55 ± 5% recovery) as compared with Control (87 ± 9%) and 8-PT-R (89 ± 8%), which indicates that adenosine receptor blockade during ischemia increases stunning. Functional recovery was similar in Control, group A (96 ± 5%), and group A + 8-PT-I (87 ± 5%), which demonstrates that if adrenergic receptors are blocked, adenosine receptor blockade during ischemia does not increase stunning. These results may indicate that the cardioprotective effects of endogenous adenosine are mediated through antiadrenergic effects exerted during coronary artery occlusion.

Non-uniform recovery of segment shortening during reperfusion following regional myocardial ischaemia despite uniform recovery of ATP

OBJECTIVE This study focused on transmural postischaemic recovery of ATP and regional contractile function related to reversible and irreversible tissue injury. METHODS Fifty anaesthetised open-chest cats were randomised into two groups. Groups I: 10 min of LAD occlusion (n = 10) and 10 min of LAD occlusion followed by 180 min of reperfusion (n = 15). Group II: 40 min of LAD occlusion (n = 10) and 40 min of LAD occlusion followed by 180 min of reperfusion (n = 15). Histochemical staining (TTC) was performed in hearts from 5 additional cats subjected to 40 min of LAD occlusion and 180 min of reperfusion. Regional function was measured by sonomicrometry in the circumferential (CIRC) and longitudinal (LONG) axis of the anterior left ventricular midwall. Myocardial blood flow was measured with radiolabelled microspheres. Adenine nucleotides in the subepi- and subendocardium were measured with high-pressure liquid chromatography after LAD occlusion and after reperfusion. RESULTS Ten minutes of ischaemia induced a transmurally uniform ATP depletion. Repletion of ATP following reperfusion was transmurally uniform. Recovery of regional shortening was non-uniform with better recovery in CIRC (76 +/- 8% vs. LONG; 46 +/- 10%, P < 0.05). Forty minutes of ischaemia induced a more severe ATP depletion in the subendocardium compared to the subepicardium. A slight recovery of ATP following reperfusion was transmurally uniform. Recovery of function was present only in CIRC (48 +/- 6%). Tissue blood flow showed a transmurally homogenous flow restriction during ischaemia and uniform recovery following reperfusion. TTC staining demonstrated predominantly subendocardial infarctions following 40 min of regional ischaemia. CONCLUSIONS Postischaemic recovery of regional function is non-uniform and independent of ATP repletion and collateral blood flow during ischaemia. Absence of functional recovery in LONG is associated with development of infarction.

Blood flow regulation during acute regional ischemia in feline hearts: Importance of postjunctional α1- and α1-adrenoceptors

Summary: Influence of postjunctional α1- and subsequent α2,-adrenergic antagonism on myocardial blood flow was measured in a group of anesthetized cats with acute occlusion of the left anterior descending coronary artery (LAD) and a control group (n = 10 for both). The relatively selective postjunctional α1-(doxazosin) and α2-adrenergic (SK& F 104078) antagonists were applied after β-adrenergic blockade (propranolol). Regional myocardial blood flow was obtained with radiolabeled microspheres. Major hemodynamic determinants for perfusion were kept constant both within and between groups by right atrial pacing and aortic obstruction. Mean coronary resistance in nonischemic myocardium was permanently lower in the occlusion group as compared with controls (p < 0.01). Subsequent α2-adrenergic antagonism reduced mean coronary resistance in controls only (p < 0.05). Cardiac output (CO) and dP/dt was reduced in LAD-occluded hearts after α2-adrenergic blockade (p < 0.01, p < 0.05). The study demonstrates the significance of postjunctional α2-adrenergic-mediated vasoconstriction in well-perfused myocardium of control hearts, whereas such vasoconstriction was deteriorated in LAD-occluded hearts. A role for myocardial α2-adrenoceptors for maintenance of global cardiac function in acute regional ischemia was also indicated.

Midazolam in combination with fentanyl/fluanisone and nitrous oxide as anaesthesia in rabbits-cardiovascular parameters

When establishing a rabbit model for cardiovascular research in our laboratory we have used midazolam in combination with fentanyl/fluanisone (MFF) and nitrous oxide as anaesthesia. In this study we focused on the effect of the anaesthetic regimen on cardiovascular parameters during open-chest surgery in 12 rabbits. Rabbits were tranquillized by intramuscular injection of fentanyl/fluanisone (0.2 ml/kg of the drug that contained 10 mg/ml fentanyl and 0.2 mg/ml fluanisone). After an intraperitoneal injection of midazolam (4 mg/kg) and additional i.m. injection of fentanyl/fluanisone (0.1 ml/kg) the rabbits were tracheotomized and ventilated on a respirator delivering a gas mixture of 50% N2O, 47.5% O2, and 2.5% CO2. The femoral vein and artery were cannulated and then rabbits received a supply of MFF intravenously. The chest was opened by midline sternotomy and the left ventricle was instrumented with piezo-electric crystals for measurement of regional left ventricular function and with a pressure catheter to measure left ventricular pressure. Radiolabelled microspheres were used to assess cardiac output and left ventricular tissue blood flow. Blood gas analysis showed no difference in the values of pH, pCO2 and pO2 between the open-chest and the closed-chest states. Mean aortic pressure was 74 ± 4 mmHg in the closed-chest state and 65 ± 4 mmHg in the open-chest state. Tissue blood flow showed that the left ventricle was well perfused, and mean tissue blood flow values varied between 1.80 and 2.36 ml/min·g. We conclude that the anaesthetic regimen used is easy to control. It is well tolerated in rabbits and is suitable for studies on myocardial contraction in rabbits.

Postjunctional α-Adrenergic Stimulation of Inotropy in Hypoperfused Myocardium Outside an Acute Infarct

Summary: The functional significance of myocardial postjunctional α-adrenergic support of inotropy in the vicinity of an acute regional ischemic zone was addressed in pentobarbital-anesthetized, β-adrenergic blocked cats with circumflex coronary artery occlusion. Regional myocardial performance was measured by ultrasonic crystals in the anterior wall perfused by the left anterior descending coronary artery (LAD) before and during postjunctional α-adrenergic antagonism (SK&F 104078 2 mg/kg). A group with unrestricted flow in the LAD (control group) was compared with a group perfused below the autoregulatory pressure range (stenosis group). End-systolic pressure–length relations during dynamic afterload elevation were calculated for assessment of regional contractility. Regional myocardial blood flow (RMBF) was measured by radioactive microspheres. SK&F 104078 did not alter regional myocardial shortening or the slope of end-systolic pressure–length relations in the control group. In the stenosis group, however, α-adrenergic antagonism produced significant deterioration of shortening as well as consistent reduction of the slope of the end-systolic pressure–length relations (p < 0.05). As a reflection of reduced demands for perfusion, impairment of midmyocardial and endocardial blood flow occurred in the stenosis group (p < 0.05). These findings imply a negative inotropic effect of SK&F 104078 in metabolically vasodilated myocardium in the vicinity of an acute ischemic region.

Gradual reduction of coronary perfusion pressure in cats: changes in transmural distribution of blood flow.

We evaluated a model for regional myocardial hypoperfusion in cats with an extracorporeal shunt line to the left main coronary artery, and investigated the effects of reduced coronary perfusion pressure on the transmural distribution of left ventricular blood flow measured with radioactive microspheres. Shunt establishment did not alter cardiac function, myocardial tissue blood flow, or its transmural distribution. An artificial shunt stenosis, which clearly reduced coronary perfusion pressure without changing cardiac function, caused reduced endocardial blood flow, slight flow reduction in mid-myocardium, and no flow change in the epicardium. When a severe stenosis was applied, causing increased end-diastolic pressure and reduced shunt flow, endocardial and mid-myocardial flow further decreased whereas epicardial blood flow remained essentially unchanged. These results demonstrate a transmural profile of the coronary autoregulation capacity.

Negative Inotropic Effect of Propranolol Is Attenuated in Underperfused Feline Heart with an Acute Ischemic Region

Summary β-Adrenergic blockade alleviates myocardial ischemia, probably largely through heart rate (HR) reduction. We hypothesized that the negative inotropic effect of β-blockade, which is believed to be potentially dangerous, is attenuated in underperfused hearts with an acute coronary artery occlusion. We studied the effect of intravenous propranolol (1 mg/kg i.v.) in feline hearts with acute circumflex coronary artery (LCX) occlusion by cross-oriented segments in normally perfused and mildly underperfused left ventricular (LV) anterior wall. A control group (n = 10) was compared with a stenosis group (n = 9) in which the mean coronary perfusion pressure was reduced (91 ± 4 g vs. 136 ± 5 mm Hg, p < 0.01). End-systolic pressure-length (ESP-ESL) relations during dynamic afterload increase and preload reduction were calculated to evaluate regional inotropy. HR and LV peak systolic blood pressure (LVSP) decreased in both groups after β-blockade (p < 0.05). Subendocardial and mid-myocardial blood flow measured by radiolabeled microspheres decreased in the control group (p < 0.05) but was unchanged in the stenosis group. Systolic shortening of circumferential segments also decreased in the control group (p < 0.05) but was unchanged in the stenosis group. ESP-ESL relations of circumferential segments shifted markedly rightward in the control group, whereas a modest rightward shift was noted in the stenosis group. This study in feline heart with acute LCX occlusion showed an attenuated negative inotropic effect of β-blockade in underperfused LV anterior wall