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Intra-aortic balloon counterpulsation (IABCP) is generally known to have a profound effect on several physiological parameters of the heart with coronary occlusion, but only few data concerning its metabolic and ultrastructural effects are thus far available. In this paper evidence is presented that IABCP acts on the metabolism and structure of the myocardium besides improving circulatory and functional parameters. IABCP thus prevents the full development of changes characteristic of the ischaemic and/or failing heart in noninfarcted and also partially in infarcted areas of the myocardium. [ABSTRACT FROM PUBLISHER]

Adrenergic regulation of the heart function is well documented by many studies. Catecholamines act through alpha(1)-, beta(1)-, beta(2)-, and beta(3)-adrenoceptors (ARs) in the heart. There are many findings about the changes of beta(1)- and beta(2)-AR in heart failure (HF). On the other hand, the role of other AR subtypes is not clear yet. We focused on determining how HF could affect gene expression and specific ligand binding to alpha(1A)-, alpha(1B)-, alpha(1D)-, beta(1)-, beta(2)-, and beta(3)-AR. Hearts from 11 patients with HF subjected to transplantation were investigated. As a control, corresponding parts from hearts not suitable for transplantation were used. We have found significantly higher mRNA levels of alpha(1A)-, alpha(1B)-,beta(1)-, and beta(2)-AR in the left ventricle of failing hearts compared to the levels in controls. beta(3)-AR mRNA levels in the left ventricle of failing hearts were not changed. No changes in mRNA levels of all receptors studied in other cardiac areas were found. On the other hand, binding studies showed a substantial decrease in left ventricles of failing hearts in all alpha(1)-AR subtypes and in beta(1)- and beta(2)-AR. However, the binding to beta(3)-AR was not changed. Our results suggest that alpha(1)-AR changes might be part of a compensatory mechanism, by which the heart suffering from the HF tries to secure its function, and it could be hypothesized that ineffective beta(3)-AR regulation might be involved in development of HF. According to our knowledge, this is the first report about the beta(3)-AR binding in HF.

Background: It has been convincingly established that cardiopulmonary bypass routinely used in cardiac surgery induces an oxidative stress. The extensive production of reactive oxygen species occurring during cardiopulmonary bypass has a deleterious effect on the endogenous antioxidant defense pool. The recovery of antioxidant enzyme activities as well as other antioxidatively substances is one of the important tasks for the effective defense of patients in the postoperative period., Aim of the Study: Oxidative stress markers and the antioxidant status and the activities of some antioxidant enzymes were studied in patients during one-week period after cardiac revascularization performed using cardiopulmonary bypass and the results were compared with patients operated by off-pump technique., Patients and Methods: Thirty-nine patients undergoing elective surgical revascularization (coronary artery bypass grafting) were divided in two groups: twenty-two patients operated using cardiopulmonary bypass (group A) and a group B of seventeen patients undergoing pump-off surgery. Blood samples were drawn before operation and then in course of the first week after surgery. The following biochemical parameters were estimated: plasma levels of total antioxidant status (TAS) and of thiobarbituric acid reactive substances (TBARS) as well as erythrocyte activities of two antioxidant enzymes--superoxide dismutase (SOD) and glutathione peroxidase (GPx)., Results: There was a significantly decreased preoperative and also postoperative levels of TAS associated with a preoperatively increased level of TBARS in group A only. In both groups of patients (especially in group B), markedly decreased activity of SOD was observed. The increase of GPx activity--especially on the third postoperative day--was not significant., Conclusions: Regardless of the surgical technique, both groups of patients had a markedly decreased antioxidant capacity with a significantly increased production of lipid peroxides especially in patients operated with cardiopulmonary bypass. The decreased antioxidant status was connected with decreased erythrocyte activity of SOD. Therefore, we recommend the regular supply of antioxidant acting substances (antioxidant vitamins and coenzyme Q10) be included in their standard therapeutic strategy especially in the preoperative period. (Tab. 2, Fig. 4, Ref: 22.)

Tedisamil is antiarrhythmic class III drug with antifibrillating/defibrillating potency linked to enhancement of intermyocyte gap junctional electrical coupling most likely via its sympathomimetic cAMP-related mechanisms. This study was designed to examine the effect of tedisamil on cAMP level in guinea pig hearts in vivo and in vitro in Langendorff preparation. The drug was administered either as a bolus into vena jugularis in dosage 1.0 and 1.5 mg/kg or into the perfusion solution at a concentration of 1.5 x 10(-6) mol/l. In additional experiments, this period was followed by brief 10 min global ischemia, induced by clamping of the aorta or perfusion. After 10 min from the onset of tedisamil administration as well as after 10 min of ischemia the ventricular tissue was immediately frozen for cAMP immunoassay. Tedisamil caused in normal heart small but significant dose-dependent increase of myocardial cAMP (pmol/mg) level in vivo 1.8 and 2.5 vs. 1.4 as well as in vitro 1.1 vs. 0.8 (p < 0.05) conditions. Ischemia itself induced accumulation of cAMP in both, in vivo and in vitro experiments, 2.6 vs. 1.4 and 1.3 vs. 0.8, respectively. The preischemic elevation of cAMP by tedisamil was not potentiated by following ischemia, on the contrary, decline of the cyclic nucleotide was detected comparing to ischemia itself. In conclusion, tedisamil increased cAMP level in normal heart and prevented additional ischemia-related elevation of this nucleotide. The results indicate modulation of myocardial cAMP level by tedisamil, which may account for its protective effect on gap junctional electrical coupling.

The absorption rate of three model drugs, i.e., pentacaine (highly lipophilic), stobadine (moderately lipophilic) and acetylsalicylic acid (hydrophilic), was studied using the chronic dog ileal loop method. The drugs were dissolved either in 0.9% unbuffered solution of NaCl or in antacid mixture. When using 0.9% NaCl, the half-lives of absorption (t1/2 (dis)) of pentacaine and stobadine were (mean +/- SD) 23.2 +/- 7.8 min and 20.8 +/- 7.2 min, respectively. For stobadine a good agreement was found between its t1/2 (dis) from the ileum and its absorption half-life determined from blood concentrations after oral administration to dogs. The absorption of acetylsalicylic acid accounted for only 10-20% of the dose introduced into the loop over 45 min; thus, a reliable value of t1/2 (dis) could not be determined. The administration of unbuffered solution of NaCl into the loop was accompanied by rapid increase of pH from acidic to basic value. The antacid mixture failed to affect the absorption rate of the drugs studied. Sampling from the ileum was limited to 35-55 min due to rapid absorption of water. These results suggest that: 1) measurement of the absorption rate of some drugs, e.g., stobadine, by using the chronic dog ileal loop method may adequately predict their absorption rate after peroral administration to the dog, 2) interactions of antacids with drug absorption in the ileum may not play a significant role because of the strong buffering capacity of the ileum, and 3) rapid absorption of water from the ileum does not allow to reliably determine the value of t1/2 (dis) for slowly absorbed drugs.

Objective: To re-evaluate the suitability of chlorpromazine and trifluoperazine to prevent postischemic reperfusion injury of the myocardium., Design: Acute occlusion (60 mins) and subsequent reperfusion (120 mins) of the left anterior descendent coronary artery with monitoring of hemodynamic, morphological and biochemical variables of the heart., Setting: Experimental study., Animals: Seventy adult mongrel dogs., Interventions: Chlorpromazine (15 mg/kg body weight) or trifluoperazine (2 mg/kg body weight) given intravenously 30 mins after the onset of occlusion., Main Results: Reperfusion alone increased the regional bloodflow and left ventricular end-diastolic pressure (P < 0.05 to 0.01), and reduced the size of the occluded area. Reperfusion also decreased the dp/dtmax, Vmax, mean aortic pressure, cardiac index, etc, but failed to improve cardiac ultrastructure and metabolism. Chlorpromazine or trifluoperazine induced a further reduction (P < 0.05 to 0.01) in infarct size, left ventricular end-diastolic pressure and systemic resistance index, and caused an increase in dp/dtmax, Vmax, cardiac index and regional bloodflow in the ischemic and border zones of the left ventricle. Moreover, these drugs preserved, to a certain extent, the metabolism of the myocardium and its ultrastructure., Conclusions: In spite of their considerable preventive effect, neither chlorpromazine nor trifluoperazine provided a complete prevention of reperfusion injury to the myocardium.

Alterations in the levels of glutathione, glutathione disulfide, malondialdehyde, and the activity of gamma-glutamyl transpeptidase in nonischemic and ischemic parts of the left ventricle and in the right ventricle were studied in canine hearts after occlusion of the left anterior descending coronary artery for 60 minutes and subsequent reperfusion for 20 minutes. Ischemia caused no significant change in malondialdehyde concentration and gamma-glutamyl transpeptidase activity in ischemic or nonischemic parts of the left ventricle, but it increased the activity of gamma-glutamyl transpeptidase in the continuously perfused right ventricle. Reperfusion of the ischemic areas of the left ventricle was accompanied by accumulation of malondialdehyde and an increase in gamma-glutamyl transpeptidase activity, not only in the reperfused and adjacent areas of the left ventricle, but also in the continuously perfused right ventricle. An increase in the level of glutathione disulfide and decrease in glutathione occurred in all parts of the myocardium during coronary occlusion; these changes were maintained in reperfusion. The findings indicate that the effects of acute occlusion and reperfusion of the left anterior descending coronary artery on myocardial concentrations of glutathione, glutathione disulfide and malondialdehyde or gamma-glutamyl transpeptidase activity are not confined to the local area.

Cardiopulmonary bypass has been successfully used in cardiac surgery for more than 39 years. In spite of many technical improvements oxygenators are still damaging to blood. We therefore decided to change the conventional CPB into biventricular bypass without an oxygenator, using the patient's lungs for autooxygenation. A double-pump system without an oxygenator was used in 11 patients undergoing aortocoronary bypass grafting. The cardiopulmonary pulmonary setup consisted of two separate systems with two roller pumps, plastic reservoirs and filters, and one cardiotomy reservoir and heat exchanger. Cannulations were performed through the right atrium and pulmonary artery for right-sided bypass, and through the left atrium and aorta for left-sided bypass. The results confirmed the full reliability of autooxygenation during CPB. All patients were well oxygenated with and inspired oxygen fraction of 30%. Values of arterial and venous O2 saturation as well as pO2 and pCO2 varied within the normal range. Platelet count decreased by 23% between interval I and IV, but only by 12% during biventricular bypass. Fibrinogen concentration decreased by 7% between interval I and IV, but only by 4% during biventricular bypass. No patient developed postperfusion syndrome. In our small series of patients, biventricular bypass was found to be simple to handle and to provide good conditions for the surgical procedure. It appears to be more physiological and less traumatic than conventional CPB. The described approach may further improve results of aortocoronary bypass grafting. (Tab. 2, Fig. 1, Ref. 12.).

The technique of surgically induced acute progressive right ventricular failure in experimental animals is described. It sumultates the hemodynamic situation of right ventricular failure in some patients after termination of extracorporeal circulation applied for carrying out procedures on the left ventricle. The described technique consists of rightsided longitudinal ventriculotomy, destruction of the tricuspid valve, and ligation of the right coronary artery. Nine control dogs died within two hours after induction of failure due to low stroke volume caused by low pulmonary and left atrial pressure. The use of rightsided support appliance draining blood from the right atrium in systole and pumping it into the trunk of the pulmonary artery in diastole by means of a membrane pump resulted in further 12 dogs in the restoration of left ventricular diastolic pressure, significant increase of aortal pressure (p less than 0.003) and stroke volume (p less than 0.003) and in a decrease of right atrial pressure (p less than 0.003). The study demonstrated that by using the described mechanical support the circulation can be adequately assisted so that the failing right side of the heart can get restored. (Tab.1,Fig.5,Ref.25.).

Activation of an intracellular calcium-calmodulin complex may play an important role in myocardial injury induced by ischemia and reperfusion. Chlorpromazine and trifluoperazine, calmodulin inhibitors, were used to enhance myocardial preservation by preventing harmful effect of intracellular calcium accumulation. The experimental model used one-hour LAD coronary occlusion and subsequent two-hour reperfusion in 70 dogs divided into four groups. Reperfusion alone significantly increased regional myocardial blood flow and left ventricular enddiastolic pressure and significantly reduced infarct size, dp/dt max, V max, mean aortic pressure, cardiac index and index of left ventricular minute work. Phenothiazines, applied at the 30th minute of occlusion significantly reduced infarct size, left ventricular enddiastolic pressure and index of systemic resistance and significantly increased dp/dt max, V max, cardiac index and regional myocardial blood flow in ischemic and border zones. The physiological results tightly correlated with the biochemical results and ultrastructural findings. The present study suggests that phenothiazines can improve cardiac performance and preservation of myocytes by preventing calcium stimulatory effect on degradative enzymes and may represent a potential clinical tool in modifying myocardial injury induced by ischemia and reperfusion.

The fine structural alteration and histochemical changes of the cardiac conduction system were studied in dogs and rats using various models of ischemic and reperfusion injury. The role of Ca2+ overload and reactive oxygen species (ROS) per se were also investigated. In all models of injury the activity of glycogen phosphorylase (histochemical indicator of the early ischemic changes) was present in nodal and conducting cells, although it was markedly diminished or absent in surrounding contractile muscle. Fine structural ischemic alterations progressed more slowly in conducting cells in comparison with working myocardial cells. Changes induced by Ca2+ paradox or ROS were reversible in conducting tissue in contrast to working myocardial tissue. The observations support the concept that conducting cells are more resistant to ischemia and also to reperfusion related injury than contractile myocardial cells.

The changes in cardiac and in total haemodynamics, occurring during the first seconds of occlusion and the subsequent desocclusion of coronary arteries were studied on 28 dogs. The most intensive changes were observed after the trunk occlusion of the left coronary artery. Simultaneously with decreasing blood inflow into the myocardium its contractility and the systolic pressure in the left ventricle and the outflow from the coronary sinus began to fall rapidly. The systolic pressure in the left ventricle decreased within the first 10 s from 24 to 13-15 kPa (180 to 100-110 mm Hg), which means that the systolic pressure fell about 1 kPa (7-8 mm Hg) per second, or 0.5-0.6 kPa (4-5 mm Hg) per systole. At the same time the end-diastolic pressure in the left ventricle also increased from zero to 3-4 kPa (25-30 mm Hg). After the trunk desocclusion of the left coronary artery the systolic pressure in the left ventricle proceeded to fall by about 2-3 kPa (15-22 mm Hg). Only then, 20-25 s after the desocclusion, blood flow in the left coronary artery began to rise intensively and 4-6 s later the myocardial contractility and the systolic pressure in the left ventricle also increased. After unclamping (50-60 s), there was an overshoot of haemodynamic values above preocclusive values and then followed the compensatory phase. This phase lasted 80-90 s and on its peak the pressure and flow parameters increased by about 50-60% above preocclusive values. During the occlusion of ramus interventricularis anterior or ramus circumflexus for 30-60 s the haemodynamic parameters changed only slightly. The same was observed during trunk occlusion of the right coronary artery (30-60 s), but in that case many extrasystoles occurred.

The effect of adrenaline and noradrenalin on the coronary circulation was studied in narcotized dogs. In 14 dogs every 20 seconds the venous blood from coronary sinus was examined. In a second series of animals the blood flow in the coronary artery and in the femoral artery was recorded continuously after intraarterial, resp. intravenous injection of catecholamines. In some experiments a constant perfusion pressure in coronary and femoral systems was maintained by help of a stabilizing device. The results of these experiments unequivocally proved that application of catecholamine was always followed by dilatation of the myocardiac and constriction of femoral vascular system. In no case catecholamines caused initial vasoconstriction of coronary vessels. The reasons for that paradoxical efficacy are discussed.

Left descending coronary ligation was performed on 70 dogs and divided into four groups. I. group - permanent occlusion (5 dogs 60 min, 5 dogs 120 min, 5 dogs 180 min), II. group - 15 dogs (60 min occlusion + 120 min reperfusion), III. group - 20 dogs (60 min occlusion, 15 mg Chlorpromazine [CPR], reperfusion 120 min), IV. group - 20 dogs (60 min occlusion, 2 mg Trifluoperazine [TFP] + 120 min reperfusion). CPR or TFP were administered 30 min after the ligation. Effect of drugs was quantified on tetrazolium stained gross sections and studied from physiological, biochemical and ultrastructural points of view. Results reveal that treatment of animals with phenothiazines revealing calmodulin inhibitory action, considerably improved the ultrastructure of myocytes in area at risk and allowed for recovery at least 60 per cent of injured myocytes after restoration of reflow. Ultrastructural findings tightly correlate with physiological and biochemical results.

Acute bilateral atrial auriectomy in anesthetized dogs reduced diuresis and natriuresis induced by both extracellular fluid volume expansion with isotonic saline and a hypertonic saline load. Since a hypertonic saline load, in contrast to isotonic saline infusion, was not accompanied by a significant increase in central venous pressure it is proposed that either increased plasma osmolality or plasma sodium concentration (or both) participate in the modulation of the atrial natriuretic mechanism.