Experimental autoimmune myocarditis in rats and therapeutic histamine H1 - H4 receptor inhibition.

Myocarditis, a life threatening disease, is still not adequately treated. Histamine plays an important role in physiology and pathophysiology of cardiovascular system. All four histamine receptors (H1R - H4R), are present in the heart. Experimental autoimmune myocarditis (EAM) was used to investigate which histamine receptor had a greater impact on the disease's progression. EAM was evoked in Lewis rats by porcine myosin immunization. Mepyramine, ranitidine and ciproxifan were used to inhibit H1R, H2R and H3R receptors, respectively, and 2,4-diaminopyrimidines: ST994, ST1012, ST1006 were ligands of H4R. Quinapril, an ACE inhibitor, served as a reference drug. Drugs were administered daily, either from 0 - 2 weeks or from 2 to 4 weeks post EAM induction. Cardiac dysfunction developed with significant decreases in left ventricular ejection fraction and fractional shortening due to dilatation and wall thickening. EAM rats treated with mepyramine and ST994 in weeks 0 - 2 had the lowest decreases. These treated with ST994, ST1012 or quinapril performed much better the following 2 weeks without therapy than did the other groups. On autopsy their hearts were smaller, less fibrotic, histopathological changes in them of a lower grade. When the treatment started with 2 weeks' delay, the ST994-treated EAM rats showed the highest median survival. H4 receptor antagonism inhibits heart remodelling, preserves heart contractility, improves survival and may be of potent therapeutic relevance in human clinics. The blockade of H1 receptor inhibits heart dilatation but does not prolong the life.

The central histamine level in rat model of vascular dementia.

The histaminergic system plays an important role in memory and learning. Deficient histaminergic transmission in the human brain in vascular dementia (VD) has been suggested. To get a better insight into the problem, a rat model of VD based on permanent bilateral occlusion of the common carotid arteries (BCCAO) leading to chronic cerebral hypoperfusion was used. Prior to the BCCAO, male Wistar rats underwent 7 days training and only those animals that positively passed the holeboard memory test were chosen for the study. The rats which were operated on were injected i.p. daily for 6 days with either a monoamine oxidase B inhibitor - PF9601N (40 mg/kg), an acetycholinesterase inhibitor - tacrine (3 mg/kg), a histamine H(3) receptor blocker - DL76 (6 mg/kg) or saline. The first retest (R1) was performed one week after the surgery while each subsequent test was 5-7 days apart. The rats were euthanized 2 or 4 weeks following the operation. The concentration of brain histamine (HA) and the activity of histamine metabolising enzymes were measured using current procedures. The BCCAO drastically increased latency and run time (p<0.001) 54 ± 30 vs. 3.4 ± 1.2 and 268 ± 18 vs. 74 ± 9, respectively, and affected working memory rather than reference memory as measured by the 1(st) retest (R1). Treatment with either PF9601N or tacrine seems to exert a positive effect on working memory. This tendency disappeared after the drug treatment stopped. Latency and run time, although they improved in R2-R4, never attained the preoperative values. The brain tissues from rats treated with PF9601N showed only 15% and 50% of untreated rat MAO B and MAO A activity, respectively, despite the drug administration having been discontinued for 3 weeks. Other drugs examined did not influence MAO enzymes. Neither did histamine N-methyltransferase activity show changes related to BCCAO nor to the treatments. The hypothalamic HA concentration was significantly reduced after BCCAO: 1.13 ± 0.1 vs. 1.91 ± 0.16. Noteworthy, the rats treated with PF9601N or DL76 had brain HA levels not significantly different from their intact counterparts. The rat vascular dementia model supports deficiency in histaminergic system in VD.

The activity of protein tyrosine kinases of rat heart after ischemia and reperfusion.

BACKGROUND: Protein phosphorylation plays a very important role in the modulation of signal transduction in many tissues including heart. The activities of protein tyrosine kinases (PTKs) of the heart are rather low but PTKs in cardiac myocytes could be involved in many processes including necrosis, apoptosis, and inflammation. All of them lead to heart failure and are the result of such conditions as ischemia and reperfusion. The aim of our study was to investigate if the ischemia and reperfusion could change the protein tyrosine kinases activities in rat cardiac myocytes. MATERIAL AND METHODS: The specific activities of PTKs were defined as (3)2P incorporation into exogenous poly(Glu, Tyr)--known as an artificial substrate for all types of protein tyrosine kinases. RESULTS: The activity of tyrosine kinases in ischemic heart was lower than in control-intact heart and amounted to 50-60% of control values. In the heart after ischemia and following reperfusion the activities of PTKs increased to 135% of control. CONCLUSIONS: Ischemia and reperfusion changed activity of PTKs. There were no differences in protein tyrosine activity between the left and right ventricles.

Activation of blood platelets after percutaneous transluminal coronary angioplasty and coronary artery bypass graft surgery.

We have evaluated the activation of platelets in blood samples taken from patients with stable angina undergoing balloon angioplasty (percutaneous transluminal coronary angioplasty [PTCA]) (n=11) or coronary artery bypass grafting (CABG) under hypothermic (n=11) or normothermic conditions (n=11). We have found that surface expression of P-selectin on platelets in whole blood from PTCA patients upon thrombin treatment was significantly reduced, as compared with control platelets from healthy subjects. This effect was partially reversed when platelets washed from the same blood sample were used, but even then P-selectin expression was significantly lower in PTCA patients than it was in control subjects. There was a significant increase in basal expression of P-selectin in blood platelets taken from patients who underwent CABG under normothermic conditions (warm blood cardioplegia) as opposed to hypothermic patients (cold crystalloid cardioplegia). These platelets retain the ability to respond to agonists, although to a much lower extent than do those from healthy control donors. The surface exposure of P-selectin on resting and thrombin-treated platelets isolated from CABG surgery patients was not different from that of the control platelets. The adhesion to fibrinogen of resting and thrombin-treated platelets from patients who underwent balloon angioplasty as well as CABG surgery under normothermic and hypothermic conditions was significantly reduced when compared with the fibrinogen of the control platelets. These results suggest that the function of platelet fibrinogen receptor is impaired in patients with stable angina pectoris and that PTCA and CABG surgery activates platelets.

Moderate systemic hypothermia and cold crystalloid cardioplegia influence on myocardial ischemic and revascularisative injury.

The number of granulocytes, their ability to generate superoxide anion (O2-) and the activities of Cu, Zn--superoxide dismutase (SOD-1), glutathione peroxidase (GSH-Px), catalase (CAT) as well as malonyldialdehyde (MDA) concentrations in erythrocytes in the blood extracted from the venous sinus and aorta under coronary artery bypass were examined with the use of St. Thomas Hospital cardioplegic solution. Specimens at the peak of ischemia of the right atrium for ultrastructural examination of the endothelial cells of capillary vessels and sarcomers were taken. The blood was obtained during cardiopulmonary bypass (CPB) before the aorta clamping and immediately after aorta declamping (peak of ischaemia) between 1-3 minute and 10-13 minute of reperfusion. Increase of the number of granulocytes both in the coronary sinus and aortal blood at all examined intervals as well as decrease in the number of ones in sinus compared with aortal blood was noted. The ability to produce superoxide anion radical decreased at the peak of ischemia and during reperfusion. The activity of SOD-1 was lower both after the period of ischemia and reperfusion. The increase in aortal blood activity during reperfusion was characteristic of GSH-Px; the activity was higher in the blood sample from the coronary sinus taken during ischemia and initial reperfusion. With the exception of the initial reperfusion the activity of CAT diminished in all observed cases. MDA concentration did not demonstrate any significant changes with the exception of the initial reperfusion in the aortal blood and later towards the end of reperfusion in the blood from the coronary sinus. Ultrastructural studies indicated overhydration of the cells both in the endothelium and the intercellular space. The obtained data demonstrate that the applied cardioplegic solution protects the myocardium from harmful effects of reactive oxygen species produced as a result of ischemia and reperfusion.

[Metabolic changes in blood oxygen in the human heart under ischemic and reperfusion conditions]. / Zmiany metabolizmu tlenowego krwi z serca ludzkiego w warunkach niedokrwienia i reperfuzji.

The number of granulocytes, their capability to generate O2-. and the activity of SOD-1, GSH-Px, Cat as well as MDA concentrations in erythrocytes in the blood extracted from the venous sinus and aorta under coronary artery bypass with use of St. Thomas cardioplegic solution were determined. The blood for examination was obtained before the institution of cardiopulmonary bypass, in the period of the deepest ischaemia (just after declamping of the aorta) and between the 1-3 minute and the 10-13 minute of reperfusion. A rise in the number of granulocytes both in the venous sinus and aortal blood at all examined intervals was noted. Capability to produce superoxide anion radicals decreased at the peak of ischemia and during reperfusion. The activity of SOD-1 was lower both after the period of ischemia and reperfusion. A rise in aortal blood activity during reperfusion was characteristic for GSH-Px; the activity was greater in the blood sampled from the coronary sinus during ischemia and initial reperfusion. With the exception of the initial reperfusion the activity of Cat diminished in all observed cases. We did not observe any significant changes in MDA concentration with the exception of the initial reperfusion in the aortal blood and later during reperfusion in the blood from the coronary sinus. The results demonstrate that the applied cardioplegic solution may protect myocardium from harmful effects of active oxygen froms produced as a results of ischemia and reperfusion.

51Cr-bleomycin in the diagnosis of tumours of the chest.

51Cr-bleomycin was used for the scintigraphic diagnosis of primary and secondary tumours of the thorax. The study was based on observations in 104 patients. The scintigraphy was performed using a gamma camera coupled to an on-line computer. Active lesions were scored using a semiquantitative scale of scores 0 to 5. Images were subdivided into 222 regions considered. In 72 of these, the presence of disease was diagnosed (64 malignant, 8 non-malignant) and 150 regions were classified as free from disease. At the decision threshold of score 2, over-all sensitivity and specificity of the scintigraphic detection of malignant tumours amounted to 97 and 79%, respectively. Inflammatory changes displayed some detectable accumulation of 51Cr-bleomycin but scores attributed to these lesions did not exceed the value of 2.