Different Effects of Cannabis Abuse on Adolescent and Adult Brain

Cannabis abuse is a common phenomenon among adolescents. The dominant psychoactive substance in Cannabis sativa is tetrahydrocannabinol (THC). However, in the past 40 years the content of the psychoactive ingredient THC in most of the preparations is not constant but has increased due to other breeding and culturing conditions. THC acts as the endocannabinoids at CB1 and CB2 receptors but pharmacologically can be described as a partial (not a pure) agonist. Recent evidence shows that activation of the CB1 receptor by THC can diminish the production of neuronal growth factor in neurons and affect other signalling cascades involved in synapsis formation. Since these factors play an important role in the brain development and in the neuronal conversion processes during puberty, it seems reasonable that THC can affect the adolescent brain in another manner than the adult brain. Accordingly, in adolescent cannabis users structural changes were observed with loss of grey matter in certain brain areas. Moreover, recent studies show different effects of THC on adolescent and adult brains and on behaviour. These studies indicate that early THC abuse can result in neuropsychological deficits. This review gives an overview over the present knowledge in this fiel

Remodeling of Cardiac Gap Junctional Cell–Cell Coupling

The heart works as a functional syncytium, which is realized via cell-cell coupling maintained by gap junction channels. These channels connect two adjacent cells, so that action potentials can be transferred. Each cell contributes a hexameric hemichannel (=connexon), formed by protein subuntis named connexins. These hemichannels dock to each other and form the gap junction channel. This channel works as a low ohmic resistor also allowing the passage of small molecules up to 1000 Dalton. Connexins are a protein family comprising of 21 isoforms in humans. In the heart, the main isoforms are Cx43 (the 43 kDa connexin; ubiquitous), Cx40 (mostly in atrium and specific conduction system), and Cx45 (in early developmental states, in the conduction system, and between fibroblasts and cardiomyocytes). These gap junction channels are mainly located at the polar region of the cardiomyocytes and thus contribute to the anisotropic pattern of cardiac electrical conductivity. While in the beginning the cell–cell coupling was considered to be static, similar to an anatomically defined structure, we have learned in the past decades that gap junctions are also subject to cardiac remodeling processes in cardiac disease such as atrial fibrillation, myocardial infarction, or cardiomyopathy. The underlying remodeling processes include the modulation of connexin expression by e.g., angiotensin, endothelin, or catecholamines, as well as the modulation of the localization of the gap junctions e.g., by the direction and strength of local mechanical forces. A reduction in connexin expression can result in a reduced conduction velocity. The alteration of gap junction localization has been shown to result in altered pathways of conduction and altered anisotropy. In particular, it can produce or contribute to non-uniformity of anisotropy, and thereby can pre-form an arrhythmogenic substrate. Interestingly, these remodeling processes seem to be susceptible to certain pharmacological treatment

Neuroprotective strategies during cardiac surgery with cardiopulmonary bypass

Aortocoronary bypass or valve surgery usually require cardiac arrest using cardioplegic solutions. Although, in principle, in a number of cases beating heart surgery (so-called off-pump technique) is possible, aortic or valve surgery or correction of congenital heart diseases mostly require cardiopulmonary arrest. During this condition, the heart-lung machine also named cardiopulmonary bypass (CPB) has to take over the circulation. It is noteworthy that the invention of a machine bypassing the heart and lungs enabled complex cardiac operations, but possible negative effects of the CPB on other organs, especially the brain, cannot be neglected. Thus, neuroprotection during CPB is still a matter of great interest. In this review, we will describe the impact of CPB on the brain and focus on pharmacological and non-pharmacological strategies to protect the brain

Inverse relationship between tumor proliferation markers and connexin expression in a malignant cardiac tumor originating from mesenchymal stem cell engineered tissue in a rat in vivo model

Recently, we demonstrated the beneficial effects of engineered heart tissues for the treatment of dilated cardiomyopathy in rats. For further development of this technique we started to produce engineered tissue (ET) from mesenchymal stem cells. Interestingly, we observed a malignant tumor invading the heart with an inverse relationship between proliferation markers and connexin expression

Effect of Angiotensin(1-7) on Heart Function in an Experimental Rat Model of Obesity

Aim: Obesity is a risk factor for the development of cardiovascular diseases. Recently it was shown that overexpression of the Mas-receptor antagonist angiotensin(1-7) could prevent from diet-induced obesity. However, it remained unclear whether diet-induced obesity and angiotensin(1-7) overexpression might also have effects on the cardiovascular system in these rats. Methods:Twenty three male Sprague Dawley rats were fed with standard chow (SD+chow, n = 5) or a cafeteria diet (SD+CD, n = 6) for 5 months. To investigate the effect of angiotensin(1-7) transgenic rats, expressing an angiotensin(1-7)-producing fusion protein in testis were used. These transgenic rats also received a 5 month's feeding period with either chow (TGR+chow, n = 6) or cafeteria diet (TGR+CD, n = 6), respectively. Hemodynamic measurements (pressure-volume loops) were carried out to assess cardiac function and blood pressure. Subsequently, hearts were explanted and investigated according to the Langendorff technique. Furthermore, cardiac remodeling in these animals was investigated histologically. Results:After 5 months cafeteria diet feeding rats showed a significantly increased body weight, which could be prevented in transgenic rats. However, there was no effect on cardiac performance after cafeteria diet in non-transgenic and transgenic rats. Moreover, overexpression of angiotensin(1-7) deteriorated cardiac contractility as indicated by impaired dp/dt. Furthermore, histological analysis revealed that cafeteria diet led to myocardial fibrosis in both, control and transgenic rats and this was not inhibited by an overproduction of angiotensin(1-7). Conclusion:These results indicate that an overexpression of circulating angiotensin(1-7) prevents a cafeteria diet-induced increase in body weight, but does not affect cardiac performance in this experimental rat model of obesity. Furthermore, overexpression of angiotensin(1-7) alone resulted in an impairment of cardiac function

Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias

Coordinated electrical activation of the heart is essential for the maintenance of a regular cardiac rhythm and effective contractions. Action potentials spread from one cell to the next via gap junction channels. Because of the elongated shape of cardiomyocytes, longitudinal resistivity is lower than transverse resistivity causing electrical anisotropy. Moreover, non-uniformity is created by clustering of gap junction channels at cell poles and by non-excitable structures such as collagenous strands, vessels or fibroblasts. Structural changes in cardiac disease often affect passive electrical properties by increasing non-uniformity and altering anisotropy. This disturbs normal electrical impulse propagation and is, consequently, a substrate for arrhythmia. However, to investigate how these structural changes lead to arrhythmias remains a challenge. One important mechanism, which may both cause and prevent arrhythmia, is the mismatch between current sources and sinks. Propagation of the electrical impulse requires a sufficient source of depolarizing current. In the case of a mismatch, the activated tissue (source) is not able to deliver enough depolarizing current to trigger an action potential in the non-activated tissue (sink). This eventually leads to conduction block. It has been suggested that in this situation a balanced geometrical distribution of gap junctions and reduced gap junction conductance may allow successful propagation. In contrast, source-sink mismatch can prevent spontaneous arrhythmogenic activity in a small number of cells from spreading over the ventricle, especially if gap junction conductance is enhanced. Beside gap junctions, cell geometry and non-cellular structures strongly modulate arrhythmogenic mechanisms. The present review elucidates these and other implications of passive electrical properties for cardiac rhythm and arrhythmogenesis

Long-Term Effects of the Endothelin A Receptor Antagonist LU 135252 and the Angiotensin-Converting Enzyme Inhibitor Trandolapril on Diabetic Angiopathy and Nephropathy in a Chronic Type I Diabetes Mellitus Rat Model

ABSTRACT Diabetic angiopathy is a serious problem in antidiabetic therapy. We wanted to investigate whether treatment with the endothelin A receptor antagonist LU 135252 or with the angiotensin-converting enzyme inhibitor trandolapril might prevent angiopathy in long-term type I diabetes mellitus. Six groups of male Wistar rats were investigated: untreated age-matched control rats, healthy controls treated with trandolapril (0.3 mg/ kg), healthy controls treated with LU 135252 (100 mg/kg), untreated diabetic rats, and diabetic rats treated with either trandolapril or LU 135252. Rats were rendered diabetic by injection of streptozotozin. Duration of the disease was 6 months. Thereafter, rats were sacrificed, and hearts, kidneys, and a mesenterial loop were removed. Hearts and kidneys were processed histologically; the mesenterial loop was perfused with saline at constant pressure for investigation of microvessels using microvideoangiometry while treated with either 30 mM KCl, 1 M acetylcholine, or 1 M sodium nitroprusside. All diabetic rats developed hyperglycemia without differences among these three groups. Diabetic rats exhibited marked anemia, which was significantly antagonized by both treatments. The heart capillaries/muscle fibers ratio was decreased significantly in diabetic animals, which was prevented fully by both treatments. Renal glomerular diameter was increased in diabetic rats. This was significantly antagonized by LU 135252 but not by trandolapril. Deposition of homogeneous eosinophilic material within the glomeruli was nearly completely prevented by LU 135252. The acetylcholine-induced vasodilation in mesenteric microvessels was significantly attenuated in diabetic rats, which was significantly antagonized by both treatments. We conclude that both angiotensin and endothelin seem to contribute to the development of diabetic angiopathy and that, in addition to angiotensin-converting enzyme inhibition, blockade of endothelin A receptors may be an interesting new approach to antiangiopathic therapy

Effects of Hypoxia and Acidosis on Cardiac Electrophysiology and Hemodynamics. Is NHE-Inhibition by Cariporide Still Advantageous?

Hypoxia often leads to severe cardiac malfunctions. It is assumed that intracellular calcium overload is -inter alia- responsible for left ventricular (LV) deterioration. Inhibition of the sodium-proton exchanger (NHE), which finally inhibits/slows calcium overload, may ameliorate cardiac function. Our aim was to evaluate cariporide, an inhibitor of NHE1 in a Langendorff-perfused heart model. To discriminate a potentially different impact of extracellular acidosis and hypoxia we examined 48 Chinchilla Bastard rabbits divided into 8 experimental groups: control group (pH = 7.4, O2 = 100%) without or with cariporide (1µM), acidosis group (pH = 7.0, O2 = 100%) without or with cariporide (1µM), hypoxia group (pH = 7.4, O2 = 40%) without or with cariporide (1µM) and hypoxia+acidosis group (pH = 7.0, O2 = 40%) without or with cariporide (1µM). Hearts were subjected to acidotic/hypoxic conditions for 90 min followed by 60 min of reperfusion. Hypoxia and hypoxia+acidosis led to a severe deterioration of LV function with a decrease in LV pressure by about 70% and an increase of end-diastolic pressure from 6.7 ± 0.6 to 36.8 ± 5.4 (hypoxia) or from 7.0 ± 0.2 to 18.6 ± 4.1 (hypoxia+acidosis). Moreover, maximum contraction velocity decreased from about 1,800 mmHg/s to 600 mmHg/s during hypoxia ± acidosis and maximum relaxation velocity deteriorated from −1,500 mmHg/s to about −600 mmHg/s. During reperfusion hearts subjected to hypoxia+acidosis recovered faster than hearts subjected to hypoxia alone, reaching control levels after 5 min of reperfusion. Electrophysiologic analysis revealed an 1.2 fold increase in both dispersion of activation-recovery interval and in total activation time in the hypoxia ± acidosis group. Cariporide application significantly improved LV hemodynamics and electrophysiology in the hypoxia group but not in the group subjected to hypoxia+acidosis. Immunohistologic analysis of cardiac specimen revealed a significant increase of factors involved in hypoxia/reperfusion injury like nitrotyrosine and poly-ADP-ribose as well as apoptosis-inducing factors like AIF or cleaved-caspase 3 in LV after hypoxia ± acidosis. ATP was reduced by hypoxia but not by acidosis. Again, cariporide mitigated these processes only in the hypoxia alone group, but not in the group with additional acidosis. Acidosis without hypoxia only marginally disturbed LV function and electrophysiology, and was not affected by cariporide. Thus, our study demonstrated that several detrimental effects of hypoxia were mitigated or abrogated by acidosis and that NHE-inhibition improved only hypoxia-induced cardiac dysfunction

Selective arterialization of a cardiac vein in a model of cardiac microangiopathy and macroangiopathy in sheep

ObjectiveSome patients with significant arteriosclerosis of the heart are not amenable to revascularization of a coronary artery because they have a combination of microangiopathy and significant macroangiopathy. We investigated the benefit of arterialization of a cardiac vein under these circumstances in an acute animal model.MethodsIn the hearts of 8 sheep, microspheres were injected into the left coronary artery; 60 minutes later, a stenosis of the left anterior descending artery was performed. After 45 minutes, retrograde venous revascularization was performed by sewing the left internal thoracic artery to the concomitant vein of the left anterior descending artery in a beating-heart technique. For flow reversal, the vein was ligated proximally to the anastomosis. The efficiency of the bypass graft was evaluated by coronary angiography and flow measurement. Cardiac output, electrocardiography, and mean arterial blood pressure were assessed in each phase of the experiment.ResultsThe ischemic state of the myocardium was confirmed by a significant decrease of cardiac output, stroke volume, and mean arterial blood pressure, and a significant elevation of the ST segment in the electrocardiography. After retrograde venous revascularization was established, cardiac output and stroke volume increased and ST elevations decreased. The grafts showed adequate flow (26.15 ± 2.08 mL/min), and reversed blood flow in the grafted vein was proved by coronary angiography.ConclusionRetrograde venous revascularization is possible and improves cardiac function in a state of acute ischemia caused by a combination of microangiopathy and macroangiopathy

Distribution of Cardiac Stem Cells in the Human Heart

Introduction. The existence of human cardiac stem cells (hCSC) and their regenerative capacity are not fully defined. The aim of this study was to identify and analyse the distribution of hCSCs by flow cytometry (FCM). Methods. Tissue samples from the left ventricle (LV) and the appendages of the right atrium (RA) and left atrium (LA) were taken during cardiac surgery. Mononuclear cells (MNCs) were isolated, labelled for the stem-cell-marker c-kit and hematopoietic-lineage markers and analysed by FCM. Results. HCSCs could be isolated from the RA, LA, and LV without significant quantitative difference between both atria (A) (RA 4.80 ± 1.76% versus LA 4.99 ± 1.69% of isolated MNCs, P = 0.922). The number of hCSCs was significantly higher in both atria compared to the left ventricle (A 4.90 ± 1.29% versus LV 0.62 ± 0.14% of isolated MNCs, P = 0.035). Conclusion. The atria contain a higher concentration of hCSC than the left ventricle. HCSCs located in the atria could serve as an endogenous source for heart regeneration