[Adrenergic regulation of the mammalian heart]. / Adrenergní regulace srdecní cinnosti savcu.

Adrenergic system in the mammalian heart plays a pivotal role in regulation of contractility and/or heart rate. At present, nine subtypes of adrenergic receptors (AR) have been identified. Among these there are six AR localized in the plasma membrane of cardiomyocytes. They mediate their effects by increases in the intracellular level of various signaling molecules which initiate diverse cellular responses. The effects of stimulation of both beta-AR by catecholamines noradrenaline and adrenaline are consistent with coupling to the Gs protein-adenylyl cyclase-cAMP-protein kinase classical pathway, with consequent protein kinase A-catalysed phosphorylation of target enzymes responsible for increased contractility and hastening of relaxation. In contrast to beta1-AR, beta2-AR can also couple to G(i) protein which causes cAMP-independent control of calcium signaling and contraction. Activation of beta-AR obviously couples to a G(i)/ nitric oxide pathway and mediates a decrease in contractile force, whereas stimulation of alpha-AR increases contractility via G protein/phospholipase C/diacylglycerol/inositoltrisphosphate/protein kinase C pathway. These findings reveal the diversity and specifity of AR subtypes and G protein interactions. They also provide new insights in understanding the differential regulation and functionality of AR subtypes in healthy and diseased hearts.

Differential display code 3 (DD3/PCA3) in prostate cancer diagnosis.

BACKGROUND: Early diagnosis of prostate cancer (PCa) in an organ-confined stage following radical treatment is the only potential curative approach in PCa. Prostatic-specific antigen (PSA) is very helpful in early diagnosis, but the main disadvantage is that it has a low positive predictive value in the range of the grey zone of 2.5-10 ng/mL, which results in a high number of needless biopsies. For this reason, new tests with better parameters are needed. One promising test is that for differential display code 3 (DD3(PCA3)), which is a prostate-specific non-coding mRNA that is highly overexpressed in prostate tumor cells. The aim of the present study was to evaluate the potential of DD3(PCA3) for mRNA in PCa diagnosis. PATIENTS AND METHODS: A total of 186 patients were examined. In a group of patients with suspected PCa, one tissue specimen core was collected for testing DD3(PCA3) expression. According to the histological verification there were 100 patients with benign prostatic hyperplasia, 12 patients with prostatic intraepithelial neoplasia and 74 patients with PCa. The total RNA was isolated and DD3(PCA3) and PSA expressions were quantified using quantitative RT real-time PCR method. The DD3(PCA3)/PSA mRNA ratio was determined for all groups. RESULTS: It was found that the levels of the mRNA expression of DD3(PCA3) were significantly higher (p<0.045) in patients with PCa than in patients with benign prostatic hyperplasia. No statistically significant differences in levels of mRNA expression of DD3(PCA3) between patients with organ-confined and those with advanced or metastatic disease, nor according to Gleason score, were found. CONCLUSION: DD3(PCA3) appears to be a promising marker for early detection of PCa and also for differential diagnosis between patients with benign prostate hyperplasia and those with PCa.

Expression of neuropeptide Y and its receptors Y1 and Y2 in the rat heart and its supplying autonomic and spinal sensory ganglia in experimentally induced diabetes.

Diabetic cardiomyopathy, involving both cardiomyocytes and the sensory and autonomic cardiac innervation, is a major life-threatening complication in diabetes mellitus. Here, we induced long-term (26-53 weeks) diabetes in rats by streptozotocin injection and analyzed the major cardiac neuropeptide signaling system, neuropeptide Y (NPY) and its receptors Y1R and Y2R. Heart compartments and ganglia supplying sympathetic (stellate ganglion) and spinal sensory fibers (upper thoracic dorsal root ganglia=DRG) were analyzed separately by real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Ventricular, but not atrial innervation density by NPY-immunoreactive fibers was diminished, and preproNPY expression was transiently (26 weeks) reduced in left atria, but remained unchanged in sympathetic neurons and was not induced in DRG neurons. In all ganglia and heart compartments, Y1R expression dominated over Y2R, and Y1R-immunoreactivity was observed on cardiomyocytes and neuronal perikarya. Atrial, but not ventricular Y1R expression was up-regulated after 1 year of diabetes. Collectively, these data show that a disturbance of the cardiac NPY-Y1R/Y2R signaling system develops slowly in the course of experimentally induced diabetes and differentially affects atria and ventricles. This is in parallel with the clinically observed imbalances of the cardiac autonomic innervation in diabetic cardiac autonomic neuropathy.

Cardiomyopathy in streptozotocin-induced diabetes involves intra-axonal accumulation of calcitonin gene-related peptide and altered expression of its receptor in rats.

Calcitonin gene-related peptide (CGRP) is a vasorelaxant and positive inotropic and chronotropic peptide that binds to the calcitonin receptor-like receptor. In the heart, upon stimulation CGRP is released from sensory nerve terminals and improves cardiac perfusion and function. In the present study, we investigated alterations in the components of the CGRP signaling system during development of diabetic cardiomyopathy. Rats received a single injection of streptozotocin. Four, 8, and 16 weeks thereafter cardiac CGRP content (radioimmunoassay), calcitonin receptor-like receptor expression (by real-time RT-PCR), and CGRP and calcitonin receptor-like receptor tissue distribution (immunohistochemistry) were assessed. CGRP content of atria and ventricles progressively increased during the 4 months following streptozotocin-treatment, while the distribution of CGRP-immunoreactive fibers was not visibly altered. Conversely, cardiac expression of calcitonin receptor-like receptor initially (4 weeks after treatment) increased but then gradually declined to 47% of control levels in both atria after 16 weeks. These quantitative changes were not associated with altered cellular distribution patterns (primarily in venous and capillary endothelium). Since sensory neurons have been reported to decrease expression of the CGRP precursor in the course of diabetes, the intra-axonal accumulation of CGRP observed here reflects impaired release, which, coupled with the down-regulation of its cognate receptor, calcitonin receptor-like receptor, may contribute to the well-documented impairment of cardioprotective functions in diabetes.