Prolonged exposure to alveolar hypoxia induces physiological changes in the pulmonary vasculature that result in the development of pulmonary hypertension. A hallmark of hypoxic pulmonary hypertension is an increase in vasomotor tone. In vivo, pulmonary arterial smooth muscle cell contraction is influenced by vasoconstrictor and vasodilator factors secreted from the endothelium, lung parenchyma and in the circulation. During chronic hypoxia, production of vasoconstrictors such as endothelin-1and angiotensin II is enhanced locally in the lung, while synthesis of vasodilators may be reduced. Altered reactivity to these vasoactive agonists is another physiological consequence of chronic exposure to hypoxia. Enhanced contraction in response to endothelin-1 and angiotensin II, as well as depressed vasodilation in response to endothelium-derived vasodilators, has been documented in models of hypoxic pulmonary hypertension. Chronic hypoxia may also have direct effects on pulmonary vascular smooth muscle cells, modulating receptor population, ion channel activity or signal transduction pathways. Following prolonged hypoxic exposure, pulmonary vascular smooth muscle exhibits alterations in K+ current, membrane depolarization, elevation in resting cytosolic calcium and changes in signal transduction pathways. These changes in the electrophysiological parameters of pulmonary vascular smooth muscle cells are likely associated with an increase in basal tone. Thus, hypoxia-induced modifications in pulmonary arterial myocyte function, changes in synthesis of vasoactive factors and altered vasoresponsiveness to these agents may shift the environment in the lung to one of contraction instead of relaxation, resulting in increased pulmonary vascular resistance and elevated pulmonary arterial pressure., L. A. Shimoda, J. S. K. Sham, J. T. Sylvester., and Obsahuje bibliografii
The contrasting pattern of cardiac inotropy induced by human peptide endothelin-1 (ET-1) has not been satisfactorily explained. It is not clear whether ET-1 is primarily responsible for increased myocardial ET-1 expression and release with resultant inotropic effects, or for the induction of myocardial hypertrophy and heart failure. There are at least two subtypes of endothelin receptors (ETA and ETB) and the inotropic effects of ET-1 differ depending on the receptor involved. Along with some other groups, we reported significant subtype-ETB endothelin receptor down-regulation in human cardiac cells preincubated with endothelin agonists (Dřímal et al. 1999, 2000). The present study was therefore designed to clarify the subtype-selective mechanisms underlying the inotropic response to ET-1 and to its ETB-selective fragment (8-21)ET-1 in the isolated rat heart. The hearts were subjected to (1-21)ET-1 and to (8-21)ET-1, or to 30 min of stop-flow ischemia followed by 40 min of reperfusion, both before and after selective blockade of endothelin receptors.The present study revealed that both peptides, ET-1 and its (8-21)ET-1 fragment, significantly reduced coronary blood flow in nmolar and higher concentrations. The concomitant negative inotropy and chronotropy were marked after ET-1, while the infusion of the ET-1(8-21) fragment produced a slight but significant positive inotropic effect. Among the four endothelin antagonists tested in continuous infusion only the non-selective PD145065 and ETB1/B2-selective BQ788 (in mmolar concentrations) slightly reduced the early contractile dysfunction of the heart induced by ischemia, whereas ETA-selective PD155080 partially protected the rat heart on reperfusion., J. Dřímal, V. Knezl, J. Dřímal Jr , D. Dřímal, K. Bauerová , V. Kettmann, A.M. Doherty , M. Štefek., and Obsahuje bibliografii
Many physiological and pathological processes in the cardiac tissue have been shown to be associated with a release of endothelin (ET) peptides and with induction of specific ET-receptors and G-protein-coupled ion channels. However, the exact mechanism regulating ET-receptors in the myocardium is controversial. The response to ET-1, the most important member of the ET family, is rapidly attenuated by down-regulation of ET-receptors. The internalization of ET-1 bound to two subclasses of specific receptors (ETA and ETB) that are abundant in the myocardium has been hypothesized to activate and/or inhibit a variety of intracellular signal transducing systems. The [125I]ET-1, BQ-3020 and selective ET-antagonists were used to study the subtype-selective component of regulation of ET-1 receptors in myocardial membranes. We determined the characteristics of [125I]ET-1 binding and [3H]thymidine incorporation in whole cell saturation studies and measured Ca 2+ channel induction and the total number of inactive Ca2+ channels in photoaffinity studies with [3H]azidopine. Here we demonstrate four important components of the complex ET-1 response in human, porcine and rat myocardium, leading to aberrant responses of cells. After ET-1 induction, adaptive subtype-ETB selective down-regulation predominated in human embryonic fibroblasts, in porcine membrane vesicles and in microsomal membranes of renal hypertensive rats, with preferential high affinity ET-1 binding to ETA receptors and with the resultant ETA mediated proliferative and mitogenic activation of human fibroblasts. The ET-1 induction was also accompanied by profound inactivation of Ca2+ channels in myocardial membranes., J. Dřímal, M. Mislovičová, A. Ismail, F. Monček., and Obsahuje bibliografii