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
Hereditary hypertriglyceridemic (hHTG) rats are characterized by increased blood pressure and impaired endotheliumdependent relaxation of conduit arteries. The aim of this study was to investigate the effect of long-term (4 weeks) treatment of hHTG rats with three drugs which, according to their mechanism of action, may be able to modify the endothelial function: simvastatin (an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase), spironolactone (an antagonist of aldosterone receptors) and L-arginine (a precursor of nitric oxide formation). At the end of 4th week the systolic blood pressure in the control hHTG group was 148±2 mm Hg and in control normotensive Wistar group 117±3 mm Hg. L-arginine failed to reduce blood pressure, but simvastatin (118±1 mm Hg) and spironolactone (124±4 mm Hg) treatment significantly decreased the systolic blood pressure. In isolated phenylephrine-precontracted aortic rings from hHTG rats endothelium-dependent relaxation was diminished as compared to control Wistar rats. Of the three drugs used, only simvastatin improved acetylcholine-induced relaxation of the aorta. We conclude that both simvastatin and spironolactone reduced blood pressure but only simvastatin significantly improved endothelial dysfunction of aorta. Prominent increase in the expression of eNOS in large conduit arteries may be the pathophysiological mechanism underlying the protective effect of simvastatin in hHTG rats., J. Török, I. L'upták, J. Matúšková, O. Pecháňová, J. Zicha, J. Kuneš, F. Šimko., and Obsahuje bibliografii
This study sought to evaluate whether consumption of polyphenol extract from Cognac (CPC) modulates platelet activation and cardiovascular reactivity in rats. Male Wistar rats were treated daily for 4 weeks by intra-gastric gavage receiving CPC at 80 mg/kg/day or vehicle (5 % glucose). Platelet adhesion and aggregation in response to different activators were assessed. Cardiac and vascular reactivity in response to various agonists as well as NO measurement by electron paramagnetic resonance technique were investigated in isolated heart and thoracic aorta. Oral administration of CPC decreased platelet aggregation induced by ADP but not by collagen. CPC did not affect adhesion to collagen. The chronotropic but not the inotropic response to isoprenaline was reduced without alteration of NO production in hearts from CPC-treated rats. CPC treatment did not affect ex vivo relaxation to acetylcholine nor NO content of rat aorta. CPC did not significantly alter the response to phenylephrine in aorta despite the participation of endothelial vasoconstrictor products. In summary, chronic treatment with CPC has no impact on ex vivo vascular and cardiac reactivity; however, it reduced heart work and platelet aggregation. These data suggest the existence of compounds in Cognac that may decrease the risk of coronary thrombosis and protect against some cardiac diseases., J. Švíglerová, J. Kuncová, L. Nalos, J. Slavíková, M. Štengl., and Obsahuje bibliografii a bibliografické odkazy
The establishment of a dose-response relationship and its quantification is the usual procedure for analysing drug action on an isolated organ. However, the time course of the effect seems to be an inherent characteristic of the agonist which produces it. In our study, we have analyzed the time-response curves of four cholinergic agonists (acetylcholine, methacholine, carbachol and bethanechol) which produce tonic contractions of the isolated rat gastric fundus. The order of affinity of agonists to muscarinic receptors on the rat fundus were carbachol > bethanechol > methacholine > acetylcholine (Ka values: 46 ±12, 84±21, 380±110 and 730±120 nM, respectively). The effective concentrations which produced 60 % of the maximal response (EC5Q) were used for establishing the time-response curves. The time-response curves were also recorded after partial alkylation of muscarinic receptors with phenoxybenzamine, after exposure of the isolated rat fundus to physostigmine and after addition of supramaximal concentrations of the agonists. The experimental time-response curve for acetylcholine was on the extreme left, followed by curves for methacholine, bethanechol and carbachol, respectively. Phenoxybenzamine and supramaximal doses of the agonists did not change the order of response development in time, but supramaximal doses shifted all curves to the left and phenoxybenzamine shifted all time-response curves to the right. Only physostigmine shifted the time-response curve for methacholine to the right. The results of our study suggest that the response rate of the isolated rat gastric fundus to cholinergic agonists depends on the intrinsic activity of these agents, but not on their affinity for muscarinic receptors.
The contraction of gastrointestinal (GI) smooth muscles is
regulated by both Ca2+-dependent and Ca2+ sensitization
mechanisms. Proline-rich tyrosine kinase 2 (Pyk2) is involved in
the depolarization-induced contraction of vascular smooth muscle
via a Ca2+ sensitization pathway. However, the role of Pyk2
in GI smooth muscle contraction is unclear. The spontaneous
contraction of colonic smooth muscle was measured by using
isometric force transducers. Protein and phosphorylation levels
were determined by using western blotting. Pyk2 protein was
expressed in colonic tissue, and spontaneous colonic contractions
were inhibited by PF-431396, a Pyk2 inhibitor, in the presence of
tetrodotoxin (TTX). In cultured colonic smooth muscle cells
(CSMCs), PF-431396 decreased the levels of myosin light chain
(MLC20) phosphorylated at Ser19 and ROCK2 protein expression,
but myosin light chain kinase (MLCK) expression was not altered.
However, Y-27632, a Rho kinase inhibitor, increased
phosphorylation of Pyk2 at Tyr402 and concomitantly decreased
ROCK2 levels; the expression of MLCK in CSMCs did not change.
The expression of P(Tyr402)-Pyk2 and ROCK2 was increased
when CSMCs were treated with Ach. Pyk2 is involved in the
process of colonic smooth muscle contraction through the
RhoA/ROCK pathway. These pathways may provide very
important targets for investigating GI motility disorders.