UMLS:C0004135 - FACTA Search

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Query: UMLS:C0004135 (ATM)
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Low-voltage-activated T-type Ca2+ channels are present in most excitable tissues including the heart (mainly pacemaker cells), smooth muscle, central and peripheral nervous systems, and endocrine tissues, but also in non-excitable cells, such as osteoblasts, fibroblasts, glial cells, etc. Although they comprise a slightly heterogeneous population, these channels share many defining characteristics: small conductance (< 10 pS), similar Ca2+ and Ba2+ permeabilities, slow deactivation, and a voltage-dependent inactivation rate. In addition, activation at low voltages, rapid inactivation, and blockade by Ni2+ are classical properties of T-type Ca2+ channels, which are less specific. T-type Ca2+ channels are weakly blocked by standard Ca2+ antagonists. Pharmacological blockers are scarce and often lack specificity and/or potency. The physiological modulation of T-type Ca2+ currents is complex: they are enhanced by endothelin-1, angiotensin II (AT1-receptor), ATP, and isoproterenol (cAMP-independent), but are reduced by angiotensin II (AT2-receptor), somatostatin and atrial natriuretic peptide. Norepinephrine enhances these currents in some cells but decreases them in others. T-type Ca2+ currents have many known or suggested physiological and pathophysiological roles in growth (protein synthesis, cell differentiation, and proliferation), neuronal firing regulation, some aspects of genetic hypertension, cardiac hypertrophy, cardiac fibrosis, cardiac rhythm (normal and abnormal), and atherosclerosis. Mibefradil is a new Ca2+ antagonist that is effective in hypertension and angina pectoris. Its favorable pharmacological profile and limited side effects appear to be related to selective block of T-type Ca2+ channels: mibefradil reduces vascular resistance and heart rate without negative inotropy or neurohormonal stimulation, and it also has significant antiproliferative actions.
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PMID:T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. 951 67

The stimulation of autocrine and paracrine factors such as basic fibroblast- (bFGF) and platelet-derived (PDGF) growth factors mediates many of the growth-promoting actions of angiotensin II. The aim of this study was to evaluate the effect of chronic AT1-receptor blockade on plasma endothelin-1 (ET-1) and growth factors levels, and on left ventricular mass, in essential hypertension (EH). The study population consisted of 16 patients with mild-moderate EH, and 25 normotensive controls. In the EH patients under basal conditions, and after 3 and 6 months of chronic therapy with Losartan 50 mg/day, we measured serum levels of ET-1, bFGF and PDGF, and tumor necrosis factor (TNF). At the same time, all patients underwent 24-h ambulatory blood pressure monitoring and an echocardiographic evaluation to measure the thickness of the posterior wall (PWT) of the left ventricle and of the interventricular septum (IVS). The healthy controls underwent the same analyses, under basal conditions, at baseline and after 3 and 6 months of observation. In the EH patients, after 3 months of AT1-receptor blockade bFGF was reduced from 13.6 +/- 0.7 to 10.9 +/- 0.7 pg/mL (P < .004), and both TNF and PDGF were significantly decreased (P < .006 and P < .007, respectively). After 6 months of therapy, ET-1 was significantly diminished in comparison with baseline (6.9 +/- 0.8 v 5.5 +/- 0.1 fmol/mL; P < .05), and the reduction in the levels of growth factors were even more significant than at 3 months of treatment. Both PWT and IVS were significantly changed after 6 months of therapy with losartan after basal evaluation (P < .05, respectively). Systolic and diastolic 24-h blood pressures declined significantly after 3 and 6 months of therapy with losartan (P < .01, respectively). It seems likely that the inhibition of the action of angiotensin II by the specific AT1-receptor blockade, by reducing circulating levels of ET-1 and those of some growth factors, may offer an advantage regarding the effect on hypertensive cardiovascular changes in human hypertension.
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PMID:Changes of plasma endothelin and growth factor levels, and of left ventricular mass, after chronic AT1-receptor blockade in human hypertension. 963 90

The effects of the nonpeptide angiotensin II AT1 receptor antagonist candesartan on responses to angiotensin II were investigated in the hindquarters vascular bed of the cat. Under constant-flow conditions, injections of angiotensin II into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Candesartan in a dose of 3 micrograms/kg i.v. decreased vasoconstrictor responses to angiotensin II in a competitive manner. However, at doses of 10-1000 micrograms/kg i.v., candesartan shifted the dose-response curve to angiotensin II to the right in a nonparallel manner, suggesting a noncompetitive blockade. The inhibitory effects of candesartan on responses to angiotensin II were long in duration, and the AT1 receptor antagonist had little effect on baseline pressures. Candesartan was without effect on vasoconstrictor responses to norepinephrine, U46619, PGF2 alpha, and BAY K8644; on biphasic responses to endothelin-1; and on vasodilator responses to acetylcholine. Candesartan significantly attenuated hindquarters vasoconstrictor responses to angiotensin III and IV with a parallel shift at the 3 micrograms/kg iv dose and a nonparallel shift to the right at the high dose of the AT1 receptor antagonist. The results of the present study indicate that candesartan is a potent angiotensin AT1 receptor antagonist that can induce both competitive and noncompetitive blockade of responses to angiotensin II, III, and IV n the hindquarters vascular bed of the cat.
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PMID:Inhibitory effects of candesartan on responses to angiotensin peptides in the hindquarters vascular bed of the cat. 963 51

The effects of bosentan (Ro 47-0203), an endothelin A and B receptor antagonist, on responses to endothelin-1, sarafotoxin 6c, angiotensin II, and arginine vasopressin were investigated in the hind-limb vascular bed of the cat. Under constant-flow conditions, intraarterial injections of endothelin-1 and sarafotoxin 6c induced biphasic changes in hind-limb perfusion pressure characterized by an initial decrease followed by a secondary increase in perfusion pressure. The vasodilator and vasoconstrictor components of the biphasic responses to endothelin-1 and sarafotoxin 6c were reduced by bosentan, and the endothelin receptor antagonist reduced baseline systemic arterial and hind-limb perfusion pressures. Bosentan decreased vasoconstrictor responses to lower doses of angiotensin II, whereas responses to higher doses of angiotensin II and responses to vasopressin, U46619, BAY K8644, norepinephrine, acetylcholine, bradykinin, levcromakalim, PGE1, adrenomedullin, and calcitonin gene-related peptide were not altered. Vasoconstrictor responses to ET-1 were not altered by the angiotensin AT1 receptor antagonist DuP 532 or the AT2 receptor antagonist PD123,319. The results of the present study show that bosentan attenuates vasodilator and vasoconstrictor responses to endothelin-1 and sarafotoxin 6c and vasoconstrictor responses to lower doses of angiotensin II in the hind-limb vascular bed of the cat. These results suggest that endothelin may be involved in mediating responses to lower doses of angiotensin II and in the maintenance of baseline tone in the systemic vascular bed of the cat.
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PMID:Analysis of effects of bosentan (Ro 47-0203), a nonpeptide endothelin ETA/ETB receptor antagonist, in the hind-limb vascular bed of the cat. 963 52

1. A set-up for computerized acquisition and evaluation of haemodynamic data was constructed. Blood flow (BF) in the superior mesenteric and femoral artery of urethane-anaesthetized rats was measured with the ultrasonic transit time shift technique. The signals for arterial blood pressure and BF were fed into a personal computer via an analogue-digital converter. Mean arterial blood pressure, heart rate and vascular conductance (CV) were calculated on-line. For subsequent analysis of the data, algorithms were programmed to filter the data, and to determine average and peak values for each parameter. 2. Systemic hypertension induced by phenylephrine (3-300 nmol kg-1), angiotensin II (0.1-3.0 nmol kg-1) and arginine vasopressin (0.03-1.0 nmol kg-1) was accompanied by constriction of the mesenteric artery. In contrast, the femoral artery responded to phenylephrine with constriction, to angiotensin II with dilatation and to arginine vasopressin with dilation followed by constriction. The haemodynamic effects of endothelin-1 (0.03-3.0 nmol kg-1) were generally biphasic, the initial hypotension being associated with dilatation, and the delayed hypertension being accompanied by constriction of both the mesenteric and femoral arterial bed. 3. Terbutaline (3-1.0 nmol kg-1) and calcitonin gene-related peptide (0.03-1 nmol kg-1) caused systemic hypotension along with mesenteric and femoral vasodilatation. 4. Telmisartan (1 mg kg-1), an angiotensin AT1 receptor antagonist, dilated the mesenteric artery, but had no effect on femoral VC. In contrast, the alpha 1-adrenoceptor antagonist prazosin (0.1 mg kg-1), dilated the femoral artery without altering mesenteric VC. Similarly, the beta-adrenoceptor antagonist propranolol (1 mg kg-1) had no effect on mesenteric VC, but constricted the femoral arterial bed. 5. These data demonstrate that the haemodynamic effects of exogenously administered drugs can widely differ between the mesenteric and femoral arterial beds of urethane-anaesthetized rats. Furthermore, vascular tone of these two arterial beds in maintained by different vasoconstrictor systems. While the femoral artery is mainly under adrenergic control, the renin-angiotensin axis is predominant in the mesenteric arterial bed. In addition, this study also demonstrates that computerized analysis enables quick and accurate estimation of haemodynamic drug effects, and is superior to 'by hand' evaluation of peak changes in the functional diameter of the vascular bed under study.
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PMID:Differential regulation of mesenteric and femoral blood flow in the rat as revealed by computerized data acquisition and evaluation. 972 24

An activated renin-angiotensin system is a major risk factor for cardiovascular events. Angiotensin II acts on AT1 and AT2 receptors. Stimulation of AT1 receptors is associated with endothelial dysfunction, mainly as the consequence of an increased vascular production of superoxide radicals, vasoconstriction, platelet activation, enhanced release of plasminogen activator inhibitor-1, activation of immediate early genes c-fos and c-jun, myocyte hypertrophy, connective tissue formation, endothelin-1 synthesis, and activation of growth factors like PDGF and TGF-beta 1. Stimulation of AT2 receptors can mitigate or abolish the growth promoting effects of AT1 receptor stimulation. The contribution of these effects--single or in combination--on the progression of atherosclerotic lesions, the phenomenon of restenosis and the process of remodeling in heart failure is being progressively elucidated. With increasing knowledge about these relationships the inhibition of AT1 receptors appears as a main target in preventive and reparative strategies in cardiovascular diseases.
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PMID:Angiotensin II and coronary artery disease, congestive heart failure, and sudden cardiac death. 983 71

Intracerebroventricular injections of [Arg8]vasopressin (500 ng/rat) or endothelin-1 (70 ng/rat) into the right lateral ventricle induced rotation along the long axis of the body (barrel rotation) in rats. Losartan (10-200 microg/rat), an angiotensin AT1 receptor antagonist, also evoked barrel rotation, which was not inhibited by vasopressin and endothelin receptor antagonists. However, barrel rotation was not observed after injections of high doses of another angiotensin II receptor antagonist, [Sar1,Ile8]angiotensin II (100 microg/rat), or after angiotensin II (10 microg/rat). The results indicate that losartan does evoke barrel rotation which may be not mediated via vasopressin and endothelin receptors.
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PMID:The angiotensin AT1 receptor antagonist, losartan, induces barrel rotation in the rat. 988 74

The effects of the nonpeptide angiotensin II (AngII) AT1 receptor blocker candesartan on responses to AngII were investigated in the hindquarters vascular bed of the cat. Under constant-flow conditions, injections of AngII into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Candesartan in a dose of 3 microg/kg intravenously (i.v.) decreased vasoconstrictor responses to AngII in a surmountable manner. At doses of 30 and 300 microg/kg i.v., candesartan shifted the dose-response curve to AngII to the right in an insurmountable manner, indicating an insurmountable blockade of AT1 receptors. The inhibitory effects of the larger doses of candesartan on responses to AngII were long in duration, and the AT1 receptor blocker had little effect on baseline pressures. Candesartan was without effect on vasoconstrictor responses to norepinephrine, U46619, PGF2alpha, vasopressin, BAY K8644; biphasic responses to endothelin-1; or on vasodilator responses to acetylcholine, albuterol, or levcromakalim. These results indicate that candesartan is a potent and selective angiotensin AT1 receptor blocker that can induce both surmountable and insurmountable AT1 receptor blockade and provide support for the hypothesis that there are "spare" AT1 receptors in the hindquarters vascular bed of the cat.
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PMID:Analysis of the effects of candesartan on responses to angiotensin II in the hindquarters vascular bed of the cat. 989 49

We investigated the effect of angiotensin II on endothelin-1 secretion in vitro and in vivo. In vivo, angiotensin II was given intravenously to 23 essential hypertensive and 8 control subjects according to different protocols: Study A, 1.0 ng x min-1 x kg-1 and 3.0 ng x min-1 x kg-1 angiotensin II for 30 min each; Study B, 1.0 ng x min-1 x kg-1 and 3.0 ng x min-1 x kg-1 angiotensin II for 120 min each; Study C, 3.0 ng x min-1 x kg-1 angiotensin II for 30 min followed by a dose increment of 3.0 ng x min-1 x kg-1 every 30 min until mean blood pressure levels increased by 25 mmHg; Study D, 1.0 ng x min-1 x kg-1 followed by 3.0 ng x min-1 x kg-1 angiotensin II for 60 min each on two different NaCl diets (either 20 mmol NaCl/day or 220 mmol NaCl/day, both for 1 week). In all in vivo studies neither plasma nor urine endothelin-1 levels changed with angiotensin II infusion. In contrast, angiotensin II (10(-9), 10(-8), 10(-7) mol/l) stimulated endothelin-1 secretion from cultured human vascular endothelial cells derived from umbilical cord veins in a time- and dose-dependent manner. The in vitro angiotensin II effects were abolished by candesartan cilexetil, an inhibitor of the membrane-bound AT1 receptor, and also by actinomycin D, an RNA synthesis inhibitor, and cycloheximide, a protein synthesis inhibitor, indicating that endothelin-1 release depended on AT1 receptor subtype and de novo protein synthesis. Our findings indicate that angiotensin II regulates endothelin-1 release by cultured endothelial cells through an AT1 receptor-dependent pathway, but does not influence circulating endothelin-1 levels in vivo.
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PMID:Angiotensin II increases the release of endothelin-1 from human cultured endothelial cells but does not regulate its circulating levels. 1002 62

This study was designed to determine whether mechanical stretch activates the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and, if so, by what mechanism. Neonatal rat/murine cardiomyocytes were cultured on malleable silicone dishes and were stretched by 20%. Mechanical stretch induced rapid phosphorylation of JAK1, JAK2, Tyk2, STAT1, STAT3, and glycoprotein 130 as early as 2 minutes and peaked at 5 to 15 minutes. It also caused gel mobility shift of sis-inducing element, which was supershifted by preincubation with anti-STAT3 antibody. Preincubation with CV11974 (AT1 blocker) partially inhibited the phosphorylation of STAT1, but not that of STAT3. Preincubation with TAK044 (endothelin-1-type A/B-receptor blocker) did not attenuate this pathway. RX435 (anti-glycoprotein 130 blocking antibody) inhibited the phosphorylation of STAT3 and partially inhibited that of STAT1. Phosphorylation of STAT1 and STAT3 was strongly inhibited by HOE642 (Na+/H+ exchanger inhibitor) and BAPTA-AM (intracellular calcium chelator), but not by gadolinium (stretch-activated ion channel inhibitor), EGTA (extracellular Ca2+ chelator), or KN62 (Ca2+/calmodulin kinase II inhibitor). Chelerythrine (protein kinase C inhibitor) partially inhibited the phosphorylation of STAT1 and STAT3. Mechanical stretch also augmented the mRNA expression of cardiotrophin-1, interleukin-6, and leukemia inhibitory factor at 60 to 120 minutes. These results indicated that the JAK/STAT pathway was activated by mechanical stretch, and that this activation was partially dependent on autocrine/paracrine-secreted angiotensin II and was mainly dependent on the interleukin-6 family of cytokines but was independent of endothelin-1. Moreover, certain levels of intracellular Ca2+ were necessary for stretch-induced activation of this pathway, and protein kinase C was also partially involved in this activation.
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PMID:Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. 1034 87

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