Effects Of TCV-116 Research Articles

Angiotensin receptor gene expression in candesartan mediated neuroprotection

Male Wistar rats were treated with an angiotensin AT1 receptor antagonist, candesartan cilexetil (TCV-116, 1 mg/kg/day) over a 4-week period. Systolic blood pressure was significantly reduced by 14% after 1 week and remained stable for the next 3 weeks compared with controls. Up-regulation of AT2, but not AT1, receptor gene expression by 3.4-fold and 5.0-fold was observed 1 and 4 weeks after treatment. Middle cerebral artery occlusion caused significantly reduced infarct volumes in TCV-116-treated rats, by about 30% when compared with control rats. Neurological scores were also improved in treated rats. These results suggest that the neuroprotective effects of TCV-116 may be mediated through AT1 receptor antagonism and AT2 receptor up-regulation.

Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis

It was reported that angiotensin II stimulates angiogenesis in vivo, and angiotensin-converting enzyme (ACE) inhibitors inhibit angiogenesis. We found that an AT1-receptor (AT1-R) antagonist, TCV-116, inhibited tumor growth, tumor-associated angiogenesis, and metastasis in a murine model. Tumor growth of Sarcoma 180 (S-180) cells and of fibrosarcoma (NFSA) cells was strongly inhibited by administration of TCV-116 in the diet at a dose of approximately 100 mg/kg/day. This reduction was accompanied with a marked reduction in tumor-associated angiogenesis. The same treatment also reduced the lung metastasis of intravenously injected Lewis lung carcinoma cells. These effects of TCV-116 were equivalent to those of the ACE inhibitor, lisinopril. In S-180 and NFSA tumor tissues, ACE and AT1a receptor (AT1a-R) mRNAs were expressed when assessed with RT-PCR. AT1b receptor and AT2 receptor, however, were not detected. Immunoreactive AT1-R was detected mainly on the neovascularized vascular endothelial cells in which expression was reduced by TCV-116 and lisinopril. These results suggested that TCV-116 inhibits the angiogenesis, growth, and metastasis of tumors highly dependent on AT1a-R blockade. Blockade of AT1a-R signaling may therefore become an effective novel strategy for tumor chemoprevention.

Effects of TCV-116 on endothelin-1 and PDGF A-chain expression in angiotensin II-induced hypertensive rats.

Angiotensin II (Ang II) has been shown to stimulate cardiac growth and collagen synthesis in cultured vascular smooth muscle cells and to increase fibroblast proliferation. Chronic infusion with Ang II increases blood pressure and activates growth mechanisms to produce hypertrophy of the heart. This study investigated the effects of an Ang II type 1 receptor antagonist, TCV-116, on preproendothelin-1 (preproET-1), ETA receptor and platelet-derived growth factor (PDGF) A-chain expression in the left ventricle of Wistar-Kyoto rats treated for 2 weeks with Ang II (200 ng x kg(-1) x min(-1)), and the relation of these effects to myocardial remodeling. Rats given Ang II alone (ANGII-V) were compared with rats also receiving TCV-116 (ANGII-TCV). In both groups, blood pressure was similar and significantly higher than in control rats. The preproET-1, ET(A) receptor and PDGF A-chain expressions in the left ventricle were significantly increased in ANGII-V compared with control rats, and were significantly suppressed in ANGII-TCV compared with ANGII-V rats. ANGII-V rats showed a significant increase of the type I collagen expression, wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis, with all these parameters being significantly improved by TCV-116. Myocardial remodeling in Ang II-induced hypertensive rats was significantly ameliorated by a subdepressor dose of TCV-116, which may have been due to a decrease in ET-1 and PDGF A-chain expression in the left ventricle.

Inhibition of the Angiotensin II Type 1 Receptor by TCV-116: Quantitation by In Vitro Autoradiography

Inhibition of angiotensin (Ang) II type 1 (AT1) receptors in various target tissues of adult Sprague-Dawley rats was studied after single oral administration of TCV-116. The effects of TCV-116 on Ang II-receptor binding were assessed by quantitative in vitro autoradiography using 125I-[Sar1,Ile8]Ang II as a ligand. Four hours after the administration of TCV-116 (1 mg/kg), Ang II-receptor binding was markedly inhibited in the kidney (20% of control), adrenal cortex (27%), thoracic aorta (57%), heart (55%) and testis (76%) where AT1 receptors predominate. In the brain, orally administered TCV-116 produced a significant inhibition of binding both to the circumventricular organs (38%), which are devoid of the blood-brain barrier (BBB), and to the discrete regions within the BBB such as the paraventricular hypothalamic nucleus (48%), nucleus of the solitary tract (60%). Twenty-four hours after the administration, Ang II-receptor binding had partly recovered to approximately 50–85% of control levels. In contrast, throughout the experimental period, Ang II-receptor binding was little affected in sites where Ang II type 2 (AT2) receptors predominate such as the adrenal medulla and the nucleus of the inferior olive. These data indicate that orally administered TCV-116 specifically binds to AT1 receptors both in peripheral tissues and the central nervous system.

Characterization of the High Sensitivity of Rabbits to the Effects of TCV-116, an Angiotensin II Receptor Antagonist

Characterization of the High Sensitivity of Rabbits to the Effects of TCV-116, an Angiotensin II Receptor Antagonist

Role of angiotensin II in reflex tachycardia during hypotension caused by a calcium channel blocker.

Blood pressure and heart rate were measured by telemetry in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) to investigate the contribution of angiotensin II to the reflex tachycardia resulting from exaggerated hypotension caused by a high dose of a calcium channel blocker. Pre-treatment with TCV-116, an angiotensin II AT1 receptor antagonist, or enalapril partially attenuated the reflex tachycardia induced by manidipine, but TCV-116 had almost no effect on the sinus tachycardia induced by isoproterenol. The suppressive effects of TCV-116 against the reflex tachycardia tended to be more obvious in WKY than in SHR, though the difference was not statistically significant. Concurrent administration of propranolol almost completely inhibited both the reflex tachycardia and the sinus tachycardia in SHR and WKY, indicating that the sympathetic nervous system contributes to both types of tachycardia. We demonstrated that angiotensin II may be involved in the reflex tachycardia induced by calcium channel blockers probably via activation of some component of the sympathetic nervous system other than postsynaptic factors at the sinus node.

Renal responses to angiotensin receptor antagonist and angiotensin-converting enzyme inhibitor in partially nephrectomized spontaneously hypertensive rats.

To investigate the role of the renin-angiotensin system (RAS) on nephrosclerosis in salt-loaded, partially nephrectomized spontaneously hypertensive rats (SHR), we evaluated the effects of angiotensin II (ANGII) blockade on the progression of nephrosclerosis with an angiotensin type 1 receptor (AT1rec) antagonist [TCV-116 (TCV)] and an angiotensin-converting enzyme (ACE) inhibitor (enalapril) at the doses equivalent in reducing systemic blood pressure (BP). SHR were five/sixths nephrectomized and were fed a high-salt diet. In addition to being significantly preventive against an increase in systolic BP, both TCV and enalapril significantly attenuated the increases in proteinuria and the renal histopathological alterations. Transcription of AT1rec mRNA in the remnant kidney was enhanced with the progression of nephrosclerosis, but was inhibited by TCV as well as enalapril. In these aspects, there were no apparent differences between effects of TCV and enalapril. The RAS system plays an important role in nephrosclerosis in partially nephrectomized SHR despite a high-salt diet, and direct ANGII blockade certainly protected the kidney against hypertensive injury in this model.

Effects of TCV-116 and CV-11974 on angiotensin II-induced responses in vascular smooth muscle cells

(±)-1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (TCV-116, Candesartan) and its active metabolite 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (CV-11974) are specific nonpeptide angiotensin AT 1 receptor antagonists. In the present study, the inhibitory potency of these two antagonists on the angiotensin II-induced responses in aortic vascular smooth muscle cells from Wystar Kyoto rats was investigated. The specific binding of 125I-angiotensin II to cells was inhibited by CV-11974 and TCV-116 with a half-maximal inhibitory concentration (IC 50) of 3 × 10 −11 M and 1 × 10 −9 M, respectively. CV-11974 and TCV-116 inhibited the angiotensin II-induced increase in [ 3H]thymidine incorporation with an IC 50 of 3 × 10 −10 and 5 × 10 −9 M, respectively. Both CV-11974 and TCV-116 (10 −7 M) completely blocked the angiotensin II-induced increase in c- fos mRNA. The inhibitory potency of the metabolite CV-11974 was about 30–100-fold higher than that of the prodrug TCV-116.

Effects of the non-peptide angiotensin II receptor antagonist TCV-116 on systemic and renal hemodynamics in dogs with renal hypertension.

The effects of TCV-116, a new non-peptide angiotensin II receptor antagonist, on systemic and renal hemodynamics were studied in conscious normotensive and renal hypertensive (2-kidney, 1-clip Gold-blatt type) dogs. When orally administered at 0.03 to 1.0 mg/kg, TCV-116 inhibited the pressor response to angiotensin II in conscious normotensive dogs in a dose-dependent fashion. The IC50 and IC100 values were 0.06 mg/kg and 0.86 mg/kg, respectively. TCV-116 at doses of 0.3 mg/kg and 1.0 mg/kg dose-dependently and persistently decreased systolic and diastolic blood pressure in both dogs with acute renal (hyperreninemic) and those with chronic renal (normoreninemic) hypertension. Even a high dose of TCV-116 (10 mg/kg, p.o.) increased effective renal plasma flow without affecting blood pressure or glomerular filtration rate in normotensive dogs. Furthermore, even at this high dose, TCV-116 did not reduce effective renal plasma flow or glomerular filtration rate in dogs with renal hypertension despite marked reduction in systemic blood pressure. The angiotensin converting enzyme inhibitor enalapril (10 mg/kg, p.o.) had renal hemodynamic effects similar to those of TCV-116. These findings indicate that TCV-116 has potent hypotensive effects not only in dogs with acute renal hypertension but also in those with chronic renal hypertension, but does not appear to adversely affect renal hemodynamics.

O-81 - Effect of TCV-116, a novel non-peptide angiotensin II receptor antagonist, on chronic congestive heart failure (II).

O-81 - Effect of TCV-116, a novel non-peptide angiotensin II receptor antagonist, on chronic congestive heart failure (II).

O-392 - Effect of TCV-116, a novel non-peptide angiotensin II receptor antagonist, on chronic congestive heart failure (CHF).

O-392 - Effect of TCV-116, a novel non-peptide angiotensin II receptor antagonist, on chronic congestive heart failure (CHF).