Angiotensin II Receptor Antagonists: An Emerging New Class of Cardiovascular Therapeutics.

Timmermans, Pieter B.M.W.M.

doi:10.1291/hypres.22.147

Cited by 97 publications

(59 citation statements)

References 19 publications

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“…Thus, the insurmountable behavior of telmisartan might be explained in part by its slow dissociation from the receptors and also by the fact that angiotensin II is not the best competitor for telmisartan at the receptor level. Although the mode of AT1 receptor antagonism probably does not play a role in defining the antihypertensive effect of the antagonist (Timmermans, 1999), it is likely that a slow off-rate from the AT1 receptor may extend the time of occupancy of the receptor protein and lengthen the duration of antagonism.…”

Section: Associationmentioning

confidence: 99%

In Vitro and in Vivo Characterization of the Activity of Telmisartan: An Insurmountable Angiotensin II Receptor Antagonist

Maillard¹,

Perregaux²,

Centeno³

et al. 2002

J Pharmacol Exp Ther

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In vitro studies have shown that telmisartan is an insurmountable angiotensin II subtype-1 (AT1) receptor antagonist. Herein, the molecular basis of this insurmountable antagonism has been investigated in vitro, and the effect of telmisartan has been compared in vivo with that of irbesartan and candesartan. Association and dissociation kinetics of telmisartan to AT1 receptors have been characterized in vitro on rat vascular smooth muscle cells (RVSMC) expressing solely the AT1 receptor subtype. In a second set of experiments, the antagonistic efficacy of single intravenous doses (0.1, 0.3, and 1 mg/kg) of telmisartan was compared with that of irbesartan (0.3, 1.0, 3.0, and 10.0 mg/kg) and candesartan (0.3 and 1 mg/kg) in conscious, normotensive, male Wistar rats. The results show that the specific binding of [ 3 H]telmisartan to the surface of living RVSMC is saturable and increases quickly to reach equilibrium within 1 h. Telmisartan dissociates very slowly from the receptor with a dissociation half-life (t 1/2 ) of 75 min, which is comparable with candesartan and almost 5 times slower than angiotensin II (AngII). In vivo, telmisartan blunts the blood pressure response to exogenous AngII dose dependently. The blockade is long lasting and remains significant at 24 h at doses Ͼ0.1 mg/kg. Ex vivo assessment of the AT1 receptor blockade using an in vitro AngII receptor binding assay shows similar results. When administered intravenously in rats, telmisartan is 10-fold more potent than irbesartan and comparable to candesartan. Taken together, our in vitro data show that the insurmountable antagonism of telmisartan is due at least in part to its very slow dissociation from AT1 receptors.

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Section: Associationmentioning

confidence: 99%

In Vitro and in Vivo Characterization of the Activity of Telmisartan: An Insurmountable Angiotensin II Receptor Antagonist

Maillard¹,

Perregaux²,

Centeno³

et al. 2002

J Pharmacol Exp Ther

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“…And also, two Ang II receptor subtypes, the AT1 and AT2 receptors, have thus far been identified (37). Blockade of the AT1 receptor has been shown to increase the Ang II concentration (38), which may then activate the AT2 receptor (39,40).…”

Section: Discussionmentioning

confidence: 99%

Effects of an HMG-CoA Reductase Inhibitor in Combination with an ACE Inhibitor or Angiotensin II Type 1 Receptor Antagonist on Myocardial Metabolism in Ischemic Rabbit Hearts

2002

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We investigated the effects of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, pravastatin, an angiotensin converting enzyme (ACE) inhibitor, temocaprilat, and an angiotensin II type 1 (AT1) receptor antagonist, CV-11974, on myocardial metabolism during ischemia in isolated rabbit hearts using phosphorus 31-nuclear magnetic resonance ( 31 P-NMR) imaging. Forty-five minutes of continuous normothermic global ischemia was carried out. Pravastatin, temocaprilat, CV-11974 or a nitric oxide synthase inhibitor, L-NAME was administered from 60 min prior to the global ischemia. Japanese white rabbits were divided into the following experimental groups, a control group (n 7), a group treated with pravastatin (P group; n 7), a group treated with pravastatin and temocaprilat (P T group; n 7), a group treated with pravastatin and CV-11974 (P CV group; n 7), and a group treated with pravastatin and L-NAME (P L-NAME group; n 7). During ischemia, P group, as well as either P T group or P CV group, showed a significant inhibition of the decreases in adenosine triphosphate (ATP) and intracellular pH (pHi) (p 0.01, respectively, at the end of ischemia compared to the control group as well as P L-NAME group), and a significant inhibition of the increase in inorganic phosphate (Pi) (p 0.01, respectively, compared with the control group as well as P L-NAME group). These results suggest that pravastatin significantly improved myocardial energy metabolism during myocardial ischemia. This beneficial effect was dependent on NO synthase.However, this beneficial effect was not enhanced by either temocaprilat or CV-11974.

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“…It has provided the opportunity to obtain the benefits of selectively blockade the RAS at the level of the AT 1 R avoiding the nonspecificity of the ACE inhibitors (Timmermans, 1999a(Timmermans, , 1999b. The present study was designed to determine the differential effects of different doses of Losartan upon the cardiac and arterial remodeling in NO-deficient rats.…”

Section: Introductionmentioning

confidence: 99%

Beneficial Effects of Angiotensin II AT1 Blocker on Cardiovascular Adverse Remodeling Due to Nitric Oxide Synthesis Blockade

Fernandes-Santos

Mandarim-de-Lacerda

2006

Int. J. Morphol.

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FERNANDES-SANTOS SUMMARY:We studied with morphological tools the effects of different doses of Losartan upon the cardiovascular remodeling in nitric oxide deficient rats. At 15 weeks of age, thirty Wistar rats were separated in six groups: control (C), L-NAME (LN), and four groups were LN was given plus Losartan at different doses (1, 5, 20 and 40 mg/kg/day). The L-NAME was given for 9 weeks, the Losartan administration starting on the 2nd week of experiment. We studied the heart, thoracic aorta and superior mesenteric artery with light microscopy and stereology. The blood pressure (BP) increased since the first week of L-NAME administration, the Losartan treatment at doses of 20 and 40 mg/kg/day was efficient to reduce BP after the 7th week of treatment. The cardiac adverse remodeling in the LN group was characterized by intense interstitial fibrosis, impairment of the myocardial microvascularization, cardiomyocyte hypertrophy and consequent loss of cardiomyocytes. The aortic wall structure (density per area of smooth muscle cell nuclei and surface density of lamellae), and the superior mesenteric artery media/lumen ratio were also strongly affected by L-NAME administration. Only in the dose equal or higher than 20 mg/kg/day Losartan showed beneficial effects treating these alterations. In conclusion, both the heart and the arterial wall of NO deficient rats suffer a marked adverse remodeling process that is efficiently treated by a dose-dependent Losartan administration. The efficiency of Losartan treatment in this model of NO synthesis blockade correlates with the hypotensor effect of the drug mainly in the high dose treatment.

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Angiotensin II Receptor Antagonists: An Emerging New Class of Cardiovascular Therapeutics.

Cited by 97 publications

References 19 publications

In Vitro and in Vivo Characterization of the Activity of Telmisartan: An Insurmountable Angiotensin II Receptor Antagonist

In Vitro and in Vivo Characterization of the Activity of Telmisartan: An Insurmountable Angiotensin II Receptor Antagonist

Effects of an HMG-CoA Reductase Inhibitor in Combination with an ACE Inhibitor or Angiotensin II Type 1 Receptor Antagonist on Myocardial Metabolism in Ischemic Rabbit Hearts

Beneficial Effects of Angiotensin II AT1 Blocker on Cardiovascular Adverse Remodeling Due to Nitric Oxide Synthesis Blockade

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