Cardiovascular Effects of L-158,809, a New Angiotensin Type 1 Receptor Antagonist, Assessed Using the Halothane-Anesthetized In Vivo Canine Model

Abstract

ABSTRACT-L-158,809 is a new angiotensin II type 1 receptor antagonist. We simultaneously assessed its antagonistic potency and cardiovascular effects with the halothane-anesthetized in vivo canine model (n = 5). L-158,809 was intravenously infused over 10 min at escalating doses of 0.03, 0.3 and 3 mg /kg. Angiotensin II (0.1 mg/kg, i.v.)-induced vasopressor and negative inotropic responses were significantly suppressed from the low dose L-158,809. Meanwhile, L-158,809 did not affect any of the cardiovascular parameters except that QTc was slightly shortened after the high dose administration. These results support the previous in vitro knowledge that L-158,809 is a highly selective angiotensin II receptor antagonist.Keywords: L-158,809, Angiotensin II, QT interval L-158,809 is a highly selective angiotensin II type 1 (AT 1 ) receptor antagonist whose affinity for AT 1 receptor has been shown to be greater than the existing angiotensin II receptor antagonists (1). Indeed, the affinity of L-158,809 for AT1 receptors is similar to that of angiotensin II itself (1). Moreover, a recent experimental study (2) has shown that L-158,809 attenuates early left ventricular remodeling during canine myocardial infarction. However, information is still limited regarding the relationship between the doses of L-158,809 that block angiotensin II receptor and those that affect the cardiovascular variables. In this study, we simultaneously assessed the in vivo angiotensin II receptor blocking action and cardiovascular effects of L-158,809, using the halothane-anesthetized, closedchest canine model (3 -5).All experiments were performed according to Guidelines for Animal Experiments, Yamanashi Medical University. Experiments were carried out using beagle dogs weighing approximately 10 kg. The animals had been fed with about 240 g /day of standard dog foods (CD-55a; CLEA Japan, Tokyo) containing 0.41 g /100 g of NaCl for >1 month in the Animal Laboratory for Research of Yamanashi Medical University. Dogs were anesthetized initially with thiopental sodium (30 mg /kg, i.v.). After intubation, 1.0% halothane vaporized with 100% oxygen was inhaled with a ventilator (SN-480-3; Shinano, Tokyo). Tidal volume and respiratory rate were set at 20 ml /kg and 15 strokes /min, respectively. To prevent blood clotting, heparin calcium (100 IU /kg) was intravenously administered.The surface lead II ECG was obtained from the limb electrodes. Corrected QT interval (QTc) was obtained using Bazett's formula (6). The systemic blood pressure was measured at the left femoral artery. A thermodilution catheter (TC-704; Nihon Kohden, Tokyo) was positioned at the right side of the heart through the right femoral vein. The cardiac output was measured by a standard thermodilution method using a cardiac output computer (MFC-1100, Nihon Kohden). The total peripheral vascular resistance (TPR) was calculated using the following basic equation: TPR = mean blood pressure / cardiac output. A quad-polar electrodes catheter was positioned at the non-coronary cusp of the a...

Sensitive and reliable proarrhythmia in vivo animal models for predicting drug‐induced torsades de pointes in patients with remodelled hearts

“…As summarized in Figure 3, conscious animal models usually have more repolarization reserve than healthy human volunteers, which may make the models less sensitive for detecting drug‐induced QT interval prolongation ( Sugiyama and Hashimoto, 2002 ; Sakaguchi et al ., 2005 ; Takahara et al ., 2005a , 2005b , 2006b ; Chiba et al ., 2006 ). The extent of repolarization is thought to be similar in healthy human volunteers and halothane‐anaesthetized dogs ( Sugiyama et al ., 1996 , 1997a , 1997b , 1999 , 2001a , 2001b , 2001c and 2001d , 2002c , 2003 , 2004a ; Sugiyama and Hashimoto, 1998 ; Usui et al ., 1998 ; Satoh et al ., 1999 , 2000a , 2000b and 2000c , 2004 , 2005 ; Chiba et al ., 2000 , 2004a , 2004b ; Shiina et al ., 2000 ; Takahara et al ., 2000 , 2003a , 2003b , 2004a , 2005b ; Yoneyama et al ., 2002 ; Yoshida et al ., 2002a ). On the other hand, both high‐risk human patients and chronic atrioventricular (AV) block animals have limited repolarization reserve and elevated inward calcium current; thus, they are most susceptible to drug‐induced QT interval prolongation and subsequent TdP ( Chiba et al ., 2000 , 2004a ; Sugiyama et al ., 2002c , 2003 ; Yoshida et al ., 2002b ; Satoh et al ., 2004 ; Takahara et al ., 2004b , 2006c ).…”

New Perspectives for Antihypertensive Sartans as Components of Co-crystals and Co-amorphous Solids with Improved Properties and Multipurpose Activity

“…EPR (eprosartan) is also derived directly from S-8308 and is the only ARB that contains a thienyl ring. Subsequently, further ARBs with the acronyms L-158809, L-158,809, YM-358, and HR 720 were synthesized. Efforts to find new ARBs are continuing, and new compounds are being synthesized all the time, and their efficacy is being analyzed. − …”

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“…L-158809 (Fig. 4) 9 , which has shown highly selective AT 1 receptor antagonist activity in halothaneanesthetized in-vivo canine model 10 . YM 358 (Fig.…”