Hemodynamic Effects of Direct Angiotensin II Blockade Compared to Converting Enzyme Inhibition in Rat Model of Heart Failure

Raya, Thomas E.; Fonken, S; Lee, Richard W.; Daugherty, Sherry; Goldman, Steven; Wong, Pancras C.; Timmermans, Pieter B.M.W.M.; Morkin, Eugene

doi:10.1093/ajh/4.4.334s

Cited by 96 publications

(28 citation statements)

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“…Administrations of AT 1 receptor antagonist, L-158809 for 2 months 24) and losartan for 6 weeks 25) prevent cardiac hypertrophy in MI rats, while that of losartan for 2 weeks does not. 26) Indeed, 2-week administration of YM358, in the present study, did not prevent cardiac hypertrophy in MI rats. However, 8-week administration of YM358 significantly decreased cardiac hypertrophy in MI-induced CHF rats.…”

Section: Discussioncontrasting

confidence: 52%

“…24,25) On the other hand, there is another report that AT 1 receptor antagonist does not prevent cardiac hypertrophy. 26) The discrepancies between these results in preventing cardiac hypertrophy might be due to the difference in treatment periods. Administrations of AT 1 receptor antagonist, L-158809 for 2 months 24) and losartan for 6 weeks 25) prevent cardiac hypertrophy in MI rats, while that of losartan for 2 weeks does not.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Angiotensin II Type 1 Receptor Antagonist, YM358, on Cardiac Hypertrophy and Dysfunction after Myocardial Infarction in Rats.

Tokioka-Akagi¹,

Fujimori²,

Shibasaki³

et al. 2002

Biological & Pharmaceutical Bulletin

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Angiotensin II (Ang II) plays an important modulatory role in the cardiovascular system under basal conditions and in various pathologies such as hypertension and heart failure.1,2) The renin-angiotensin system (RAS) and the sympathetic nervous system have been postulated to play a role in regulating cardiac cell growth. Indeed, Ang II is a potent, direct stimulant of protein synthesis and growth in cultured cardiac myocytes. 3,4) Ang II has been implicated in the development of cardiac hypertrophy and fibrosis after myocardial infarction (MI) in humans, as well as in animal models. 5,6) Inhibition of Ang II formation by angiotensin converting enzyme (ACE) inhibitors or blockade through the angiotensin II type 1 (AT 1 ) receptor by antagonists actually attenuates myocardial hypertrophy 7,8) and ventricular fibrosis. 9)Heart failure is the final form of disease following progression of cardiac hypertrophy and fibrosis caused by hypertension or valvular heart disease, or progression of ischemic heart disease such as angina or MI.10) Rats with MI induced by left coronary artery ligation are used as experimental models representing pathophysiological alterations similar to those seen in chronic heart failure (CHF) in humans. 11,12) It is also known that ventricular hypertrophy and remodeling describe a series of pathological changes after ischemia. In MI rats, plasma Ang II concentration significantly rises 1 week after coronary ligation, and the elevation is maintained for 5 weeks.13) Seven weeks after MI in rats, characters of LV remodeling and dysfunction are developed and the expression of cardiac AT 1 receptor mRNA is enhanced. 14),4]triazole potassium salt monohydrate) is a potent, nonpeptide competitive AT 1 receptor antagonist, which has been verified for its specificity on Ang II in in vitro study.15) The efficacy of YM358 in treating hypertension is well established in animal models. 16,17) Additionally, YM358 and enalapril delayed the progression of heart failure in a rat model with cardiac volume-overload. 18)Since Ang II has been purported to be a trophic hormone which may induce the cardiac hypertrophy which is detrimental in heart failure, it would be expected that an AT 1 receptor antagonist, YM358, blunts the progress of heart failure.As obsolete MI was considered to be one of the major factors leading to CHF, YM358 was orally and chronically administered to MI rats with heart failure, and time course changes of cardiac weights and hemodynamic parameters were investigated in the present study. MATERIALS AND METHODS AnimalsMale Wistar rats (12 weeks old) were obtained from Japan SLC Inc. (Shizuoka, Japan). The rats were kept at a controlled room temperature of 22°C under a 12-h lightdark cycle, and provided with regular rat chow and tap water. They were used after an acclimatization period of at least 3 d. The experiments were performed under the regulations of the Animal Ethical Committee of Yamanouchi Pharmaceutical.Myocardial-Infarction Surgery Under anesthesia, MI surgery was performed using the ...

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Effects of Angiotensin II Type 1 Receptor Antagonist, YM358, on Cardiac Hypertrophy and Dysfunction after Myocardial Infarction in Rats.

Tokioka-Akagi¹,

Fujimori²,

Shibasaki³

et al. 2002

Biological & Pharmaceutical Bulletin

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“…Numerous studies have demonstrated that the beneficial effects of ACE inhibitors on cardiac function and survival were similar to those of Ang II type 1 antagonists in the rat MI model (26,41). Lisinopril treatment at a dose of 20 mg /kg per day or less has also been reported to improve cardiac function and survival in MI rats (10,24).…”

Section: Discussionmentioning

confidence: 93%

Possible Roles of Cardiac Chymase After Myocardial Infarction in Hamster Hearts

Jin

Takai

Yamada

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-The significance of cardiac chymase after myocardial infarction (MI) was evaluated using a hamster model of MI. At 1, 3, 7, 14, 28 and 56 days after MI, tissues were removed for measurements of angiotensin-converting enzyme (ACE) and chymase activities. The mean infarct size 3 days after left coronary artery ligation was 47.3 ± 5.9% of the left ventricle circumference. The ratio of left ventricle weight to body weight was significantly increased from 3 days after MI. The level of plasma renin activity in the MI hamsters was significantly increased at the early phase of MI (1 -3 days), while no significant changes in plasma ACE activity were observed. The ACE activity in the infarcted left ventricle was significantly increased starting from 3 days after MI and this increase was sustained up to 28 days. The chymase activity in the infarcted left ventricle was significantly increased starting from 1 day after MI and this increase was sustained up to 56 days. The number of chymase-positive mast cells in the infarcted left ventricle was significantly higher than in the sham group 3 and 7 days after operation. Treatment with an angiotensin (Ang) II type 1 receptor antagonist (candesartan cilexetil, 10 mg / kg per day) starting 3 days before the induction of MI significantly reduced the mortality rate during 14 days of observation following MI, whereas treatment with an ACE inhibitor (lisinopril, 20 mg / kg per day) did not. A significant improvement in hemodynamics (maximal negative and positive rates of pressure development, left ventricular systolic pressure and enddiastolic pressure, mean arterial blood pressure) was observed by the treatment with candesartan cilexetil, but not with lisinopril, 3 and 14 days after MI. These results suggested that Ang II produced by chymase may participate in the pathophysiologic state after MI in hamsters.

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“…Based on this finding, we have reached the conclusion that the RAS is closely associated with the occurrence of cardiac hypertrophy and renal disorders in THM. However, some researchers suggest that the organ protection of ACEIs is due to the inhibition of AII, [15][16][17][18][19][20] while others suggest that it is due to an enhancement of bradykinin rather than inhibition of AII. [21][22][23][24][25] Moreover, it is reported that an ACEI increased thereceptor density of myocytes and augmented the response to isoproterenol, while an AT1R antagonist did not have the same effects.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of a Subdepressor Dose of L-158,809, an Angiotensin II Type 1 Receptor Antagonist, on Cardiac Hypertrophy and Nephropathy Via the Activated Human Renin-Angiotensin System in Double Transgenic Mice With Hypertension

et al. 1998

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he Tsukuba hypertensive mouse (THM) is a hypertensive animal model prepared by introducing human renin and angiotensinogen genes into C57BL/6 mouse. 1 In THM, the cause of hypertension is known to be a single factor, an enhancement of the reninangiotensin system (RAS). In THM, angiotensin II (AII) is 3-5 times higher in serum and that in the heart and kidney is 4-5 times higher compared to C57BL/6 mice. 2 At 6 weeks of age, when blood pressure measurement becomes possible, THM already show elevated blood pressure. In THM, the occurrence of severe cardiac hypertrophy and glomerulosclerosis, in comparison with the degree of hypertension, has been reported. 3 L -158,809 [5,7-dimethyl-2-ethyl-3-[{2'-(1H-tetrazol-5-yl)is a selective AII receptor antagonist with high potency, good per os absorption, long duration and antihypertensive efficacy after a single dose equal to that of angiotensin converting enzyme inhibition, and does not have AII agonist activity. 4,5 The affinity of L-158,809 for the AII type 1 receptor (AT1R) and its potency for the inhibition of AII responses in a variety of tissues and in vitro preparations is subnanomolar (IC50=0.2-0.8 nmol/L). L-158,809 is 50-200 times more potent than losartan, an AT1R antagonist, and 5-15 times more potent than the metabolite, EXP3174. Indeed, the affinity of L-158,809 for AT1R is similar to that of the natural hormone, AII. With respect to the subtypes of AII receptors, L-158,809 has high selectivity for the AT1R, as does losartan, unlike PD-123,177 and PD-121,981, which are selective for AII type 2 receptor (AT2R). Unlike other AT1R antagonists, the inhibitory activity of L-158,809 is observed shortly after per os administration, and the duration of activity is greater than 24 h for both intravenous and per os administration. Moreover, the per os to intravenous potency ratio is 0.8. Therefore, L-158,809 is the most potent AT1R antagonist described to date.In the present study, L-158,809 was administered to THM, and its curative effects on cardiac hypertrophy and nephropathy were examined. Methods Animals and DrugsNine male THM were assigned to each of an L-158,809 dosage group (0.3 mg/kg per day) and a no-dosage group. Nine age-matched male C57BL/6 mice were used as normal controls. In the L-158,809 group, the drug was dissolved in drinking water and administered for 8weeks from the age of 20 weeks. All the mice were euthanized at 28 weeks of age. The mice were bred in an air-conditioned room at 22±2°C and humidity of 50±10%, with a 12-h light period (from 7.00 h to 19.00 h). They were fed a breeding The effects of L-158,809, an angiotensin II type 1 receptor antagonist, on cardiac hypertrophy and nephropathy were examined using Tsukuba hypertensive mice (THM) carrying both human renin and angiotensinogen genes. Nine male THM aged 20 weeks were assigned to each of a no-dosage group and an L-158,809 dosage group, and L-158,809 was administered for 8 weeks. Nine age-matched male C57BL/6 mice were used as normal control animals. At 28 weeks of age, all of the mice w...

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Hemodynamic Effects of Direct Angiotensin II Blockade Compared to Converting Enzyme Inhibition in Rat Model of Heart Failure

Cited by 96 publications

References 0 publications

Effects of Angiotensin II Type 1 Receptor Antagonist, YM358, on Cardiac Hypertrophy and Dysfunction after Myocardial Infarction in Rats.

Effects of Angiotensin II Type 1 Receptor Antagonist, YM358, on Cardiac Hypertrophy and Dysfunction after Myocardial Infarction in Rats.

Possible Roles of Cardiac Chymase After Myocardial Infarction in Hamster Hearts

Inhibitory Effects of a Subdepressor Dose of L-158,809, an Angiotensin II Type 1 Receptor Antagonist, on Cardiac Hypertrophy and Nephropathy Via the Activated Human Renin-Angiotensin System in Double Transgenic Mice With Hypertension

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