Evidence for a Putatively New Angiotensin II-generating Enzyme in the Vascular Wall

Okunishi, Hideki; Miyazaki, Mizuo; Toda, Noboru

doi:10.1097/00004872-198406000-00010

Cited by 171 publications

(90 citation statements)

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“…The control cumulative concen tration-response curve for Ang II (1 x 10-10-3 x 10 ' M) was first obtained. As previously reported (20), responses to Ang II were stabilized with sufficient reproducibility after the second or third doses; therefore, the response after the third or fourth dose was regarded as the control response for the respective strips. After the maximum contractile response was reached, the strips were rinsed four times over a 1-hr period and were allowed to relax to the baseline tension.…”

Section: Methodsmentioning

confidence: 96%

Pharmacological Profiles of a Novel Non-peptide Angiotensin II Type I Receptor Antagonist HR720 In Vitro and In Vivo

Jin

Song

Oka

et al. 1997

Japanese Journal of Pharmacology

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ABSTRACT-The pharmacological properties of 2-butyl-4-(methylthio)-1- [[2 [[[(propylamino)carbonyl] amino] sulfonyl](1,1 biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate (HR720), a novel non-peptide angiotensin (Ang) II type I (AT1) receptor antagonist, were characterized in both in vitro and in vivo systems. In vitro autoradiography using 125I-[Sar1,IIe8]Ang II as a ligand revealed that HR720 competitively inhibited the specific binding of the ligand to the adrenal cortex. The IC50 value for the adrenal cortex was 1.5 x 10-8 M, and the IC50 for medulla was 1.4 x 10-6 M. Similar results were obtained in the adrenal cortex with CV-11974, a known potent AT1-receptor antagonist. Since AT1 receptors are known to predominate in the adrenal cortex and AT2-receptors in the adrenal medulla, it is considered that HR720 is highly selective for AT, receptors. HR720 inhibited the Ang II-induced contraction of isolated rabbit aortic strips and hu man gastroepiploic arteries in a noncompetitive manner, pD'2=9.40 and 9.62 for rabbit aorta and human artery, respectively. With CV-11974, pD'2 values of 9.84 in isolated rabbit aorta and 10.00 in human artery were obtained. HR720 did not affect the norepinephrine-, serotonin or KCl-induced contraction even at a concentration of 1 x 10-5 M. In anesthetized hamsters, HR720 induced a dose-dependent inhibition of the pressure response to Ang II. The potency of HR720 to antagonize the Ang II-induced pressure response was similar to that of CV-11974. These results demonstrate that HR720 is a potent and selective AT1 -receptor antagonist. Keywords:Renin-angiotensin system, Angiotensin II, Receptor, Antagonist, Isolated vesselThe renin-angiotensin system (RAS) plays a critical role in blood pressure regulation and in fluid and electrolytes homeostasis; it is also involved in the pathogenesis of many cardiovascular diseases (1, 2). The RAS consists of a cascade of enzymatic reactions leading to formation of angiotensin (Ang) II which is a powerful vasoconstrictor. The angiotensin converting enzyme (ACE) inhibitors have clearly demonstrated the beneficial effect of pharmacological inhibition of the RAS in the treatment of hypertension and congestive heart failure (3). Recent studies have suggested that ACE inhibitors effectively prevented the progression of atherosclerosis in high cholesterol loaded rabbit aorta (4, 5) and inhibited the progression of renal damage in the rat model of chronic renal failure (6, 7), indicating the involvement of Ang II in such pathological disorders. However, there are many reports on the unwanted side effects of ACE inhibitors such as cough and angioedema resulting from the lack of * To whom correspondence should be addressed .specificity of ACE inhibitors for Ang I (8, 9). Moreover, ACE inhibitors interfere with the kinin metabolism (10). Recent studies have demonstrated that Ang II can also be formed in non-ACE-dependent manner in several species of animals including humans (11-13). In view of these limitations of ACE inhibitors, selective blocking of Ang I...

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Section: Methodsmentioning

confidence: 96%

Pharmacological Profiles of a Novel Non-peptide Angiotensin II Type I Receptor Antagonist HR720 In Vitro and In Vivo

Jin

Song

Oka

et al. 1997

Japanese Journal of Pharmacology

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“…Reciprocally, when less AT1R antagonist is bound to the AT1Rs, an ACE inhibitor will reduce the production of Ang II available to compete with the antagonist. The alternative proposed to this physiological explanation is that an AT1R antagonist in combination with an ACE inhibitor blocks the effects of Ang II generated by pathways other than renin and ACE, such as CAGE (chymotrypsin-like angiotensin generating enzyme) 22 or chymase. 23 …”

Section: Concept Of Combined Ras Blockade By Ace Inhibitors and At1r mentioning

confidence: 99%

Combined Blockade of the Renin-Angiotensin System With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Antagonists

2004

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“…The pellet was then homogenised in 5 volumes of 10 mmol/L sodium-phosphate buffer (pH 7.4) containing 2 mol/L KCl and 0.1% Nonidet P-40, kept overnight at 4°C and centrifuged again. Aliquots of the supernatants were used for the parallel determination of ACE 17 and chymase 15 activities by our method reported previously.…”

Section: Measurement Of Ace and Chymase Activitiesmentioning

confidence: 99%

“…We have found that in vascular tissues in rats and rabbits, Ang I is converted to Ang II by ACE alone, while in humans, monkeys, dogs, and hamsters, Ang I is possibly converted by both ACE and chymase. [14][15][16] These species-dependent pathways of vascular Ang II production strongly suggest the involvement of Ang II produced by chymase, and may be the cause of the apparent discrepant action of ACE inhibitors in the rat and human studies. Ang II-producing ability in human blood vessels is approximately 70% dependent on chymase, and only 30% dependent on ACE.…”

Section: Introductionmentioning

confidence: 99%

Effect of an angiotensin II receptor antagonist, candesartan cilexetil, on canine intima hyperplasia after balloon injury

et al. 1999

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The roles of angiotensin (Ang) II as produced by two different enzymes, angiotensin-converting enzyme (ACE) and chymase, were investigated in a canine experimental model where intima hyperplasia was induced by balloon catheterization in the common carotid and femoral arteries. The animals received oral candesartan cilexetil (3 mg/kg) or enalapril (10 mg/kg) twice a day for 5 weeks. After 1 week of active drug therapy, the common carotid and femoral arteries were unilaterally injured by balloon catheterization. In the common carotid arteries, both ACE and chymase activities were increased by the injury, with the increase in chymase activities being greater than that in ACE activities. In the femoral arteries, ACE, but not chymase, activities were significantly increased by the injury. Both candesartan cilexetil and enalapril reduced blood

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Evidence for a Putatively New Angiotensin II-generating Enzyme in the Vascular Wall

Cited by 171 publications

References 0 publications

Pharmacological Profiles of a Novel Non-peptide Angiotensin II Type I Receptor Antagonist HR720 In Vitro and In Vivo

Pharmacological Profiles of a Novel Non-peptide Angiotensin II Type I Receptor Antagonist HR720 In Vitro and In Vivo

Combined Blockade of the Renin-Angiotensin System With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Antagonists

Effect of an angiotensin II receptor antagonist, candesartan cilexetil, on canine intima hyperplasia after balloon injury

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