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Volume 124 (2004)
- Issue 6 Pages 375-
- Issue 5 Pages 301-
- Issue 4 Pages 201-
- Issue 3 Pages 135-
- Issue 2 Pages 69-
- Issue 1 Pages 3-
Volume 124, Issue 2
Displaying 1-6 of 6 articles from this issue
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Reviews: Further Pharmacological Objectives in the Renin-Angiotensin System
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Seiji TAKASHIMA2004 Volume 124 Issue 2 Pages 69-75
Published: 2004
Released on J-STAGE: July 26, 2004
JOURNAL FREE ACCESSAngiotenesin II (AGII) is known to induce cardiac hypertrophy. Prolonged hypertrophy leads to reduced cardiac performance. The cardiac protective effect of AGII antagonist implies the potential role of AGII in the transition from cardiac hypertrophy to heart failure. Here we report a new mechanism of HB-EGF mediated cardiac hypertrophy induced by AGII. HB-EGF is a EGF family growth factor synthesized as the membrane anchored form and released by protease cleavage to activate its receptor. In cultured cardiomyocytes, AGII induced the transactivation of EGF receptor, which was blocked by metalloproteinase inhibitor KBR-7785 and HB-EGF-neurtralizing antibody #19. Both KBR-7785 and #19 attenuated the cardiac hypertrophy by AGII in vitro and in vivo. Thus we conclude that AGII activates metalloproteinase and sheds HB-EGF. Released HB-EGF bound to EGF receptor, leading to the cardiac hypertrophy. Recently, similar transactivation of EGF receptor by a GPCR agonist has been reported in various organs, indicating that EGF receptor transactivation by HB-EGF might play the general role of pharmacological reaction by AGII.
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Denan JIN, Shinji TAKAI, Yukiko OKAMOTO, Michiko MURAMATSU, Mizuo MIYA ...2004 Volume 124 Issue 2 Pages 77-82
Published: 2004
Released on J-STAGE: July 26, 2004
JOURNAL FREE ACCESSMast cell-derived chymase seems to be important in the regulation of local angiotensin (A) II formation in cardiovascular tissues. In human heart, chymase accounts for 80% of A II formation. Therefore, the chymase-dependent A II pathway may play an important role in the pathogenesis of A II-related cardiovascular diseases. For example, cardiac chymase was activated earlier than ACE and this activation lasted longer than that of ACE after myocardial infarction (MI) in hamsters. Treatment with a specific chymase inhibitor treatment, but not an ACE inhibitor, improved post-MI survival as well as cardiac function and the extent of the beneficial effects was similar to that observed for an AT1-receptor antagonist treatment in this model. The survival benefit after MI seems to be related to an antiarrhythmic effect of the chymase inhibitor because chymase inhibition reduces the incidence of ventricular arrhythmias during periods of heart ischemia in a dog MI model. Thus, an antiarrhythmic effect of the chymase inhibitor may contribute to a reduction in mortality rate during the acute phase after MI.
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Minoru YOSHIYAMA, Takashi OMURA, Jyunichi YOSHIKAWA2004 Volume 124 Issue 2 Pages 83-89
Published: 2004
Released on J-STAGE: July 26, 2004
JOURNAL FREE ACCESSWe investigated the effects of the aldosterone blocker eplerenone alone and in combination with angiotensin II type 1 receptor antagonist on ventricular remodeling in rats with left ventricular (LV) dysfunction after extensive myocardial infarction (MI). Adding an aldosterone antagonist to an ACE inhibitor reduces mortality and morbidity in heart failure. Starting 1 day after MI, rats were treated with placebo, eplerenone (100 mg/kg/day), the angiotensin type 1 receptor antagonist candesartan (1 mg/kg/day), or a combination of both for nine weeks. Both monotherapies attenuated the rise in LV end-diastolic dimension (LVDd) and LV end-diastolic volume (LVEDV) compared with placebo, whereas combined treatment further attenuated LVDd and LVEDV and significantly improved LV function. Increased collagen type I and III gene expressions in the noninfarcted LV myocardium from MI placebo rats was attenuated by candesartan, but almost completely prevented by eplerenone and eplerenone/candesartan. The addition of eplerenone to candesartan prevented the increases in LV gene expression of ANP and BNP more effectively than either monotherapy. The aldosterone blocker eplerenone improved LV remodeling in rats with LV dysfunction after extensive MI. Combination therapy with an candesartan substantially potentiates this effect by a complementary prevention of LV fibrosis, cardiac hypertrophy, and molecular alterations.
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Takayoshi TSUTAMOTO2004 Volume 124 Issue 2 Pages 90-100
Published: 2004
Released on J-STAGE: July 26, 2004
JOURNAL FREE ACCESSRandomized aldactone evolution study (RALES) and eplerenone post-AMI heart failure efficacy and survival study (EPHESUS) had shown that aldosterone blockade (AB) with standard therapy resulted in a reduction in mortality in patients with congestive heart failure (CHF) and acute myocardial infarction (AMI). However, the mechanism for the beneficial effect of AB remains unknown. To evaluate the effect of spironolactone (Spi) on left ventricular (LV) remodeling, 34 CHF patients with DCM were randomly divided into the Spi (+) or Spi (-) groups. Four months of treatment with Spi improved the LV volume and mass. To evaluate the effect of Spi on post-infarct LV remodeling, 134 patients with first anterior AMI were randomly divided into the Spi (+) or Spi (-) groups after revascularization. LV ejection fraction was significantly improved after 1 month in the Spi (+) group compared with that in the Spi (-) group. LV end-diastolic volume index was significantly suppressed in the Spi (+) group compared with that in the Spi (-) group. Transcardiac extraction of aldosterone through the heart was significantly suppressed in the Spi (+) group and was significant lower in the Spi (+) group compared with the Spi (-) group. These findings indicate that AB combined with standard therapy can prevent LV remodeling in patients with CHF and AMI, suggesting that the failing heart is the target organ of the aldosterone.
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Akira NISHIYAMA, Youichi ABE2004 Volume 124 Issue 2 Pages 101-109
Published: 2004
Released on J-STAGE: July 26, 2004
JOURNAL FREE ACCESSOur recent efforts have been focused on the mechanisms responsible for the progression of aldosterone-induced renal injury. We have demonstrated in rats that chronic treatment with aldosterone (0.75 µg/H, SC) and 1% NaCl (in drinking solution) results in severe proteinuria and glomerular injury, characterized by cell proliferation and mesangial matrix expansion. Increased renal cortical NAD(P)H oxidase expression, reactive oxygen species (ROS) generation, and mitogen-activated protein kinase (MAPK) activation were also observed. Treatment with a selective mineralocorticoid receptor antagonist, eplerenone(0.125% in chow), or an antioxidant, tempol (3 mM in drinking solution), prevented elevations of ROS levels and MAPK activity, as well as ameliorating glomerular injury, indicating that aldosterone-induced glomerular injury is associated with redox-sensitive MAPK activation. In vitro studies showed that mineralocorticoid receptors are highly expressed in rats mesangial cells, particularly in the cytoplasm. Aldosterone (100 nM) application activates MAPK and causes cellular proliferation and deformation. These data suggest that aldosterone contributes to the progression of glomerular injury through its direct actions.
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Technical Note
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Megumu YOSHIMURA, Hidemasa FURUE, Go KATO, Atsushi DOI, Masaharu MIZUN ...2004 Volume 124 Issue 2 Pages 111-118
Published: 2004
Released on J-STAGE: July 26, 2004
JOURNAL FREE ACCESSSlice preparations as well as acutely dissociated and cultured neurons from various regions in the CNS have been widely used to analyze pharmacological properties of synaptic responses and receptors expressed at the pre- and post-synaptic sites. However, the essential properties are not obviously different from neuron to neuron. These characteristics of neurons in the CNS make it difficult to elucidate their functional significances. It is, therefore, preferable that the pharmacological analysis should be made from identified neurons by stimulation of identified inputs. The in vivo patch-clamp recording technique allows us to clarify the synaptic responses evoked by the various known natural stimuli applied to the skin or other parts and makes it possible to interpret with more certainty the behavioral changes by synaptic plasticity observed at the single cell level. Although the in vivo technique has obvious advantages in analysis of physiological responses, this method is, however, confined so far to neurons located at the near surface of the CNS for pharmacological analysis, because of the diffusion problem of the chemical to deeper neurons. Thus, combinatorial studies with dissociated or cultured neurons or with slice preparations are clearly required for further understanding of pharmacological properties of neurons in the CNS.
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