Kazuyoshi Tadokoro

Fasudil, a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats.

Objective The present study was designed to clarify whether the Rho–Rho-kinase pathway is involved in the process of hypertensive glomerulosclerosis and to assess the therapeutic effect of fasudil, a specific Rho-kinase inhibitor. Method and results Dahl salt-sensitive rats (DS) and Dahl salt-resistant rats (DR) were fed a high-salt diet at 6 weeks of age. Fasudil (30 mg/kg per day) was administered for 7 weeks to DS starting at the age of 11 weeks. After 7 weeks, untreated DS were characterized by decreased kidney function, increased proteinuria, abnormal morphological findings, increased adrenomedullin and atrial natriuretic peptide (ANP) levels, and increased renal messenger RNA expression of RhoB, Rho-kinaseα, Rho-kinaseβ, collagen I and collagen III, and transforming growth factor-beta (TGF-β) in the renal cortex compared with DR. Chronic fasudil treatment significantly improved renal function (serum creatinine, –26%; blood urea nitrogen, –41%; creatinine clearance, +42%), proteinuria (–24%) and histological findings (glomerular injury score, –49%; afferent arteriolar injury score, –17%) without changing blood pressure compared with untreated DS. Interestingly, long-term fasudil treatment decreased the plasma adrenomedullin (–25%) and ANP (–49%), but did not change the plasma renin or aldosterone. Furthermore, fasudil significantly decreased the messenger RNA expression of TGF-β (–20%), collagen I (–23%), and collagen III (–24%) in the renal cortex. However, there were still significant differences in the aforementioned parameters between DR and fasudil-treated DS. Conclusion These results suggest that the Rho–Rho-kinase pathway may be partly responsible for the pathogenesis of hypertensive glomerulosclerosis independently of blood pressure in DS, and that chronic inhibition of the Rho–Rho-kinase pathway may be a new strategy for treating hypertensive nephrosclerosis.

Renoprotective Effect of Chronic Adrenomedullin Infusion in Dahl Salt-Sensitive Rats

The present study was designed to examine whether chronic adrenomedullin infusion has renoprotective effects in hypertensive renal failure and the mechanism by which chronic adrenomedullin infusion exerts its effects. Dahl salt-sensitive rats and Dahl salt-resistant rats were fed a high salt diet starting at 6 weeks of age. Recombinant human adrenomedullin or vehicle was infused for 7 weeks in 11-week-old Dahl salt-sensitive rats. Dahl salt-resistant rat was used as a control. After 7 weeks, untreated Dahl salt-sensitive rats were characterized by decreased kidney function, abnormal morphological findings, increased hormone levels, increased renal tissue angiotensin II levels, and altered mRNA expressions of transforming growth factor &bgr; (TGF-&bgr;) and components of the renin-angiotensin system compared with Dahl salt-resistant rats. Chronic adrenomedullin treatment significantly improved renal function (serum creatinine −87%, creatinine clearance +114%, urinary protein excretion −59%) and histological findings (glomerular injury score −54%) without changing mean arterial pressure compared with untreated Dahl salt-sensitive rats. Interestingly, long-term human adrenomedullin infusion decreased the endogenous rat adrenomedullin level (−97%) with a slight increase of human adrenomedullin level. Chronic adrenomedullin treatment also significantly inhibited the increase of plasma renin concentration (−269%), aldosterone level (−82%), and renal tissue angiotensin II levels (−60%). Furthermore, adrenomedullin infusion significantly decreased the increases of mRNA expressions of TGF-&bgr; (− 63%), angiotensin-converting enzyme (−137%), renin (−230%), and angiotensinogen (−38%) in renal cortex. These results suggest that increased endogenous adrenomedullin plays a compensatory role in chronic hypertensive renal failure and that long-term adrenomedullin infusion has renoprotective effects in this type of hypertension model, partly via inhibition of the circulating and renal renin-angiotensin system.

Idiopathic ventricular arrhythmias arising from the pulmonary artery: prevalence, characteristics, and topography of the arrhythmia origin.

BACKGROUND The characteristics of idiopathic ventricular tachycardias (VTs) or idiopathic premature ventricular contractions (PVCs) arising from the pulmonary artery (PA) have not been sufficiently clarified. OBJECTIVE The purpose of this study was to clarify the prevalence, characteristics, and preferential sites of idiopathic VT/PVCs arising from the PA (PA-VT/PVCs). METHODS Data obtained from 276 patients with idiopathic VT/PVCs who underwent radiofrequency (RF) catheter ablation were analyzed. RESULTS Twelve VT/PVCs (4%) were PA-VT/PVCs, and their onset (34 +/- 14 years) was the youngest among all subgroups. Because those QRS morphologies were similar to VT/PVCs arising from the right ventricular outflow tract (RVOT-VT/PVC) and the earliest ventricular activation was from the RVOT, an initial ablation was performed in the RVOT in all patients. However, RF catheter ablation at the RVOT resulted in a QRS morphology change in all patients, so thereafter PA mapping and ablation was performed. A characteristic potential during sinus rhythm and/or the arrhythmia was recorded at the successful PA ablation site in all patients. A perfect or good pace map was obtained in 7 (70%) of 10 patients. The successful ablation site was the septal side of the PA close to the posterolateral attachment in 9 patients (75%) and the septal side close to the anterior attachment in the remaining 3 (25%). No PA-VT/PVCs recurred during follow-up of 27 +/- 13 months. CONCLUSION PA-VT/PVCs should always be considered when the ECG suggests RVOT-VT/PVCs and RF catheter ablation in the RVOT results in both a failed ablation and a change in QRS morphology. PA-VT/PVCs often originate from the septal side of the PA.

Chronic administration of adrenomedullin attenuates transition from left ventricular hypertrophy to heart failure in rats

Abstract—Acute administration of adrenomedullin (AM) exerts beneficial hemodynamic, renal, and neurohormonal effects in heart failure (HF). However, chronic effects of AM administration on HF remain unknown. This study sought to examine the effect of chronic infusion of AM on progression of HF in rat. Human recombinant AM was administered by osmotic minipump for 7 weeks in the HF model of Dahl salt-sensitive rats. The effect was compared with vehicle and diuretic treatment group. Chronic AM infusion significantly decreased left ventricular end-diastolic pressure, right ventricular systolic pressure, right atrial pressure, and left ventricular weight/body weight (P <0.01 for all). AM significantly attenuated the increase in circulating renin-aldosterone, endogenous rat AM, and atrial natriuretic peptide levels (P <0.01 for all). AM also inhibited the myocardial tissue levels of angiotensin II and atrial and brain natriuretic peptide (P <0.01 for all). These changes were associated with the improvement of cardiac output and systemic vascular resistance (both P <0.05). Furthermore, AM improved left ventricular end-systolic elastance (P <0.01). These improvements were greater in the AM than in the diuretic group, although both drugs similarly decreased systolic blood pressure and increased urinary sodium excretion. Kaplan-Meier survival analysis showed that AM significantly prolonged survival time compared with diuretic (P <0.05) and vehicle (P <0.01) treatment groups. These results suggest that endogenous AM plays a compensatory role in HF and that chronic AM infusion attenuates progression of left ventricular dysfunction and improves survival, at least in part, through inhibition of circulating and myocardial neurohormonal activation.

Ventricular Adrenomedullin System in the Transition From LVH to Heart Failure in Rats

Abstract—We investigated whether adrenomedullin (AM) participates in the pathophysiology during the transition from left ventricular hypertrophy (LVH) to heart failure (HF). We used the Dahl salt-sensitive (DS) rat model, in which systemic hypertension causes LVH at the age of 11 weeks, followed by HF at the age of 18 weeks. Two molecular forms of AM levels in the plasma and myocardium at the LVH stage were significantly elevated compared with those in controls, and they were further increased at the HF stage. Interestingly, the LV tissue AM-mature/AM-total ratio was higher only in the HF group than in controls and LVH. The LV tissue AM-mature/AM-total ratio, AM-mature, and AM-total concentrations had close relations with the LV weight/body weight (r =0.72, r =0.79, and r =0.70, respectively; all P <0.001). AM gene expression was significantly increased at the LVH stage and was further increased at the HF stage. Furthermore, gene expression of AM receptor system components such as calcitonin receptor–like receptor (CRLR), receptor activity–modified protein 2 (RAMP2), and RAMP3 were significantly increased at the stage of LVH and HF. Regarding other neurohumoral factors, plasma renin and aldosterone levels were not increased at the LVH stage but were increased at the HF stage, whereas atrial natriuretic peptide was increased in both the plasma and myocardium at the LVH stage and was further increased at the HF stage. These results suggest that induction of the cardiac AM system, including the ligand, receptor, and amidating activity, may modulate pathophysiology during the transition from LVH to HF in this model.

Altered gene expression of adrenomedullin and its receptor system and molecular forms of tissue adrenomedullin in left ventricular hypertrophy induced by malignant hypertension.

To investigate the pathophysiological role of adrenomedullin (AM) in left ventricular hypertrophy (LVH) in hypertension, we measured the plasma level, left ventricle (LV) tissue level, and mRNA abundance of AM and the mRNA abundance of the AM receptor system in the LV. We also analyzed the molecular forms of AM in the plasma and LV tissue and investigated the relationships between AM and the degree of LVH. We studied the following three groups: control Wistar Kyoto rats (WKY), control spontaneously hypertensive rats (SHR), and deoxycorticosterone acetate (DOCA)-salt SHR (D-SHR). We measured AM-mature, active form, and AM-total (active form+inactive form) in plasma and the LV by a newly developed immunoradiometric assay. Gene expression of AM was measured by Northern blot analysis and gene expression of AM receptor system components, such as calcitonin receptor-like receptor (CRLR), receptor activity modifying protein 2 (RAMP2), and RAMP3 was measured by the reverse transcription polymerase chain reaction method. After 3 weeks of DOCA treatment, D-SHR was characterized by higher blood pressure, LV weight, and plasma atrial natriuretic peptide levels compared with those in the other two groups. Plasma AM-mature and AM-total levels were significantly higher in D-SHR than in the other two groups, whereas there were no significant differences in the AM-mature/AM-total ratio among the three groups. On the other hand, LV tissue AM-mature and AM-total levels were also significantly higher in D-SHR than in the other two groups, and the AM-mature/AM-total ratio was significantly higher in LV tissues than in plasma. Furthermore, the LV tissue AM-mature/AM-total ratio was significantly higher in D-SHR compared with the other two groups. The LV tissue AM-mature/AM-total ratio was significantly correlated with LV weight/body weight (r=0.92, p<0.001). The gene expression levels of AM, CRLR, RAMP2, and RAMP3 in the LV were significantly higher in D-SHR than in the other two groups. These results suggest that the AM amidating enzyme activity, ligand, and receptor system are all upregulated in the LV hypertrophy in this malignant hypertensive rat model. Considering that AM serves as a local antihypertrophic autocrine and/or paracrine factor, the induction of AM system observed here may modulate the pathophysiology of LV hypertrophy in certain forms of malignant hypertension.

Cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, inhibits cardiac myocyte hypertrophy induced by endothelin.

We investigated the direct effects of cerivastatin on hypertrophy of cultured rat neonatal myocytes induced by endothelin and the mechanism by which cerivastatin exerts its effects. Endothelin significantly increased [14C]phenylalanine ([14C]Phe) incorporation, atrial natriuretic peptide (ANP) release, ANP mRNA expression and cell size. Cerivastatin significantly reduced the increase in [14C]phenylalanine incorporation, ANP peptide release, ANP mRNA expression and cell size induced by endothelin, but pravastatin did not. Exogenous mevalonate completely prevented the inhibitory effect of cerivastatin on [14C]phenylalanine incorporation, ANP release and cell size. Cotreatment with geranylgeranyl pyrophosphate also attenuated the effect of cerivastatin on [14C]phenylalanine incorporation, but cotreatment with farnesyl pyrophosphate or squalene did not. Furthermore, both Rho inhibitor C3 exoenzyme and Rho-dependent kinase inhibitor, (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide.2HCl (Y27632) significantly decreased [14C]phenylalanine incorporation, ANP secretion, ANP mRNA expression and cell size. Cerivastatin decreased endothelin-induced Rho protein expression, and mevalonate and geranylgeranyl pyrophosphate reversed this effect. These results suggest that cerivastatin directly attenuates cardiac hypertrophy induced by endothelin in cultured rat myocytes partly by inhibition of the Rho pathway.

Left atrial catheter ablation promotes vasoconstriction of the right coronary artery.

Background: Multiple cardiac ganglia are present in the left atrial (LA) region, and marked changes in autonomic nervous activity can occur after left atrial catheter ablation (CA) for atrial fibrillation (AF). Vasospastic angina involving the inferior wall of the left ventricle has been reported as a complication shortly after LACA.

Maximum Ventricular Dyssynchrony Predicts Clinical Improvement and Reverse Remodeling during Cardiac Resynchronization Therapy

Background: Tissue synchronization imaging (TSI) and tissue tracking imaging (TTI) might facilitate the evaluation of ventricular dyssynchrony.

Alteration of renal adrenomedullin and its receptor system in the severely hypertensive rat: effect of diuretic

OBJECTIVE We investigated the pathophysiological role of the renal adrenomedullin (AM) system, including the ligand, receptor, and amidating activity, in severe hypertensive rats. METHOD We studied three groups: control Wistar Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), and diuretic-treated SHR-SP. We measured AM-mature, active form, and AM-total (active form+inactive form) in plasma and renal tissues, and mRNA levels of AM and AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein (RAMP) 2, and RAMP3 in renal tissues. RESULTS SHR-SP had higher blood pressure, plasma neurohumoral factors, and lower renal function than WKY. SHR-SP had higher AM-mature and AM-total levels in plasma and renal tissues than WKY. Although the plasma AM-mature/AM-total ratio was similar in the two groups, AM-mature/AM-total ratio in renal tissues was higher in SHR-SP than in WKY. In addition, mRNA levels of AM in the renal cortex and medulla and the mRNA levels of CRLR, RAMP2, and RAMP3 in the renal cortex were higher in SHR-SP than in WKY. Chronic diuretic treatment decreased blood pressure and improved kidney function and neurohumoral factors, with reductions in plasma and renal AM system. CONCLUSION Upregulation of circulating and renal AM system may modulate pathophysiology in SHR-SP.