Hidenori Urata

Angiotensin II-forming pathways in normal and failing human hearts.

Reduced preload and afterload to the heart are important effects of angiotensin converting enzyme (ACE) inhibitors in the treatment of congestive heart failure. However, since angiotensin II (Ang II) directly increases the strength of myocardial contraction, suppression of Ang II formation by ACE inhibitors could potentially reduce the beneficial effects of Ang II on the failing heart. To study how ACE inhibition suppresses cardiac Ang II formation in man, we characterized ACE-dependent and ACE-independent Ang II-forming pathways in eight normal and 24 failing human hearts obtained at cardiac transplantation. Ang II-forming activity in left ventricular (LV) membrane preparations was assessed by measuring the conversion of [125I]angiotensin I (Ang I) to [125I]Ang II. LV [125I]Ang II-forming activity in normal hearts (35.5 +/- 2.7 fmol/min/mg, n = 8) was not different from that in hearts from patients with ischemic cardiomyopathy (25.5 +/- 2.9 fmol/min/mg, n = 9) and was 48% lower (p less than 0.001) in hearts from patients with idiopathic cardiomyopathy (18.5 +/- 1.9 fmol/min/mg, n = 15).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II Antagonist Prevents Electrical Remodeling in Atrial Fibrillation

BACKGROUND The blockade of angiotensin II (Ang II) formation has protective effects on cardiovascular tissue; however, the role of Ang II in atrial electrical remodeling is unknown. The purpose of this study was to investigate the effects of candesartan and captopril on atrial electrical remodeling. METHODS AND RESULTS In 24 dogs, the atrial effective refractory period (AERP) was measured before, during, and after rapid atrial pacing. Rapid atrial pacing at 800 bpm was maintained for 180 minutes. The infusion of saline (n=8), candesartan (n=5), captopril (n=6), or Ang II (n=5) was initiated 30 minutes before rapid pacing and continued throughout the study. In the saline group, AERP was significantly shortened during rapid atrial pacing (from 149+/-11 to 132+/-16 ms, P<0.01). There was no significant difference in AERP shortening between the saline group and the Ang II group. However, in the candesartan and captopril groups, shortening of the AERP after rapid pacing was completely inhibited (from 142+/-9 to 147+/-12 ms with candesartan, from 153+/-15 to 153+/-14 ms with captopril, P=NS). Although rate adaptation of the AERP was lost in the saline group, this phenomenon was preserved in the candesartan and captopril groups. CONCLUSIONS The inhibition of endogenous Ang II prevented AERP shortening during rapid atrial pacing. These results indicate for the first time that Ang II may be involved in the mechanism of atrial electrical remodeling and that the blockade of Ang II may lead to the better therapeutic management of human atrial fibrillation.

Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation

UNLABELLED The purpose of the present study was to evaluate the effect of angiotensin II type 1 receptor (AT1R) antagonist on chronic structural remodeling in atrial fibrillation (AF). BACKGROUND We previously reported that an AT1R antagonist, candesartan, prevents acute electrical remodeling in a rapid pacing model. However, the effect of candesartan on chronic structural remodeling in AF is unclear. METHODS Sustained AF was induced in 20 dogs (10 in a control group and 10 in a candesartan group) by rapid pacing of the right atrium (RA) at 400 beats/min for five weeks. Candesartan was administered orally (10 mg/kg/day) for one week before rapid pacing and was continued for five weeks. The AF duration, atrial effective refractory period (AERP) at four sites in the RA, and intra-atrial conduction time (CT) from the RA appendage to the other three sites were measured every week. RESULTS The mean AF duration in the control group after five weeks was significantly longer than that with candesartan (1,333 +/- 725 vs. 411 +/- 301 s, p < 0.01). The degree of AERP shortening after five weeks was not significantly different between the two groups. The CT from the RA appendage to the low RA after five weeks with candesartan was significantly shorter than that in the control (43 +/- 14 vs. 68 +/- 10 ms, p < 0.05). The candesartan group had a significantly lower percentage of interstitial fibrosis than the control group (7 +/- 2% vs. 16 +/- 1% at the RA appendage, p < 0.001). CONCLUSIONS Candesartan can prevent the promotion of AF by suppressing the development of structural remodeling.

Cellular localization and regional distribution of an angiotensin II-forming chymase in the heart.

The human heart is a target organ for the octapeptide hormone, angiotensin II (Ang II). Recent studies suggest that the human heart contains a dual pathway of Ang II formation in which the major Ang II-forming enzymes are angiotensin I-converting enzyme (ACE) and chymase. Human heart chymase has recently been purified and its cDNA and gene cloned. This cardiac serine proteinase is the most efficient and specific Ang II-forming enzyme described. To obtain insights into the cardiac sites of chymase-dependent Ang II formation, we examined the cellular localization and regional distribution of chymase in the human heart. Electron microscope immunocytochemistry using an anti-human chymase antibody showed the presence of chymase-like immunoreactivity in the cardiac interstitium and in cytosolic granules of mast cells, endothelial cells, and some mesenchymal interstitial cells. In the cardiac interstitium, chymase-like immunoreactivity is associated with the extracellular matrix. In situ hybridization studies further indicated that chymase mRNA is expressed in endothelial cells and in interstitial cells, including mast cells. Tissue chymase levels were determined by activity assays and by Western blot analyses. Chymase levels were approximately twofold higher in ventricles than in atria. There were no significant differences in chymase levels in ventricular tissues obtained from non-failing donor hearts, failing ischemic hearts, or hearts from patients with ischemic cardiomyopathy. These findings suggest that a major site of chymase-dependent Ang II formation in the heart is the interstitium and that cardiac mast cells, mesenchymal interstitial cells, and endothelial cells are the cellular sites of synthesis and storage of chymase. In the human heart, because ACE levels are highest in the atria and chymase levels are highest in ventricles, it is likely that the relative contribution of ACE and chymase to cardiac Ang II formation varies with the cardiac chamber. Such differences may lead to differential suppression of cardiac Ang II levels during chronic ACE inhibitor therapy in patients with congestive heart failure.

Increased Chymase-Dependent Angiotensin II Formation in Human Atherosclerotic Aorta

Locally formed angiotensin II (Ang II) and mast cells may participate in the development of atherosclerosis. Chymase, which originates from mast cells, is the major Ang II-forming enzyme in the human heart and aorta in vitro. The aim of the present study was to investigate aortic Ang II-forming activity (AIIFA) and the histochemical localization of each Ang II-forming enzyme in the atheromatous human aorta. Specimens of normal (n=9), atherosclerotic (n=8), and aneurysmal (n=6) human aortas were obtained at autopsy or cardiovascular surgery from 23 subjects (16 men, 7 women). The total, angiotensin-converting enzyme (ACE)-dependent, and chymase-dependent AIIFAs in aortic specimens were determined. The histologic and cellular localization of chymase and ACE were determined by immunocytochemistry. Total AIIFA was significantly higher in atherosclerotic and aneurysmal lesions than in normal aortas. Most of AIIFA in the human aorta in vitro was chymase-dependent in both normal (82%) and atherosclerotic aortas (90%). Immunocytochemical staining of the corresponding aortic sections with antichymase, antitryptase or anti-ACE antibodies showed that chymase-positive mast cells were located in the tunica adventitia of normal and atheromatous aortas, whereas ACE-positive cells were localized in endothelial cells of normal aorta and in macrophages of atheromatous neointima. The density of chymase- and tryptase-positive mast cells in the atherosclerotic lesions was slightly but not significantly higher than that in the normal aortas, and the number of activated mast cells in the aneurysmal lesions (18%) was significantly higher than in atherosclerotic (5%) and normal (1%) aortas. Our results suggest that local Ang II formation is increased in atherosclerotic lesions and that chymase is primarily responsible for this increase. The histologic localization and potential roles of chymase in the development of atherosclerotic lesions appear to be different from those of ACE.

Antihypertensive and volume-depleting effects of mild exercise on essential hypertension.

After a general clinical observation period of over 4 weeks, 20 essential hypertensive subjects (Japanese) were randomly divided into two groups. One group (n = 10; 4 men and 6 women; 51.4 +/- 2.8 years of age) agreed to physical training using bicycle ergometer exercise with the intensity at blood lactate threshold for 60 minutes three times a week for 10 weeks, while the other group (n = 10; 4 men and 6 women; 51.0 +/- 2.9 years of age) did no particular physical training and was followed once a week as the control. Changes in blood pressure, hemodynamics, and humoral factors of the exercised group were compared with values in the controls. The following significant changes were found only in the exercised group. Blood pressure was significantly (p less than 0.01) reduced. Whole blood and plasma volume indices were significantly reduced (p less than 0.05, p less than 0.01, respectively). The change in ratio of serum sodium to potassium positively correlated with the change in systolic blood pressure (r = 0.76, p less than 0.02). Plasma norepinephrine concentrations both at rest and at the workload of blood lactate threshold during graded exercise tests were significantly reduced (p less than 0.05, p less than 0.02 respectively) after 10 weeks of exercise training. The change in the resting level of plasma norepinephrine positively correlated with that in the mean blood pressure. No such changes were observed in the control group. In both groups, body weight and urinary sodium excretion showed no statistically significant changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in Tissue Angiotensin II–Forming Pathways by Species and Organs In Vitro

Angiotensin (Ang) II plays an important role in cardiovascular homeostasis, not only in the systemic circulation but also at the tissue level, and is involved in the remodeling of the heart and vasculature under pathological conditions. Although alternative Ang II-forming pathways are known to exist in various tissues, the details of such pathways remain unclear. The aim of this study was to examine tissue Ang II-forming activities and to identify the responsible enzyme in several organs (lung, heart, and aorta) in various species (human, hamster, rat, rabbit, dog, pig, and marmoset). Among the organs examined, the lung contained the highest Ang II-forming activity. The responsible enzyme for pulmonary Ang II formation was angiotensin I-converting enzyme (ACE) in all of the species except the human lung, in which a chymaselike enzyme was dominant. In the heart, the highest total Ang II-forming activity was observed in humans, and a chymaselike enzyme was dominant in all of the species except rabbit and pig. Aorta exhibited a relatively high total Ang II-forming activity, with a predominance of chymaselike activity in all of the species except rabbit and pig, in which ACE was dominant. Our results indicate that there were remarkable differences in Ang II-forming pathways among the species and organs we examined. To study the pathophysiological roles of ACE-independent Ang II formation, one should choose species and/or organs that have Ang II-forming pathways similar to those in humans.

Chymase-dependent angiotensin II forming system in humans

Recent studies have provided evidence that human cardiovascular tissues contain components of the renin angiotensin system: angiotensinogen, renin, angiotensin I converting enzyme (ACE), chymase, and angiotensin (Ang) II receptors. It is likely that locally produced Ang II plays an important role in cardiovascular homeostasis in autocrine and paracrine fashions and may also be involved in remodeling of the heart and vasculature in pathological conditions. In addition to ACE, a cardiac Ang II-forming serine proteinase (human heart chymase) has been identified in the left ventricle of the human heart. The different cellular and regional distribution of ACE and heart chymase in the heart as well as in blood vessels implies distinct pathophysiological roles of these two Ang II-forming enzymes. Several reports indicate that both ACE dependent and ACE independent Ang II formation appears to take place in hypoxic or ischemic heart or blood vessel in vivo and seems to be involved in their pathological changes. However, chymase dependent Ang II formation, chymostatin sensitive but aprotinin insensitive, does not explain all of ACE independent Ang II formation. Therefore, it has become quite important to clarify the detailed mechanisms of the tissue Ang II formation in humans and their contribution to the pathophysiological changes in cardiovascular diseases.

Effect of acute exercise on plasma immunoreactive — atrial natriuretic factor☆

The effect of acute exercise on plasma immunoreactive-atrial natriuretic factor (IR-ANF) was studied in 5 healthy young males subjected to graded exercise on a bicycle ergometer at four different work intensities (approx. 30, 50, 70, and 90% VO2max respectively). Except for the final exercise period, which was continued until exhaustion, all the others were of 30 min duration. Venous blood samples were obtained in the last 2 min of each exercise period. The plasma IR-ANF response to exercise was similar to that of heart rate and systolic blood pressure in that mild exercise in the first stage (corresponding to approx. 30% VO2 max) caused a striking increase of plasma IR-ANF concentrations with a further augmentation in the next stages and a levelling off at exhaustion. Plasma arginine-vasopressin (AVP) and aldosterone (ALDO) rose significantly only in the last two stages, and the highest concentrations were observed at exhaustion. In conclusion, acute exercise stimulates ANF secretion in proportion to the intensity of exercise, while concomitant increases in plasma AVP and ALDO occur only when the work load exceeds the blood lactate (BLA) threshold.

Mast cell chymase limits the cardiac efficacy of Ang I–converting enzyme inhibitor therapy in rodents

Ang I-converting enzyme (ACE) inhibitors are widely believed to suppress the deleterious cardiac effects of Ang II by inhibiting locally generated Ang II. However, the recent demonstration that chymase, an Ang II-forming enzyme stored in mast cell granules, is present in the heart has added uncertainty to this view. As discussed here, using microdialysis probes tethered to the heart of conscious mice, we have shown that chronic ACE inhibitor treatment did not suppress Ang II levels in the LV interstitial fluid (ISF) despite marked inhibition of ACE. However, chronic ACE inhibition caused a marked bradykinin/B2 receptor-mediated increase in LV ISF chymase activity that was not observed in mast cell-deficient KitW/KitW-v mice. In chronic ACE inhibitor-treated mast cell-sufficient littermates, chymase inhibition decreased LV ISF Ang II levels substantially, indicating the importance of mast cell chymase in regulating cardiac Ang II levels. Chymase-dependent processing of other regulatory peptides also promotes inflammation and tissue remodeling. We found that combined chymase and ACE inhibition, relative to ACE inhibition alone, improved LV function, decreased adverse cardiac remodeling, and improved survival after myocardial infarction in hamsters. These results suggest that chymase inhibitors could be a useful addition to ACE inhibitor therapy in the treatment of heart failure.