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Invasive mucinous adenocarcinoma (IMA), formerly referred to as mucinous bronchioloalveolar carcinoma, is a rare variant form of invasive adenocarcinoma and is radiologically characterized by dense pneumonic consolidation, ground-glass opacity and nodules. By contrast, large, thin-walled cysts are rare. We herein report the case of a 75-year-old man with IMA presenting as a large, irregularly shaped cystic lesion. The histological diagnosis was based on specimens obtained during a bronchoscopy. The patient underwent lobectomy followed by anticancer chemotherapy for residual intrapulmonary metastases. Of note, the small metastatic nodules transformed into cystic lesions with thin walls and fused, forming a large, multiloculated cystic lesion. Typical pneumonic consolidation appeared in the pericystic parenchyma later during the clinical course. The available literature on this rare radiological manifestation was also reviewed and discussed. Clinicians should be aware of thin-walled cystic lesions as they may be an unusual radiological finding in IMA.

A 65-year-old man was diagnosed with small cell lung cancer with multiple liver metastases. Three days after initiating chemotherapy, he experienced abdominal discomfort with hypotension. Computed tomography revealed a ruptured liver metastasis and the presence of hemorrhagic ascites. Transcatheter arterial embolization to the appropriate hepatic artery in concomitant with supportive therapies successfully stabilized his condition. Unlike with hepatocellular carcinoma, the rupture of a liver metastasis and associated hemoperitoneum is very rare in patients with lung cancer. We comprehensively reviewed the literature and found 10 similar cases with this serious condition. Physicians should therefore be aware of the risk of hemoperitoneum caused by ruptured liver metastases in patients with lung cancer.

BACKGROUND Recently, we reported that transient treatment of genetically hypertensive rats with high-dose angiotensin receptor blocker (ARB) causes regression of established hypertension. In this study, we investigated whether treatment with candesartan or nifedipine controlled-release (CR) resulted in a sustained regression of hypertension in humans. METHODS Patients aged 30 to 59 years with untreated stage 1 essential hypertension and a family history of hypertension were treated with the antihypertensive agents candesartan (n = 124) or nifedipine CR (n = 120). After 1 year of treatment (phase 1), the medications were tapered and discontinued (phase 2). During phase 2, home and office blood pressures were monitored for another year to assess posttreatment reoccurrence of stage 1 hypertension. RESULTS In phase 1, after 1 year of treatment a similarly substantial BP decrease was seen in the candesartan (-24.5/16.1 mm Hg) and nifedipine (-26.8/18.0 mm Hg) groups. In phase 2 there was a substantial reoccurrence of hypertension; at the study end, only 1 patient was able to continue without antihypertensive medication. However, a Kaplan-Meier analysis revealed a significant delay of reoccurrence of hyper tension (P = 0.0001) in the candesartan group. CONCLUSIONS One year of treatment with candesartan or nifedipine CR was not associated with marked regression of hypertension in humans at the standard doses used in this trial. However, withdrawal of candesartan was associated with a slightly longer delay before restarting medications. Further studies with larger doses of candesartan given over a longer time are required to determine whether such a regimen may induce sustainable and clinically relevant reversal of hypertension and alteration in its natural history.

Background: Thalamic lesions give rise to a variety of clinical syndromes such as pure sensory stroke, ataxic hemiparesis, and rarely involuntary movements including chorea. Generally and classically, lacunar infarction in the subthalamic nucleus has been regarded as the lesion mainly responsible for hemi-chorea and hemi-ballismus, on the basis of previous anatomical studies. Case Presentation: This report describes the case of an 81-year-old man who developed sudden-onset pure hemi-chorea in the right limbs resulting from an acute phase of left thalamic lacunar infarction detected on a diffusion-weighted image (DWI) in an MRI study. The patient had no other neurological symptoms such as ataxic hemiparesis and sensory disturbance. A single-photon emission computed tomography (SPECT) study using the 99m TcECD Patlak plot method demonstrated significant perfusional asymmetry between the right and left thalami (p = 0.0035), consistent with the left thalamic lesion on DWI. Conclusion: It is speculated that this perfusional asymmetry, in particular the hypoperfusion in the left thalamus, detected by SPECT might play the most important role in the contralateral pure hemi-chorea as a rare neurological manifestation in this case.

Mycobacterium avium complex (MAC) infection is a major medical concern in Japan because of its increased prevalence and associated mortality. A common radiological feature in pulmonary MAC infection is a mixture of two basic patterns: fibrocavitary and nodular bronchiectatic; however, lobar consolidation is rare. We report an 83‐year‐old man with lobar caseous pneumonia caused by pulmonary MAC infection. Radiological findings were predominantly composed of dense lobar consolidation and ground‐glass opacity. A diagnosis was made in accordance with the clinical and microbiological criteria set by the American Thoracic Society. A histological examination of lung specimens obtained by using a bronchoscope revealed a caseous granulomatous inflammation with an appearance of Langhans cells. The patient was treated using combined mycobacterium chemotherapy with an initial positive response for 6 months; however, the disease progressed later. We suggest that an awareness of lobar pneumonic consolidation as a rare radiological finding in pulmonary MAC infection is important.

微小変化群のネフローゼ症候群に合併した急性腎障害に対して血漿交換が著効した2例を経験したので報告する．症例1は39歳男性，症例2は33歳女性である．2例とも，メチルプレドニゾロンのパルス療法を行ったが，急性腎障害となり血液濾過透析が必要になった．血清アルブミン濃度は，症例1が1.8mg/dL，症例2が1.6mg/dLといずれも低値であった．アルブミンの静脈内投与は急性腎障害に対していずれも無効であった．3回の血液濾過透析を施行したが，急性腎障害が改善しないため5％アルブミン溶液による血漿交換を行った．血漿交換の終了時期には尿量は著増し，その後急速に腎機能は改善し，その後の血液濾過透析は不要となった．腎生検所見は微小変化群の所見であり，著明な足突起の癒合を伴っており，急性尿細管壊死の所見は認めなかった．蛋白尿は血漿交換後に症例1では3日後から，症例2では翌日から減少し始めた．血漿交換の急性腎障害に対する有効性は単に重症の低アルブミン血症の補正のみでは説明は困難であると考えられた．血液中に存在する何らかの病因物質の除去とステロイドパルス療法との相乗効果が関与していた可能性が示唆された．

血液透析歴3年の85歳, 女性. 透析中に吐血, 上部消化管内視鏡検査で出血性胃潰瘍を認め入院となった. 症状は一時改善したが, その後腹部膨満が出現, 腹部CTを施行したところイレウス所見を認めた. 以後, 水様性の下痢便が出現し, 持続した. 4週間後に再度施行した腹部CTで大腸の拡張, 直腸壁の肥厚を認めたため, 下部消化管内視鏡検査を施行, 肉眼的所見より潰瘍性大腸炎と診断された. 治療としてプレドニゾロン40mg/日を点滴静注したが症状の改善はなく, 全身状態は悪化し, 永眠した. 剖検による病理診断では結腸をはじめとする全身性AAアミロイドーシスであったが, 先行する慢性炎症性疾患は認めなかった. 抗生剤に反応しない, 持続する下痢症ではアミロイドーシスを疑うことの重要性が示唆され, また, 透析患者の原因が同定できなかったAAアミロイドーシスの合併例はまれと考えられた.

Background. Angiotensin II (Ang II) is involved in the direct inhibition of renin release from juxtaglomerular (JG) cells in the kidney as the negative feedback loop of the renin-angiotensin system. Ang II also modulates renin release via the sympathetic nervous system, since the renal sympathetic nerves stimulate renin release, and the interaction of the sympathetic nervous system with Ang II has been demonstrated to occur at multiple levels.

症例は60歳, 男性. 1987年11月, 慢性糸球体腎炎による慢性腎不全のため腹膜透析 (CAPD) に導入された. CAPD施行中に腹膜炎を4回繰り返した. 1994年4月, CAPDの効率低下によると思われる全身浮腫, 意識障害を呈したため血液透析 (HD) に変更, 症状は改善した. 同年10月, 腹痛, 腹部膨満感が出現し持続した. 1995年1月より嘔吐を繰り返すようになり, 同年1月13日, 当院に入院した. 腹部は膨隆し波動を触知したが, その他に特記すべき異常所見を認めなかった. 腹部の単純X線, CTではニボー形成, 著明な腹水, 腹膜の肥厚を伴う一塊となった腸管がみられた. 腹水は血性, 浸出性で細胞診はclass IIであった. 硬化性腹膜炎と診断し, 3か月に亘り禁食, 高カロリー輸液を続けたが, 次第に全身状態が悪化し死亡した. 本症の発生頻度は低いが, 栄養状態の不良より死亡する確率は高い. 長期に亘るCAPDの合併症として本症は再認識されるべき疾患である.

34歳女性. 21歳で全身性エリテマトーデス (SLE) を発症し, 胸膜炎, ループス腎炎を発症するが, prednisolone療法や免疫抑制剤で軽快していた. 1995年5月頃から四肢に紫斑が出現し, 血小板減少 (5,000/μl), 貧血 (ヘモグロビン7.6g/dl), LDH高値 (1,035IU/l) を指摘され入院. 入院後, 脳梗塞を発症し, 末梢血塗抹標本で微小血管障害性溶血性貧血を認め, 血小板減少と併せて血栓性血小板減少性紫斑病 (TTP) と診断した. また, 抗カルジオリピン抗体は陽性であったが, 抗リン脂質抗体症候群の既往はなかった. 3回の血漿交換により, 血液像は一時的に改善したが, 血漿交換中止後5日目には血小板は再び減少. 血漿輸注を400mlから開始したところ, 血小板は増加. 血液像を見ながら20日間で血漿輸注を漸減中止した. 中止後血小板数は減少せず, 退院後4か月を経過したがTTPの再燃を認めていない. 抗カルジオリピン抗体はTTP寛解後も陽性でありTTPへの関与は不明であった. 本例は, 血漿交換の再燃に血漿輸注を行い寛解に導入できたTTPの1例であり, 血漿交換が有効であれば, 再燃時には血漿輸注のみで寛解導入しうる可能性を示唆した.

Summary: In order to explore the clinical course of Japanese patients with systemic lupus erythematosus (SLE) in end-stage renal failure, the clinical findings from 26 patients who had received haemodialysis were analysed. Each patient was followed for 72 months from the onset of clinical lupus nephritis to the initiation of haemodialysis. In most patients, renal disease progressed to end-stage renal failure despite clinical quiescence of SLE, which remained inactive throughout haemodialysis treatment. Seven patients (27%) had clinically active SLE with high dose prednisolone (mean; 49.3 mg per day) at initiation of haemodialysis. These patients had relatively rapid progression of their renal failure and 2 patients died within 1 month of their first haemodialysis. During the follow-up period from starting haemodialysis for an average of 44 months, most patients received ongoing haemodialysis while their SLE remained clinically inactive. Six patients (23%) died, 5 of those within 1 month from starting hemodialysis. the results of this long-term follow up of a large number of haemodialysis patients with lupus nephritis indicate that: (i) most patients with lupus nephritis undergoing haemodialysis have an excellent survival rate; and (ii) patients with active SLE at initiation of haemodialysis have a high mortality rate (within 1 month). We therefore conclude that more effective treatment for SLE in the presence of renal failure is required for these patients.

Human prochymase is packaged with heparin in mast cell granules and appears to be activated by dipeptidylpeptidase I. We show that a high affinity interaction between heparin and prochymase allows the 2-residue propeptide to be cleaved by dipeptidylpeptidase I. A conserved Glu in the propeptide is necessary for this heparin effect. Following propeptide cleavage, capture of the newly generated NH2 terminus by an "activation groove" on the enzyme activates the enzyme and concurrently prevents a progressive degradation of the NH2 terminus by dipeptidylpeptidase I. Surrogate peptide studies show that the activation groove is unoccupied in prochymase and is specific for the chymase NH2 terminus. These observations indicate that heparin is an important cofactor in the prochymase activation process and explain how dipeptidylpeptidase I, a nonspecific processing enzyme, can effect a specific cleavage of the zymogen propeptide.

The objective of the present study was to quantify the expression of angiotensin II type 1 (AT1) receptor transcripts in human blood cells-platelets and mononuclear leucocytes-from 10 normal healthy volunteers during the alterations in the renin-angiotensin system. A quantitative assay employing reverse transcription-polymerase chain reaction (RT-PCR) was utilized. Oral administration of furosemide, 40mg for 2 days, under mild salt restriction (50mEq NaCl/day) for 6 days stimulated the rennin-angiotensin system resulting in significant increases in plasma renin activity (PRA) (1.84±0.12vs. 1.05± 0.17ng/l/s; P

The heart and the kidneys act in tandem to regulate blood pressure, vascular tone, diueresis and to maintain intravascular volume homeostasis. Besides, the kidneys have a neuroendocrine function with interdependent physiological actions regulated by the renin-angiotensin-aldosterone system, sympathetic nervous system, and vasopressin and aterial natriuretic peptide. To investigate these complex pathophysiological mechanisms, a canine model for Congestive Heart Failure (CHF) compromised with Renal Dysfunction (RF) was used, to characterize the hemodynamic and neurohumoral aspects of renal function in 21 dogs. Five dogs were used as controls. Bipolar epicardial pacemaker leads were implanted at the apex of the right ventricle in 8 dogs and the dogs were subjected to ventricular pacing at 250-270 beats/min with an external pacemaker (Nihon Kohden) for a period of 11-21 days. This rapid pacing produced CHF. RF was induced by removal of the right kidney with ligation of the small branches of the left kidney in 8 dogs. Three dogs of each of the CHF and RF groups were used to produce CHF and RF in combination; one dog died due to infection. The glomerular filtration rates of the dogs with RF, CHF and CHF+RF were significantly lower than those of the controls, although among the dogs with RF, CHF and CHF+RF, there were no significant differences. In spite of no differences in blood pressure and renal hemodynamics, the levels of plasma renin activity, norepinephrine and vasopressin of CHF+RF group were significantly higher than those of RF and CHF groups. Taken together, these data suggest that in patients with CHF compromised by RF neurohumoral factors are maximally activated.

Rapid right ventricular pacing could induce congestive heart failure in conscious dogs with significant increase in plasma concentration of arginine vasopressin (AVP) (from 1.2 +/- 0.2 to 3.4 +/- 0.6 pg/ml). In this experimental model of heart failure, oral administration of the selective AVP V1 receptor antagonist OPC-21268 significantly increased cardiac output and improved renal function without significant changes in serum electrolytes and hormones. Oral administration of the selective AVP V2 receptor antagonist OPC-31260 induced marked water diuresis, which resulted in significant increases in serum sodium concentration, plasma renin activity, and plasma concentration of AVP, although it did not produce hemodynamic improvement. Combined administration of OPC-21268 and OPC-31260 showed supra-additive hemodynamic responses as well as additive renal and metabolic responses, i.e., it showed prolonged decrease in mean arterial pressure and profound increase in cardiac output. These results suggest that AVP plays a significant role in elevation of vascular tone through V1 receptors and plays a major role in retaining free water through V2 receptors in this model of heart failure. Furthermore, combined administration of V1 and V2 receptor antagonists could induce not only metabolic and hormonal responses but also more beneficial hemodynamic responses than those observed following treatment with V1 receptor antagonist alone.

In conscious dogs, 36-h water deprivation induced a significant increase in renal blood flow (RBF) with elevation of the plasma arginine vasopressin (AVP) concentration to 9.6 +/- 1.8 pg/ml. To simulate such a condition, a mild elevation of plasma AVP was produced by infusing AVP intravenously at a dose of 0.1 ng.kg-1.min-1 for 20 min. The plasma AVP concentration then increased to 6.8 +/- 0.7 pg/ml. This dose of AVP increased the RBF by 21.7 +/- 2.6% and decreased the renal vascular resistance by 18.1 +/- 2.3% without significant changes in mean arterial pressure, cardiac output, or heart rate. The mechanism of this renal vasodilatory action was examined using newly developed, orally effective, selective AVP antagonists OPC-21268 (a V1-receptor antagonist) and OPC-31260 (a V2-receptor antagonist). In 36-h water-deprived dogs, V2-receptor blockade with OPC-31260 significantly decreased the RBF by 20.5 +/- 2.6% without significant changes in cardiac output. The exogenous AVP-induced renal vasodilatory response tended to be augmented when V1 receptors were blocked by pretreatment with OPC-21268, but the change did not achieve statistical significance. On the other hand, V2-receptor blockade by either pretreatment with OPC-31260 or simultaneous infusion of OPC-31260 inhibited this vasodilatory response. Furthermore, intravenous infusion of 1-desamino-8-D-arginine vasopressin (DDAVP) at a dose of 0.3 ng.kg-1 x min-1 for 20 min significantly increased the RBF by 36.5 +/- 1.7%, and this DDAVP-induced renal vasodilation was inhibited by simultaneous infusion of V2-receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was designed to elucidate the abnormalities in both the parasympathetic and sympathetic nervous systems in borderline hypertension. Utilizing the cold pressor test (CPT) for evaluation of the sympathetic nervous system and R-R interval variation for the assessment of the parasympathetic nervous system, fifteen male patients (37±4 y.o.) with borderline hypertension (mean arterial pressure=111±2mmHg) and age-matched normotensive controls participated in this study. The cold face test (CFT), which is able to evaluate the trigeminal-vagal-cardiac and trigeminal-sympathetic-peripheral vasculature pathways, was also employed to evaluate the balance between these two divisions of the autonomic nervous system. The coefficient of variation (CV) of R-R interval variation in the borderline hypertensives was significantly smaller than that in the controls (3.9±0.3vs. 6.3±0.4%, P

Objective The aim of this study was to investigate the role of depressor systems in glucocorticoid-induced hypertension. Methods The serial changes in cardiorenal hemodynamics, urinary excretions of kallikrein and prostaglandins (PGE2 and the prostacyclin derivative 6-keto-PGF1 alpha) before, and during the administration of both low and high doses of dexamethasone (9 alpha-fluoro-16 alpha-methylprednisolone) and after the cessation of dexamethasone were examined in conscious trained dogs. In addition, pressor responses to prostaglandin, bradykinin, bradykinin antagonist and indomethacin were studied during the administration of dexamethasone. Results High-dose dexamethasone induced a significant elevation in mean arterial pressure (MAP) that was accompanied by a significant reduction in the urinary excretion of kallikrein, PGE2 and 6-keto-PGF1 alpha. In contrast, low-dose dexamethasone treatment had no significant effect upon MAP but induced a transient elevation in the urinary excretion of kallikrein, PGE2 and 6-keto-PGF1 alpha. Furthermore, additional oral administration of indomethacin produced a significant elevation in MAP in dogs treated with low-dose dexamethasone; but did not affect the hemodynamics of animals with high-dose dexamethasone. Whilst i.v. administration of either bradykinin or prostacyclin induced a significant reduction in MAP in high-dose but not low-dose dexamethasone-treated dogs, administration of a competitive bradykinin antagonist, D-Arg-[Hyp3, Thi5,8, D-Phe7]-bradykinin induced a significant elevation in MAP in low-dose but not high-dose dexamethasone-treated dogs. Conclusion Depressor systems play an important role in regulation of blood pressure in glucocorticoid-treated dogs.

Changes in the levels of aldosterone synthase cytochrome P-450, a recently identified enzyme in rat adrenals, were studied in response to the renin-angiotensin system and K stimuli. As examined by an immunoblot technique, the zona glomerulosa mitochondria from rats fed on a low Na-normal K diet (8.6 mmol Na+ and 207 mmol K+/kg of diet) or a low Na-high K (0.2 M KCl in drinking water) diet for 4-10 days contained significantly higher amounts of aldosterone synthase cytochrome P-450 than those from rats fed on a normal diet (86 mmol Na+ and 207 mmol K+/kg of diet). Activities of the enzyme were also found to increase by about 10-fold on day 10. In concert with these changes, both plasma renin activity and plasma aldosterone concentration increased, indicating that the renin-angiotensin system was activated in these rats. Feeding with a normal Na-high K diet also induced significantly higher levels of both amount and activity of aldosterone synthase cytochrome P-450 together with an elevated serum K concentration on day 4, though they all decreased to near the control level on the following days. On the other hand, when enalapril malate, an angiotensin I-converting enzyme inhibitor, was administered to the low Na-normal K rats, the increases in the amount and activity of the enzyme as well as in plasma aldosterone concentration were suppressed altogether. However, the enalapril administration to the low Na-high K rats suppressed the increases only partially. These results indicate that the aldosterone synthase cytochrome P-450 is an ultimate target of the regulation of aldosterone biosynthesis by angiotensin II and K.

The effects of low-dose endothelin on systemic haemodynamics and vasoactive hormones were examined in conscious dogs. In addition, we examined the effects of endothelin on pressor responses to noradrenaline and angiotensin II and the baroreflex regulation of heart rate in conscious dogs. Continuous infusion of 40 fmol/kg per min endothelin for 40 min induced a mild but significant reduction in mean arterial pressure from 89.1 +/- 1.7 to 82.7 +/- 2.0 mmHg (P less than 0.05), associated with decreases in total peripheral resistance 20 min later. A 400 fmol/kg per min dose of endothelin, on the other hand, induced a gradual elevation of mean arterial pressure from 89.2 +/- 2.3 to 96.8 +/- 2.0 mmHg (P less than 0.05), associated with increases in total peripheral resistance over 30 min. The 40 fmol/kg per min dose of endothelin infusion induced a significant reduction in plasma arginine vasopressin (AVP; P less than 0.05) and elevations of plasma atrial natriuretic peptide (ANP; P less than 0.05), plasma prostaglandin E2 (PGE2; P less than 0.05) and plasma 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha; P less than 0.05). The 400 fmol/kg per min dose produced elevations of AVP, ANP, PGE2 and 6-keto-PGF1 alpha (P less than 0.05). Pressor responses to noradrenaline and angiotensin II were significantly attenuated during continuous infusion of 40 fmol/kg per min endothelin, whereas 400 fmol/kg per min endothelin did not induce any significant changes compared with the control. Furthermore, baroreflex sensitivity was attenuated with 40 fmol/kg per min endothelin but did not show any significant changes at 400 fmol/kg per min.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of a small dose (2 pmol/kg) of human calcitonin gene-related peptide I on plasma renin activity and hormones, including, aldosterone, ACTH, cortisol, AVP and ANH, were investigated in 14 conscious dogs. In addition, we studied the effects of calcitonin gene-related peptide on aldosterone secretion when it is stimulated by angiotensin II and ACTH. An intravenous bolus injection of 2 pmol/kg of calcitonin gene-related peptide raised plasma renin activity (by 216%, p−1 ·min−1 of angiotensin II produced an elevation of aldosterone (by 186%, p

Previous studies have shown that transient treatment of animal models of hypertension with an angiotensin receptor blocker (ARB) causes a sustained decrease in blood pressure values that persists even after the drug treatment is discontinued (J Am Soc Nephrol 12: 659–666, 2001; Nephron 91: 710–718, 2002; Hypertens Res 30: 63–75, 2007). These results have been shown to be clinically relevant by the recent TROPHY study (N Engl J Med 354: 1685–1697, 2006). We have recently found that transient treatment with an ARB may also cause regression of established hypertension in hypertensive rats (J Am Soc Nephrol 18: 157A, 2007). The Short Treatment with the Angiotensin Receptor Blocker Candesartan Surveyed by Telemedicine (STAR CAST) study is a prospective, randomized, open, blinded end-point study in patients aged 30–59 with a positive family history of hypertension that will be conducted in several centers in Japan. The aim of the study is to evaluate the antihypertensive drug withdrawal success rate, the median duration of drug withdrawal, and the changes in home and office blood pressure values in patients with mild hypertension after tapering and withdrawal of antihypertensive treatment following treatment for 1 year with the ARB candesartan or the calcium channel blocker (CCB) nifedipine slow-release. A unique feature of this study is the use of a home blood pressure monitoring telemedicine system (i-TECHO) to allow frequent evaluation of the changes in blood pressure in the trial patients. This study will be the first clinical study to examine if regression from stage 1 (mild) hypertension to prehypertension (high-normal blood pressure) is possible using an ARB or CCB.

Plasma and urine norepinephrine, epinephrine and home blood pressure were measured in 48 young hypertensive men (mean age, 21 years) and 25 matched normotensive controls. Plasma samples were drawn following 30 min rest in the clinic and 24 h urine samples were collected at home. Twenty-one hypertensive patients were given a single dose of clonidine (150 micrograms orally). Changes in blood pressure, heart rate and plasma norepinephrine were assessed. Twenty-five of the hypertensive patients were found to have a normal home blood pressure (defined from records of the normotensive subjects). The other group of patients maintained a high home blood pressure. In comparison to normal subjects, patients with a high home blood pressure were characterized by higher urinary norepinephrine and epinephrine excretion and higher plasma epinephrine. Patients with a normal home blood pressure had normal heart rate at home, normal plasma and urinary catecholamines. However, the two groups of hypertensives could not be distinguished on the basis of clinic blood pressure, plasma or urinary catecholamines due to considerable overlap. At 90 min after oral clonidine administration, the plasma norepinephrine and blood pressure levels were decreased in both groups of hypertensives to a similar extent. The changes in heart rate were significantly smaller in patients with a high home blood pressure than in those with a normal home blood pressure. These results suggest that the patients with a high home blood pressure tended to have a high sympathetic nerve activity. However, the two groups of hypertensives could not be separated on the basis of plasma or urinary catecholamine measurements.

In conscious deoxycorticosterone acetate (DOCA) salt-hypertensive dogs, the angiotensin-converting enzyme (ACE) inhibitors captopril and imidaprilat significantly decreased mean arterial pressure (MAP) and significantly increased urine flow rate, effective renal plasma flow (ERPF), glomerular filtration rate, and urinary sodium excretion. However, the angiotensin type 1 (AT1) receptor antagonist losartan caused a significant increase only in urinary sodium excretion without significant changes in MAP, urine flow rate, ERPF, and glomerular filtration rate. Simultaneous infusion of a bradykinin receptor antagonist inhibited the ACE inhibitor-induced reduction in MAP and increase in ERPF. DOCA salt treatment markedly suppressed plasma angiotensin II (ANG II) concentration (P < 0.001), although it decreased renal ANG II content only slightly (P < 0.05). Comparison of the expression of renal AT1 receptor mRNA in control kidneys with that in DOCA salt-hypertensive kidneys revealed no significant change. These results suggest that, in low-renin hypertension, inhibition of the relatively maintained ANG II production in the kidney participates in the natriuretic action of ACE inhibitors. However, hypotensive and other renal effects are mainly due to the action of bradykinin.

Ichihara A, Suzuki H, Murakami M, Naitoh M, Matsumoto A, Saruta T. Interactions between angiotensin II and norepinephrine on renin release by juxtaglomerular cells. Eur J Endocrinol 1995:133:569–77. ISSN 0804–4643 While the interactions between angiotensin II (Ang II) and norepinephrine (NE) on cardiovascular responses are well known, their effects on renin responses are not. We determined the renin secretion rate (RSR) and intracellular calcium level in juxtaglomerular cells harvested from Sprague-Dawley rats using a radioimmunoassay and a two-dimensional calcium analyzer. The effect of Ang II and NE was inhibitory on RSR and stimulatory on intracellular calcium. The NE-induced RSR response was amplified in the presence of Ang II (20 nmol/l), The NE-induced intracellular calcium response was also potentiated by the Ang II. There was a significant correlation (r = 0.994, p < 0.0001) between the changes in the RSR and those in intracellular calcium levels. Losartan (0.1 μmol/l), an Ang II type I receptor antagonist, blocked the Ang II threshold RSR responses and completely abolished the Ang II-related enhancements. The exclusion of calcium from the buffer reduced the maximal RSR response to NE but did not prevent the enhancement, suggesting the importance of the mobilization of intracellular calcium in the mechanism. The Ang Il-induced RSR was amplified in the presence of NE (0.2 μmol/l), The Ang II-induced intracellular calcium response was also potentiated by the NE. A significant correlation (r = 0.996, p < 0.0001) between the changes in the RSR and the changes in intracellular calcium levels was also noted. Prazosin (1 μmol/l), an α1-adrenoceptor antagonist, blocked the NE threshold RSR responses and abolished the agonist-related enhancements. The calcium-free buffer diminished this amplication with a slight decrease in the maximum RSR response to Ang II. In juxtaglomerular cells, Ang II and NE amplified each other's RSR responses via an increase in intracellular calcium levels. These responses were mediated by the activation of Ang II type I receptors and α1-adrenoceptors, respectively. Takao Saruta, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan

Objective : To determine whether the central nervous system has a pressor or a depressor role in glucocorticoid-induced hypertension. Methods : Intracerebroventricular dexamethasone or its receptor antagonist, RU 38486, was administered in 20 trained conscious dogs. In addition, intracerebroventricular RU 38486 was administered in dogs treated with oral dexamethasone. Results : Intracerebroventricular dexamethasone induced a dose-related reduction in blood pressure accompanied by decreased heart rate and cardiac output. In contrast, intracerebroventricular RU 38486 caused a slight but not significant elevation in blood pressure. Total peripheral resistance showed no significant change throughout the treatment with dexamethasone or RU 38486. In contrast, oral dexamethasone caused significant elevation of blood pressure associated with increased total peripheral resistance and reduced heart rate. In hypertensive dogs treated with oral dexamethasone, intracerebroventricular RU38486 elicited a more severe form of hypertension accompanied by an attenuation of the heart rate and a reduction in cardiac output. Intracerebroventricular dexamethasone induced a significant reduction in plasma levels of adrenocorticotrophic hormone, cortisol, arginine vasopressin and noradrenaline. In addition, simultaneous central administration of RU38486 with intracerebroventricular dexamethasone blocked the reduction in blood pressure and heart rate completely. Conclusion : The present data strongly suggest that endogenous glucocorticoid in the central nervous system may not have a role in the regulation of systemic haemodynamics and hormones under resting conditions, but does play an important part during the glucocorticoid excess state, for example glucocorticoid hypertension caused by oral treatment with dexamethasone. The glucocorticoid in the central nervous system opposed the elevation of blood pressure in glucocorticoid-induced hypertension by attenuating the reduction in heart rate and cardiac output via direct stimulation of glucocorticoid receptors in the brain.

OBJECTIVES The relationship between plasma renin activity, plasma angiotensin II (Ang II) or aldosterone levels and peripheral blood cells (mononuclear leucocytes and platelets) Ang II type 1 (AT1) receptor messenger RNA (mRNA) levels were examined in both primary and secondary hypertensive patients. DESIGN AND METHODS The subjects were 30 patients with primary hypertension, five with primary aldosteronism, five with renovascular hypertension and five normotensive controls with renal cell carcinoma. Blood was collected from each patient for estimation of plasma renin activity and plasma Ang II and aldosterone concentrations, and for isolation of mononuclear leucocytes and platelets, which were then used to measure AT1 receptor mRNA with reverse-transcription polymerase chain reaction. RESULTS Platelet AT1 receptor mRNA levels were inversely correlated with plasma Ang II levels, and mononuclear leucocyte receptor mRNA levels were positively correlated with plasma Ang II levels in patients with primary hypertension. In contrast, in secondary hypertension both platelets and mononuclear leucocytes AT1 receptor mRNA, which were elevated, were reduced after removal of the adrenal tumour or correction of stenosis of the renal artery. CONCLUSIONS Platelet AT1 receptors, which were used to reflect physiologically important sites such as vascular smooth muscle, were shown to be regulated in a different manner from mononuclear leucocyte receptors. In patients with primary aldosteronism and renovascular hypertension the plasma aldosterone level was shown to be an important factor upregulating AT1 receptor mRNA.

To investigate whether changes in renal blood flow induced by nondepressor doses of L-arginine, the precursor of nitric oxide, are mediated by a sympathetic neural mechanism, we examined the following in conscious rabbits: (1) the effects of intravenous infusion of L- or D-arginine (15 to 200 mumol/kg per minute) on renal blood flow and renal sympathetic nerve activity with or without intravenous infusion of a nonpressor dose of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, and (2) the effects of L-arginine on renal blood flow after renal denervation with or without L-NMMA pretreatment. In renal innervated rabbits, L-arginine (100 and 200 mumol/kg per minute) increased renal blood flow by 9 +/- 2 and 16 +/- 3 mL/min (P < .05, respectively) and decreased renal sympathetic nerve activity by 12 +/- 4% and 19 +/- 3% of control (P < .05, respectively). In contrast, no changes occurred in any variable during D-arginine infusion. L-NMMA attenuated the renal blood flow and renal sympathetic nerve activity responses to L-arginine (P < .05). In renal denervated rabbits, L-NMMA also attenuated the renal blood flow responses to L-arginine (P < .05) and abolished them (P < .05) compared with those in renal innervated rabbits. All renal blood flow responses to L-arginine were accompanied by parallel changes in plasma L-citrulline concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Recently, we demonstrated that glucocorticoid potentiates inositol triphosphate production evoked by angiotensin II in vascular smooth muscle cells. To clarify this mechanism, we investigated the effects of dexamethasone on the modulation of angiotensin II type 1 receptor and on postreceptor mechanisms in vascular smooth muscle cells. The number of angiotensin II type 1 receptors began to increase after 12 hours' incubation with dexamethasone. After 48 hours, the Bmax value reached 27 +/- 3 fmol/mg protein in dexamethasone-treated cells and 15 +/- 3 fmol/mg protein in control cells. However, binding affinity did not change. A glucocorticoid antagonist, RU 38486, completely blocked these effects of dexamethasone. Also, to elucidate the effects of dexamethasone on postreceptor mechanisms, GTP analogue-induced inositol trisphosphate production in permeabilized cells was examined. Pretreatment with 1 mumol/L dexamethasone for 48 hours did not affect these inositol trisphosphate productions. Moreover, dexamethasone had no effect on the level of Gq alpha protein. Furthermore, steady-state levels of angiotensin II type 1 receptor messenger RNA were increased 2.2 +/- 0.3-fold after 30 minutes' exposure to 1 mumol/L dexamethasone and 7.8 +/- 0.4-fold after 24 hours. We conclude that glucocorticoid induced expression of the angiotensin II type 1 receptor gene and resulted in an increase in the number of angiotensin II type 1 receptors through the glucocorticoid-specific receptor, without significant effect on postreceptor systems in vascular smooth muscle cells.

Pathogenesis of hypertension in Cushing's syndrome has remained controversial. A 56-year-old Japanese man with Cushing's syndrome due to adrenal carcinoma has been followed up for more than 6 years. During the followup period, left adrenalectomy and hemihepatectomy due to metastatic lesion were performed. Blood pressure, serum cortisol, and urinary excretion of 17-OHCS, as well as other routine biochemicals, have been measured periodically. These data revealed that there is a marked correlation between the levels of blood pressure and serum cortisol or urinary excretion of 17-OHCS. This finding suggests that cortisol production by tumor is a determinant factor in hypertension in Cushing's syndrome.

1. The effects of l-arginine on systemic and renal haemodynamics were investigated in conscious dogs. l-Arginine was administered intravenously at doses of 15 and 75 μmol min−1 kg−1 for 20 min. 2. Mean arterial blood pressure, heart rate and cardiac output were not changed significantly by l-arginine infusion. However, l-arginine infusion induced a significant elevation of renal blood flow from 50 ± 3 to 94 ± 12 ml/min (means ± sem, P < 0.01). 3. Simultaneous infusion of NG-monomethyl-l-arginine (0.5 μmol min−1 kg−1) significantly inhibited the increase in renal blood flow produced by l-arginine (15 μmol min−1 kg−1) without significant changes in mean arterial blood pressure or heart rate. 4. Pretreatment with atropine completely inhibited the l-arginine-induced increase in renal blood flow, whereas pretreatment with indomethacin attenuated it (63 ± 4 versus 82 ± 10 ml/min, P < 0.05). 5. A continuous infusion of l-arginine increased renal blood flow in the intact kidney (55 ± 3 versus 85 ± 9 ml/min, P < 0.05), but not in the contralateral denervated kidney (58 ± 3 versus 56 ± 4 ml/min, P > 0.05). 6. These results suggest that intravenously administered l-arginine produces an elevation of renal blood flow, which may be mediated by facilitation of endogenous acetylcholine-induced release of endothelium-derived relaxing factor and vasodilatory prostaglandins.

The serial changes in systemic and renal hemodynamics, water and electrolyte balances and various vasoactive hormones were examined in 12 conscious dogs before, during (10 days) the administration of dexamethasone (DEX: 0.5 mg/kg/day) and after the cessation of DEX. In addition, during the administration of DEX, pressor responses to angiotensin II, norepinephrine, an angiotensin II analogue, saralasin, and an alpha-1-blocker, prazosin, were studied. Abrupt elevation of blood pressure to 106 +/- 5 mmHg on Day 1 (vs. 91 +/- 6 mmHg control: P less than 0.05) associated with marked increases in total peripheral resistance (P less than 0.01) was shown in DEX treated animals. Accompanied with these changes, renal blood flow increased to 146 +/- 12 ml/min (vs. 103 +/- 8 ml/min control: P less than 0.05) on Day 1 and maintained. In contrast, the results of serial alterations in hormones could not show any significant changes except significant elevations in atrial natriuretic peptide and reductions of cortisol and arginine vasopressin. Also, marked natriuresis and diuresis were observed in DEX administration dogs. Pressor response to norepinephrine was significantly increased and administration of either saralasin and prazosin significantly reduced the blood pressure of DEX treated animals. These results in DEX-treated conscious dogs confirmed our previous findings in human and rats. Glucocorticoid-induced hypertension mainly depends on the increases in total peripheral resistance but not volume factors.

The effects of the angiotensin-converting enzyme inhibitor captopril on blood pressure, heart rate, plasma prolactin, and renin activity were examined in a single-blind, placebo-controlled trial on 30 patients with essential hypertension (15 given drug, 15 placebo). Captopril, 25 mg administered orally, reduced the blood pressure and increased the plasma renin activity. Captopril decreased mean plasma prolactin from 17.5 +/- 1.4 ng/mL to 9.1 +/- 1.0 ng/mL (p less than 0.001). Significant correlation was found between captopril-induced change from control values of plasma prolactin (delta plasma prolactin) vs delta plasma renin activity (r = -0.688, p less than 0.001). These results suggest that acute administration of captopril was accompanied by a reduction in plasma prolactin and that this reduction may be of clinical significance during therapy of hypertension.

An autopsy case of an elderly man with Takayasu's arteritis and atherosclerosis is presented. Ischemic signs and symptoms including anginal attack were aggravated with activity of arteritis despite administration of prednisolone throughout the entire course. The autopsy revealed severe atherosclerosis over the aorta and its branches, and arteritis in the fibrotic stage in localized area. Vessels of vital organs including heart and kidneys, did not show Takayasu's arteritis but were atherosclerotic. This case highlights the numerous problems encountered in the treatment of elderly patients with vasculitis such as Takayasu's arteritis.

Objective : To study the different cardiac and renal hemodynamic effects of an angiotensin converting enzyme inhibitor and an angiotensin II receptor antagonist in experimental heart failure in conscious dogs. Design and methods : We compared the effects of the angiotensin converting enzyme inhibitor, captopril, with those of the angiotensin II (Ang II) subtype-1 receptor antagonist, losartan, on hemodynamics and hormonal changes in congestive heart failure by rapid ventricular pacing on conscious dogs. Furthermore, we characterized the Ang II receptors in canine heart, using the canine cardiac membrane fraction in heart failure. Results : Acute intravenous administration of captopril improved the cardiac output by 19% (P

This study examined the effects of calcitonin gene-related peptide (CGRP) on aldosterone secretion both in vivo and in vitro. Intravenous administration of CGRP (0.01 micrograms/kg) in 6 conscious dogs produced a significant decrease in plasma aldosterone concentration from 68 +/- 12 pg/ml to 28 +/- 11 pg/ml (p less than 0.05) despite a mild but significant elevation of plasma renin activity. In an in vitro study using isolated rabbit adrenal glomerulosa cells CGRP reduced the basal aldosterone secretion in a dose-related manner and furthermore 10(-9) M CGRP inhibited the aldosterone secretion stimulated by 10(-8) M angiotensin II. From these results it is suggested that CGRP has an inhibitory effect on aldosterone secretion.

1. The effects of endothelin on systemic and renal haemodynamics and plasma concentrations of neuroendocrine hormones including plasma renin activity, aldosterone, adrenocorticotropic hormone, Cortisol, catecholamines and arginine vasopressin were investigated in 18 conscious dogs. 2. Bolus injection of 4 pmol of endothelin/kg did not cause any significant changes in haemodynamics. Mean arterial pressure was elevated by both doses of 40 pmol/kg [91 ± 2 to 99 ± 2 mmHg (12.1 ± 0.3 to 13.2 ± 0.3 kPa), P < 0.05] or 200 pmol/kg [93 ± 2 to 107 ± 3 mmHg (12.4 ± 0.3 to 14.3± 0.4 kPa), P < 0.01], the latter dose increasing cardiac output (14%, P < 0.05) and heart rate (9%, P < 0.05), and the former reducing these parameters (14% and 8%, P < 0.05, respectively). 3. In contrast with the various changes in systemic haemodynamics, renal blood flow transiently increased immediately after bolus injection in a dose-dependent manner (28%, P < 0.05, 50%, P < 0.01 and 110%, P < 0.01 with 4, 40 and 200 pmol of endothelin/kg, respectively). This transient elevation of renal blood flow was followed by a gradual decrease (16%, P < 0.05; 31%, P < 0.01 and 36%, P < 0.01) at 10 min. 4. All neurohormones were elevated in a dose-dependent manner. 5. Among these hormones, arginine vasopressin and plasma renin activity reached a peak level at 5 min (from 2.21 ± 0.45 to 6.37 ± 0.60 pmol/l, P < 0.01, and from 0.65 ± 0.08 to 1.09 ± 0.10 pmol of angiotensin 1 h−1 ml−1P < 0.01, respectively) after bolus injection of 200 pmol of endothelin/kg, whereas adrenocorticotropic hormone and Cortisol reached a peak level at 15 min (from 6.0 ± 0.7 to 18.2 ± 1.5 pmol/l, P < 0.01, and from 4.4 ± 0.9 to 16.5 ± 2.7 × 10−2 μmol/l, P < 0.01, respectively). 6. These results suggest that endothelin is a potent vasoconstrictive peptide in vivo with a marked effect on the renal vascular system, and that it induces elevation of vasoactive hormones directly and/or through central effects.