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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.

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)

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)

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.

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.

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.