Improvement of accessory symptoms of hypertension by TSUMURA Orengedokuto Extract, a four herbal drugs containing Kampo-Medicine Granules for ethical use: a double-blind, placebo-controlled study.

A double-blind, placebo-controlled study was conducted to evaluate the efficacy, safety, and utility of TSUMURA Orengedokuto Extract Granules for Ethical Use (TJ-15) as a treatment for the accessory symptoms of hypertension. Two capsules of the study drug were administered orally 3 times daily (i.e., before meals) for 8 weeks. Among 265 patients enrolled in the study, 134 were assigned to the TJ-15 group and 131 were assigned to the placebo group, of whom 204 patients (103 in the TJ-15 group and 101 in the placebo group) were included in the efficacy and utility analyze and 251 patients (128 in the TJ-15 group and 123 in the placebo group) were included in the safety analysis. Efficacy was significantly higher in the TJ-15 group based on the total score for the accessory symptoms of hypertensions which was the primary efficacy endpoint (Wilcoxon's rank sum test, p=0.013). When each accessory symptom of hypertension was assessed separately, efficacy was higher for hot flushes and facial suffusion in the TJ-15 group (Wilcoxon's rank sum test, p=0.034, and 0.022, respectively). There were no significant differences between the TJ-15 and the placebo groups with respect to the decrease of blood pressure or the antihypertensive effect. There was also no significant difference between the two groups with regard to the overall safety rating. The utility rating was significantly higher in the TJ-15 group than in the placebo group (Wilcoxon's rank sum test, p=0.016). In conclusion, TJ-15 was superior to placebo with respect to efficacy, safety, and utility for the treatment of accessory symptoms of hypertension.

Cellular component of vascular calcification. Fibroblasts are essential for calcium deposition in cultured cells.

It has been reported that calcium deposition and calcium content in cultured human aortic smooth muscle cells (SMC) increased when the cells are incubated in a medium with a high phosphate concentration (2 mM). To determine the cellular components or soluble factors contributing to the deposition, we cultured commercially available SMC, fibroblasts (Fb) and endothelial cells (Ed). These cells and their mixtures were incubated for 10 days in normal or high-phosphate media. Calcium crystals were stained by the von-Kossa staining and counted in the defined area. Calcium content was measured by a colorimetric assay. SMC were incubated in high-phosphate media (up to 2 mM) or beta-glycerophosphate (beta-GP) media, resulting in no obvious deposition of calcium crystals, irrespective of the coating of type I collagen on the dish. Next, various combinations of cells were cultured, and a significant number of depositions were observed only when Fb were included in the combination. The calcium content was significantly higher in cultures of SMC and Fb. The calcium deposition on single or mixture of the cells did not increase compared with control when cells were incubated in a high concentration of phosphate, cultured in the existence of beta-GP or uremic serum. We therefore conclude that Fb, rather than SMC or Ed, are essential for calcium deposition and calcium accumulation in culture. Phosphate concentration in the medium and uremic serum did not influence the deposition of calcium.

Changes in osteoprotegerin and markers of bone metabolism during glucocorticoid treatment in patients with chronic glomerulonephritis.

It is well known that long-term glucocorticoid treatment causes osteoporosis, but the precise mechanism remains unclear. Recently, osteoprotegerin (OPG) has been identified as a cytokine that inhibits osteoclast differentiation. We have previously demonstrated that serum OPG is suppressed by glucocorticoids. Therefore, the present study was carried out to clarify the interrelationships between OPG and other markers of bone metabolism during glucocorticoid treatment. Thirteen patients (7 men, 6 women; 44.1 +/- 5.9 years old) with chronic glomerulonephritis who were to be treated with glucocorticoids for the first time were chosen for this study. Markers of bone metabolism, including serum OPG, osteocalcin (OC), bone-specific alkaline phosphatase activity (bAP), parathyroid hormone (PTH), tartrate-resistant acid phosphatase (TRAP), and bone mineral density (BMD), were measured before and during the treatment period. Glucocorticoids significantly reduced BMD of the lumbar spine in the 6 month treatment period (p < 0.01). Serum OPG was decreased significantly by glucocorticoids within 2 weeks (p < 0.001), and serum TRAP, a marker of bone resorption, was markedly increased (p < 0.001). On the other hand, there were no remarkable changes in serum PTH. Serum OC and bAP, markers of bone formation, were transiently reduced during the treatment period (p < 0.01). Furthermore, only serum OPG was positively and independently correlated with percentage BMD of age-matched reference (%AMR). These findings imply that glucocorticoid-induced bone loss develops rapidly via enhanced bone resorption and suppressed bone formation. Moreover, the increased bone resorption caused by glucocorticoids may be, at least in part, mediated by inhibition of OPG, not increment of PTH.

Tolerability and safety of a calcium channel blocker in comparison with a diuretic in the treatment of elderly patients with hypertension: secondary analysis of the NICS-EH.

A randomized prospective controlled study, the National Interventional Cooperative Study in Elderly Hypertensives (NICS-EH), previously demonstrated that the preventive effect of the long-acting calcium channel blocker nicardipine on the cardiovascular endpoint was similar to that of the diuretic, trichlormethiazide. The present report is a sub-analysis in which we compare the tolerability and safety of the calcium channel blocker with that of a diuretic in the long-term treatment of elderly hypertensives. A total of 429 elderly patients with hypertension were assigned to the nicardipine group or the diuretic group by the double-dummy method and were followed up for 5 years. Two hundred four patients in the nicardipine group and 210 patients in the diuretic group were analyzed. The incidences of fatal and nonfatal cardiovascular (CV) events in the two groups were comparable, and there was no significant difference in the cumulative event-free rate. However, the total incidence of adverse reactions, including non-CV events and unfavorable BP changes, was 31 cases (15.2%) in the nicardipine group, which was significantly lower than the 47 cases (22.4%) in the diuretic group (log-rank: p=0.026, G. Wilcoxon: p=0.01). The total number of medical endpoints, including CV events, the withdrawal of the patient from the study, was 52 (25.5%) in the nicardipine group, which was significantly lower than the 65 (31.0%) in the diuretic group (log-rank: p=0.078, G. Wilcoxon: p=0.044). It was concluded that sustained-release nicardipine is better tolerated, as it exhibits a lower incidence of medical-related withdrawals such as adverse drug reactions, non-cardiovascular events and unfavorable BP responses during the treatment.

Erythropoietin regulates vascular smooth muscle cell apoptosis by a phosphatidylinositol 3 kinase-dependent pathway.

BACKGROUND: Recent studies have shown that several cytokines could induce apoptosis in vascular smooth muscle cells (VSMCs) via the induction of nitric oxide (NO). In the present study, we explored whether human recombinant erythropoietin (rHuEPO) has a modulatory effect of apoptosis on interleukin-1beta (IL-1beta) or NO donor sodium nitroprusside (SNP)-induced apoptosis in rat cultured VSMCs. METHODS: The quantitation of apoptosis among VSMCs was assessed by nuclear morphological analysis with fluorescent DNA-binding dye Hoechst 33258. Apoptotic changes were also confirmed by the detection of DNA fragmentation. The expression of EPO receptor (EpoR), cellular protein tyrosine phosphorylation, including EpoR and Janus kinase (JAK) 2, and the association of p85 subunit of phosphatidylinositol 3 kinase (PI3-kinase) to tyrosine-phosphorylated proteins, including EpoR, were explored by using Western blotting analysis combined in part with immunoprecipitation. RESULTS: rHuEPO inhibited the apoptosis induced by IL-1beta or SNP in a dose- and time-dependent manner. The anti-apoptotic effects of rHuEPO were diminished in the presence of a tyrosine kinase (TK) inhibitor genistein or anti-EpoR antibody. After stimulation with rHuEPO, EpoR and JAK 2 were tyrosine phosphorylated, and p85 subunits were associated with EpoR. Also, rHuEPO induced phosphorylation of Akt through a PI3-kinase-dependent pathway. The phosphorylation of Akt and the anti-apoptotic effects of rHuEPO were diminished in the presence of a PI3-kinase inhibitor, wortmannin. CONCLUSION: Our present study demonstrates that rHuEPO inhibites IL-1beta or SNP-induced VSMC apoptosis. The TK-dependent pathway, particularly the PI3-kinase-dependent pathway, seems to be critical to the countervailing effect of rHuEPO on IL-1beta and SNP-induced VSMC apoptosis.

Difference in the incidence of cough induced by angiotensin converting enzyme inhibitors: a comparative study using imidapril hydrochloride and enalapril maleate.

To compare the incidence of cough between two angiotensin converting enzyme (ACE) inhibitors, imidapril and enalapril, comparative crossover study was performed in 489 patients (228 men and 261 females) with essential or renal parenchymal hypertension. Patients were randomly assigned to one of two treatment groups, a group receiving imidapril for 12 wk (Period I) followed by enalapril for 12 wk (Period II), and a group in which the order of drugs was reversed. The occurrence of cough during treatment was monitored by questionnaire in all cases. There were no differences in background characteristics between the two groups. The incidence of cough during Period I was 15.2% (32/210) in the group initially treated with imidapril (Group IE) and 38.6% (85/220) in the group initially treated with enalapril (Group EI), the difference being statistically significant (p < 0.001). During Period I, decrease in blood pressure was observed in 63.9% (115/180) of Group IE and 64.6% (115/178) of Group EI patients. In approximately half of the patients in Group EI who developed cough during Period I and in whom the treatment was subsequently switched to imidapril, cough subsequently disappeared. It was concluded that the incidence of cough was significantly less under imidapril than under enalapril treatment, while there was no difference in the antihypertensive effects of the two ACE inhibitors.

Effect of lipid-lowering strategies on tubular cell biology.

BACKGROUND: Interstitial fibrosis and the development of renal cysts are crucial phenomena in renal disease progression. While 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been shown to reduce the progression of several experimental nephropathies, the mechanism of their potential protective effect remaines unclear. METHODS: The antiproliferative, apoptotic, and fibrinolytic effects of HMG-CoA reductase inhibitors were assessed in primary cultured rat (rPTCs) and mouse proximal tubule cells (mPTCs), in isolated rat proximal tubules, and in vivo in 5/6 nephrectomized rats (Nx). RESULTS: In vitro, lovastatin inhibited rPTC proliferation in a manner selectively prevented by mevalonate, farnesyl-, or geranylgeranyl-pyrophosphate (FPP or GGPP). Lovastatin reduced membrane-bound p21ras and fetal calf serum-induced c-fos and c-jun protein expression. Gel shift assay showed that lovastatin reduced activated protein-1 (AP-1) binding activity. In vivo, lovastatin inhibited tubular cell proliferation after Nx, as measured by proliferative cell nuclear antigen staining. Lovastatin-treated mPTCs displayed nucleus cleavage and DNA ladder formation, which were prevented by GGPP. Like C3 exoenzyme, lovastatin induced actin filament disruption, which preceded evidence of apoptosis. Lovastatin increased tissue-type plasminogen activator (PA) and decreased PA inhibitor activities and antigens; these effects were prevented by mevalonate and GGPP but not FPP, and were reproduced by C3 exoenzyme in a manner insensitive to GGPP. CONCLUSIONS: HMG-CoA reductase inhibitors decreased proliferation, increased apoptosis, and enhanced fibrinolytic activity of renal tubular cells via modulation of different isoprenylated proteins. These effects could participate to reduce the progression of renal diseases.

Atrial natriuretic peptide enhances IL-1 beta-stimulated nitric oxide production in cultured rat vascular smooth muscle cells.

OBJECTIVE: To elucidate the effect of atrial natriuretic peptide (ANP) on cytokine-induced nitric oxide (NO) production, we examined whether ANP affects IL-1 beta-stimulated NO production and inducible NO synthase (iNOS) mRNA expression in cultured rat vascular smooth muscle cells (VSMC). METHODS: VSMC were incubated with test agents for 24 h. The nitrite concentration of the culture medium, a stable-end product of NO, was measured by the column reduction method. NOS mRNA expression was analyzed by Northern blotting. The intracellular cAMP content was measured by enzyme immunoassay. cAMP-dependent kinase (PKA) activity was determined by a PKA assay system. RESULTS: IL-1 beta stimulated nitrite production in VSMC. ANP (10 nM to 1 mM) enhanced the nitrite production and iNOS mRNA expression in the presence of IL-1 beta. Both 8-bromo-guanosine 3',5'-cyclic monophosphate (8-br-cGMP) and dibutylyl adenosine 3',5'-cyclic monophate enhanced IL-1 beta-induced nitrite production. The effects of these two nucleotide donors on the nitrite production were not additive, suggesting a common pathway. KT 5720, an inhibitor of PKA, abolished the enhancement of nitrite production by ANP and 8-br-cGMP, while KT 5823, an inhibitor of cGMP-dependent protein kinase, did not inhibit the enhancement. In the in vitro assay 8-br-cGMP increased PKA activity. CONCLUSIONS: ANP and cGMP enhanced IL-1 beta-induced NO production in VSMC. PKA rather than PKG may be involved in the enhancement.

HMG-CoA reductase inhibitors induce apoptosis in mouse proximal tubular cells in primary culture.

Renal cyst formation in polycystic diseases or after nephron reduction is attributed to enhanced tubular cell proliferation with unbalanced cell death. The induction of tubular cell death could be effective to reduce renal cyst formation. In this study, we examined the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on apoptosis in mouse proximal tubular (MPT) cells in primary culture. After treatment with HMG-CoA reductase inhibitors, the extracted DNA was analyzed by gel-electrophoresis under ultraviolet light. Apoptosis was evaluated quantitatively by estimating the ratio of fragmented DNA over intact DNA. For morphologic studies, cells were stained with Hoechst 33,258. DNA ladder pattern of 200 kDa typical of apoptosis and significant increase in DNA fragmentation were seen after 24 hours of treatment with lovastatin, a HMG-CoA reductase inhibitor. Staining with the Hoechst dye revealed cleavage of nucleus into pieces under the same condition. Geranylgeranylpyrophosphate (20 microM) and mevalonate (500 microM) completely reversed the effect of lovastatin, while farnesylpyrophosphate (20 microM) partially reversed it. Other products of HMG-CoA pathway such as cholesterol, ubiquinone, dolichol, and isopentenyladenine had no effect. Perillic acid and alpha-hydoxyfarnesylphosphonic acid, isoprenylation inhibitors, induced apoptosis of the cells. A treatment with lovastatin caused actin filament disruption. Cytochalasin D, an inhibitor of actin polymerization, induced apoptosis. Interleukin-1 beta-converting enzyme inhibitor II, a protease inhibitor, had no effect on the apoptosis induced by either HRI or cytochalasin D. The present study suggests that in mouse proximal tubules, HMG-CoA reductase inhibitors induce apoptosis via inhibition of isoprenoid production, and disruption of actin filaments may play a role in the apoptosis induction.

Propylthiouracil-induced rapidly progressive glomerulonephritis associated with antineutrophil cytoplasmic autoantibodies.

We present a case study of a 52-year-old female patient with hyperthyroidism which had been diagnosed at the age of 35. However, the malfunction of thyroid had been poorly controlled. Thyroid function was returning to normal after the administration of propylthiouracil (PTU) 300 mg/day, however purpura appeared in both lower extremities. Renal function deteriorated rapidly, and the patient was admitted to our hospital. According to the biopsies, leukocytoclastic vasculitis in the skin was apparent, and crescent formation was observed in the glomerulus. Serological examination revealed positive antineutrophil cytoplasmic autoantibodies (ANCA) against proteinase 3 (Pr3) and myeloperoxidase (MPO). Antinuclear autoantibody was positive. After cessation of PTU and administration of prednisolone, the purpura disappeared and ANCA were becoming negative. Renal function recovered gradually. Thyroid function was kept within normal range using iodine solution. Thus, it is strongly suggested that PTU-induced rapidly progressive glomerulonephritis associated with ANCA.

New technique for time series analysis combining the maximum entropy method and non-linear least squares method: its value in heart rate variability analysis.

A new technique for time series analysis, which is a combination of the maximum entropy method (MEM) for spectral analysis and the non-linear least squares method (LSM) for fitting analysis, is described. In this technique, the MEM power spectral density (MEMPSD) is calculated using a very large lag that could diminish the lag dependence of dominant periods estimated by the MEM analysis. The validity of this large lag is confirmed by the LSM, given that the ten dominant MEM periods are known quantities. To validate the MEM plus LSM technique, it is compared with autoregressive (AR) modelling, by analysing heart rate variability under pharmacological interventions (phenylephrine and trinitroglycerine), using 16 young males. The results indicate that the MEMPSD, when compared with the ARPSD, has numerous periods that could reproduce the original time series much more accurately, as revealed by the LSM analysis. However, both the low- and high-frequency powers with MEMPSD and ARPSDs shift in the expected directions in accordance with the pharmacological effects on the cardiovascular system. The implications of these results are discussed from the theoretical and practical standpoints of the MEM plus LSM technique, compared with AR modelling.

Comparative hypertensionology-renal dopaminergic activity in experimental hypertensive rats.

In our laboratory, it had been found that the renal natriuretic and depressor systems are suppressed in essential hypertension, and that suppression of the dopaminergic system may be primary and dominant in this condition. Moreover, close relationships among the renal dopamine, kallikrein-kinin, and prostaglandin systems have also been found. Therefore, we attempted to evaluate the pathogenetic and pathophysiological role of renal dopamine in connection with renal kallikrein-kinin and prostaglandin systems in various experimental hypertensive models. Two kidney 1 clip hypertensive rats (2K1C), 5/6 reduced renal mass hypertensive rats (5/6 RRM), deoxycorticosterone acetate-salt hypertensive rats (DOCA-salt), spontaneously hypertensive rats/Izumo (SHR/Iz), Dahl salt sensitive hypertensive rats/John Rapp (Dahl/Jr), Dahl/Iwai (Dahl/Iw), and respective controls were employed in this study. Urinary excretions of free dopamine (uDA), kallikrein (uKAL), and prostaglandin E2 (uPGE2) were measured before, during and after treatment in each of these hypertensive models. In these experimental hypertensive models, renal dopamine in DOCA-salt and SHR/Iz, and renal kallikrein in 2K1C, 5/6 RRM and two types of Dahl strains were primarily and dominantly suppressed in the renal natriuretic and depressor systems. Renal dopamine was transiently suppressed in Dahl/Jr, and PGE2 was suppressed in the two types of Dahl strains. Compensatory augmentation of renal kallikrein was found in DOCA-salt and SHR/Iz, and that of PGE2 was found in 5/6 RRM and DOCA-salt. Although these three renal natriuretic depressor systems are suppressed in Dahl/Jr, the dominantly suppressed system is not renal dopamine but renal kallikrein. Thus, it was summarized that, 1) decreased renal dopamine production is important in the pathogenesis of human essential hypertension, 2) pressor mechanisms of experimental hypertensive rats are different from human essential hypertension, 3) decreased renal dopamine is important in DOCA-salt and SHR/Iz, 4) decreased renal kallikrein is the dominant mechanism in the pathogenesis of 2K1C, 5/6 RRM, Dahl/Jr and Dahl/Iw hypertensive rats, and 5) we have to be careful when considering human essential hypertension through results taken from experimental rat hypertensive models.

[Treatment of elderly patients with hypertension--complications and current drug therapy].

To investigate current drug therapy for elderly hypertensive patients, we performed a case-card study at Sapporo Medical University and its branch hospitals. The case-card was designed to show prescriptions given for hypertension, complications, and blood pressure. In the 2897 valid cases, calcium antagonists were prescribed in 76.3%, followed by beta-blockers (31.4%), angiotensin-converting enzyme inhibitors (ACE-I) (25.1%) and natriuretic diuretics (18.1%). When the patients were divided into an elderly group (> or = 65 y.o., n = 1475), beta-blockers and ACE-I were found to be more frequently used in the non-elderly group, and diuretics were more frequently prescribed in the elderly group. Calcium antagonists were the most frequently used drugs, irrespective of age. As monotherapy drugs, calcium antagonists were chosen most frequently in both groups. Diuretics were the second most frequently used drug in the elderly group, but beta-blockers occupied that position in the younger group and these patients as a whole. In the elderly group, the manner of prescription was analyzed according to major complications. In patients with ischemic heart disease, beta-blockers and diuretics were used more frequently than in patients without that condition. Diuretics were prescribed more frequently in patients with renal dysfunction. Calcium antagonists and ACE-I were used more frequently in the patients with diabetes mellitus. The same differences were found in the non-elderly patients with those complications. However, among patients with stroke, calcium antagonists were more frequently used in the elderly group and ACE-I were performed in the younger patients. In conclusion, calcium antagonists were used very often regardless of age, and the other drugs were used according to age-dependent differences in pathophysiologic mechanism.

Captopril potentiates the myocardial infarct size-limiting effect of ischemic preconditioning through bradykinin B2 receptor activation.

OBJECTIVES: To investigate the role of kinin in preconditioning against infarction, the present study assessed the effect of captopril, a kininase II inhibitor, on preconditioning and arterial plasma kinin levels. BACKGROUND: Recent studies suggest a possible contribution of kinin to preconditioning against infarction. However, its role and the site of kinin production remain uncharacterized. METHODS: Six groups of rabbits (n = 6 to 13) underwent 30-min coronary occlusion and 3-h reperfusion. The infarct size and area at risk were determined by tetrazolium staining and fluorescent particles, respectively. Arterial blood was sampled under baseline conditions, before the 30-min ischemia and after reperfusion for radioimmunoassay of the kinin level. RESULTS: Infarct size expressed as a percentage of area at risk (%IS/AR) was 42.9 +/- 2.9% (mean +/- SEM) in the control group, 34.5 +/- 3.3% in the group preconditioned with 2 min of ischemia/5 min of reperfusion and 41.7 +/- 5.1% in the group given captopril (1 mg/kg body weight) alone before the 30-min ischemia. These %IS/AR values were not significantly different between the three groups. However, a combination of captopril and subsequent preconditioning with 2 min of ischemia markedly limited %IS/AR to 21.2 +/- 2.4%. This potentiation of 2 min of preconditioning by captopril was not observed when 2 micrograms/kg body weight of Hoe 140, a specific bradykinin B2 receptor antagonist, was administered before preconditioning (%IS/AR = 41.2 +/- 5.7%), whereas Hoe 140 alone did not modify infarct size (%IS/AR = 38.5 +/- 5.1%). Arterial plasma kinin levels were comparable between the control rabbits, the group given captopril alone and the group that received captopril plus 2 min of preconditioning at baseline (3.8 +/- 1.0, 6.3 +/- 1.9 and 5.2 +/- 1.7 pg/ml, respectively), and there was no significant change in kinin levels after the captopril injection or the combination of captopril plus 2 min of preconditioning. CONCLUSIONS: The present results indicate that captopril is capable of potentiating preconditioning without increasing the arterial kinin level and that the beneficial effect of captopril can be inhibited by Hoe 140. These findings support the hypothesis that kinin produced locally in the heart during preconditioning may contribute to the cardioprotective mechanism through bradykinin receptor activation.

Bilateral deoxycorticosterone-secreting adrenocortical adenoma.

A case of a 58-year-old man with bilateral deoxycorticosterone (DOC)-secreting adrenocortical adenoma is reported. Before surgery, plasma levels of DOC and corticosterone were markedly elevated, but both adrenal hormone levels normalized after the surgical removal of the bilateral adrenal tumors. The histologic examination revealed bilateral adrenocortical adenoma, but curiously, the tissue concentrations of DOC and corticosterone were elevated only in the right adrenal gland.

Suppression of the degradation of adenine nucleotides during ischemia may not be a sufficient mechanism for infarct size limitation by preconditioning.

Preconditioning is known to decelerate degradation of the tissue adenine nucleotides during ischemia and to delay ischemic myocardial necrosis. However, it is not known whether these two phenomena are related. To obtain an insight into this question, the present study examined whether adenosine and B2 receptor antagonists, which block the infarct size-limiting effect of preconditioning, modify the interstitial purine levels during preconditioning and subsequent sustained ischemia. In pentobarbital anesthetized open-chest rabbits, a microdialysis probe was placed in the territory of a branch of the left coronary artery, and perfused with Ringer solution. Preconditioning was performed with 5 min ischemia/5 min reperfusion. Dialysate adenosine and inosine were elevated from the baseline values of 0.064 +/- 0.011 and 0.329 +/- 0.044 microM to 0.189 +/- 0.069 and 4.106 +/- 1.451 microM, respectively during preconditioning, but their elevation during a subsequent 20 min of ischemia was significantly lower compared with that in the non-preconditioned myocardium. This suppression of the purine accumulation during ischemia by preconditioning was not abolished by 2 micrograms/kg of Hoe 140, a specific B2 receptor antagonist, or by 10 mg/kg of 8-phenyltheophylline, a non-selective adenosine receptor antagonist. Since the doses of Hoe 140 and 8-phenyltheophylline are sufficient to block the infarct size-limiting effect of preconditioning, the present results suggest that there is a dissociation between the suppression of adenine nucleotide degradation during ischemia by preconditioning and the enhancement of myocardial resistance against infarction. Thus, it is unlikely that a reduction of adenine nucleotide utilization by preconditioning is sufficient to protect the myocardium against ischemic necrosis.

The role of renal dopaminergic activity in the pathophysiology of essential hypertension.

Although the pathogenesis of essential hypertension still remains unclear, it is now generally accepted that the kidney is deeply involved in the pathophysiology of this disease. This paper therefore, reviews current knowledge of the role of renal dopaminergic activity in essential hypertension. This is believed to be one of the most important renal diuretic and depressor systems. Suppression of urinary excretion of free dopamine (DA) is observed in essential hypertensives, particularly in those with low plasma renin activity (LRH) who demonstrate body fluid volume expansion. An increased natriuretic response to exogeneously administered DA is found, particularly in LRH, and suppressed biosynthesis of DA from L-dopa in the kidney has been suggested. Furthermore, this suppression of renal dopaminergic activity was also observed in young normotensive subjects with an apparent family history of hypertension before any evidence of hypertension emerged. From these findings, it is concluded that the decrease in renal dopaminergic activity is involved, at least in part, not only in the pathophysiology of essential hypertension, but also in the pathogenesis of this disease.

Detection of impaired fatty acid metabolism and dyskinesis in hypertrophic cardiomyopathy with iodine-123-BMIPP.

Metabolic imaging using 123I-labeled 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) and Fourier phase analysis of gated blood-pool data were performed in a 60-yr-old woman with idiopathic hypertrophic cardiomyopathy. Dyskinetic wall motion was identified as a markedly delayed phase angle in the left ventricular apex, which was well perfused but highly hypertrophied like other ventricular segments. Fatty acid imaging, however, clearly demonstrated highly reduced activities in the apex, although there were no abnormalities in regional systolic function or in 201TI uptake in other hypertrophied regions. Contrast left ventriculography revealed a midventricular collapse of the left ventricle at end-systole due to markedly hypertrophied ventricular walls and dyskinesis at the apex. Thus, dyskinetic wall motion in the apex closely correlated not only with cardiac hypertrophy but also with impaired fatty acid uptake. These findings were unrelated to the myocardial perfusion state per se. Fatty acid imaging using BMIPP may contribute to the detection of myocyte degeneration not visible using conventional imaging modalities. It may also provide etiological information on regional dysfunction in hypertrophic cardiomyopathy.

Role of renal dopaminergic activity on renal sodium-water metabolism in congestive heart failure.

1. The role of the renal dopaminergic system in water-sodium metabolism in heart failure remains unclear. 2. In this study, the urinary free dopamine excretion (uDA), delivery of L-dopa to renal proximal tubules (plasma L-dopa x creatinine clearance (Ccr)), and the production of dopamine in the kidney [uDA/(plasma L-dopa x Ccr)] were investigated in patients with congestive heart failure (n = 30) and in normal controls (n = 12). In both groups, endogenous Ccr, urinary excretion of sodium (UNaV), fractional excretion of sodium (FENa), plasma noradrenaline concentration (pNA) and plasma L-dopa concentration were also estimated. 3. uDA, plasma L-dopa, delivery of L-dopa and dopamine production in the kidney showed successively lower values in congestive heart failure with progression in NYHA functional class. 4. UNaV (r = 0.458, P < 0.05) and Ccr (r = 0.539, P < 0.01) positively correlated with uDA. Linear correlations were found between left ventricular ejection fraction and uDA (r = 0.574, P < 0.01), pNA (r = -0.495, P < 0.01) or plasma L-dopa (r = 0.423, P < 0.05). 5. From these findings, it was suggested that (i) uDA was clearly suppressed in patients with CHF, and (ii) the possible mechanisms of its suppression might be due to decrease of delivery of L-dopa into the proximal tubules and suppressed production of dopamine from L-dopa in the kidney.