Estimation of pesticide runoff from paddy fields to rural rivers.

The runoff characteristics of pesticides from paddy fields to rural rivers were investigated over a period of three years in Hokkaido Prefecture, Japan. High pesticide concentrations were usually observed in rivers during pesticide application periods. In one year, the growth of rice seedlings slowed down after transplantation owing to low temperatures and lack of sunshine, and many farmers delayed herbicide application. In that year, high-concentration runoff of herbicides in rivers was observed 1-3 weeks later than in average years. The pesticide runoff rates ranged from 0.3% for fenthion to 42% for benfuresate. The runoff rates of pesticides applied post-flood were large. Furthermore, the larger the water solubility of the pesticide, the larger the runoff rate. The highest concentrations of herbicides in paddy water were observed on the day of application or 1-2 days later, and the concentrations decreased exponentially afterwards. The half-lives of the herbicides ranged from 1.2 days for pretilachlor and esprocarb to 5 days for simetryn; the concentrations of the herbicides in paddy water had decreased to 1/10 of their initial concentrations by about 7 days after application. Therefore, the runoff amounts of pesticides from paddy fields could be decreased by improving irrigation-water management.

Runoff characteristics of particulate pesticides in a river from paddy fields.

Runoff characteristics of particulate pesticides from paddy fields have been intensively observed in the Koise River in Japan. The 8 pesticides that are applied to paddy fields were analyzed in both particulate and dissolved forms. The concentrations and the detection frequencies of particulate pesticides were lower than those of dissolved pesticides. The particulate pesticide concentrations in the river water were evaluated based on the soil sorption coefficient, particulate organic carbon concentration, and dissolved pesticide concentrations. The particulate pesticide concentrations in the river were higher than evaluated concentrations because the paddy soil contained more pesticides than did suspended solids in the river water discharged during rain events, and because the desorption rates of pesticides were slow. In observations made during rains, the particulate pesticide concentrations increased with the increases in both the discharge rate and the concentrations of suspended solids. The particulate loading was slight compared with dissolved loading, but particulate pesticides may be influenced by enclosed areas such as a lake or estuary because under such conditions particulate matter settles vertically and the pesticide decomposition rate in sediment is slow compared with that in water.

Left ventricular mass relates to average systolic blood pressure, but not loss of circadian blood pressure in stable hemodialysis patients: an ambulatory 48-hour blood pressure study.

Although left ventricular hypertrophy (LVH) is a common complication which contributes substantially to high cardiovascular mortality and morbidity in end-stage renal failure, whether changes in blood pressure and alterations of circadian variation of blood pressure occur between the hemodialysis (HD) day and the interdialytic day, and if so, whether they influence the left ventricular mass (LVM) remain unknown. Thirty-five consecutive stable patients who had had a hematocrit value greater than 25% for the previous 6 months, who had been on the same antihypertensive drugs during this period, and who underwent HD 3 times a week were included. Echocardiograms were recorded after HD and then ambulatory blood pressure monitoring was recorded every hour for 48 h. The mean interdialytic body weight gain was less than 5% of dry weight. Patients with LVH had a higher average systolic blood pressure (SBP) at predialysis, postdialysis, on the HD day and on the interdialytic day than those without LVH despite the higher antihypertensive therapy rate. The majority of patients with LVH showed concentric hypertrophy and higher plasma natriuretic peptide levels. Irrespective of the presence of LVH, the average blood pressure value did not change between the HD day and the interdialytic day, and a loss of circadian blood pressure variation was observed on both the HD and interdialytic days. Univariate analysis revealed that LVM was significantly correlated with the average SBP at predialysis, postdialysis, on the HD day, on the interdialytic day and over 48 h (r= 0.48, r=0.61, r=0.67, r=0.67, r=0.73, respectively; all p<0.05). Multiple regression analysis revealed that 48-h SBP was independently associated with the LVM index. These results suggest that neither the loss of circadian blood pressure variation nor the changes of blood pressure between the HD and interdialytic days was of major etiologic importance in the development of LVH, and that the absolute value of the 48-hour average SBP may be an important risk factor for concentric LVH in stable HD patients.

Measurement of serum low density lipoprotein-cholesterol in patients with hypertriglycemia.

Low density lipoprotein-cholesterol (LDL-c) concentration measured by a homogeneous enzymatic assay was reported to correlate well with the modified beta-quantification assay, especially in samples with high triglyceride (TG) concentration. In this study, we evaluated a homogeneous enzymatic assay, Cholestest-LDL assay system, in hypertriglycemic patient samples, and found that 56% (9/16) of serum samples with intermediate TG concentrations (2.27-4.52 mmol/L) showed more than 10% discrepancy with concentration by the modified beta-quantification assay. Such serum samples originated from patients with hyperglycemia of type II a (three cases), type II b (two cases), type III (one case), and type IV (six cases). Differential staining of cholesterol and triglyceride after agarose gel electrophoresis revealed that these serum samples contained significant amounts of intermediate fractions between pre-beta- and beta-lipoproteins. Since lipoprotein (a), which migrates between pre-beta- and beta-lipoproteins, is not correlated with the discrepancy, we believe the intermediate fraction consists of intermediate density lipoprotein (IDL) and a chylomicron remnant. A part of IDL and chylomicron remnant, which contain a significant amount of triglyceride, might be measured as LDL-c by the homogeneous enzymatic assay, but not by the modified beta-quantification assay.

Long-term inhibition of renin-angiotensin system sustains memory function in aged Dahl rats.

The Dahl salt-sensitive (DS) rat, a genetic model of salt-induced hypertension in humans, is more likely to develop severe vascular injuries than a rat with spontaneous hypertension. We designed an experiment to scrutinize the effects of renin-angiotensin inhibition on cognitive dysfunction in the aged, normotensive DS with a passive avoidance test. Eighteen months of treatment with a very low dose of the angiotensin-converting enzyme (ACE) inhibitor cilazapril (2.5 microg/mL in drinking water) or the angiotensin II type 1 receptor antagonist E4177 did not reduce blood pressure throughout the experiment, although in the low dose cilazapril group (12.5 microg/mL in drinking water), blood pressure dropped within 6 months after treatment began. The cilazapril treatments dose-dependently improved memory function in the aged, normotensive DS fed a low-salt diet compared with the untreated, control rats. This improvement was associated with significant increases in hippocampal CA1 cells and capillary densities in the CA1 regions compared with those in the untreated DS. Similarly, E4177 slightly improved the memory dysfunction observed in the aged DS. The cells in the hippocampal CA1 region were restored slightly, but the capillary densities were not influenced by the receptor antagonist. On the other hand, the ACE inhibitor and receptor antagonist both attenuated urinary protein excretions with an improvement of glomerular sclerosis. These data suggest that long-term treatment with an ACE inhibitor improves memory dysfunction probably through restoration of capillary and hippocampal cells. The effects are due to the inhibition of the angiotensin II type 1 receptor and probably to the enhancement of the kallikrein-kinin system.

Amlodipine, a long-acting calcium channel blocker, attenuates morning blood pressure rise in hypertensive patients.

1. The effects of once-daily calcium channel blockers with different plasma half-lives on diurnal blood pressure changes were examined in hypertensive patients. 2. Patients with essential hypertension, nine men and 13 women aged 61 +/- 2 years, were treated with amlodipine or nitrendipine in a random cross-over design for 12-16 weeks each. The study drugs were given once daily as monotherapy (n = 8) or in combination with other classes of antihypertensive drugs (n = 14). The plasma half-life of amlodipine is as long as 36 h, while that of nitrendipine is 10 h. At the end of each treatment period, 24 h ambulatory blood pressure and pulse rate were monitored. 3. Average office blood pressure was comparably controlled below 140/90 mmHg by either amlodipine or nitrendipine, both in the monotherapy and the combination therapy groups; however, pulse rate was greater in nitrendipine than in amlodipine either in the monotherapy (by 6 b.p.m., P < 0.05) or in the combination therapy (by 5 b.p.m., P < 0.01). 4. In 24 h blood pressure monitoring, morning (05.30-09.00 h) blood pressure was higher in nitrendipine than in amlodipine by 6/4 mmHg in the monotherapy (P < 0.05) and by 7/5 mmHg in the combination therapy (P < 0.03), although the blood pressure in the remainder of the 24 h did not differ between the two treatment periods. In addition, pulse rate in the daytime (09.30-18.00 h) was greater in nitrendipine than in amlodipine by 6 b.p.m. in the monotherapy (P < 0.01) and by 7 b.p.m. in the combination therapy (P < 0.02). 5. These results suggest slow pharmacokinetics of amlodipine provides an advantage in controlling morning blood pressure and mitigating reflex activation of the sympathetic nervous system.

High salt intake potentiates the renal vascular and glomerular damage caused by low doses of angiotensin II in uni-nephrectomized rats.

OBJECTIVE: We recently reported that the renin-angiotensin system plays an important role in the progression of vascular and kidney injuries, even in Dahl salt-sensitive rats with volume-dependent hypertension. In this study, we investigated whether a high-salt diet increases susceptibility to kidney injury induced by angiotensin II in normotensive, uni-nephrectomized Sprague-Dawley rats, which mimics the condition of salt-volume repletion and blunted renin-angiotensin system. METHODS: The rats were fed either a low-salt (0.3% NaCl) or a high-salt (4% NaCl) diet and divided into five groups: two control groups with a low-salt or a high-salt diet without angiotensin II infusion (saline infusion), and three angiotensin II groups (angiotensin II infusion, 10 or 50 ng/kg per min with high-salt diet, 50 ng/kg per min with low-salt diet, subcutaneously). The rats were kept on these regimes for 8 weeks. The blood pressure was measured every week. Functional and morphological alterations in the kidney were assessed at the end of the experiment RESULTS: There were no differences in the arterial blood pressures of the five experimental groups. However, angiotensin II infusion increased the weights of the heart and aortic walls in a dose-dependent manner in the high-salt groups. There was also a dose-dependent increase in proteinuria, N-acetyl-beta-D-glucosaminidase activity (NAG) excretion, and additional glomerular and arterial injuries in the kidney, associated with angiotensin II infusion in the high-salt groups. In the rats given a higher dose of angiotensin II, the high-salt diet significantly increased the weights of the heart and aortic walls and exacerbated the renal function and morphological injuries, compared to the low-salt group. High-salt diet alone increased the kidney and heart weights. However, it did not significantly influence the results of the morphological and functional study. On the other hand, angiotensin II infusion on a low-salt diet showed a trend towards glomerular damage; however, the effects were small and not significant. Similarly, there were few effects of angiotensin II infusion on morphology and functional study on a low-salt diet CONCLUSION: These data clearly show that a high-salt intake increases susceptibility of the kidney to injuries induced by low doses of angiotensin II in normotensive, uni-nephrectomized rats.

Angiotensin II subtype-1 receptor antagonists improve hemodynamic and renal changes without affecting glucose metabolisms in genetic rat model of non-insulin-dependent diabetes mellitus.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether treatment with an angiotensin II (ANGII) subtype-1 receptor antagonist delays the onset of NIDDM and attenuates diabetic nephropathy in the OLETF rat. OLETF rats fed a regular chow were treated with ANGII subtype-1 receptor antagonists (E4177 or TA606) for 22 weeks. Hemodynamic changes, glucose metabolism, and the effects on diabetic nephropathy were examined. Systolic blood pressure increased in OLETF rats in an age-dependent manner. OLETF rats exhibited increases in plasma concentrations of glucose and insulin and developed glucosuria at the age of 28 weeks. The changes in glucose metabolism were associated with proteinuria and an increase in urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG). Morphologic investigation revealed nodular lesions in glomeruli in the OLETF rats. The ANGII receptor antagonist treatment abolished the blood pressure elevation. However, the treatment did not affect plasma glucose and insulin levels and did not significantly reduce glucosuria. Nodular lesions in glomeruli were not improved by the treatment. However, the receptor antagonists significantly reduced proteinuria and urinary NAG excretion. Multivariate analyses revealed that proteinuria was determined by systolic blood pressure, lipid metabolism, and glucose levels in plasma. ANGII subtype-1 antagonism does not improve glucose metabolism in the OLETF rat model of NIDDM, which has abnormalities in the glucose-uptake system. Blood pressure elevation and part of the proteinuria associated with NIDDM depends on the renin-angiotensin system rather than glucose metabolisms per se.

Regression of glomerular injury by kallikrein infusion in Dahl salt-sensitive rats is a bradykinin B2-receptor-mediated event.

AIMS: We investigated whether kallikrein infusion attenuates renal injury in Dahl salt-sensitive rats with hypertension and assessed the role of bradykinin-nitric oxide axis in the renal protection using HOE-140, the bradykinin type-2 (B2) receptor specific antagonist. METHODS: Subdepressor dose of purified rat urinary kallikrein (RUK) (400 ng/day) was continuously infused through the jugular vein by an osmotic mini-pump for 4 weeks in Dahl salt-sensitive (Dahl S) rats fed a high-salt (2% NaCl) diet. RESULTS: Blood pressure increased in a time-dependent manner in Dahl S rats fed a high-salt diet. The RUK infusion did not influence the elevation of blood pressure in Dahl S rats. However, the RUK infusion significantly decreased urinary protein excretion, and increased glomerular filtration rate, as compared with untreated high-salt Dahl S rats. Morphological investigation disclosed that the RUK infusion significantly attenuated glomerulosclerosis and arterial and tubular injuries in the kidney of hypertensive Dahl S rats. The RUK infusion produced an increase in urinary excretions of nitric oxide and cyclic guanosine monophosphate. In addition, the RUK infusion enhanced the generation of nitric oxide from the kidney slices. The functional and morphological effects of the RUK infusion on the kidney were completely lessened by co-administration of the bradykinin B2-receptor antagonist, HOE-140. CONCLUSION: Long-term infusion of subdepressor dose of rat urinary kallikrein attenuates functionally and morphologically the progression of renal injury in Dahl rats susceptible to salt-induced hypertension, and that the protection is mediated by stimulation of bradykinin B2 receptor.

Comparison between cilnidipine and nisoldipine with respect to effects on blood pressure and heart rate in hypertensive patients.

Cilnidipine is a new and unique 1,4-dihydropyridine calcium antagonist that has both L-type and N-type voltage-dependent calcium channel blocking actions. We compared the effects of cilnidipine and another once-daily dihydropyridine calcium antagonist, nisoldipine, on 24-h blood pressure and heart rate in patients with essential hypertension. We enrolled 10 hypertensive outpatients [9 men and 1 woman; age, 55+/-3 yr (means+/-SEM)] in this study. Their ambulatory blood pressure and heart rate were monitored for 24 h at intervals of 30 min with a portable recorder (TM-2425) after 8 wk of treatment with cilnidipine (5 to 20 mg once daily) and after 8 wk of treatment with nisoldipine (5 to 20 mg once daily). The order of the two treatments was randomized. Blood pressure and heart rate measurements for a 24-h period were analyzed for four segments of the day: morning (06:00 to 11:30), afternoon (12:00 to 17:30), nighttime (18:00 to 23:30), and sleeping time (0:00 to 5:30). Blood pressure levels were similar during the two treatment periods for each 6-h segment of the day. Heart rate was significantly higher during treatment with nisoldipine than during treatment with cilnidipine in the morning segment [by 4.1+/-1.3 beats/min (p < 0.05)] and the afternoon segment [by 6.4+/-3.6 beats/min (p< 0.05)]. These results suggest that cilnidipine is effective as a once-daily antihypertensive agent and causes reflex tachycardia less than does nisoldipine.

Comparison of 24-hour blood pressure, heart rate, and autonomic nerve activity in hypertensive patients treated with cilnidipine or nifedipine retard.

We compared the effects of cilnidipine and nifedipine retard on 24-h blood pressure (BP), heart rate (HR), and autonomic nerve activity in patients with essential hypertension. Cilnidipine is a novel and unique 1,4-dihydropyridine calcium antagonist that has the L-type and N-type voltage-dependent calcium channel-blocking action. Fourteen hypertensive outpatients (four men and 10 women; aged 64 +/- 2 years, mean +/- SEM) were enrolled in this study. Their ambulatory BP and electrocardiogram were monitored for 24 h at intervals of 30 min with a portable recorder after a 4-week drug-free period, after a 4-week treatment period with cilnidipine (5 or 10 mg once daily), and after a 4-week treatment period with nifedipine retard (10 or 20 mg twice daily). The order of the three periods was randomized. Autonomic nerve activity was evaluated by a power spectral analysis of HR variability, by using the high-frequency (HF) component as an index of parasympathetic nerve activity and the ratio of the low-frequency (LF) component to the HF component (LF/HF) as an index of sympathovagal balance. Cilnidipine and nifedipine retard significantly reduced the 24-h BP of these patients to similar extents (cilnidipine, -11 +/- 3/-6 +/- 1 mm Hg; nifedipine retard, -15 +/- 3/-6 +/- 2 mm Hg). Cilnidipine did not change the 24-h average HR, whereas nifedipine retard significantly increased it (+3.3 +/- 1.4 beats/min; p < 0.05). Nifedipine retard significantly increased the LF/HF ratio in the daytime and the nighttime. Such changes were limited to the daytime in the treatment period with cilnidipine. These results suggest that cilnidipine is effective as a once-daily antihypertensive agent and had less influence on autonomic nervous system and HR than did nifedipine retard.

Angiotensin-Converting Enzyme Inhibition Delays Onset of Glucosuria With Regression of Renal Injuries in Genetic Rat Model of Non-Insulin-Dependent Diabetes Mellitus.

BACKGROUND: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether angiotensin inhibition influences the onset of NIDDM and brings about a regression of renal injury in diabetes mellitus. METHODS AND RESULTS: Six-week-old OLETF rats were treated with the angiotensin-converting enzyme (ACE) inhibitors imidapril or enalapril for 16 weeks. Systolic blood pressure is increased in an age-dependent manner in OLETF rats. In this study, the elevation in systolic blood pressure was dose-dependently reduced by ACE inhibitor treatment. In OLETF rats, plasma concentrations of insulin and glucose increased and the glucosuria occurred at the age of 22 weeks. Simultaneously, OLETF rats exhibited proteinuria and nodular lesions in glomeruli. The ACE inhibitor treatment almost completely reduced glucosuria, and also decreased plasma concentrations of insulin and glucose in OLETF rats. ACE inhibitor treatment lessened the proteinuria and attenuated morphologically the severity of nodular lesions in OLETF rats. Moreover, increases in plasminogen activator inhibitor 1 (PAI-1) in OLETF rats were reduced by the ACE inhibitor treatment, and the improvement of glomerular lesions was related to decreases of PAI-1 and angiotensin II levels in plasma but not to improvement of glucose metabolism. CONCLUSIONS: ACE inhibitors delay onset of NIDDM with attenuation of kidney injury. The regression of kidney lesions is probably due to angiotensin reductions but not to glucose metabolism per se. ACE inhibitor drug therapy may be useful in preventing NIDDM and the subsequent renal injury in patients with NIDDM.

Serum N-acetyl-beta-D-glucosaminidase activity in a genetic rat model of non-insulin-dependent diabetes mellitus.

Serum N-acetyl-beta-D-glucosaminidase activity (NAG) is a possible predictor of vascular injury in hypertension. We assessed whether the activity of this enzyme reflects vascular damage in a genetic rat model of non-insulin-dependent diabetes mellitus (NIDDM) in humans. Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a regular chow were treated with the angiotensin converting enzyme (ACE) inhibitor imidapril for 16 wk. Systolic blood pressure increased in a time-dependent manner in the untreated OLETF rats as compared with that in the control Long-Evans Tokushima (LET) rats. The blood pressure elevation was associated with increases in cardiac and aortic weight. Imidapril treatment significantly attenuated the blood pressure elevation and reduced the increases in cardiac and aortic weight. The untreated OLETF rats had higher plasma glucose and insulin concentrations than did the LET rats and presented with glucosuria at the age of 22 wk. Imidapril treatment strikingly decreased plasma glucose levels and the glucosuria. Plasma insulin concentrations decreased, approaching those of the non-diabetic control LET rats. ACE inhibitor treatment attenuated the nodular lesions in the glomeruli of OLETF rats and improved the kidney function. Serum NAG activity increased significantly by 35% in the untreated rats; this increase was attenuated significantly by imidapril treatment. The reduction in serum NAG activity correlated with improvement in cardiovascular injury. In contrast, there were no changes in urinary NAG excretion in the three OLETF rat groups. In addition, NAG excretion did not correlate with indices of cardiovascular injury. These data suggest that serum NAG activity is useful in predicting injury in the cardiovascular system in rats with diabetes mellitus.

Long-term infusion of kallikrein attenuates renal injury in Dahl salt-sensitive rats.

We investigated whether long-term infusion of kallikrein would attenuate renal injury in salt-induced hypertension in Dahl salt-sensitive (Dahl S) rats. A subdepressor dose of purified rat urinary kallikrein (RUK) (700 ng/day) was infused intravenously by an osmotic minipump for 4 weeks in male Dahl S rats fed a high-salt (2% NaCl) diet. This dose did not affect the time-dependent elevation of blood pressure. However, urinary protein excretion was significantly decreased, and the glomerular filtration rate was increased. These beneficial effects were reflected morphologically by an attenuation of the glomerulosclerotic lesions and tubular injury seen in the hypertensive Dahl S rats. The kallikrein infusion increased the urinary excretion of bradykinin and stimulated the excretion of cyclic GMP, suggesting that the kallikrein-kinin-prostaglandin and nitric oxide axes were enhanced by the RUK infusion. The alterations induced by such infusion were potentiated by the concomitant administration of the angiotensin converting enzyme inhibitor alacepril. These studies indicated that long-term replacement with rat tissue kallikrein attenuates renal injury in hypertensive Dahl S rats, and this is probably mediated by an enhanced function of the kallikrein-kinin-prostaglandin and nitric oxide systems.

The implication of renin-angiotensin system on renal injury seen in Dahl salt-sensitive rats.

Angiotensin II (Ang II) progresses to remodeling of the cardiovascular system through nonhemodynamic as well as hemodynamic effects. There have been few data in vivo on whether subpressor concentration of Ang II is exerted to injure directly the cardiovascular system in hypertension. To test this hypothesis, we investigated, using Dahl salt-sensitive (Dahl S) rats, whether subpressor dose of Ang II progresses to cardiovascular injury observed in salt-induced hypertension. Recent studies have provided evidence that renin-angiotensin inhibition protects against renovascular injury in human hypertension as well as in experimental animals. Particularly in the case of Dahl salt-sensitive rats, a genetic model of volume-dependent hypertension in humans, they are likely to develop more severe arterial and renal injuries than those seen in spontaneously hypertensive rats with similar blood pressure levels. The mechanism of the susceptibility to hypertensive injuries is uncertain; however, renin-angiotensin inhibition significantly improved morphologic and functional injuries in the kidney of Dahl S rats. Conversely, subpressor dose of Ang II infusion exacerbated renal function and progressed to glomerulosclerotic lesions. Alterations of Ang II concentration in physiologic range influenced morphologic and functional injuries in Dahl S rats. Multivariate analysis revealed that activity of the renin-angiotensin system is an independent risk factor to glomerular injury in salt-induced hypertension. These data are in favor of the therapeutic strategy in human hypertension that inhibition of renin-angiotensin system is of value to produce beneficial effects of blood pressure reduction on organ injuries.

Thromboxane inhibition potentiates antihypertensive effects of alpha 1 adrenoceptor antagonists in the rat.

We investigated the influence of the vascular and renal thromboxane system on the antihypertensive effects of the alpha 1 adrenoceptor antagonist (alpha 1 blocker) bunazosin in spontaneously hypertensive rats (SHR). SHR were treated for 2 weeks with the alpha 1, blocker bunazosin (0.5 mg/kg body weight/day). The systolic blood pressure immediately declined with bunazosin treatment, and then rose toward the level observed in untreated SHR. This antihypertensive effect was accompanied by a decrease in the ratio of prostacyclin to thromboxane A2 in the vascular wall and the kidney. A subdepressor dose of the thromboxane synthase inhibitor OKY-046 lessened the thromboxane generation during bunazosin treatment, and synergistically potentiated the antihypertensive action of the alpha 1 blocker. Such synergy was also observed between OKY-046 and prazosin, an alternative alpha 1 blocker, but not with amosulalol, an alpha 1 blocker having no quinazoline moiety. alpha 1 blockers with a quinazoline moiety dose-dependently stimulate thromboxane generation in cultured smooth muscle cells from SHR. These data indicate that alpha 1 blockers enhance thromboxane generation in the arterial wall and kidney, thereby contributing to the lessening of the antihypertensive effects observed during alpha 1 blocker treatment.

Endothelin-mediated effect of erythropoietin on blood pressure and renal hemodynamics in hypertensive rats.

Erythropoietin (EPO) has been reported to induce hypertension in hemodialysis patients with family history of hypertension. In this study, to reveal the mechanism of EPO-induced hypertension, we examined the acute effect of EPO on blood pressure (BP) and renal hemodynamics in genetically hypertensive rats, and we also tested the effect of BQ-123, an endothelin ETA-receptor blocker, on EPO-induced changes in hemodynamics. Male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY), aged 9-12 wk, were anesthetized, and BP was monitored through the carotid artery. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured before and after an intravenous injection of EPO (1,000 U/kg body wt). In another group of SHR, BQ-123 was continuously infused (1.2 mg.kg body wt-1.h-1) during the experiments. The acute injections of EPO increased BP significantly in SHR in a dose-dependent manner, whereas WKY did not show a significant increase in BP after EPO injections. The effect of EPO on BP in SHR was blocked by BQ-123. In SHR, an acute injection of EPO decreased RPF significantly (from 1.78 +/- 0.16 to 1.49 +/- 0.18 ml.min-1.100 g body wt-1, P < 0.05) without a change in GFR, whereas WKY did not show significant changes in either RPF or GFR. The effect of EPO on RPF in SHR was completely blocked by BQ-123 (from 1.92 +/- 0.26 to 1.88 +/- 0.28 ml.min-1.100 g wt-1, NS). EPO caused a significant increase in plasma endothelin ET-1 in SHR (from 2.3 +/- 0.6 to 6.3 +/- 1.6 pg/ml, P < 0.05), but not in WKY. In conclusion, acute administration of EPO raised blood pressure and reduced RPF in SHR, and these vasoconstrictive effects of EPO are mediated via ETA receptors by an enhanced ET-1 release.

Hachimi-jio-gan extract protects the kidney from hypertensive injury in Dahl salt-sensitive rat.

We investigated whether the Chinese herbal remedy, Hachimi-jio-gan extract, attenuates the renal injury seen in salt-induced hypertension in Dahl salt-sensitive (Dahl S) rats. Administration of this extract for 5 weeks dose-dependently decreased systolic blood pressure in Dahl S rats fed with a high-salt (2% NaCl) diet. This blood pressure reduction was associated with a decrease in cardiac mass and in thickness of the aortic wall. Urinary excretion of prostaglandin E2 was increased and glomerular filtration rate was improved with this treatment. Glomerulosclerosis and arterial injury in the kidney were morphologically improved. These data suggest that Hachimi-jio-gan extract exhibits an antihypertensive effect, which is associated with partial resolution of renal injury in salt-induced hypertension.

Hydrochlorothiazide Increases Efferent Glomerular Arteriolar Resistance in Spontaneously Hypertensive Rats.

BACKGROUND: Micropuncture studies were performed to determine the intrarenal hemodynamic effects of two conventional antihypertensive agents, hydrochlorothiazide (HCTZ) and hydralazine (HYDR) alone and in combination. METHODS AND RESULTS: Male spontaneously hypertensive and normotensive Wistar Kyoto rats (19 weeks old) were treated for 3 weeks with vehicle (control), HCTZ (80 mg/kg/d), HYDR (5 mg/kg/d), or combined therapy (HCTZ 30 mg/kg/d and HYDR 2 mg/kg/d). Each treatment significantly reduced arterial pressure while effective renal plasma flow, glomerular filtration rate and single nephron glomerular filtration rate were unaffected by any treatment in either strain. In spontaneously hypertensive rats HCTZ decreased single nephron plasma flow (111 +/- 8 to 84 +/- 4 nL/min; P <.05) but, despite this reduction, glomerular pressure remained unchanged (51.4 +/- 0.7 to 52.1 +/- 0.8 mmHg) attributable to increased efferent glomerular resistance (1.58 +/- 0.14 to 2.11 +/- 0.12 10 U; P <.05). By contrast, HYDR increased single nephron plasma flow (to 147 +/- 8 nL/min; P <.01) and decreased efferent glomerular resistance (to 1.09 +/- 0.09 U; P <.05). Combined treatment produced responses similar to HCTZ when used alone, thereby nullifying the beneficial efferent glomerular resistance effects: single nephron plasma flow +/- fell (to 89 +/- 7 nL/min; P <.05) and efferent glomerular resistance increased (to 2.05 +/- 0.17 U; P <.05). In Wistar Kyoto rats, HCTZ and combined treatment had no effect. HCTZ alone induced glomerular ischemia that was associated with efferent glomerular arteriolar constriction in these spontaneously hypertensive rats. CONCLUSIONS: These findings provide a possible explanation for the lack of improved renal target-organ damage in controlled multicenter trials employing thiazide diuretics.

Successful erythropoietin treatment for severe anemia in nephrotic syndrome without renal dysfunction.

A 62-year-old woman presented with nephrotic syndrome and severe anemia although the renal function was not impaired. Renal biopsy revealed the histology of membranoproliferative glomerulonephritis, and the proteinuria was resistant to steroid therapy. Iron deficiency, bleeding and other causes of anemia were ruled out, however, her serum erythropoietin level was inappropriately low. The anemia was rapidly corrected by administration of recombinant human erythropoietin. It is suggested that inappropriately low erythropoietin level, in part at least, accounts for the anemia in nephrotic syndrome. It is proposed that erythropoietin therapy should be taken into consideration for severe anemia in nephrotic syndrome even when the renal function is not impaired.