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.

Antihypertensive effect of interleukin-2 in salt-sensitive Dahl rats.

We investigated the effects of interleukin-2, which stimulates the proliferation and maturation of thymus-derived lymphocytes, on hypertension and organ injuries in genetically hypertensive rats. Interleukin-2 (5 x 10(4) U/kg body wt) was subcutaneously injected into Dahl salt-sensitive rats fed a 4% NaCl diet and spontaneously hypertensive rats once a week for 10 weeks. The effects on blood pressure, cardiovascular hypertrophy, and renal function were evaluated. Interleukin-2 treatment lowered blood pressure in Dahl salt-sensitive rats (162 versus 187 mm Hg, P < .005). This antihypertensive effect was associated with an increase in glomerular filtration rate (589 versus 428 mL/d per 100 g body weight, P < .005) and reduction in cardiac weight (268 versus 305 mg/100 g body weight, P < .05). Interleukin-2 also alleviated the marked glomerular sclerosis in Dahl salt-sensitive rats (glomerular injury score, 151 versus 220; P < .001). In contrast, interleukin-2 did not affect the development of hypertension or organ injuries in spontaneously hypertensive rats. Histologically, glomerular and arterial lesions of the kidney were much less marked in spontaneously hypertensive rats than in Dahl salt-sensitive rats. These data indicate that interleukin-2 ameliorates the development of hypertension and cardiac and renal injuries in Dahl salt-sensitive rats.

Glomerular dynamics and morphology of aged spontaneously hypertensive rats. Effects of angiotensin-converting enzyme inhibition.

Relationships between glomerular dynamics and renal injury, micropuncture and histological studies were assessed in 73 week-old normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats divided into untreated and angiotension-converting enzyme inhibitor-treated (quinapril; 3 mg/kg/day; for 3 weeks) groups. Urinary protein excretion (UPE) and histologic arteriolar (AIS) and glomerular (GIS) injury scores were determined. Mean arterial pressure (MAP) of untreated SHR was increased compared with WKY (200 +/- 6 vs 119 +/- 4 mm Hg; P < 0.01), effective renal plasma flow (ERPF) was reduced (1.47 +/- 0.21 vs 3.06 +/- 0.26 ml/min/per g; P > 0.01), and filtration fraction (FF) and total renal vascular resistance (RVR) of SHR were increased (P < 0.01). Single-nephron plasma flow (SNPF) of untreated SHR was decreased (174 +/- 17 vs 80 +/- 9 ml/min; P < 0.01), and single-nephron filtration fraction and afferent arteriolar resistance (RA) were increased (19.4 +/- 1.8 vs 30.0 +/- 2.5% and 1.90 +/- 0.25 vs 9.05 +/- 1.35 U, respectively; both P < 0.01). Despite reduced SNPF, glomerular capillary pressure (PG) increased (49.7 +/- 0.7 vs 53.8 +/- 1.3 mm Hg; P < 0.05), the result of efferent arteriolar constriction (1.15 +/- 0.18 vs 2.84 +/- 0.36 U; P < 0.01). Untreated SHR had higher UPE (13.9 +/- 1.5 vs 42.8 +/- 3.2; mg/100 g per day; P < 0.01) and GIS and AIS scores than WKY (4.3 +/- 1.1 vs 64.3 +/- 8.4 and 16.6 +/- 3.1 vs 96.3 +/- 14.4; both P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Interferon gamma attenuates hypertensive renal injury in salt-sensitive Dahl rats.

Evidence has been provided that the immunological mechanism is involved in the genesis or maintenance of hypertension. In the present study, we investigated the effects of interferon gamma, a potent immunomodulator derived from lymphocytes, on hypertension and organ damage in Dahl salt-sensitive rats and in spontaneously hypertensive rats. Subcutaneous injection of interferon gamma (5 x 10(4) units/kg body wt once a week for 10 weeks) reduced blood pressure in Dahl salt-sensitive rats fed a 4% high salt diet (174 versus 194 mm Hg, p less than 0.025). This blood pressure reduction was associated with an improvement of renal functions, an increase in glomerular filtration rate (690 versus 569 ml/day/100 g body wt, p less than 0.05), and decreases in urinary protein excretion (48 versus 78 mg/day/100 g body wt, p less than 0.025) and urinary N-acetyl-beta-D-glucosaminidase excretion (143 versus 183 milliunits/day/100 g body wt, p less than 0.05). Morphological investigation showed a marked resolution of the vascular injuries seen in untreated Dahl salt-sensitive rats, e.g., intimal and medial hyperplasia, with infiltration of inflammatory cells, and significant amelioration of the glomerular sclerotic changes. In contrast, interferon gamma affected neither blood pressure nor renal functions in spontaneously hypertensive rats. These data indicate that interferon gamma ameliorates the development of hypertension and vascular and renal injuries in Dahl salt-sensitive rats. The resolution of vascular and renal injuries contributes, in part, to the antihypertensive action of interferon gamma.

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.

Genetic predisposition to hypertension facilitates blood pressure elevation in hemodialysis patients treated with erythropoietin.

PURPOSE: This study investigated the hypothesis that a genetic predisposition to hypertension is involved in the etiology of the elevation in blood pressure induced by human recombinant erythropoietin (rHuEPO). PATIENTS AND METHODS: Blood pressure changes after 10 weeks of treatment with rHuEPO were compared between 26 patients with a positive family history of hypertension and 27 with a negative family history. RESULTS: Mean blood pressure was significantly increased in patients with a positive family history of hypertension (+8.8 mm Hg, p < 0.001). In contrast, the change was not significant in those whose family history was negative (+1.8 mm Hg, not significant). The mean blood pressure of 14 of 26 patients with a positive family history of hypertension increased by more than 10%, whereas such an increase occurred in only 2 of 27 patients with a negative family history (p < 0.001). The two groups were similar in terms of the total dose of rHuEPO given, the degree to which their anemia improved, and their basal blood pressures. CONCLUSION: It appears that hemodialysis patients with a positive family history of hypertension are susceptible to developing hypertension during treatment with rHuEPO.

Effects of thiazide diuretic on vascular eicosanoid system of spontaneously hypertensive rats.

To assess the role of the vascular eicosanoid system in thiazide therapy, we examined the aortic eicosanoid system of spontaneously hypertensive rats (SHR) treated with trichloromethiazide for 2 weeks. The blood pressure reduction caused by the thiazide treatment was associated with a significant decrease in vascular vasodepressor prostacyclin (PGI2) generation, whereas neither nifedipine nor captopril treatment lowered vascular PGI2 generation. The thiazide diuretic directly lowered PGI2 synthase activity in cultured vascular smooth muscle cells (VSMC), thereby decreasing PGI2 generation in the VSMC and probably in the aortic wall. This direct inhibitory effect on vascular PGI2 generation was not observed with either furosemide or indapamide. Thus, vascular PGI2 generation is reduced with trichloromethiazide, partly through its direct inhibition of PGI2 synthase; this has possible relevance to the non-beneficial effects of thiazide diuretics on the vascular sclerotic changes.

Antihypertensive effects of cicletanine and renal protection in Dahl salt-sensitive rats.

We designed experiments to reveal the antihypertensive properties of cicletanine, a novel antihypertensive drug, in Dahl salt-sensitive (Dahl-S) rats. Cicletanine (39 mg/kg body weight per day for 6 weeks) ameliorated the development of hypertension in Dahl-S rats fed a high-salt (4% NaCl) diet. This blood pressure reduction was associated with a decrease in heart weight and vascular wall thickness. Moreover, urinary prostacyclin (PGl2) excretion was increased with cicletanine treatment, being inversely related to systolic blood pressure. Proteinuria and urinary excretion of n-acetyl-beta-D-glucosaminidase were decreased and glomerular filtration rate was increased with this treatment. Morphological investigation revealed an improvement in glomerulosclerosis, renal tubular damage and intrarenal arterial injury in the salt-induced hypertensive rats. In contrast, trichloromethiazide, which decreased blood pressure to the same extent as cicletanine, lowered urinary PGl2 excretion and generally did not ameliorate the deteriorated renal functions and morphological abnormalities. Thus, these data indicate that cicletanine ameliorates the development of hypertension in Dahl-S rats and protects the cardiovascular and renal systems against the injuries seen in the hypertension. The enhanced vasodepressor PGl2 synthesis probably participates, to some extent, in these beneficial properties of long-term cicletanine treatment.

Inhibition of protein synthesis and antiproliferative effect of the angiotensin converting enzyme inhibitor trandolaprilat in rat vascular smooth muscle cells.

OBJECTIVE: To investigate the effect of the angiotensin converting enzyme (ACE) inhibitor trandolaprilat on vascular smooth muscle cell growth, and to analyse its mechanism of action. DESIGN: Aortic vascular smooth muscle cells (VSMC) from Wistar-Kyoto rats were cultured, and cell proliferation was analysed using a cell synchrony technique. METHODS: Proliferative activity was assessed by [3H]-thymidine uptake and doubling time. Protein synthesis was assessed by [3H]-leucine incorporation. Actin formation was measured using sodium dodecylsulphate-polyacrylamide slab gel electrophoresis and a densitometric assay. The effect of trandolaprilat on translational protein synthesis was also examined using the cell-free protein synthesis system of reticulocyte lysate and messenger RNA from VSMC. RESULTS: Trandolaprilat decreased [3H]-thymidine uptake and increased the doubling time of randomly cycling VSMC. The cell synchrony study revealed that this antiproliferative effect was due to increased transition time from S to G2-M. Decreased cell cycle progression during G2-M was reflected by inhibition of cellular protein synthesis during this period. Cellular protein in randomly cycling VSMC was also decreased by trandolaprilat. This decreased protein synthesis was probably produced by inhibition of RNA translation. CONCLUSIONS: The ACE inhibitor trandolaprilat reduces VSMC proliferation by lengthening the G2-M phase of the cell cycle, and produces a decrease in cellular protein content. This effect is probably mediated by inhibition of protein synthesis at the translational level.

Subpressor dose of angiotensin II increases susceptibility to the haemodynamic injury of blood pressure in Dahl salt-sensitive rats.

OBJECTIVE: To investigate the effects of subpressor doses of angiotensin II (Ang II) on the progression of renal injuries in Dahl salt-sensitive (Dahl-S) rats with hypertension. METHODS: Rats were fed a high-salt (4% NaCl) diet and given an Ang II infusion (10 or 50 ng/kg per min, subcutaneously) for 4 weeks. RESULTS: The plasma Ang II concentration achieved in the high-dose Ang II infusion was lower than that in low-salt (0.3% NaCl) normotensive rats. The Ang II infusion did not affect systolic blood pressure, cardiac hypertrophy or weight of thoracic aorta. However, the high-dose Ang II infusion increased proteinuria by 58%, enhanced the urinary N-acetyl-beta-D-glucosaminase index by 77% and reduced the glomerular filtration rate by 37%. The impaired renal function was associated with a progression of glomerulosclerotic lesions. Neither tubular nor arterial lesions were exacerbated. The infusion did not influence prostacyclin production or urinary cyclic GMP excretion. CONCLUSION: A subpressor dose of Ang II infusion impairs renal function with progression of glomerulosclerosis, and these alterations may be due to increased susceptibility of the glomerulus in Dahl-S rats to Ang II-induced injuries. Such a mechanism might underlie a predisposition to hypertension-induced organ damage seen in Dahl-S rats with salt-induced hypertension.

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.

Possible radical scavenging properties of cicletanine and renal protection in Dahl salt sensitive rats.

Much interest in cicletanine, a novel antihypertensive drug, has grown because it uniquely stimulates prostacyclin (PGI2) production and may, thereby, provide further cardiovascular protection. We postulated that cicletanine may be an antioxidant, and assessed its ability to protect the kidney in Dahl salt-sensitive (Dahl S) rats on a high salt diet. Cicletanine eradicated in vitro a stable radical, DPPH, and decreased the lipid peroxidation both in rat brain homogenate and in a xanthine-xanthine oxidase (X-XOD) superoxide generating system. Furthermore, cicletanine attenuated the inhibition of PGI2 synthase activity by 15HPETE. However, cicletanine did not exhibit superoxide dismutase-like activity in X-XOD system, suggesting that it behaves primarily as a hydroxy radical scavenger. A 6 week cicletanine treatment reduced blood pressure in Dahl S rats fed a high salt diet, and ameliorated functional and morphological injury to the kidney. This attenuation of glomerular sclerosis correlated with the attenuation of lipid peroxidation in the kidney homogenate. These data indicate that cicletanine is an antioxidant that protects the kidney from salt-induced hypertension in Dahl salt-sensitive strain rats.

Possible role of prostacyclin synthase in altered prostacyclin generation in DOCA-salt hypertensive rats.

Prostacyclin (PGI2) synthase is one of the key enzymes for vasodepressor PGI2 biosynthesis in the vascular wall. In this study, we attempted to define the alterations in PGI2 synthase and its role in the PGI2 generation in the vascular wall of deoxycorticosterone acetate (DOCA)-salt rats. The PGI2-generating capacity was enhanced significantly when DOCA-salt rats established hypertension, whereas the generation of other arachidonate metabolites, eg, PGE2, PGF2 alpha, and thromboxane, was unaltered. Moreover, the increase in PGI2 generation was associated with an increase in PGI2 synthase activity in the vascular wall. Indeed, the averaged PGI2 generating capacity was closely correlated to the averaged PGI2 synthase activity in DOCA-salt hypertensive rats and three lines of control rats. Incontrast, phospholipase C and phospholipase A2, both of which liberate arachidonate for PGI2 synthesis, were rather lowered in DOCA-salt hypertensive rats. These data clearly indicate that vascular PGI2 generation is increased in the development of DOCA-salt hypertension and that PGI2 synthase is mainly responsible for this enhancement. The increased PGI2 synthase may be relevant to the blood pressure elevation and is expected to have beneficial effects on the vascular protection in hypertension.

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.

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.

Rapid smooth muscle cell growth and endogenous prostaglandin system in spontaneously hypertensive rats.

Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit rapid cell growth. In this study, to reveal the mechanisms of the quick VSMC growth, we analyzed the alterations in the respective periods of the proliferating cell cycle, and investigated the role of the endogenous prostaglandin system in this rapid cell growth. The VSMC from SHR showed increased [3H]thymidine uptake and shortened doubling time, compared with Wistar-Kyoto rats (WKY). These properties were mainly due to both shortened transition time from G0/G1 to S and shortened G2 duration. There was a difference neither in the DNA-replication rate nor in the mitotic period. Generating capacity for vasodepressor prostaglandins was significantly reduced in the VSMC from SHR, particularly in the G0/G1 period. When the endogenous prostaglandin synthesis was inhibited by 10(-5) mol/L indomethacin, the transition from G0/G1 to S was shortened. This alteration was eliminated by supplementation with OP41483, a stable prostacyclin analog. In contrast, the alteration in the G2 duration was unaffected by indomethacin. These data indicate that the rapid VSMC growth in SHR is mainly due to the shortening of both the G0/G1 and G2 period, and that the impaired prostaglandin system is responsible, at least in part, for the shortened G0/G1 duration.

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.

A new adenosine subtype-1 receptor antagonist, FK-838, attenuates salt-induced hypertension in Dahl salt-sensitive rats.

We investigated the effects of the adenosine type-1 receptor antagonist FK-838 on salt-induced hypertension in Dahl-Sea salt-sensitive (Dahl S) rats. Dahl S rats fed a high-salt (4% NaCl) diet for 4 weeks were treated with FK-838 or hydrochlorothiazide for 4 weeks and alterations in kidney function and morphologic changes were assessed. FK-838 attenuated the development of hypertension in Dahl S rats, and caused a decrease in aortic weight in a dose dependent fashion. The adenosine antagonist did not produce any detectable metabolic disturbance. The blood pressure reduction by FK-838 was associated with attenuation of glomerular and arterial injury in the kidney. The renal protective effect of FK-838 treatment was associated with a reduction of plasma renin activity and plasma aldosterone concentration. In contrast, the thiazide diuretic, which produced almost the same blood pressure reduction as FK-838, did not attenuate renal damage. These data indicate that adenosine A1 receptor antagonism reduces salt-induced hypertension and the consequent renal injuries.

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.

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.