Effect of methyldopa on renal function in rats with L-NAME-induced hypertension in pregnancy.

BACKGROUND: Pregnancy-induced hypertension is characterized by an increased sympathetic activity and probably by a decreased synthesis/activity of nitric oxide. The aim of the present study is to evaluate whether the beneficial action of the sympathetic antagonist methyldopa (a first-choice hypotensive agent in the treatment of PIH) may be associated to changes in nitric-oxide synthesis. METHODS: Forty pregnant Wistar rats received L-NAME (NO synthase inhibitor, 9-10 mg/kg/day) from mid-pregnancy (day 11) through to term. Some rats were treated with daltroban (TxA receptor antagonist, 60 mg/kg/day), diltiazem (calcium channel blocker, 30 mg/kg/day), methyldopa (central adrenergic antagonist, 400 mg/kg/day) or L-arginine (260 mg/kg/day) from mid-pregnancy. The effect of the different treatments on systolic blood pressure (SBP), creatinine clearance (CCR), urine protein excretion (UP) and urinary nitrate excretion (UNO(3), representing urine NO metabolite) were evaluated and the results compared with those found in normal pregnancy. Normal pregnant rats receiving similar treatment were used as controls. RESULTS: In normal pregnant (P) rats, SBP values decreased from 94 +/- 2 to 83 +/- 3 mm Hg at the end of pregnancy (p < 0.01) and CCR augmented significantly. Drug treatment had no significant effect. In NAME-treated rats, at the same period, the SBP augmented from 92 +/- 1 to 129 +/- 1.8 mm Hg (p < 0.01). At the end of pregnancy, NAME rats had significantly lower CCR values and higher UP excretion when compared with P rats. UNO(3) increased significantly in P and in P rats treated with methyldopa. As expected, in NAME rats UNO(3) excretion was significantly reduced. Treatment with methyldopa normalized SBP, improved CCR and proteinuria and was associated with an increase in UNO(3). Similar results were obtained with L-arginine treatment. Diltiazem lowered SBP significantly but had no effect on renal function or UNO(3) and daltroban had no effect. CONCLUSION: The increased UNO(3) found in NAME rats treated with methyldopa suggests that the vasoconstriction secondary to chronic NO inhibition may be partially related to an increased sympathetic activity. The efficient action of the sympathetic antagonist methyldopa may be due not only to its antihypertensive effects but also by its stimulating effect on NO synthesis leading also to an improvement of renal function.

Chronic exogenous hyperinsulinaemia-induced hypertension in pregnant rats: effect of chronic treatment with l-arginine.

Recent studies have shown that maternal hyperinsulinaemia is a risk factor for the development of hypertension in pregnancy. Experimentally, pregnant rats with chronic exogenously induced hyperinsulinaemia (P-INS rats) have increased blood pressure at the end of gestation. This is associated with a blunted elevation of the excretion of the urinary metabolites of nitrate (UNO(x)). In the present study, we aimed to evaluate the mechanism(s) of the increase in blood pressure in this model. Four groups were studied: normal pregnant rats (P rats), P-INS rats, P-INS rats treated with L-arginine (2 g/l in the drinking water) (L-ARG rats) and hyperinsulinaemic virgin rats (V-INS rats). Systolic blood pressure (SBP), UNO(x) excretion (on ingestion of a controlled low-nitrate diet), urine noradrenaline (norepinephrine) and plasma endothelin levels were evaluated. Rats were killed on day 22 of pregnancy. Five P-INS rats were not killed at this time, in order to measure SBP 30 and 60 days after delivery. Fetal number and fetal body weight were evaluated. At the end of pregnancy, a 10+/-3% increase in SBP was found in P-INS rats, contrasting with a fall of -15+/-4% in P rats (P<0.01). In the L-ARG group at the end of pregnancy, SBP values had fallen by -14+/-2%, to values comparable with those of P rats. The increase in UNO(x) excretion was 175+/-38% in P rats, 106+/-12% in L-ARG rats and 41+/-8% in P-INS rats (P<0.01 compared with P and L-ARG groups). No differences were found in the urinary excretion of noradrenaline or in the plasma levels of endothelin-1 between the pregnant groups. Fetal number was similar in all groups, but fetal body weight was lower for P-INS rats compared with P and L-ARG rats. Thus the blood pressure response to L-arginine strongly suggests that a decrease in NO availability may be the main pathogenic mechanism involved in the development of hypertension in this model.

Low molecular weight heparin reduces proteinuria and modulates glomerular TNF-alpha production in the early phase of adriamycin nephropathy.

BACKGROUND/AIM: Heparin has been shown to be renoprotective in a number of experimental nephropathies. The inflammatory component in the early phase of Adriamycin (ADR) induced nephropathy has been established. A microdose of low molecular weight heparin (Fragmin; F) has been noted to exert immunomodulatory effects independent of its anticoagulant activity. We assessed the effects of microdoses of F on daily proteinuria and glomerular production of tumor necrosis factor alpha (TNF-alpha) and prostaglandins 8 and 15 days after induction of ADR nephropathy. METHODS: Following intravenous injection of ADR (7 mg/kg) to Wistar rats weighing 200 +/- 20 g, F 20 microg/day/rat s.c. was administered for 8 and 15 days (groups F8 and F15). The respective control groups (C8 and C15) received normal saline subcutaneously. Proteinuria, serum albumin, and creatinine clearance were evaluated on days 8 and 15. The production of TNF-alpha and prostaglandins from glomerular supernatants was measured by radioimmunoassay on days 8 and 15. RESULTS: F significantly reduced proteinuria (mg/day) on day 8: 13.6 +/- 1.2 in F8 versus 40.3 +/- 2.7 in C8 (p = 0.008). The glomerular production of TNF-alpha (pi/ml) was significantly lower on day 8 in rats treated with F: 356 +/- 33 in F8 versus 764 +/- 81 in C8 (p = 0.006). A decrease in the prostaglandin E2/thromboxane B2 ratio was noted in the F group between 8 and 15 days (1.1 in F8 vs. 0.9 in F15, p = 0.005) which principally reflects an increase of thromboxane B2. The antiproteinuric effect of F shown after 8 days was no longer present after 15 days (354 +/- 91 mg/day in F15 vs. 499 +/- 69 mg/day in C15, p = 0.33). The same trend was seen for the glomerular production of TNF-alpha. Light microscopy and immunohistochemistry for interstitial and glomerular macrophages were negative. CONCLUSION: The lowering effect of microdoses of F on the proteinuria seen during the early phase of ADR nephropathy may be mediated by a decreased production of glomerular TNF-alpha, supporting the anti-inflammatory action of low molecular weight heparin.

Role of thromboxane in the altered vascular reactivity of pregnant rats with adriamycin nephropathy.

BACKGROUND: Pregnant rats with adriamycin nephropathy (ADRP rats) develop hypertension and have an increased vascular reactivity to noradrenaline in the isolated mesenteric bed in vitro. We have shown previously that the administration of daltroban, a specific thromboxane receptor antagonist, prevented hypertension in ADRP rats. METHODS: We measured the effect of daltroban (10(-5) mol/l) on the vasoconstrictory response to noradrenaline (1-10 micromol/l) in the isolated mesenteric bed of ADRP rats at the end of pregnancy, as compared with normal pregnant and adriamycin-treated virgin rats. In further experiments, we measured the changes of flow induced by increasing concentrations of the thromboxane analogue, U46619 (10(-7)-10(-6) mol/l). Finally, changes of flow were assessed in arteries maximally constricted with U46619 (10(-6) mol/l), during perfusion in the presence of increasing concentrations of daltroban (10(-7)-10(-5) mol/l). RESULTS: Daltroban diminished the response to noradrenaline in all groups, shifting the concentration-effect curve to the right. However, at maximal concentrations of noradrenaline, daltroban was ineffective in all rats, except in ADRP animals. The vasoconstrictory response to U46619 was significantly reduced in all pregnant rats, both normal and adriamycin-treated. Daltroban progressively released the vasoconstriction induced by U46619 in all groups. However, this vasodilator response was attenuated in the adriamycin-treated rats, the slopes of their curves being smaller than those of the respective untreated groups (0.038 +/- 0.006 in virgin rats vs 0.063 +/- 0.011 in controls, P < 0.05; and 0.015 +/- 0.005 in ADRP vs 0.028 +/- 0.008 in normal pregnancy, P < 0.05). CONCLUSIONS: The findings could be explained by enhanced occupancy of thromboxane receptors by an endogenous agonist, possibly PGH2, as a consequence of either increased levels of the autacoid or increased number of affinity receptors.

Animal models of preeclampsia.

Some of the maternal symptoms of preeclampsia can be produced by uterine ischemia, although no quadriped spontaneously exhibits this disease. It may be that the combination of upright posture and uteroplacental ischemia are necessary for manifestation of the full syndrome. Chronic nitric oxide synthase inhibition in rats produces a pattern of change that resembles the symptoms of preeclampsia, and the preeclamptic-like response of rats with adriamycin nephropathy and hyperinsulinemia is associated with endothelial dysfunction. These models are definitely of use in preeclampsia research, but because this disease only occurs spontaneously in primates, the definitive studies on preeclampsia will, of necessity, be clinical.

Altered vascular reactivity following partial nephrectomy in the rat: a possible mechanism of the blood-pressure-lowering effect of heparin.

BACKGROUND: This study was designed to assess whether the antihypertensive effect of heparin in rats after renal mass reduction (RMR) is related to changes in nitric oxide activity, and to study in vitro the altered behaviour of resistance-sized arteries induced by chronic administration of heparin. METHODS: Male Wistar rats were assigned to one of two experimental protocols. In the first protocol, RMR rats received heparin (250 units/day s.c.) and tail systolic blood pressure (SBP) was measured weekly for 4 weeks. In a subgroup, urinary nitrate excretion (UNO3) and in vitro vascular reactivity of isolated perfused mesenteric arterial beds were measured 2 weeks after RMR. The second protocol assessed whether inhibition of NO synthesis with L-NAME (70 mg/l added to the drinking water) prevents the blood-pressure-lowering effect of heparin. RESULTS: In untreated RMR rats SBP increased from 111+/-3 mmHg to 127+/-5 mmHg at 2 weeks and 139+/-5 mmHg at 4 weeks. In contrast, in RMR rats treated with heparin, SBP was 114 +/-3 mmHg at 2 weeks and 115+/-4 mmHg at 4 weeks (P<0.05 for both). Treatment with L-NAME increased SBP both in untreated and heparin-treated RMR groups. Two weeks after nephrectomy daily urinary nitrate increased significantly more in RMR rats treated with heparin than in untreated RMR rats (22+/-2 vs 14.2+/-2.3 micromol/day, P<0.05). In vitro studies performed at 2 weeks showed that vessels of untreated RMR rats had a blunted vasodilator response to acetylcholine that was restored to levels similar to that of controls in the heparin-treated group. CONCLUSIONS: These results suggest that, in rats after renal ablation, heparin may exert its antihypertensive effect, at least in part, by affecting the altered behaviour of resistance vessels during the development phase of hypertension. Increased NO production may contribute to this effect.

Chronic exogenous hyperinsulinemia in pregnancy: a rat model of pregnancy-induced hypertension.

Insulin resistance and hyperinsulinemia are associated with essential hypertension. There is also evidence of hyperinsulinemia in women who developed hypertension in pregnancy (P). The present study examines whether chronic hyperinsulinemia in pregnant rats plays a role in the development of hypertension in pregnancy. A sustained-release insulin pellet was implanted subcutaneously in 15 Wistar rats (P-INS) 1 wk before and on day 7 of pregnancy; 14 control rats were sham-implanted (P-SHAM). Tail-cuff systolic BP (SBP), serum triglycerides, glucose, insulin, renal function, and urinary excretion of Na+ and of metabolites of nitric oxide were determined throughout pregnancy. Data were analyzed by ANOVA with basal body weight as covariate analysis of covariance. Results are expressed as the mean +/- SD. Body weight; water and food intake; urine volume; creatinine clearance; and level of proteinuria at the end of pregnancy were similar in both groups. The number of fetuses was 9 +/- 2.3 in P-INS versus 11 +/- 2.4 in pregnant control rats (P < 0.05). Before mating, SBP was similar, but at the end of pregnancy SBP was 110 +/- 18 mmHg in P-INS versus 85 +/- 12 mmHg in pregnant rats (P < 0.05). Serum triglycerides and Na+ were also higher in P-INS rats. The fractional excretion of Na+ was 3.1 +/- 1.0 versus 4.4 +/- 1.5, respectively (P < 0.01). The percent increase in nitric oxide metabolite excretion was 233 +/- 14 versus 370 +/- 17%, respectively (P < 0.01). Chronic hyperinsulinemia, without sugar supplementation, and hypertriglyceridemia may cause a decrease in the synthesis of nitric oxide in P-INS rats. The development of hypertension in these rats may be associated with an impaired vasodilatation, together with an increased renal sodium reabsorption.

Nitric oxide and vascular reactivity in pregnant rats with adriamycin nephropathy.

1. In previous studies we have shown that, after the administration of adriamycin, hypertension developed in rats who became pregnant (adriamycin-pregnant rats), whereas virgin animals remained normotensive. Subsequently, we showed that this hypertension was prevented by administration of L-arginine, suggesting that deficient synthesis of nitric oxide may be pathogenetic in this model. 2. To further assess the role of nitric oxide in this model, we measured mean arterial blood pressure after administration of L-arginine to adriamycin-pregnant rats or of NG-nitro-L-arginine-methyl ester (L-NAME) to normal pregnant rats. In other experiments, we assessed the response of isolated perfused arterial mesenteric vessels, precontracted with noradrenaline, to acetylcholine, L-arginine or L-NAME. 3. Blood pressure was decreased in normal pregnant rats, whereas it was elevated in adriamycin-pregnant rats. L-NAME treatment increased blood pressure in normal pregnant rats and L-arginine decreased it in adriamycin-pregnant rats. 4. Mesenteric vessels of adriamycin-pregnant rats exhibited an exaggerated vasoconstrictory response to noradrenaline, when compared with the blunted response observed in normal pregnancy. The addition of L-NAME in vitro induced a further contraction, significantly greater in normal pregnant rats. The vasodilatory response to acetylcholine and L-arginine was greater in vessels from adriamycin-pregnant rats. In contrast, responses to either nitroprusside or diazoxide were similar in all groups. 5. The results suggest a state of reduced nitric oxide synthesis in rats with adriamycin nephropathy, leading to vascular maladaption and hypertension in pregnancy.

Pregnancy-induced hypertension in rats with adriamycin nephropathy is associated with an inadequate production of nitric oxide.

Hypertensive complications are relatively common in pregnancy, particularly in the presence of preexisting renal disease. Although the pathogenesis of such complications is still unknown, recent animal studies have suggested that it may be related to impaired synthesis of nitric oxide (NO). Rats with adriamycin nephropathy develop a "preeclamptic-type" pregnant state characterized by elevated blood pressure, lack of hyperfiltration, and enhanced proteinuria. Preliminary studies with this model have implicated inadequate NO synthesis in the development of preeclamptic-like pregnancy. The aim of the present study was to confirm this hypothesis. Pregnant rats, both normal (PREG) and those with adriamycin nephropathy (AN-PREG), received 100 mg/L N omega-nitro-L-arginine methyl ester PO from the middle of gestation to term (day 11, term approximately 22 days). One group of AN-PREG rats received either L-arginine or D-arginine (2 g/L) from midpregnancy. At term, systolic pressure, mean arterial pressure, urinary metabolites of NO, creatinine clearance, and urinary protein were assessed. At term, compared with virgin rats with adriamycin nephropathy, untreated AN-PREG rats had increased systolic pressure, mean arterial pressure, and proteinuria (mean arterial pressure, 124 +/- 2.5 versus 99.7 +/- 1.6 mm Hg [P < .05]; proteinuria, 434 +/- 58 versus 216 +/- 63 mg/d [P < .05]). Creatinine clearance did not change (1.68 +/- 0.23 versus 1.35 +/- 0.09 mL/min, P = NS). In PREG rats, urinary metabolites of NO increased approximately threefold at term pregnancy compared with control. By contrast, in AN-PREG rats, excretion of urinary metabolites of NO increased only by approximately 1.7-fold (P < .01) versus PREG rats. With the exception of AN-PREG rats, inhibition of NO synthesis with N omega-nitro-L-arginine methyl ester enhanced blood pressure and decreased creatinine clearance but did not influence proteinuria. Excretion of urinary metabolites of NO was similarly inhibited in all rats. In AN-PREG rats, L-arginine normalized blood pressure (91 +/- 2.15 mm Hg) and lowered proteinuria partially but significantly. D-Arginine had no effect. In summary, AN-PREG rats are unable to adequately increase NO synthesis when physiologically required. Correction of this deficit by L-arginine treatment induced a significant clinical improvement.

Efficacy of low felodipine dose monotherapy in mild-to-moderate hypertension: a comparison between office and ambulatory blood pressure monitoring.

The efficacy and tolerability of felodipine, in a low dose of 5-10 mg daily was assessed in 32 patients with mild-to-moderate hypertension, aged 53 +/- 11 years. The results of office vs 24 h ambulatory blood pressure measurements (ABPM) were compared. Inclusion criteria included an office systolic and diastolic blood pressure (SBP/DBP) > 140/90 mm Hg and a 24 h ABPM SBP/DBP > 135/85 mm Hg. Felodipine was initiated at a dose of 5 mg daily. At day 28 of the study, if office DBP > 90 mm Hg, the dose was doubled to 10 mg daily. At the end of the study (day 84), 24 h ABPM was done again. Side effects were noted throughout the study. Four patients dropped out during the study (two due to headache, one due to pedal edema and one rejected further participation). Of the remaining 28 patients, at day 28, 12 required an increased dose of 10 mg/day. At the end of the study, office BP was below 140 90 mm Hg in 71% of the patients. In the whole group BP decreased from 158 +/- 15/101 +/- 8.4 to 138 +/- 9/85 +/- 5 mm Hg, P < 0.001. ABPM showed that BP was normalized in 82% of the patients. It decreased from 146.8 +/- 9.56/94.8 +/- 7.4 to 130.2 +/- 10.6/83 +/- 6.3 mm Hg, P < 0.001. BP was similarly reduced in working and sleeping hours, with preservation of the circadian rhythm. Heart rate was unaffected by the drug. Five patients showed persistently elevated SBP on office measurements while on ABPM, the values were within normal limits. This finding confirms the existence of a white coat effect in patients with proven hypertension and the superiority of ABPM over office BP measurements in clinical investigations. In summary, ABPM showed that the antihypertensive effect of felodipine was sustained throughout normal 24 h, including the critical (as regards cardiovascular morbidity) awakening hours.

Effect of recurrent pregnancies on the evolution of adriamycin nephropathy.

BACKGROUND: In rats with incipient adriamycin nephropathy, pregnancy increases urine protein excretion and mean arterial pressure, with no changes in the glomerular filtration rate. Renal histology is normal and the glomerular TxB2/PGE2 ratio is increased. METHODS: In the present study we evaluated the influence of repeated pregnancies on the evolution of adriamycin nephropathy. Two weeks after a first delivery, rats were mated again and were followed till 35 days after the second delivery. RESULTS: In pregnant rats with adriamycin nephropathy, urine protein excretion and mean arterial pressure returned to values identical to those found in age-sex-matched virgin rats with adriamycin nephropathy. At the end of the second pregnancy, mean arterial pressure and urine protein excretion were again elevated, compared with virgin rats with adriamycin nephropathy. Thirty-five days after the second delivery, urine protein excretion and mean arterial pressure remained elevated, 296 +/- 50 mg/day vs 115 +/- 26 and 121 +/- 4 vs 110 +/- 1 mmHg respectively, P < 0.05. Glomerular filtration rate remained unchanged 0.84 +/- 0.09 vs 0.79 +/- 0.09 ml/min in virgin rats with adriamycin nephropathy. The glomerular TxB2/PGE2 ratio was decreased, contrasting with the first pregnancy. At the end of the second pregnancy, histological examination of the kidneys in rats with adriamycin nephropathy revealed a significant increase in mesangial expansion. It was even more marked 35 days later, at the last follow-up, with a semiquantitative score of 162 +/- 29 vs 81 +/- 20 in virgin adriamycin nephropathy rats, P < 0.05. CONCLUSIONS: In rats with adriamycin nephropathy, repetitive pregnancies seem to aggravate the natural course of the disease in an irreversible fashion. The earlier changes in glomerular prostanoid synthesis, particularly on thromboxane, may play a pathogenic role by activating mesangial cell matrix synthesis.

Adriamycin-related hypertension in pregnant rats: response to a thromboxane receptor antagonist.

1. In previous works we have described the development of hypertension and aggravation of proteinuria in rats who became pregnant after the administration of Adriamycin. This was associated with an increase in the glomerular thromboxane B2-prostaglandin E2 ratio. 2. To assess the pathogenetic role of thromboxane in this model, female Wistar rats were mated 2 weeks after receiving Adriamycin (3.5 mg/kg intravenously). Rats were then treated with the thromboxane-receptor antagonist daltroban, 60 mg day-1 kg-1 orally, beginning on day 11 of pregnancy. Systolic blood pressure, proteinuria and the urinary excretion of thromboxane B2, 6-keto-prostaglandin F1 alpha and prostaglandin E2 were measured serially before mating, and on days 14 and 21 of pregnancy. The results were compared with those in Adriamycin-(treated) pregnant rats not treated with daltroban, Adriamycin-treated virgin rats and normal virgin or pregnant rats either treated or untreated with daltroban. 3. In daltroban-treated pregnant and virgin rats treated with Adriamycin, systolic blood pressure remained normal, whereas it increased significantly (P < 0.05) in untreated animals. On day 14, blood pressure was higher in non-daltroban-treated Adriamycin-treated pregnant rats than in non-daltroban-treated Adriamycin-treated virgin rats. Treatment had no effect on blood pressure in normal virgin or pregnant rats. Proteinuria was higher in pregnant rats treated with Adriamycin than in Adriamycin-treated virgin rats, but it was not reduced by daltroban.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of diltiazem and methyldopa on gestation-related renal complications in rats with adriamycin nephrosis. Relationship to glomerular prostanoid synthesis.

BACKGROUND: In the presence of pre-existing renal disease, occurrence of hypertension during pregnancy may compromise renal function and aggravate proteinuria. In pregnant rats with early adriamycin nephropathy, this is associated with an increase in the glomerular TxB2:PGE2 ratio. In the present study we evaluated the effect of blood-pressure control on renal function and its relationship with glomerular prostanoid synthesis. DESIGN OF THE STUDY: Pregnant Wistar rats with adriamycin nephropathy received diltiazem, 30 mg/kg/day or methyldopa, 400 mg/kg/day from mid-gestation. Mean arterial pressure (MAP), inulin clearance (CIN), urine protein excretion (UP) and glomerular prostanoid synthesis were measured. Results were compared with (i) untreated pregnant rats with adriamycin nephropathy, (ii) virgin rats with adriamycin nephropathy, and (iii) normal virgin or (iv) pregnant normal rats. RESULTS: MAP increased in untreated pregnant rats with adriamycin nephropathy (P < 0.01 versus virgin rats with adriamycin nephropathy), contrasting with the physiological decrease observed in normal pregnant rats. Diltiazem and methyldopa decreased MAP to normal values. In untreated pregnant rats with adriamycin nephropathy CIN decreased and proteinuria increased significantly at the end of gestation. Treatment with diltiazem and methyldopa augmented GFR, but only diltiazem decreased UP significantly. It was associated with an increased glomerular PGE2 synthesis. CONCLUSION: We conclude that in rats with adriamycin nephropathy, antihypertensive treatment improved GFR. Diltiazem also decreased urinary protein excretion, associated with a normalization of the glomerular TxB2:PGE2 ratio.

Pregnancy-induced hypertension in rats with early adriamycin nephropathy.

In up to 60% of women with chronic renal disease an elevation of blood pressure is seen during pregnancy. The pathogenesis of this complication may be related to a diminished synthesis of vasodilatory substances by endothelial cells and to an increased sensitivity to vasopressor hormones such as angiotensin II. Previous experimental studies in rats with early chronic renal disease (adriamycin nephropathy, AN) have shown that this pregnancy-induced hypertension is associated with a lowered synthesis of glomerular PGE2. In the present study the vascular response to vasoactive substances was evaluated. In AN rats the sensitivity to an acute infusion of angiotensin II was augmented, whilst it was blunted in normal pregnant rats. Chronic treatment with the thromboxane-(Tx)-receptor antagonist, daltroban (60 mg/kg/day, p.o.) administered from mid-pregnancy induced a similar reduction in blood pressure in both AN virgin and pregnant rats. This suggests that adriamycin per se may induce vascular damage which may interfere with the normal vascular adaptation to pregnancy. Stimulation of NO synthesis with L-arginine decreased MAP values significantly in PAN rats but did not modify them during normal pregnancy. In additional experimental inhibition of the endothelial-derived relaxing factor (EDRF), nitric oxide (NO) synthesis with NAME from mid-pregnancy significantly increased SBP and MAP in normal rats. By contrast, in PAN rats chronic NAME treatment had no effect. In summary, the development of hypertension in pregnant rats with AN may be associated to endothelial cell dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium loading and renal prostaglandins in old rats.

1. Previous studies have shown that altered synthesis of prostaglandins (PGs) in the kidney of ageing rats contributes to impaired Na conservation during sodium deprivation. In the present study, we wished to assess whether the disturbance of prostaglandin synthesis also affects the response to sodium loading in old rats. 2. We measured the urinary excretion of thromboxane B2 (TXB2), 6-keto PGF1 alpha (6KPGF1 alpha) and PGE2 in young (3-4 months) and old (20-21 months) rats after 24, 48 and 72 h of Na loading. In a separate protocol, we measured prostanoid synthesis by isolated glomeruli, cortical homogenates, medullary and papillary slices from young and old rats in basal conditions and after 15 days of dietary Na loading. 3. Young and old rats excreted similarly the Na load. The urinary excretion (U) of TXB2 and 6KPGF1 alpha were unchanged during Na load in young rats. U6KPGF1 alpha, which was significantly higher in old rats and UTXB2 which also tended to be elevated, decreased in old rats with Na loading. Sodium loading was associated with a transient increase of UPGE2 in young, but not in old rats. 4. TXB2 synthesis was increased in all portions of the kidneys of old rats. 6KPGF1 alpha production was elevated in glomeruli and cortex and that of PGE2 in cortex. In medulla and papilla only TXB2 synthesis was enhanced. 5. Sodium loading did not significantly change prostanoid synthesis in the kidneys of young rats. In old rats, glomerular and cortical TXB2 decreased whereas medullary and papillary 6KPGF1 alpha increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of timing of antihypertensive therapy on glomerular injury: comparison between captopril and diltiazem.

Recent studies have suggested that the progression of experimental chronic renal disease may be prevented by early use of antihypertensive drugs. It is unclear, however, whether such therapies may also affect established and progressive renal disease. In the present study we compared the effects of captopril (CEI) and diltiazem (CCB), started either at week 10 or at week 24 on the evolution of adriamycin nephropathy (AN). Rats were studied at weeks 7, 16, 24, 32, and 38 of the disease. None of the treatments influenced the development of nephrotic range proteinuria. The use of CCB from week 10 was even associated with increased proteinuria. The moderate hypertension of ADR rats was reduced to the same degree with both drugs. Inulin clearance (GFR) was significantly reduced in all ADR rats. However, in ADR rats treated with CEI from week 10 and in those treated with CCB from week 24, the GFR was relatively higher. Glomerular injury, evaluated by semiquantitative methods, was not ameliorated by CEI treatment. Earlier CCB treatment (week 10) worsened glomerular lesions, whilst CCB treatment initiated at week 24 reduced significantly the degree of mesangial expansion and focal glomerular sclerosis. We conclude that, in addition to their common antihypertensive action, the specific effect of drug therapy seems to be crucially time dependent.

Adriamycin nephropathy: a model to study effects of pregnancy on renal disease in rats.

The influence of pregnancy on the evolution of primary renal disease is still a matter of controversy. Hypertension and derangement of renal function may occur. The pathophysiology of these complications is poorly understood. In the present study, we assessed the influence of pregnancy on the evolution of adriamycin (Adr) nephropathy. Four groups of animals were studied: 1) control virgin rats (C), 2) normal pregnant rats (NP), 3) virgin rats with nephropathy (Adr), and 4) pregnant rats with nephropathy (Adr-P). Inulin clearance measured at the end of pregnancy in awake rats was similar in NP (1.68 +/- 0.20 ml/min) and C (1.39 +/- 0.03 ml/min). In Adr-P rats, it tended to decrease (1.22 +/- 0.7 vs. 1.93 +/- 0.44 ml/min in Adr rats). Mean arterial pressure was increased in Adr-P rats (137 +/- 2.5 vs. 95 +/- 3.2 mmHg in NP; P < 0.001). Urinary protein excretion was 216 +/- 61 mg/day in Adr-P compared with 28.7 +/- 18 mg/day in Adr (P < 0.001). A significant increase in the glomerular thromboxane B2-to-prostaglandin E2 ratio was found in Adr-P rats (1.15 +/- 0.26 vs. 0.52 +/- 0.12 in Adr rats; P < 0.03). In NP rats, no change was observed. Kidneys and placentas were normal on light and electron microscopy. Thus pregnant rats with adriamycin nephropathy developed a clinical picture with several features of preeclampsia. Changes in glomerular prostanoid synthesis might play a role in the development of this complication.

Altered prostaglandin synthesis and impaired sodium conservation in the kidneys of old rats.

1. The aim of this investigation was to study the role of prostaglandins in the impaired Na+ conservation of the ageing kidney. 2. We measured the urinary excretion of thromboxane B2, 6-keto-prostaglandin F1 alpha and prostaglandin E2 in young (3-4 months) and old (20-21 months) rats after 12, 24 and 36 h of Na+ deprivation. In a separate protocol, we measured prostanoid synthesis by isolated glomeruli, cortical homogenates, medullary slices and papillary slices from young and old rats in basal conditions and after 15 days of dietary Na+ deprivation. 3. In the acute study, urinary excretion of 6-keto-prostaglandin F1 alpha and prostaglandin E2 decreased in young but not in old rats. Urinary excretion of prostaglandin E2 was lower in old rats, but did not vary significantly with Na+ deprivation. 4. In old rats, thromboxane B2 synthesis was increased in all the portions of the kidney except the medulla. Production of 6-keto-prostaglandin F1 alpha was elevated in glomeruli and tended to increase in the cortex. Prostaglandin E2 synthesis was also elevated in the cortex. Thromboxane B2 synthesis tended to increase in the medulla and was enhanced in the papilla. After Na+ deprivation, only glomerular prostaglandin E2 synthesis increased in young rats. In old rats, cortical and papillary synthesis of 6-keto-prostaglandin F1 alpha increased, whereas prostaglandin E2 synthesis did not change. 5. The results suggest increased thromboxane synthesis in the ageing kidney. Increased prostacyclin and prostaglandin E2 synthesis may be an attempt to counteract enhanced thromboxane production.(ABSTRACT TRUNCATED AT 250 WORDS)