Prevention of systemic and regional haemodynamic alterations, hypercreatininemia, hyperuremia and hyperphosphatemia by losartan in hypertension with acute renal failure.

Patients with pre-existing hypertension are at a particular risk of fatal outcome due to acute renal failure (ARF). We investigate the effects of angiotensin II type-1 receptor blocker (ARB) losartan, on haemodynamics and biochemical parameters in adult male spontaneously hypertensive rats (SHR) with ischemia/reperfusion ARF. SHR were randomly selected in three experimental groups: sham-operated group (SHAM), ARF group, and ARF+LOS group (losartan, 10 mg/kg/b.w. given by infusion during the period of three hours after reperfusion). Beside the improvement of systemic haemodynamics 24 h after reperfusion, losartan significantly increased renal blood flow (RBF: 19.33±3.29 ml/min/kg vs. 8.03±1.04 ml/min/kg, p<0.05) and decreased renal vascular resistance (RVR) compared to ARF (8.85±1.21 mmHg × min × kg/ml vs. 19.90±2.35 mmHg × min × kg/ml, p<0.001). Plasma creatinine (Pcr), urea (Pu) and phosphates (Pphos) were significantly reduced in ARF+LOS group compared to ARF group (Pcr: 99.11±14.56 µmol/l vs. 242.71±20.25 µmol/l, p<0.001; Pu: 33.72±4.69 mmol/l vs. 61.90±3.93 mmol/l, p<0.001; 2.7±0.42 mmol/l vs. 5.57±0.61 mmol/l, p<0.01). Our results demonstrate that losartan improves systemic and regional haemodynamic and biochemical parameters in hypertension with ARF.

The effects of iron-containing superoxide dismutases on haemodynamic parameters in spontaneously hypertensive rats.

The product of FeSOD activity is hydrogen peroxide (H2O2). Furthermore, FeSOD can modify the chemical versatility of NO into its redox-active forms: nitrosonium cation (NO+) and nitroxyl anion (NO-). All of these low molecular weight species are vasoactive and, in particular, NO- induces calcitonin gene-related peptide (CGRP) synthesis (known to be the most potent relaxation-promoting peptide). In this study the effects of bolus infusions of iron-containing superoxide dismutase (FeSOD) and of superoxide dismutase containing both iron and manganese (FeMnSOD) on the arterial blood pressure (MAP), the arterial blood pressure (CO) and the total vascular resistance (TVR) in spontaneously hypertensive (SH) rats were determined. Bolus infusion of FeSOD induced a biphasic response in the MAP (an initial increase was followed by a significant decrease). At the end of the experiment the MAP returned to its basal value. FeMnSOD (the enzymatically inactive form of FeSOD) had no effect on the MAP in these experiments. Bolus infusions of FeSOD and of FeMnSOD had no effect either on the both the CO or on the TVR in SH rats. Our results indicate that arterial relaxation changes mediated by NO- may be important for regulation of blood pressure in SH rats.

Influence of carvedilol on chronic renal failure progression in spontaneously hypertensive rats with adriamycin nephropathy.

BACKGROUND: In this study, the effects of carvedilol, antihypertensive (alpha-beta blocker) agent with antiproliferative and antioxidative properties, on slowing down of chronic renal failure (CRF) progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy were examined. METHODS: Eighty adult (24 weeks) SHR were divided into four groups: CONTROL GROUP: 20 SHR; ADR group: 20 SHR treated with ADR (2 mg/kg i.v. twice in 20 days); ADR-C group: 20 SHR treated with ADR and with carvedilol (30 mg/kg/day); ADR-CC group: 20 SHR treated with carvedilol and captopril (60 mg/kg/day). Systolic blood pressure was measured every two weeks, renal blood flow (RBF), mean arterial pressure (MAP) and renal vascular resistance (RVR) were determined at Weeks 6 and 12, creatinine clearance and proteinuria at Weeks -3 (see measurements), 6 and 12. The rats were sacrificed at Weeks 6 and 12 after the second ADR injection. Glomerular sclerosis, tubulointerstitial and blood vessel changes were determined by semiquantitative scoring. RESULTS: Carvedilol decreased systolic blood pressure. It decreased RVR and MAP, and increased RBF significantly. Carvedilol also significantly decreased interstitial infiltration in the early phase of the study, slowed down the development of interstitial fibrosis and tubular atrophy and decreased blood vessel changes. The hemodynamic and morphological effects of carvedilol were associated with slowing down the CRF progression as well as a mild decrease in proteinuria. Captopril addition to carvedilol improved its effects especially on prevention of tubulointerstitial changes. CONCLUSIONS: Results of this experimental study showed beneficial effect of carvedilol and its combination with captopril on CRF progression, indicating that clinical studies are warranted.

Regional hemodynamics after chronic nitric oxide inhibition in spontaneously hypertensive rats.

BACKGROUND: Inhibition of nitric oxide (NO) synthase by L-arginine analogs is associated with elevation of blood pressure in rats. Because endothelium-dependent vasomotion in different vascular beds is not homogenous, the aim of this study was to characterize and compare regional hemodynamic responses in carotid, femoral, and renal vascular beds after chronic NO inhibition in spontaneously hypertensive rats. The possible role of circulating endothelin and renin angiotensin systems in mediating the effects of chronic NO inhibition was also studied. METHODS: Systemic and regional hemodynamics, left ventricular mass, plasma renin activity, and plasma endothelin-1 were determined in control and Nomega-nitro-Larginine methyl ester (L-NAME)-treated (10 mg/kg/day, 4 weeks) spontaneously hypertensive rats. RESULTS: L-NAME treatment increased arterial pressure and total peripheral and regional vascular resistance and decreased cardiac output, stroke volume, and regional blood flow. An increase in blood flow ratio and a decrease in vascular resistance ratio between carotid and renal as well as femoral and renal vascular beds in rats treated with L-NAME was found. Blood flow and vascular resistance ratios between femoral and carotid vascular beds remained unchanged. L-NAME increased plasma renin activity and left ventricular weight/body weight ratio, whereas plasma endothelin-1 was not modified. CONCLUSIONS: The results of this study showed that the renal circulation seemed to be more sensitive to the effects of chronic NO inhibition than carotid and femoral vascular beds. Simultaneous activation of the renin angiotensin system may further potentiate cardiovascular effects of chronic NO inhibition. No evidence that circulating endothelin-1 plays a role in this model of hypertension was found.

L-arginine reduces tubular cell injury in acute post-ischaemic renal failure.

BACKGROUND: The pathophysiology of renal ischaemia, resulting in tubular cell injury and leading to acute renal failure (ARF), remains unclear. An ever-increasing number of investigations focus on a possible role of nitric oxide (NO) in regulating circulation during ARF. In this context, we investigated the influence of chronic stimulation or inhibition of NO synthesis, or both, on haemodynamic parameters, histology and plasma renin activity (PRA) after ischaemia-reperfusion injury of rat kidneys. METHODS: Experiments were performed on adult, male Wistar rats. Before induction of ARF, a group of animals was treated with a NO synthesis inhibitor (L-NAME) and another group was treated with a precursor of NO synthesis (L-arginine). The animals received those substances for 4 weeks. Control groups received the same amount of tap water for 4 or 8 weeks and were divided into groups with ARF (4 weeks--ARF group and 8 weeks ARF group) and a sham-operated group. Another group of rats was treated first with L-NAME and then with L-arginine in their drinking water, for 4 weeks for each of these two substances. All parameters were evaluated 24 h after the induction of ischaemic ARF or the sham operation. RESULTS: Our results show that such long-term stimulation of NO release by L-arginine improved renal haemodynamics in the ischaemic form of ARF. Renal blood flow (RBF) increased by 96% in the L-arginine-treated rats with ARF compared with the group with ARF alone. Inhibition of NO synthesis worsens renal haemodynamics after ARF. However, this aggravation can be reversed by L-arginine. The rate of water reabsorption was reduced in all groups with ARF, but this reduction was least in the group treated with L-arginine. The rate of Na+ reabsorption was reduced in all groups 24 h after renal ischaemia, but a significant decrease was observed after the inhibition of NO synthesis. Histological examination of the kidney specimens showed that morphological changes were least in the rats treated with L-arginine, when compared with all other groups with ARF. Nevertheless, the lesions were most prominent in the L-NAME+ARF group. In this group, the areas of corticomedullar necrosis were more widespread in comparison with other groups, especially the L-arginine group where only swelling of the proximal tubular cells was observed. Treatment with L-NAME was not accompanied by any significant alteration in the plasma concentration of angiotensin I (ANG I), while in the group treated with L-arginine ANG I had a tendency to decrease. CONCLUSIONS: Acute post-ischaemic renal failure may be alleviated by administering the NO substrate (L-arginine). NO acts cytoprotectively on tubular epithelial cells in ischaemia--reperfusion injury of rat kidney. Evidence of this comes from both histopathological findings and increased tubular water and sodium reabsorption. However, inhibition of NO synthesis (provoked by L-NAME) worsens renal haemodynamics and aggravates morphological changes after ARF. These aggravations can, however, be reversed by L-arginine.

Effects of captopril on morphologic changes in kidney of spontaneously hypertensive rats with adriamycin nephropathy.

Antihypertensive therapy has been shown to slow down the progression of chronic renal failure. Angiotensin converting enzyme inhibitors and calcium antagonists have been emphasized as the agents with the most protective effect. Our previous study showed that captopril slowed down renal function deterioration in the early course of adriamycin (ADR) nephropathy in spontaneously hypertensive rats (SHR). The present study was undertaken with the aim to examine morphologic changes associated with that slower renal function deterioration. Adult (24 weeks) female SHR were randomly divided into the following groups: the control group (n = 12) was given tap water to drink; the adriamycin (ADR) group (n = 25) was treated with ADR; the ADR-captopril (ADR-C) group (n = 27) was treated with ADR and thereafter with captopril (60 mg/kg/day). Rats were sacrificed at weeks 6, 12 and 18 and histologic analysis was semiquantitatively performed. In the control group the glomeruli exhibited only minor changes at the end of the study. In the ADR group slight glomerular mesangial hypercellularity appeared in the sixth week and progressed in focal and segmental sclerosis. Some glomeruli showed segmental proliferation and increased fibrular matrix of a tuft adherent to a fibrocellular crescents. In the ADR-C group, glomeruli with a slight increase of mesangial matrix were seen at the end of the sixth week, mesangial hypercellularity developed until the end of the sixth week, mesangial hypercellularity developed until the end of the 12th week and segmental glomerulosclerosis until the end of the study. Semiquantitative analysis revealed that the mean semiquantitative scores for mesangial expansion and glomerular sclerosis were significantly lower in ADR-C group than in ADR group throughout the study. We concluded that captopril slowed down mesangial expansion and reduced the development of glomerular sclerosis.

Factors affecting the ability of the renal medulla to exert an antihypertensive function.

To examine whether changes in renomedullary osmolality and the activity of the renin-angiotensin system may influence the ability of the renal medulla to exert an antihypertensive function, rats were exposed to several manoeuvers. These affected either the medullary osmolality or the renin-angiotensin system (salt or saccharose load, salt depletion, treatment with captopril alone or in combination with salt depletion). A comparison of the antihypertensive capacity of the renal medulla was studied by transplanting renal medullae from the various groups into one-kidney one-clip hypertensive rats. A significant and quantitatively similar reduction in blood pressure was observed in hypertensive rats that received transplants of the medullae from control, salt or saccharose loaded rats and captopril treated rats. In contrast, medullae from salt depleted rats did not affect blood pressure when transplanted into hypertensive animals. The addition of captopril restored the antihypertensive function of renal medulla in salt depleted rats. The results do not support the view that osmolality of the renal medulla regulates its antihypertensive capacity, and suggest that angiotensin II may restrain renomedullary antihypertensive function.

Antihypertensive action of heparin: role of the renin-angiotensin aldosterone system and prostaglandins.

Chronic subcutaneous administration of heparin consistently lowers blood pressure in hypertensive rats. This antihypertensive effect is related at least in part to a concomitant decrease in hematocrit. Groups of spontaneously hypertensive (SHR) and normotensive Wistar (NWR) rats were treated with subcutaneous heparin (700 U/d) for 6 weeks. Weekly determinations of systolic blood pressure (tail-cuff) and hematocrit were done. Peripheral plasma renin activity, plasma aldosterone, plasma prostaglandins (PGs) (PGF2 alpha, PGI2), thromboxane A2, and urinary kallikrein were measured. Blood pressure responses of acute and chronic heparin treatment to vasoconstrictor substances, including angiotensin I, angiotensin II, and norepinephrine, were determined. As before, heparin produced a significant (P < .01) decrease in hematocrit in both SHRs and NWRs, but a parallel decrease in blood pressure was noted only in SHRs. A significant (P < .001) increase in plasma renin activity was found in heparin-treated SHRs and NWRs; however, a corresponding elevation of plasma aldosterone level was noted only in heparin-treated NWR. Plasma aldosterone level significantly (P < .01) decreased in heparin-treated SHRs. Plasma PGs and urinary kallikrein levels were not different among the groups. The blood pressure responses to vasoconstrictor substances were essentially similar among the heparin-treated and control groups. These findings suggest that PGs or kallikrein have a slight or no role in determining the antihypertensive effect of heparin. Conversely, the results suggest that a reduced aldosterone level contributes to the antihypertensive mechanism of heparin.

The effect of acute and chronic hematocrit changes on cardiovascular hemodynamics in spontaneously hypertensive rats.

Heparin given over a long term by a subcutaneous route consistently lowers blood pressure in the hypertensive rat models. The decrease in blood pressure is accompanied by a parallel decrease in hematocrit suggesting a causal relationship between hematocrit and blood pressure. The aim of this study was to define the relationships between acute and chronic hematocrit changes and blood pressure in the normotensive and hypertensive states. Normotensive Wistar (NWR) and spontaneously hypertensive (SHR) rats were used. Hematocrit was decreased acutely by blood-letting, and chronically by treatment with either heparin (H) or phenylhydrazine (P) for 4 weeks. Acute and chronic hematocrit increase was accomplished by packed cells transfusion. Systolic blood pressure was measured weekly; and at the end of the experimental period, plasma volume, cardiac output, and mean arterial pressure were obtained. Acute hematocrit decrease or increase (hematocrit ranging from 25 to 65%) did not affect blood pressure in either strain of rats; whereas chronic hematocrit changes (hematocrit ranging from 35 to 61%) significantly affected blood pressure only in SHR. Thus, chronic hematocrit decrease induced by H or P resulted in a significant fall in blood pressure compared to control (201 +/- 3 v 175 +/- 4, 167 +/- 4 mm Hg, respectively; P < .05). Conversely, a chronic hematocrit increase resulted in a significant rise in blood pressure (201 +/- 3 v 219 +/- 4 mm Hg; P < .05). Similar hematocrit changes produced in NWR, as in SHR, did not affect blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitotic activity and cell deletion in ventral prostate epithelium of intact and castrated oxytocin-treated rats.

Previous study has shown that oxytocin (OT) attenuated the postcastration regression of ventral prostate epithelium in rats. To decide if this effect is associated with stimulation of cell division or improvement of cell survival, metaphase index of secretory cells and frequency of apoptotic bodies in the epithelium, combined with stereological parameters, were determined in the present study. OT was injected subcutaneously in a dose of 0.25 IU/100 g/d during 5 postorchiectomal days and the same treatment was applied to intact rats. Only the prostate of castrated animals responded to OT. They had greater total volume of the epithelium, total number and metaphase index of secretory cells, but lower frequency of apoptotic bodies. These findings demonstrate the ability of OT to stimulate mitotic activity and to diminish mortality of secretory cells caused by orchiectomy.

The response of rat adrenal zona fasciculata and zona reticularis to oxytocin treatment.

The response of the adrenal zona fasciculata (ZF) and zona reticularis (ZR) to oxytocin (OT) was examined in male rats using a stereological method. The 10-day administration of 0.25 IU OT/100 g daily caused an enlargement of ZF due to cell hypertrophy associated with striking lipid accumulation. The volume of ZR was decreased, this change being the consequence of the reduced cell population. The possible site of OT action is discussed.

Streptozotocin-induced diabetes mellitus lowers blood pressure in spontaneously hypertensive rat.

There are conflicting reports showing that alloxan or streptozotocin-induced diabetes in rat increases, decreases or does not alter blood pressure. Since hypertension influences organ-specific diabetic complications, this study was designed to examine the effects of streptozotocin-induced diabetes on blood pressure (BP), hemodynamics and heart weight in spontaneously hypertensive (SHR) and normotensive Wistar (NWR) rats. In order to control the influence of weight loss on BP affected by diabetes, we have examined the effect of weight loss without diabetes on BP, hemodynamics and heart weight in SHR. Weight loss parallel to that in diabetic SHR was induced in a group of SHR by food restriction (fasting). Significant (P less than .05) decreases in systolic and direct BP were observed in diabetic SHR. This hypotensive effect was accompanied by a significant (P less than .05) decrease in total peripheral resistance, but no change in cardiac output. These blood pressure and hemodynamic findings in diabetic SHR were complimented by a significant (P less than .05) reduction in left ventricular weight to body weight ratio. On the contrary, fasting SHR with weight loss equivalent to that in diabetic SHR showed no change in BP or total peripheral resistance. Further, fasting SHR revealed a significant (P less than .05) increase in heart weight to body weight ratio. The weight loss of equal magnitude induced by streptozotocin-induced diabetes in NWR did not have any effect on BP or hemodynamics. In addition, like fasting SHR, diabetic NWR showed a significant (P less than .05) increase in left ventricular weight to body weight ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereologic analysis of ventral prostate of oxytocin-treated rats.

Ventral prostate response to oxytocin (OT) was examined in intact and castrated adult rats. The treatment consisted of 10 daily subcutaneous injections of 0.25 IU OT per 100 g body weight, which for orchiectomized rats began immediately after surgery. OT induced prostatic response only in castrated animals. Stereologic analysis revealed changes in the epithelial component, its total volume and surface being increased. The acinar lumen as well as the glandular weight were also enhanced. A possibility that the ventral prostate is the target organ for OT is discussed.

The response of rat adrenal medulla to oxytocin.

Effects of oxytocin (OT) on the adrenal chromaffin tissue of male rats were examined by coupled morphometric and biochemical techniques. Synthetic OT was administered in doses of 0.14 and 0.25 IU/100 g/d during 7 or 10 consecutive days and the effects were followed 1, 24, 72 and 168 hours after the last injection. The function and structure of chromaffin cells were affected by the higher dose of OT only. They caused divergent responses on their amine contents. Adrenaline, noradrenaline and dopamine contents were increased, while serotonin content was decreased. These changes were different in duration and time of incidence. Stereological analysis showed an enhanced number of chromaffin cells and an increase in their total volume. The parallelism between the changes in chromaffin cell number and the catecholamine content strongly suggests a mitogenic effect of the applied OT.