Differential effects of DOCA on renal and gastrointestinal handling of sodium and potassium in pigs

Young, male pigs eating standard pig chow, ad libitum, received approximately 170 mEq Na and 290 mEq K per day. Electrolyte intake, urinary and fecal electrolyte output, and plasma electrolyte levels were determined daily in 12 deoxycorticosterone acetate (DOCA)-treated pigs and in 6 control pigs. Daily Na and K balances (dietary intake - urinary + fecal output) were calculated. DOCA caused a reduction in urinary Na output from 1.53 mEq/kg/day to 0.57 mEq/kg/day during the first 48 hr following implantation. Escape from the renal sodium retaining effect of DOCA was complete within 3 days, with urinary Na output returning to pre-DOCA levels. Fecal Na output decreased from 0.65 mEq/kg/day during the preimplant period to 0.13 mEq/kg/day during the postimplant period. No escape from GI Na retention occurred by Day 15. Plasma Na rose to significantly higher levels by Day 15. Sodium balance was significantly elevated in DOCA-treated pigs for that first 48 hr postimplant. Urinary K output decreased from 3.50 mEq/kg/day to 1.74 mEq/kg/day during the first 2 days, but returned toward preimplant levels by Day 4. Fecal K output was increased for the first week, and thereafter returned to preimplant levels. Plasma K fell from 3.9 to 2.9 mEq/liter by Day 15. Potassium balance fell slightly in both experimental and control animals. No significant differences in potassium balance were present between the two groups. The control pigs showed no significant changes in plasma electrolyte concentration or in electrolyte balance. It is concluded that DOCA has differential effects on renal and gastrointestinal handling of electrolytes and that DOCA may induce an intracellular shift of potassium in pigs.     

Relationship of hypokalemia to metabolic alkalosis in the intact Yucatan miniature boar following implantation of deoxycorticosterone-acetate (DOCA) or d-aldosterone

1. Normo-kalemic Yucatan miniature boars were implanted with deoxycorticosterone-acetate (DOCA) or d-aldosterone (Aldo) to evaluate the relationship of hypokalemia to the pathogenesis of metabolic alkalosis following mineralocorticoid administration. 2. Serum potassium was significantly less than control within 24 hr, serum bicarbonate significantly elevated within 4 days and pH 1-2 days later with no significant differences between DOCA and Aldo. 3. These data demonstrate that pre-existing potassium deficits are not required for the development of alkalosis with mineralocorticoid administration, DOCA and Aldo are equally effective, co-existing hypokalemia is necessary in the genesis, and perhaps maintenance, of metabolic alkalosis with excess mineralocorticoids, and hypokalemia is not a consequence of the alkalosis.     

Acute renal function in chronically sympathectomized deoxycorticosterone acetate-treated miniature swine

We recently validated a swine model in which chronic treatment with 6-hydroxydopamine (6-OHDA) produced an effective sympathectomy. These sympathectomized swine demonstrated a significantly attenuated hypertensive response when treated with deoxycorticosterone acetate (DOCA). Because renal nerve activity is elevated and important in controlling renal function and blood pressure in the DOCA swine model, we wanted to study the effect of chronic sympathectomy on acute renal hemodynamics and tubular function. Kidney function was assessed in 14 DOCA-treated miniature swine, 8 of which were sympathectomized by chronic treatment with 6-OHDA, while 6 served as controls. Effective renal sympathectomy in this model has been previously confirmed by a significant reduction (97%) of norepinephrine in renal cortical tissue. When anesthetized, mean arterial pressure and renal blood flow were similar between the two groups. Glomerular filtration rate was lower by 43%, urine flow rate by 71%, sodium excretion by 66%, and potassium excretion by 48% in the 6-OHDA DOCA animals. All of these parameters were significantly different from the intact DOCA controls. These results indicate that anesthetized, chronically sympathectomized swine exhibit decreased renal excretory function. The changes in renal function may have been due to the development of a tubular or glomerular supersensitivity to circulating antinatriuretic factors, since the 6-OHDA group had a 28% greater pressor response to the alpha-agonist phenylephrine and a significantly greater fall in mean arterial pressure in response to alpha-blockade with prazosin when compared with the controls. These changes in renal function may also explain why the 6-OHDA animals demonstrated a slight increase in mean arterial pressure in response to DOCA. Because acute renal denervation in DOCA-treated swine produces a diuresis and natriuresis, this study affirms that there may be important functional differences in acutely versus chronically denervated kidneys for which the implications under normal physiologic conditions are unknown.     

Critical opening pressure and reactivity of tail vessels in conscious hypertensive rats.

The possible role of increased vascular reactivity in the mechanism of experimental hypertension was studied by measurements of the critical opening pressure (COP) of tail vessels in conscious rats. In hypertension induced by administration of desoxycorticosterone acetate (DOCA) and replacement of the drinking water by 1% NaCl solution (DOCA-NaCl hypertension), and in one-kidney Goldblatt renovascular hypertension, the raised level of blood pressure was associated with an increased COP of the tail vessels when measured both before and after ganglionic blockade. In rats treated with either DOCA alone or 1% NaCl alone there was no significant increase in systolic blood pressure (SBP) or COP relative to the corresponding controls. In all four experimental series intravenous infusion of angiotensin or norepinephrine in conscious ganglion-blocked rats produced dose-dependent increases in SBP and COP. In DOCA-NaCl hypertensive rats but not in renovascular hypertensives, nor in rats treated with DOCA alone or 1% NaCl alone, the increase in COP for a given increment in dose of angiotensin or norepinephrine was significantly greater than in the control rats. It is concluded that in DOCA-NaCl hypertension there is a true increase in the reactivity of the smooth muscle of the resistance vessels to angiotensin and norepinephrine. In renovascular hypertension this is not the case and other factors must therefore be involved in causing the increased blood pressure and COP.     

Enhanced depressor effect of muscimol in the DOCA/NaCl hypertensive rat: evidence for altered GABAergic activity in brain

To elucidate the role of the central gamma-aminobutyric acid (GABA) system in the maintenance of deoxycorticosterone (DOCA)NaCl hypertension, the responses of mean arterial pressure (MAP), plasma norepinephrine (NE), and epinephrine (EP) to intracerebroventricular (ICV) administration of muscimol, a GABA agonist, and the responses of MAP to bicuculline, a GABA antagonist, and to clonidine, an alpha 2-adrenoceptor agonist known to lower blood pressure by inhibiting sympathetic tone, were examined in conscious, unrestrained 4 week DOCA/NaCl hypertensive rats and age-matched uninephrectomized control rats. Muscimol (50-1000 ng/300 g, ICV) caused dose-dependent decreases in MAP which were greater in DOCA/NaCl rats than in controls. Basal plasma NE and EP were significantly higher in DOCA/NaCl rats than in controls. Muscimol (1000 ng/300 g, ICV) induced decreases in plasma EP which were greater in DOCA/NaCl rats than in controls without changing NE levels in either group. Bicuculline (3 micrograms/300 g, ICV) caused increases in MAP which were the same in both groups. The depressor response to clonidine (5 micrograms/300 g) was greater in DOCA/NaCl rats than in controls. These results suggest that the activity of the central GABAergic system is altered in the rat with established DOCA/NaCl hypertension and that the alteration in central GABAergic function may be related to the increased sympathoadrenal activity and the maintenance of hypertension in this model.     

Influence of 4-week and 8-week exercise training on the pharmacokinetics and pharmacodynamics of intravenous and oral azosemide in rats

Cytochrome P450 expression was determined in the livers of control, 4-week exercised (4WE) and 8-week exercised (8WE) rats. Even though the 4-week and 8-week exercise training caused 53 and 25% increases, respectively, in total cytochrome P450 contents in the liver, exercise training did not cause any changes in the levels of P450 1A2 (which primarily metabolizes azosemide), 2E1 and 3A23 in the liver, as assessed by both Western and Northern blot analyses. Also, exercise training failed to alter the activity of NADPH-dependent cytochrome P450 reductase. The plasma concentrations of norepinephrine and epinephrine were significantly (2 to 3 folds) higher in 4WE rats than in controls, presumably due to physical stress, but the catecholamine levels in 8 WE rats returned to control levels. After intravenous administration (10 mg/kg of azosemide), the amount of unchanged azosemide excreted in 8-h urine (Ae(Azo, 0-8 h)) was significantly greater (46% increase) in 4WE rats than that in control rats. This resulted in a significantly faster (82% increase) renal clearance of azosemide. However, the nonrenal clearances were not significantly different between control and 4WE rats. The significantly greater Ae(Azo, 0-8 h) in 4WE rats was mainly due to a significant increase in intrinsic active secretion of azosemide in renal tubules and not due to a decrease in the metabolism of azosemide. After oral administration (20 mg/kg), Ae(Azo, 0-8 h) was also significantly greater (264%) in 4WE rats and this again was due to a significant increase in intrinsic active renal secretion of azosemide and not due to an increase in gastrointestinal absorption. After both intravenous and oral administration, the 8-h urine output was not significantly different between control and 4WE rats although Ae(Azo, 0-8 h) increased significantly in 4WE rats. This could be due to the fact that the urine output reached a plateau at 10 mg/kg after intravenous administration and 20 mg/kg after oral administration of azosemide to rats and possibly due to increase in plasma antidiuretic hormone levels and aldosterone production in 4WE rats.     

Cerebral intraventricular 6-hydroxydopamine prevents vascular changes in the mineralocorticoid hypertensive rat

The effect of cerebral intraventricular administration of 6-hydroxydopamine (6-OHDA) on blood pressure and vascular smooth muscle responsiveness in deoxycorticosterone acetate (DOCA)-treated rats was assessed. Rats treated with 6-OHDA and DOCA had significantly lower systolic blood pressures (142 +/- 8 mm Hg) than rats treated with DOCA alone (185 +/- 5 mm Hg). After 5 weeks of DOCA treatment, femoral arteries and aortae were excised from these rats, cut helically into strips, and placed in a muscle bath to record isometric force. Dose-response curves to serotonin were shifted to the left in femoral arteries from DOCA-treated rats compared to both control and 6-OHDA-DOCA-treated rats (ED50: DOCA = 6.8 X 10(-8) M, control = 27.9 X 10(-8) M, 6-OHDA-DOCA = 13.4 X 10(-8) M). Arachidonic acid, the prostaglandin precursor, produced greater maximal contractions in femoral artery strips of DOCA-treated rats (358 +/- 56 mg) than in those from controls (115 +/- 31 mg). The maximal response to arachidonic acid in arteries from 6-OHDA-DOCA rats (203 +/- 78 mg) was not different from control values. Ouabain produced a greater maximal response in aortic strips from DOCA rats (658 +/- 165 mg) compared to those from control (196 +/- 72 mg) or 6-OHDA-DOCA (309 +/- 87 mg) rats. We conclude that increased vascular responsiveness to serotonin, arachidonic acid, and ouabain in DOCA hypertensive rats is secondary to a central action of the mineralocorticoid.     

Lack of renal effects of DOCA, ACTH, spironolactone, and angiotensin II in Squalus acanthias

Angiotensin II was infused intravenously in spiny dogfish sharks (Squalus acanthias). There were no significant effects on arterial blood pressure, glomerular filtration rate, urine flow, or Na excretion either in comparison with pre- and postinfusion values or in comparison with values measured in a control group of fish given elasmobranch saline intravenously. In other dogfish, glomerular filtration rate, urine flow, and Na and K excretory rates were measured for 3 days following implantation of desoxycorticosterone (DOCA), adrenocorticotropin (ACTH), or spironolactone; a control group was given no drug. There were no significant differences between these four groups of fish with respect to any of the measured parameters. These results suggest that the dogfish kidney is not a target organ for several substances known to affect renal function, either directly or indirectly, in other animals.     

Adrenalectomy and steroid treatment in obese (ob/ob) and diabetic (db/db) mice

Adrenalectomy in young obese (ob/ob) and the diabetic (db/db) mouse slowed body weight gain. Treatment of adrenalectomized ob/ob mice with cortisone or deoxycorticosterone acetate (DOCA) significantly increased weight gain in a dose-related manner. Cortisone had no effect on weight gain on lean mice and treatment with dehydroepiandrosterone sulfate was without effect on either ob/ob or lean mice. The increment in body weight of adrenalectomized ob/ob mice treated with corticosterone and DOCA was associated with an increase in body weight and an increase in food intake. When adrenalectomy was performed at twenty-three days of age (five days before weaning), animals carrying the (db/db) genotype remained lighter than their normal littermates. These data document the importance of the adrenal gland and its steroids for the development and maintenance of many features of the obese or diabetes mouse.     

Urinary enzyme excretion in acute and subacute experimental lithium administration

Blood lithium (Li) levels, renal functional parameters and urine excretion of enzymatic activities having different intracellular sites were investigated on rats submitted to acute and subacute Li chloride administration. In acute experiments increased levels of all detected enzymes were assayed following Li single doses of 5 and 10 mEq/kg b.w. In subacute poisoning, urine output of lactate dehydrogenase, aspartate transaminase and alanine transaminase was significantly over the basal ranges following 15 days in concomitance with marked elevation of plasma Li levels and exhibited progressive increase until 30 days; on the 10th day following Li withdrawal, elevated excretion of enzymatic activities was still assayed. The results are in agreement with data about the localization of the histologic lesions involving different sites of the nephron in acute Li poisoning and the distal tubular tract in subacute toxicity. In subacute administration the output of cytoplasmic and mitochondrial activities can be assumed as an index of damage of the nephron cells which can persist following Li withdrawal. Our findings indicate that the urine enzyme assay is a valuable tool to detect renal damage in experimental Li nephropathy.     

Reversal of diabetes by allogenic islet transplantation without immunosuppression

Streptozotocin-induced diabetes is temporarily reversed following the allo-transplantation of BALB/c (H-2d) islet tissue to normal CBA (H-2k) recipients, but by 2-4 week post-transplantation these animals return to their initial diabetic condition. Organ culture of allogeneic islet tissue in 95% O2 and 5% CO2 for 7 days prior to transplantation reduces the immunogenicity of the tissue, and cultured allografts give prolonged (greater than 110 days) reversal of diabetes in normal allogeneic recipients. The non-fasting blood sugar level remains in or very close to the normal range, urine glucose output is one to two orders of magnitude less than that of diabetic control animals and allografted animals regain their pre-morbid body weight within 60 days of transplantation. Surgical removal of the allograft results in a rapid return of the animal to the initial diabetic condition.     

The effects of hypoxemia with progressive acidemia on fetal renal function in sheep

In order to determine the effects of fetal hypoxemia on renal blood flow, glomerular filtration rate (GFR) and urethral and urachal urine output, we examined the effects of 3 h maternally-induced (9% O2, 3% CO2, 88% N2) fetal hypoxaemia on 10 chronically-instrumented fetal sheep between 127-135 days of gestation. Fetal arterial pH fell significantly during the second and third hours of hypoxia and this coincided with a significant increase in fetal arterial blood pressure (P less than 0.05). During the second hour of hypoxia, with mild acidaemia, fetal GFR decreased significantly and then, during the third hour, fetal GFR, urethral and total urine output were significantly elevated. During the 2-h recovery period urachal and total, but not urethral urine output, were significantly elevated (P less than 0.05). The data suggested that the increase in GFR and urine output measured during the third hour of hypoxia and the recovery period may reflect a pressure diuresis.     

mPGES-1 deletion potentiates urine concentrating capability after water deprivation

PGE(2) plays an important role in the regulation of fluid metabolism chiefly via antagonizing vasopressin-induced osmotic permeability in the distal nephron, but its enzymatic sources remain uncertain. The present study was undertaken to investigate the potential role of microsomal PGE synthase (mPGES)-1 in the regulation of urine concentrating ability after water deprivation (WD). Following 24-h WD, wild-type (WT) mice exhibited a significant reduction in urine volume, accompanied by a significant elevation in urine osmolality compared with control groups. In contrast, in response to WD, mPGES-1 knockout (KO) mice had much less urine volume and higher urine osmolality. Analysis of plasma volume by measurement of hematocrit and by using a nanoparticle-based method consistently demonstrated that dehydrated WT mice were volume depleted, which was significantly improved in the KO mice. WD induced a twofold increase in urinary PGE(2) output in WT mice, which was completely blocked by mPGES-1 deletion. At baseline, the KO mice had a 20% increase in V(2) receptor mRNA expression in the renal medulla but not the cortex compared with WT controls; the expression was unaffected by WD irrespective of the genotype. In response to WD, renal medullary aquaporin-2 (AQP2) mRNA exhibited a 60% increase in WT mice, and this increase was greater in the KO mice. Immunoblotting demonstrated increased renal medullary AQP2 protein abundance in both genotypes following WD, with a greater increase in the KO mice. Similar results were obtained by using immunohistochemistry. Paradoxically, plasma AVP response to WD seen in WT mice was absent in the KO mice. Taken together, these results suggest that mPGES-1-derived PGE(2) reduces urine concentrating ability through suppression of renal medullary expression of V(2) receptors and AQP2 but may enhance it by mediating the central AVP response.     

"Pink urine" in morbidly obese patients following gastric partitioning.

A pink coating on the inner surface of plastic urinary tubing, which gave the impression that the urine was pink, had frequently been noted 4 to 24 hours following gastric partitioning by means of a stapler in morbidly obese patients. A study was therefore done in 187 such patients as well as in 14 patients of normal weight who had undergone abdominal surgery of comparable magnitude. Postoperatively "pink urine" was observed in 32% of the obese patients but in none of the nonobese patients; however, a pink sediment remained following centrifugation of urine collected postoperatively from all the obese patients. Microscopy of this sediment showed crystals of uric acid dihydrate; these were infrequent in the preoperative specimens but present in high concentration in the postoperative specimens, particularly those of "pink urine". X-ray diffraction analysis confirmed the nature of the crystals. Preoperatively the obese patients had high-normal serum levels of uric acid. Postoperatively in all the groups of patients the serum levels of uric acid decreased while the urine levels and the urinary clearance of uric acid increased; the last two values, however, were significantly greater, both preoperatively and postoperatively, in those who were morbidly obese. Compared with the patients who did not have "pink urine" the patients with "pink urine" were significantly more obese and had a significantly lower postoperative urine pH. The latter also had a marked postoperative increase in urine osmolality and were the only patients to have a significant postoperative decrease in urine output. Thus, the pink colour of this group''s urine was attributed to precipitation of uric acid crystals, fostered by a decrease in pH and an increase in concentration of the urine.     

Increased release of atrial natriuretic polypeptides in rats with DOCA-salt hypertension

This study compared atrial and plasma concentrations of immunoreactive alpha-rat atrial natriuretic polypeptide (i alpha-rANP) in rats given tap water (control), a 1% saline solution (salt), deoxycorticosterone acetate (DOCA) and DOCA plus 1% saline solution (DOCA-salt) after 1 and 8 weeks of treatment. DOCA (100 mg/kg) was given by implanting a piece of silicon rubber impregnated with DOCA subcutaneously. Atrial i alpha-rANP increased, while plasma i alpha-rANP decreased with time in all groups. Atrial concentration of i alpha-rANP was significantly lower in the DOCA-salt group than in the other groups at 1 week, and was reduced in the DOCA and DOCA-salt groups as compared to the control group at 8 weeks. On the other hand, plasma concentration of i alpha-rANP was significantly higher in the DOCA and the DOCA-salt groups than in the control group at 1 week; the DOCA and DOCA-salt group values were also higher than the control and salt group values at 8 weeks. Atrial concentration of i alpha-rANP was inversely correlated with systolic blood pressure in the all rats at 1 week (r = 0.48, p less than 0.001) and at 8 weeks (r = 0.33, p less than 0.05). Plasma concentration of i alpha-rANP was positively correlated with systolic blood pressure at 8 weeks (r = 0.37, p less than 0.05). In addition, there was a significant positive correlation between plasma/atrial ratio of i alpha-rANP concentration and systolic blood pressure at either stage (r = 0.41, p less than 0.01 at 1 week; r = 0.40, p less than 0.01 at 8 weeks). Thus, it seems likely that the release of ANPs is increased in response to expansion of extracellular fluid volume or elevation of blood pressure, modifying the development of hypertension in DOCA-salt rats.     

Chronic infusion of angiotensin-(1-7) into the lateral ventricle of the brain attenuates hypertension in DOCA-salt rats

Angiotensin-(ANG)-(1-7) is known by its central and peripheral actions, which mainly oppose the deleterious effects induced by accumulation of ANG II during pathophysiological conditions. In the present study we evaluated whether a chronic increase in ANG-(1-7) levels in the brain would modify the progression of hypertension. After DOCA-salt hypertension was induced for seven days, Sprague-Dawley rats were subjected to 14 days of intracerebroventricular (ICV) infusion of ANG-(1-7) (200 ng/h, DOCA-A7) or 0.9% sterile saline. As expected, on the 21st day, DOCA rats presented increased mean arterial pressure (MAP) (≈40%), and impaired baroreflex control of heart rate (HR) and baroreflex renal sympathetic nerve activity (RSNA) in comparison with that in normotensive control rats (CTL). These changes were followed by an overactivity of the cardiac sympathetic tone and reduction of the cardiac parasympathetic tone, and exaggerated mRNA expression of collagen type I (≈9-fold) in the left ventricle. In contrast, DOCA rats treated with ANG-(1-7) ICV had an improvement of baroreflex control of HR, which was even higher than that in CTL, and a restoration of the baroreflex control of RSNA, the balance of cardiac autonomic tone, and normalized mRNA expression of collagen type I in the left ventricle. Furthermore, DOCA-A7 had MAP lowered significantly. These effects were not accompanied by significant circulating or cardiac changes in angiotensin levels. Taken together, our data show that chronic increase in ANG-(1-7) in the brain attenuates the development of DOCA-salt hypertension, highlighting the importance of this peptide in the brain for the treatment of cardiovascular diseases.     

还原型谷胱甘肽治疗儿童葡萄糖-6-磷酸脱氢酶缺乏症中的临床效果研究

目的:研究还原型谷胱甘肽治疗儿童葡萄糖-6-磷酸脱氢酶(G-6-P-D)缺乏症并发急性溶血的临床疗效,为临床治疗提供参考。方法:选取我院2015年6月-2017年6月因葡萄糖-6-磷酸脱氢酶(G-6-P-D)缺乏症并发急性溶血的患儿78例并将其随机分为两组,每组39例。对照组予以停用氧化类药物,卧床休息,水化、碱化尿液,贫血严重者输注去白红细胞治疗;观察组在对照组基础上加用还原型谷胱甘肽治疗。观察和比较两组患儿第1天、第2天、第3天小便恢复率以及平均恢复时间,血清总胆红素第3天、第5天恢复率、平均恢复时间及平均住院时间。结果:治疗后,观察组第1天、第2天、第3天小便恢复率分别为51.3%、92.3%、100%,对照组分别为25.6%、64.1%、89.7%,观察组第1天、第2天、第3天小便恢复率均显著高于对照组(P0.05);观察组及对照组小便恢复正常平均时间分别为1.8±0.7天、2.6±0.9天,观察组明显短于对照组(P0.05);观察组第3天、第5天血清总胆红素恢复率分别为71.8%、100%,对照组为46.2%、97.4%;观察组和对照组血清总胆红素恢复正常平均时间分别为3.6±0.9天、4.1±1.0天;平均住院时间分别为2.3±0.6天、2.8±0.6天;观察组小便及血清总胆红素平均恢复时间(P0.05)、平均住院时间均显著短于对照组(P0.05)。结论:在儿童葡萄糖-6-磷酸脱氢酶缺乏并发急性溶血中应用还原型谷胱甘肽可增强其治疗疗效,缩短治疗疗程。     

Comparison of red and white muscle wet weight changed by age, denervation and morbid states

[Na]i, [K]i and wet weight of the extensor digitrum longus (EDL) and soleus (SOL) muscles of 9- and 52-week-old rats were measured for 7 days after sectioning of the sciatic nerve. The changes in wet weight of the EDL and SOL muscles of rats over 52 weeks and those of morbid state rats were also measured. There was no significant difference in wet weights between the EDL and SOL muscles in infant rats, but the EDL muscle became much heavier than the SOL muscle with aging. The decrease in rate of growth of wet weight of the EDL and SOL muscles caused by denervation, was greater in young rats than in mature rats. In addition, the rate of decrease was greater in the SOL muscles than in the EDL muscles in both young and mature rats. The [Na]i increased while [K]i was decreased by denervation, and the net Na+ increase and the net K+ loss were greater in young rats than in mature rats. The changing rate was more remarkable in the EDL muscles than in the SOL muscles throughout the aging process. During DOCA treatment over 4 weeks, the decrease of muscle wet weight was greater in the EDL muscles. The mechanisms which serve to maintain normal muscle wet weight in the SOL muscle after denervation or treatment with DOCA, were discussed.     

Changes of hypothalamic and plasma vasopressin in rats with deoxycorticosterone-acetate induced salt appetite.

Mineralocorticoids play a predominant role in development of salt appetite and hypertension. Since vasoactive peptides could mediate the central effects of mineralocorticoids, we evaluated changes of immunoreactive (IR) arginine vasopressin (AVP) in the paraventricular (PVN) and supraoptic (SON) hypothalamic nucleus during DOCA-induced salt appetite. In one model, rats having free access to water and 3% NaCl during 9 (prehypertensive stage) or 21 days (hypertensive stage) received DOCA (s.c., 10 mg/rat/in alternate days). A decrease in the IR cell area, number of IR cells and staining intensity was obtained in magnocellular PVN of rats treated during 9 days. After 21 days IR cell area and number of cells in the PVN also decreased, but staining intensity of remaining cells was normal. The same parameters were unchanged in the SON. In another model, animals treated with DOCA during 9 days had only access to 3% NaCl or water. The IR cell area in PVN and SON significantly increased in mineralocorticoid-treated and control animals, both drinking 3% NaCl. Staining intensity (PVN and SON) and number of IR cells (PVN) also augmented in DOCA-treated animals drinking salt respect of a group drinking water. Plasma AVP in rats treated with DOCA and offered salt and water, exhibited a 2-2.5 fold increase at the time of salt appetite induction. Plasma AVP was substantially higher in rats drinking salt only, while the highest levels were present in salt-drinking DOCA-treated rats. Thus, peptide depletion in the PVN may be due to increased release, because reduced levels of hypothalamic and posterior pituitary AVP were measured in this model. In rats drinking salt only the substantial increase of IR AVP in the PVN and SON, may be due to dehydration and hyperosmosis. Because DOCA-salt treated rats showed higher AVP levels in the PVN compared to untreated rats drinking salt only, it is possible that DOCA sensitized PVN cells to increase AVP production. The results suggest the vasopressinergic system could mediate some central functions of mineralocorticoids.     

Effect of combination of renin inhibitor and Mas-receptor agonist in DOCA–salt-induced hypertension in rats

To investigate the combined effect of aliskiren, a renin inhibitor, and AVE 0991, a Mas-receptor agonist, in experimental hypertension (HT) in rats. HT was produced by administration of deoxycorticosterone acetate (DOCA) and mean arterial blood pressure (MABP) was assessed by tail-cuff method. Treatments were started from 4th week onwards and were continued for 9 days. A significant increase in MABP was noted after 1 week in DOCA control rats, as compared with the base line value. A stable HT developed after 4 weeks of DOCA administration. Treatments with aliskiren and AVE 0991 alone, dose-dependently decreased MABP in DOCA-treated rats. Further, combination of low doses of aliskiren and AVE 0991 significantly reduced MABP, as compared with DOCA control rats and with either drug alone in low doses. It may be concluded that treatment with aliskiren produced down-regulation of both harmful Ang II–AT1-receptor and survival Ang(1–7)/Mas-receptor axis of RAAS. Treatment with combination of low doses of aliskiren and AVE 0991, for the first time, has been shown to produce synergistic blood pressure lowering effect. Therefore, combination of renin inhibitor with Mas-receptor agonist may prove beneficial for the treatment of hypertensive patients.