Skeletal resistance to the calcemic action of parathyroid hormone in uremia: role of 1,25 (OH)2 D3

Studies were carried out to investigate the role of 1,25(OH)2D3 in the skeletal resistance to the calcemic action of parathyroid hormone. The change in serum calcium after the intravenous infusion of 2 U of parathyroid extract (PTE)/kg body wt/hr for eight hours was evaluated in thyroparathyroidectomized (T-PTX) dogs before, and one, two and three days after, induction of uremia by bilateral ureteral ligation (11 dogs) or by bilateral nephrectomy (8 dogs). In another six nephrectomized and T-PTX dogs, 0.68 ug of 1, 25 (OH)2D3/day was given on the day of nephrectomy and for two days thereafter. Serum creatinine in each day of the study was not different among the three groups. The study also included the evaluation of the effect of sham operation (five dogs) and the administration of 1,25 (OH)2D3 to dogs with normal renal function (four dogs) on the calcemic response to PTE, as well as the reproducibility of such a response in the same animal. The results showed that 1) the calcemic response to PTE was markedly impaired after one day of bilateral ureteral ligation or nephrectomy, but the impairment was more severe after nephrectomy; 2) the calcemic response to PTE after two or three days of bilateral ureteral ligation was similar to that seen at one day after nephrectomy; 3) 1, 25 (OH)2D3 partially restored the calcemic response to PTE in the nephrectomized animals to levels similar to those seen after one day of bilateral ureteral ligation; 4) sham operation did not affect the response to PTE, and repeated infusion of PTE produced similar changes in the concentrations of serum calcium. The data indicate that (a) a deficiency of 1,25 (OH)2D3 is at least partly responsible for the skeletal resistance to the calcemic action of PTH in uremia; (b) uremia, per se, may also contribute to this phenomenon; and (c) the kidney after one day of complete bilateral ureteral ligation may still produce 1,25 (OH)2D3, but this ability is compromised after two days of ureteral obstruction.     

The Renin-Angiotensin System and Thirst: A Reevaluation. II. Drinking Elicited in Rats by Caval Ligation or Isoproterenol.

Ligation of the inferior vena cava and administration of isoproterenol have been shown to stimulate renin secretion and to augment water intake in rats. However, the present experiments suggested that the plasma renin activities produced by these treatments do not account for more than 20% of the observed drinking behavior. Direct measurements of arterial blood pressure further indicated that nephrectomized rats go into hypotensive shock after caval ligation or isoproterenol treatment. Drinking was elicited in these hypotensive animals by systemic injection of hypertonic NaCl solution, renin, or Pitressin, or by intracranial injection of angiotensin, but in each case a rapid increase in blood pressure also was observed. Thus, it appears that nephrectomy reduces water intake in these animals by undermining their general capacity to behave rather than by removing a specific dipsogenic stimulus. These and other results suggested that drinking elicited in rats by caval ligation or isoproterenol is not mediated by the renin-angiotensin system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Elevated des-AngI-angiotensinogen levels by nephrectomy and adrenalectomy

This study investigates the time course of plasma levels of angiotensinogen (Aogen) and of the Aogen metabolite des-AngI-angiotensiongen (des-AngI-Aogen) in nephrectomized rats with and without adrenals for 24 h. After nephrectomy the plasma Aogen levels increased 5-fold over the following 24 h. The increase is significantly lower after sham nephrectomy (3.7-fold, P < 0.05) and if the kidneys are withdrawn without decapsulization (2.4-fold, P < 0.05). A small and transient increase arise after nephrectomy plus adrenalectomy (1.6-fold after 8 h, P < 0.005). After adrenalectomy alone Aogen levels continuously shrink to 38% of control values after 24 h. Plasma des-AngI-Aogen levels increase 2.1- to 3.7-fold 24 h after the different nephrectomy procedures. In connection with recent findings these data support the notion that the increase in Aogen plasma levels after bilateral nephrectomy is triggered by renin, released during surgery. High plasma levels of des-AngI-Aogen after nephrectomy indicate that AngI is generated by tissue renin, e.g., in the adrenals. This suggests that after nephrectomy the plasma des-AngI-Aogen levels should be a valuable proof for the evaluation of the amount of generated angiotensin.     

Erratum to Stricker.

Reports an error in the article "The The Renin-Angiotensin System and Thirst: A Reevaluation. II. Drinking Elicited in Rats by Caval Ligation or Isoproterenol" by Edward M. Stricker (Journal of Comparative and Physiological Psychology, 1977, Vol. 91, No. 6, pp. 1220-1231), one line was printed incorrectly. On page 1228, the third line in the left-hand column reads "protin after 2 U/100 g hog renin"; the entire first sentence should read as follows: Three other nephrectomized rats were anesthetized 50 min after .33 mg/kg isoproterenol, 5 min after 2 U/100 g hog renin had been given. (The following abstract originally appeared in record 2005-09077-001) Ligation of the inferior vena cava and administration of isoproterenol have been shown to stimulate renin secretion and to augment water intake in rats. However, the present experiments suggested that the plasma renin activities produced by these treatments do not account for more than 20% of the observed drinking behavior. Direct measurements of arterial blood pressure further indicated that nephrectomized rats go into hypotensive shock after caval ligation or isoproterenol treatment. Drinking was elicited in these hypotensive animals by systemic injection of hypertonic NaCl solution, renin, or Pitressin, or by intracranial injection of angiotensin, but in each case a rapid increase in blood pressure also was observed. Thus, it appears that nephrectomy reduces water intake in these animals by undermining their general capacity to behave rather than by removing a specific dipsogenic stimulus. These and other results suggested that drinking elicited in rats by caval ligation or isoproterenol is not mediated by the renin-angiotensin system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Participation of renal, but not of submaxillary renin in the homeostasis of the blood pressure after experimentally induced hypotension in mice

While hypotension elicited a marked increase in plasma renin concentration in conscious normal mice, no increase was provoked in previously nephrectomized mice in spite of the high renin content of their submaxillary glands. The role of the increased release of renal renin for the homeostasis of the blood pressure was shown by the decrease in pressure which followed blockade of the renin system. Contrary to Saralasin which did not change the blood pressure in nephrectomized mice, injections of SQ 20.881 did in some mice result in a decrease in blood pressure, which was probably caused by its ability to inhibit bradykininases. Both Saralasin and SQ 20.881 elicited marked increases in plasma renin in normal, but not in nephrectomized mice, showing that, while renal renin release is controlled by the plasma angiotensin II concentration, this does not apply to submaxillary renin release.     

Cause of the continuous rise in plasma renin concentration after removal of manipulated submaxillary glands in nephrectomized mice

After gentle manipulation with subsequent removal of the submaxillary glands in nephrectomized mice there is a vast increase in the concentrations of high molecular weight renin ("prorenin"?) as well active renin in plasma. The increase in active renin is continuous even after removal of glands as well as kidneys. Using in vitro incubation and replacement transfusion experiments, the continuous rise was found not to be due to activation of the high molecular weight renin. The continous increase could instead be shown to be due to a rapid transfer of submaxillary lymph and (or) interstitial fluid to the surrounding tissues, with a subsequent slower release from these tissues to the blood. Continued release of renin from extra-submaxillary tissue-depots is probably also the cause of the continuance of the high plasma renin concentrations for several hours after the removal of the manipulated glands, which contrast with the much more rapid decline in the concentration after injection of extracts of submaxillary glands as well as after injection of pure submaxillary renin.     

Regulation of compensatory kidney hypertrophy by its own products

1. The ligation of blood vessels of one kidney of adult rats resulted in the compensatory hypertrophy of the other kidney. In most animals the rate of hypertrophy was indistinguishable from that observed after unilateral nephrectomy, but in a few cases the onset was retarded when the renal artery alone had been ligated and the collateral circulation increased.2. When the blood vessels of one kidney of adult rats were ligated and the cortex was excised, the rate of compensatory renal hypertrophy was similar to that observed after unilateral nephrectomy.3. In animals operated for simultaneous partial hepatectomy and unilateral nephrectomy, there was no sign of compensatory renal hypertrophy while the liver was undergoing regeneration. Renal hypertrophy started after 7 days, when about 98% of the amount of liver removed had been regenerated.4. Neither aseptic autolysis of one kidney following suppression of its blood supply, nor unilateral nephrectomy affected the rate of liver regeneration after simultaneous partial hepatectomy.5. Total splenectomy did not affect the rate of compensatory renal hypertrophy following unilateral nephrectomy.6. The heterotopic graft of renal cortical, but not of medullary, cells inhibited compensatory renal hypertrophy in adult rats. The removal of the graft after 14 days was followed by the resumption of compensatory hypertrophy.7. The inhibiting action of fractions of renal cortical extracts fractionated on Sephadex G100 resin and DEAE-52 cellulose were assayed on the ;growth' of renal explants reared in vitro. The final material, though only partially purified, proved to have an inhibiting activity between 250 and 500 times greater than that of the initial extract.8. When injected into unilaterally nephrectomized rats, the partially purified extract from the renal cortex had an inhibiting effect on compensatory renal hypertrophy.9. Immunofluorescence technique showed that the partially purified cortical extract affected the proximal convoluted tubes specifically, irrespective of animal species.     

Inhibition of transmembrane K transfer in ureter-ligated dogs infused with KCl

In anuric dogs loaded with K by infusion with 2 meq KCl/kg per h until prelethal hyperkalemic cardiotoxicity appears, the extent of transmembrane K transfer depends on the origin of the anuria. Animals with bilateral ureter ligation transfer a mean of 1.2 meq/kg to intracellular fluid, while those with bilateral nephrectomy transfer more than 2.5 times as much (3.1 meq/kg). Further, if dogs with functioning kidneys are ureter ligated or nephrectomized after approximately 45 min of K loading, K transfer ultimately falls as infusion continues. The fall is precipitate and over 90% in ligated animals; but it is gradual, and only 10% in those that are nephrectomized. Finally, K transfer, because of the absence of insulin, is negligible in K-loaded pancreatectomized dogs with bilateral ureter ligation, but fairly substantial in pancreatectomized animals with bilateral nephrectomy. The data suggest that ureter ligation and hyperkalemia activate a renal mechanism that interferes with the transfer of infused K to intracellular fluid. The mechanism may involve the renin-angiotensin II-aldosterone system to a limited degree.     

Metabolic responses to preexercise meals containing various carbohydrates and fat

Renal function was examined after unilateral release, bilateral release or unilateral release and contralateral nephrectomy in three groups of rats following 24 h of bilateral ureteral obstruction (BUO). Excretion of water, sodium and urea was significantly greater in rats with unilateral release of BUO than in a single kidney of rats with bilateral release of BUO, in spite of similar levels of glomerular filtration rate (GFR) and effective renal plasma flow. Rats with unilateral release of obstruction and contralateral nephrectomy had a significantly lower GFR than the other two groups. These rats also responded with greater increases in fractional sodium and water excretion to the administration of exogenous atrial peptide. The results demonstrate a marked compensatory increase in sodium and water excretion in rats with unilateral release of the obstruction which serves to maintain homeostasis of fluid and salt. They also suggest a possible influence of the continuously obstructed kidney on the function of the postreleased kidney. The results also provide experimental support for a greater recovery of renal excretory function after bilateral release of obstruction.     

Pathogenesis and characterization of hyperglucagonemia in the uremic rat

The pathogenesis of hyperglucagonemia and of the alterations in the pattern of circulating immunoreactive glucagon (IRG) associated with renal insufficiency was studied in rats in which a comparable degree of uremia was induced by three different methods, i.e., bilateral nephrectomy, bilateral ureteral ligation, and urine autoinfusion. Nephrectomized and ureteral-ligated rats were markedly hyperglucagonemic (575 +/- 95 pg/ml and 492 +/- 54 pg/ml, respectively), while IRG levels of urine autoinfused animals (208 +/- 35 pg/ml) were similar to those of control rats (180 +/- 26 pg/ml), indicating that uremia per se does not account for the hyperglucagonemia observed in renal failure. Similarly, plasma IRG composition in this group of animals was indistinguishable from that of controls, in which 88.2 +/- 5.9% of total IRG consisted of the 3,500-mol wt fraction. The same component was almost entirely responsible (82.6 +/- 4.1%) for the hyperglucagonemia observed in ligated rats, while it accounted for only 57.6 +/- 5.0% of the circulating IRG in nephrectomized animals. In the latter group, 36.8 +/- 6.6% of total IRG had a mol wt of approximately 9,000, consistent with a glucagon precursor. This peak was present in samples obtained as early as 2 h after renal ablation and its concentration continued to increase with time reaching maximal levels at 24 h. These results confirm that the kidney is a major site of glucagon metabolism and provide evidence that the renal handling of the various circulating IRG components may involve different mechanisms. Thus, the metabolism of the 3,500-mol wt fraction is dependent upon glomerular filtration, while the uptake of the 9,000-mol wt material can proceed in its absence, as long as renal tissue remains adequately perfused. This finding suggests that the 9,000-mol wt component may be handled by peritubular uptake.     

Effects of zinc deficiency on endogenous antioxidant enzymes and lipid peroxidation in glomerular cells of normal and five-sixths nephrectomized rats

We evaluated the effects of zinc deficiency on the activities of endogenous antioxidant enzymes and lipid peroxidation in rat glomerular cells (GCs). Male Sprague-Dawley rats (n = 48) were fed a zinc-deficient diet and deionized distilled water for 1 week to induce zinc deficiency. Half of the rats (zinc-deficient group) continued on this diet for 4 weeks, and the other half (zinc-replete group) were maintained on the same diet but with zinc-supplemented water (150 mg/Lzinc sulfate solution). Half of each group underwent five-sixths nephrectomy, while the other half underwent a sham operation. Another 12 normal rats (controls) were fed standard rat chow (containing 23.4% protein and 70 ppm zinc) and drank deionized distilled water. The zinc-deficient rats, including sham and five-sixths nephrectomized rats, showed severe growth retardation and poor appetite. Their mean plasma zinc concentrations were half that of normal control rats, but their plasma copper concentration was significantly higher than that of the control rats. Zinc supplementation corrected the abnormality of plasma zinc and copper concentrations and the loss of body weight in zinc-deficient rats. Zinc-deficient rats exhibited lower renal creatinine clearance and higher GC-malondialdehyde (GC-MDA) than zinc-replete rats. The remnant kidney of all five-sixths nephrectomized rats, including zinc-deficient and zinc-replete rats, showed a compensatory elevation in renal creatinine clearance and increased GC-MDA concentrations. Zinc concentrations in the renal cortex were decreased in zinc-deficient rats and the activities of GC-superoxide dismutase and GC-glutathione peroxidase were increased, while zinc-replete rats exhibited normal activities of GC-superoxide dismutase and GC-glutathione peroxidase. We suggest that zinc deficiency enhances the formation of reactive oxygen species but does not affect the activities of endogenous antioxidant enzymes in glomerular cells.     

Tissue-specific regulation of IRS-1 in unilaterally nephrectomized rats

Insulin stimulates the tyrosine kinase activity of its receptor, resulting in the phosphorylation of its cytosolic substrate, insulin receptor substrate 1 (IRS-1). IRS-1 is also a substrate for different peptides and growth factors, and a transgenic mouse "knockout" for this protein does not have normal growth. However, the role of IRS-1 in kidney hypertrophy and/or hyperplasia was not investigated. In the present study we investigated IRS-1 protein and tyrosine phosphorylation levels in the remnant kidney after unilateral nephrectomy (UNX) in 6-week-old male Wistar rats. After insulin stimulation the levels of insulin receptor and IRS-1 tyrosine phosphorylation were reduced to 79 +/- 5% (P < 0.005) and 58 +/- 6% (P < 0.0001), respectively, of the control (C) levels, in the remnant kidney. It is possible that a circulating factor and/or a local (paracrine) factor playing a role in kidney growth can influence the early steps of insulin action in parallel. To investigate the hypothesis of a circulating factor, we studied the early steps of insulin action in liver and muscle of unilateral nephrectomized rats. There was no change in pp185 tyrosine phosphorylation levels in liver (C 100 +/- 12% vs UNX 89 +/- 9%, NS) and muscle (C 100 +/- 22% vs UNX 91 +/- 17%, NS), and also there was no change in IRS-1 phosphorylation levels in both tissues. These data demonstrate that after unilateral nephrectomy there is a decrease in insulin-induced insulin receptor and IRS-1 tyrosine phosphorylation levels in kidney but not in liver and muscle. It will be of interest to investigate which factors, probably paracrine ones, regulate these early steps of insulin action in the contralateral kidney of unilaterally nephrectomized rats.     

The renin-angiotensin-aldosterone system in mother and fetus at term

Plasma renin activity, renin substrate, angiotensin II, aldosterone and cortisol were measured concurrently and renin concentration calculated in plasma from mothers during labor and delivery, from cord and from newborn infants. The renin-angiotensin-aldosterone system was found strongly stimulated in both mother and fetus. The high values of plasma renin activity in fetus were due exclusively to the high renin concentrations the substrate concentration being normal. In the mother, however, the markedly elevated renin substrate resulted in a doubling of relative values of renin activity compared to renin concentration. Therefore gradients of renin and renin substrate across the placenta are established, but the resulting renin activity is similar on both sides and the levels of generated angiotensin II are also nearly indentical with a good correlation between these last parameters. Aldosterone is as elevated in mother as in fetus whereas cortisol, due to its binding to transcortin, is twice as high in mother as in fetus. No correlation was found between renin activity or concentration of angiotensin II and aldosterone or cortisol indicating that other factors controlling aldosterone are involved.     

Effects of ethinylestradiol on the renin-angiotensin-aldosterone-system and on plasma transcortin in women and men

The effects of ethinylestradiol (1 mug/kg body weight daily) on plasma renin substrate concentration, other factors of the renin-aldosterone-system, and on the cortisol-binding capacity of transcortin were determined in 8 young men and 9 young women. The absolute and relative elevation of plasma renin substrate after 5, 14, and 24 days of ethinylestradiol administration was significantly (P less than 0.001) greater in females than males. Control and posttreatment transcortin levels were also higher in women than men, but the percentage increase did not differ between males and females. It is likely that sex differences in the response of plasma renin substrate to the estrogen are due to differences in hepatic synthesis and/or release of renin substrate. In females, plasma renin activity, angiotensin II concentration, and urinary aldosterone excretion rose significantly although less markedly than plasma renin substrate concentration, while in males only the increase in plasma angiotensin II concentration was significant. These results indicate that no safe conclusions on metabolic effects of estrogen treatment in women can be drawn from experiments carried out in male subjects.     

Effect of estrogen upon the juxtaglomerular apparatus and the renin-angiotensin system in rats

Administration of 1.5 mg/kg of estriol intramuscularly and 15 mg/kg of stilbestrol disulfate intraperitoneally daily for 15 days caused an increase in plasma renin substrate (PRS), accompanied by an increase in plasma renin activity (PRA) and a slight decrease in plasma renin concentration (PRC). Contrary to the slight suppression of PRC, juxtaglomerular granulation index (JGI) was significantly increased in rats treated by estrogen. In the rats which developed hypertension by estrogen PRA, PRC and JGI were a little higher than those in the rats which remained normotensive after the same estrogon treatment, but these differences were not statistically significant. Therefore, it seems rather difficult to attribute the development of estrogen hypertension only to the quantitative changes in the renin-angiotensin system.     

Immunohistochemistry of unclassified sex cord-stromal tumors of the testis with a predominance of spindle cells

Onpi-to (TJ-8117) is a herbal medicine composed of five crude drugs (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber). Our previous experiments have demonstrated that TJ-8117 suppressed the development of glomerulosclerosis and retarded the deterioration of renal function in 5/6 nephrectomised rats. In the present study, the effects of TJ-8117 and (-)Epicatechin-3-O-gallate (ECG), which is a component of Rhei Rhizoma, on glomerular cell proliferation, extracellular matrix accumulation and glomerular hypertrophy were investigated in 5/6 nephrectomized rats. Male Wistar rats (170-180 g) were subjected to 5/6 nephrectomy, and TJ-8117 (0.32%, 0.64%) or angiotensin-converting enzyme inhibitor, captopril (CAP 0.08%) was administered daily by mixing in normal chow and ECG (2 mg, 8 mg/100 ml) by drinking water from the day after 5/6 nephrectomy. Following 5/6 nephrectomy, glomerular cell poliferation was increased and reached a maximum at 1 week in the untreated control rats, but was suppressed significantly at 1 and 2 weeks after treatment with TJ-8117 and at only 1 week after treatment with CAP. Extracellular matrix accumulation was detected after 1 week and increased gradually until 4 weeks in the control rats, whereas it was significantly inhibited in both the TJ-8117- and CAP-treated rats. In addition, immunohistochemistry revealed that TJ-8117 significantly inhibited the increase of fibronectin, and tended to reduce type I and type IV collagen at 4 weeks. Furthermore, TJ-8117 suppressed glomerular hypertrophy at 4 weeks. Systolic blood pressure (SBP) and urinary protein excretion (UP) were higher in the control rats than sham-operated rats. TJ-8117 prevented this increase of SBP and UP at 1 week. ECG also suppressed glomerular cell proliferation and the increase of SBP and UP at 1 week after 5/6 nephrectomy. These findings suggest that ECG was one of active components of TJ-8117. These results suggest that TJ-8117 suppressed proliferating changes in glomeruli at an early stage in 5/6 nephrectomized rats, and inhibited the development of glomerulosclerosis.     

Role of the kidney in regulating plasma immunoreactive beta-melanocyte-stimulating hormone

An analysis of the factors that influence the increase in plasma immunoreactive beta-melanocyte-stimulating hormone (beta-MSH) concentration in chronic renal failure showed that: (a) the increase correlated with the increase in serum creatinine concentrations; (b) beta-MSH was not cleared from the plasma by haemodialysis; (c) beta-MSH concentrations increased with length of time on dialysis and increased further after bilateral nephrectomy but there was no further increase with time; (d) beta-MSH levels decreased to normal after renal transplantation; and (e) beta-MSH was excreted in urine only when plasma levels rose to well above those of chronic renal failure (in Nelson's syndrome). These findings suggest that the kidney regulated plasma beta-MSH by a non-excretory mechanism and is the major site of beta-MSH metabolism.     

Binding of thiopental to plasma proteins: effects on distribution in the brain and heart

Thiopental-14C (30 mg and 10 muCi/kg) was injected intravenously into rats 36-48 hours following bilateral nephrectomy and one minute after pretreatment with sulfadimethoxine (30 mg/kg, iv). Control groups of normal and sham-operated animals were used. The distributions of radioactivity in plasma, brain, and heart 1, 5, and 30 minutes after injection were examined. Uremic and sulfonamide-pretreated rats showed significantly higher levels of 14C in brain and heart and more free thiopental in plasma at each time than did control animals. There was a significant correlation between the free thiopental in plasma and total drug concentrations in the brain and heart. Uremic rats bound less thiopental in plasma compared with controls in spite of normal total plasma protein and albumin concentrations. It is concluded that reduced protein binding of thiopental leads to accelerated distribution and increased drug concentrations in the brain and and heart.     

An experimental model of the effect of uremia on cyclosporin A availability

BACKGROUND: The aim of the study was to determine whether or not uraemia has an effect on cyclosporine A intestinal resorption. METHODS AND RESULTS: Model experiments were conducted in rats to monitor the effect of acute uraemia (bilateral nephrectomy) on the kinetics of cyclosporine A. Using intragastric tube, Cyclosporine A was administered to one group of rats in the form of Consupren (Galena, Czech Republic) and to another group in the form of Sandimmune (Sandoz, Switzerland), at a dose of 10 mg/kg/24 h either case. Blood levels of cyclosporine A were determined using RIA and specific and non-specific antibodies (cyclosporine and its metabolites). Cyclosporine A kinetics in nephrectomized rats was compared with that in control rats and in rats undergoing sham nephrectomy. The blood levels of cyclosporine A were significantly lower, and the area under the curve (AUC) of blood cyclosporine A in nephrectomized rats significantly smaller than in control rats. No significant differences in the evaluated parameters after Consupren or Sandimmune were observed. CONCLUSIONS: Our findings support the hypothesis that uraemia decreases cyclosporine A availability. The results suggest that the changes in cyclosporine A kinetics in nephrectomized rats following Consupren and Sandimmune administration are of the same character.     

Solution of methodological problems in prorenin measurement and investigations of tissue renin-angiotensin systems in the female reproductive tract

The literature has been provided with conflicting results concerning prorenin in rat plasma. The cause was investigated and we characterized severe methodological problems. Prorenin is in rats measured by its enzymatic property after trypsin activation. Besides activating prorenin, trypsin appeared to degrade renin substrate (angiotensinogen) and formed an unstable 'blank' which interfered in the prorenin measurement. An interfering sulphydryl enzyme was also found in plasma from nephrectomized rats. Identical 'blank' problems were also found in other animals such as pigs and cattle. These problems were solved and a new validated method was developed enabling the study of active renin and prorenin in species other than humans. Plasma prorenin was found primarily to originate from kidneys in rats as in other species although minor contribution of other tissues was likely. Evidence has accumulated during recent years supporting the existence of local tissue RAS's in ovary and uteroplacental unit. The presence of active renin and prorenin in female reproductive organs were verified in cattle and pigs. A marked species difference was found. Secretion of prorenin to plasma only seemed to take place in humans suggesting primarily a local function of reproductive RAS's. The concentration of prorenin varies during follicular maturation and pregnancy in reproductive tissues and fluids. A tissue incubation method was developed to study the bovine ovarian RAS in-vitro. The presence, formation, secretion and degradation of active renin in bovine ovarian follicles in-vitro indicate that active renin--and not prorenin as suggested earlier--is important in mediating effects of tissue RAS. Angiotensin II receptors are also present in high and varying densities in the ovary, uterus and placenta. Several potential effects, mediated through auto- or paracrine actions, are suggested. Ovarian RAS may affect oocyte maturation, ovulation, steroidogenesis and angiogenesis. The uteroplacental RAS may affect decidualization, angiogenesis, hormone synthesis, local blood flow and uterine contraction. Effects may, according to the marked species difference of RAS, vary between species. The understanding of tissue RAS's is in its infancy. The ovary seems to be a very good model in study of tissue RAS's and their possible relations to the bloodborne RAS. Further investigation may also benefit the reproductive endocrinology.