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Department of Physiology, Semmelweis Medical University, H-1444 Budapest 8, Hungary
(Received 23 December 1975)
The role of the renin-angiotensin system (RAS) in the control of aldosterone secretion in the rat has been a subject for disagreement for more than a decade (cf. Müller, 1971). Recent investigations of the effect of synthetic angiotensin II on isolated glomerulosa cells (Haning, Tait & Tait, 1970; Brecher, Tabacchi, Pyun & Chobanian, 1973; Williams, McDonnell, Raux & Hollenberg, 1974; Mendelsohn, Mackie & Mee, 1975) failed again to give concordant results concerning even the efficiency of the octapeptide.
Information on the physiological function of the RAS may be obtained by experiments studying the response of aldosterone secretion rate to an evoked increase in endogenous renin activity. A situation where the RAS may be expected to play a mediator role in aldosterone regulation is the reduction of renal perfusion pressure. The effect of this manoeuvre on aldosterone
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SUMMARY
Glomerular filtration rate (GFR), renal plasma flow (RPF) and solute-free water reabsorption (TcH2O) were measured in anaesthetized intact and hypophysectomized rats and in hypophysectomized rats treated with corticotrophin (ACTH). GFR and RPF were measured by [14C]inulin and [3H]p-aminohippuric acid clearances. In agreement with previous reports, these two functions were found to be reduced by hypophysectomy. Infusion of vasopressin increased TcH2O in the intact rat but failed to produce a significant change in the hypophysectomized rat. Treatment of hypophysectomized rats with ACTH restored the effects of vasopressin on TcH2O. ACTH also increased the RPF of hypophysectomized rats to normal values, but only partially restored GFR.
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SUMMARY
1. The effects of an aldosterone blocking agent (SC-11927) and of corticotrophin, aldosterone and cortisol on renal function were tested on infant rats aged 1 to 17 days.
2. SC-11927 had no effect on the Na/K ratio in the urine of rats until they were 12 days old.
3. d-Aldosterone depressed the Na/K ratio on the 1st day after birth, potassium concentration increased but a decrease in sodium concentration was not seen until the 6th day.
4. Cortisol elevated the Na/K ratio on the 1st day after birth, both sodium and potassium concentration increased. At 6 days potassium concentration alone was increased.
5. Corticotrophin did not affect the composition of the urine until the animals were 12 days old when the potassium concentration increased.
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Abstract
Oxytocin was administered to virgin female rats at doses of 25–200 pmol/min during 0·077 mol NaCl/l infusion at 150 μl/min on each day of the oestrous cycle. The resultant rates of urine flow, glomerular filtration (GFR) and electrolyte excretion were determined. Oxytocin caused significant increases in urine flow (P<0·001) and sodium excretion (P<0·001); both responses being dose-dependent (P<0·02 and P<0·01 respectively). Significant variations in the renal responsiveness to the hormone occurred over the 4 days of the oestrous cycle. On oestrus the lowest dose of 25 pmol oxytocin/min produced a significant increase in urine flow (from 139·5 ± 4·3 to 165·6 ± 7·1 μl/min, P<0·005) and a dose of 50 pmol/min produced a significant increase in sodium excretion (from 10·6 ± 0·1 to 14·5 ± 0·7 μmol/min, P<0·005). Significant increases in urine flow and sodium excretion were seen on pro-oestrus with hormone administration rates of 50 and 100 pmol/min respectively and on dioestrus day 2 with a rate of 100 pmol/min. On dioestrus day 1 no increase in urine flow or sodium excretion was seen over the dose range of oxytocin administration. A dose of 100 pmol oxytocin/min significantly increased GFR on pro-oestrus and dioestrus day 2, but not on the other 2 days of the cycle. The circulating hormone concentrations produced by oxytocin infusion were similar on each day of the cycle and so could not account for the differences seen. Therefore, these results suggest varying renal responsiveness to oxytocin during the reproductive cycle of the female rat.
Journal of Endocrinology (1997) 154, 347–353
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Both guanosine 5′-triphosphate (GTP) and 5′-guanylylimidodiphosphate (GMP-PNP) inhibited the specific binding of 125I-labelled calcitonin to tubular membranes purified from rat renal cortex. The number of receptor sites was reduced but the affinity of calcitonin for its receptors remained unchanged. Guanosine 5′-triphosphate and GMP-PNP were active at much lower concentrations (10 μmol/l) than other nucleotides. Their inhibitory effects could not be explained by chelation and persisted after the washing of pre-incubated membranes. Neither of these guanyl nucleotides was able to modify the rate of degradation of 125I-labelled calcitonin.
Guanosine 5′-triphosphate and GMP-PNP also activated adenylate cyclase under basal conditions and in the presence of calcitonin, the maximum effect being obtained at a concentration of 100 μmol/l, but did not modify fluoride-sensitive adenylate cyclase. The affinity of calcitonin for the enzyme was higher in the presence of these guanyl nucleotides, particularly with GMP-PNP. The concentrations of calcitonin corresponding to 50% maximum adenylate cyclase activation (K m) for the reaction without guanyl nucleotides, with GTP and with GMP-PNP were 1·9, 0·67 and 0·06 nmol/l respectively.
The relationship between the number of receptors occupied and adenylate cyclase activity was calculated from Hill equations derived from binding experiments and enzyme assays after incubation for 25 min. The values obtained with and without guanyl nucleotides were clearly different since the occupancy of the same percentage of receptors corresponded to much greater activation of adenylate cyclase when guanyl nucleotides were present. These data show that at the concentration at which it is found in the plasma, calcitonin can activate renal adenylate cyclase only in the presence of guanyl nucleotides.
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Abstract
The effect of three oxytocin receptor antagonists on the renal actions of oxytocin and vasopressin was investigated in conscious male rats infused with hypotonic saline. Infusion of oxytocin at 100 pg/min produced plasma concentrations of 12·7 ± 3·3 pmol/l and led to significant increases in sodium excretion, urine flow and glomerular filtration rate (GFR). The increase in sodium excretion of 42 ± 9% during oxytocin infusion was significantly decreased by all three antagonists to 15 ± 5% (10 ng [mercapto-proprionic acid1,d-Tyr(Et)2, Thr4,Orn8]-oxytocin/min), 13 ± 5% (5 ng desGly9[d-Trp2,Thr4,Orn8]-dC6oxytocin/min) and 4 ± 5% (1 ng d(CH2)5[Tyr(Me)2,Thr4,Orn8,Tyr(NH2)9]-vasotocin/min). Similarly, the increase in urine production of 22 ± 5% associated with oxytocin infusion was significantly decreased to 4 ± 3% (5 ng desGly9[d-Trp2,d-Thr4,Orn8]-dC6oxytocin/min) and 1 ± 4% (1 ng d(CH2)5[Tyr(Me)2,Thr4,Orn8,Tyr(NH2)9]-vasotocin/min). All three antagonists blocked the oxytocin-induced increase in GFR when infused at 10 ng/min. Infusion of vasopressin at 160 pg/min produced plasma concentrations of 10·1 ± 2·1 pmol/l and this led to a significant increase in sodium excretion and a significant decrease in urine flow rate. None of the antagonists had any effect on the natriuretic or antidiuretic actions of vasopressin suggesting that different receptors are involved in these renal actions of the two peptides.
Journal of Endocrinology (1997) 152, 257–264
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A comparison of the renal response to extracellular fluid volume expansion (5% body weight) was made between 25 normal and 25 chronically hypophysectomized rats. The extracellular fluid compartments averaged 25 ± 1% of body weight in both groups during control, fasted conditions. Extracellular fluid volume increased to 33 ± 1% in hypophysectomized and 34 ± 2% in normal rats during expansion, based on body weight. In addition, filtration fraction was similar in both normal and hypophysectomized rats during control (0·29 ± 0·03 and 0·26 ± 0·02 respectively) and infusion of Ringer–Locke solution (0·24 ± 0·05 and 0·27 ± 0·05 respectively). Thus our results cannot be explained by differences in the degree of expansion or failure to increase filtration in proportion to plasma flow. During infusion of isotonic Ringer–Locke solution, fractional water and sodium excretion both averaged 5·1% in normal rats and only 1·3% and 0·82% respectively in hypophysectomized rats. The ratio of single nephron to whole kidney filtration rate failed to increase as much in hypophysectomized compared with normal rats. Significant increases of fractional volume excretion occurred in both groups by the end of the accessible portion of the proximal tubule. However, fractional water reabsorption was depressed significantly more in normal (mean = 37%) than in hypophysectomized rats (mean = 19%). Fractional water reabsorption in distal tubules was similar in both groups during expansion. Arterial pressure was lower in hypophysectomized rats under control conditions, but showed similar changes during expansion compared with normal rats. Passage time decreased significantly in all groups after Ringer–Locke infusion, but remained prolonged in hypophysectomized rats in proximal and distal tubules. It is concluded that chronic hypophysectomy results in a less efficient renal excretion of volume and sodium chloride load. This inefficiency appears to be related in part to (1) failure of the proximal tubule to depress water reabsorption to a level equivalent to normal rats, and (2) failure to re-distribute flow to outer cortical glomeruli following extracellular fluid volume expansion in hypophysectomized rats.
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ABSTRACT
The renal and endocrine actions of atrial natriuretic peptide (ANP) administered at a rate to induce plasma concentrations within the physiological range have been re-examined in conscious rats in which body fluid volume was maintained by infusion of replacement fluid at a rate to match spontaneous urine losses (servo-controlled replacement) throughout experimentation. The involvement of vasopressin in the actions of ANP was assessed by comparing the responses induced in Brattleboro (DI) and Long–Evans (LE) rats.
A rate of ANP administration inducing a less than twofold increment in circulating ANP concentration evoked a small but significant diuresis and natriuresis. In contrast to previous studies during which body fluid balance had not been maintained and the response to ANP was transient, renal responses were rapid in onset and sustained over the period of hormone administration. The change in renal excretion occurred without concomitant changes in mean arterial blood pressure, haematocrit or glomerular filtration rate, and without consistent alterations in the circulating concentrations of angiotensin II, vasopressin, aldosterone or corticosterone. Furthermore, although small differences between the two strains in the character of the response could be demonstrated, the evoked response was of similar magnitude in vasopressin-replete and -deficient animals.
In summary, in conscious rats in which body fluid volume was maintained, the profile of the diuretic and natriuretic responses evoked by low-rate ANP administration was different from that previously observed in anaesthetized and/or constantly infused preparations; being rapid in onset and sustained. The similarity in the renal effects observed following ANP administration in LE and DI rats in the present study suggests that vasopressin is not a prerequisite for the renal actions of ANP evoked by plasma concentrations within the physiological range.
Journal of Endocrinology (1993) 138, 413–420
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In the sheep fetus, pulmonary and renal concentrations of angiotensin-converting enzyme (ACE) increase towards term in parallel with the prepartum surges in plasma cortisol and tri-iodothyronine (T(3)). The ontogenic change in pulmonary ACE has been shown to be induced, at least in part, by cortisol but the role of the thyroid hormones is unknown. Therefore, this study investigated the effects of thyroid hormones on tissue ACE concentration in fetal sheep during late gestation. Pulmonary and renal ACE concentrations were measured in sheep fetuses after experimental manipulation of thyroid hormone status by fetal thyroidectomy and exogenous hormone infusion. In intact fetuses, pulmonary and renal ACE concentrations increased between 127-132 and 142-145 days of gestation (term 145 +/- 2 days), coincident with the prepartum rises in plasma cortisol and T(3). The ontogenic increment in pulmonary ACE concentration was abolished when the prepartum surge in T(3), but not cortisol, was prevented by fetal thyroidectomy. At 143-145 days, ACE concentration in the lungs and kidneys of the thyroidectomised fetuses were both lower than those in the intact fetuses. In intact fetuses at 127-132 days, pulmonary ACE was upregulated by intravenous infusions of either cortisol (2-3 mg/kg per day) or T(3) (8-12 microg/kg per day) for 5 days. Renal ACE was unaffected by cortisol or T(3) infusion. Therefore, thyroid hormones have an important role in the developmental control of pulmonary and renal ACE concentration in the sheep fetus towards term. In addition, the prepartum rise in plasma T(3) appears to mediate, in part, the maturational effect of cortisol on pulmonary ACE concentration.
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ABSTRACT
The effects of treatment for 11 days with human growth hormone (hGH; 140 μg/day), thyroxine (T4; 3 μg/day) and hGH + T4 on renal growth and content of insulin-like growth factor-I (IGF-I) in hypophysectomized rats have been compared with saline-treated hypophysectomized animals and intact control animals. Right kidney weight and kidney weight/body weight ratio remained low in the saline-treated group (313±9 vs 694±28 mg in controls on day 11, P<0·001 and 3·4±0·12 × 10−3 vs 4·2±0·10× 10−3, P< 0·005 respectively). In T4- and hGH-treated animals, kidney weight gain was similar (to 420 ± 14 and 450±22 mg on day 11 respectively, P>0·05), whilst the increase was greater in the group given hGH + T4 (to 572 ±34 mg, P< 0·001 compared with hGH- and T4-treated groups). The kidney weight/body weight ratio became normal in the T4- and hGH + T4-treated animals but remained low in the hGH-treated group. The renal content of IGF-I was low in the salinetreated animals throughout the study (92±10 ng/g on day 11 vs 219±8 ng/g in control animals, P< 0·001), but increased to a maximum of 88% above baseline on day 1 in the group given T4. In the hGH-and hGH + T4-treated groups, renal IGF-I concentration rose to a peak of 317% above baseline on days 2 to 4, then fell to the values seen in control animals on day 11 (hGH: 242±18 ng/g; hGH + T4: 320 ± 41 ng/g; controls: 219 ± 8 ng/g; P> 0·05 for all comparisons). Thus treatment with hGH or T4 results in similar kidney weight gain, despite a greater rise in the renal concentration of IGF-I in the hGH-treated animals. Treatment with both hGH + T4 leads to an increase in the renal concentration of IGF-I similar to that seen with hGH treatment alone, but a larger increase in kidney weight, suggesting that T4 does not stimulate renal growth via the IGF-I pathway and that growth promotion by hGH and T4 is additive.
Journal of Endocrinology (1993) 136, 399–406
