Local inhibition of nitric oxide temporarily stimulates aldosterone secretion in conscious sheep in vivo.

The effect of localized blockage of endogenous nitric oxide (NO) on basal aldosterone secretion was studied in conscious sheep with autotransplanted adrenal glands. We have shown that infusion of the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 130 microg/l blood flow) significantly stimulated basal aldosterone secretion rate (ASR). This stimulatory effect was seen up to 4 h of infusion. Beyond this time point, however, the elevated ASR level was not sustained, and it was seen to drop markedly to lower than control values at 5 h. L-NAME had no effect on cortisol secretion rate (FSR) during the first 4 h of infusion, but a significant reduction in FSR was seen by the 8-h time point. Adrenal blood flow was consistently decreased in association with long L-NAME infusion. Additionally, L-NAME was shown to have no effect on aldosterone secretion when infused systemically. We conclude that the relationship between NO and aldosterone secretion is an inhibitory one, in which NO seems to have a negative effect on basal aldosterone secretion.

Effect of adrenomedullin infusion on basal and stimulated aldosterone secretion in conscious sheep with cervical adrenal autotransplants.

In vivo and in vitro studies have shown conflicting effects of adrenomedullin (ADM) on the secretion of steroid hormones from the adrenal gland. While some investigators report no effect of this peptide on the output of various hormones, others have reported both stimulatory and inhibitory roles for ADM. We have shown that basal aldosterone secretion rate (ASR), in conscious sheep with cervical adrenal autotransplants, did not change when ADM was infused directly into the adrenal arterial supply. While not affecting basal ASR, ADM did produce pronounced increases in adrenal blood flow (BF). This elevation of BF in association with ADM infusion was seen in all subsequent experiments. When aldosterone output was acutely stimulated by angiotensin II (AngII), potassium chloride (KCl) and adrenocorticotrophic hormone (ACTH), ADM was seen to drastically reduce the secretion of aldosterone with all agonists studied. After pre-exposure to ADM, all three agonists increased ASR but the magnitude of the responses were somewhat blunted. ADM did not have the same effect on cortisol secretion stimulated by ACTH, suggesting that the ability of this peptide to influence adrenal gland function is limited to the zona glomerulosa. In conditions of chronic elevation of aldosterone levels, such as in Na deficiency, ADM did not display the same inhibitory abilities seen in the acute stimulation experiments. Hence, ADM has been shown to have a direct, inhibitory role on the acute stimulation of aldosterone by AngII, KCl and ACTH while not affecting basal or chronic aldosterone secretion or cortisol secretion stimulated by ACTH.

Late steps of aldosterone biosynthesis: sheep are not rats.

1. The last three steps of aldosterone biosynthesis have been demonstrated to be catalysed by a single enzyme, referred to as CYP11B (or P450(11) beta) in cow, pig, sheep and bullfrog and as CYP11B2 (or P450aldo) in rat, human, mouse and hamster. 2. The related enzyme CYP11B1 (also referred to as P450(11) beta) in rat, human, mouse and hamster does not have aldosterone synthesis activity, but no such enzyme has been reported in the cow, pig or sheep to date. 3. Exclusive aldosterone secretion in the zona glomerulosa (ZG) of the adrenal cortex in species such as rat, human, mouse and hamster could be ascribed to the restricted distribution of CYP11B2 to the same region in the adrenal cortex. 4. In other species, such as cow, pig and sheep, the CYP11B enzyme is expressed throughout the adrenal cortex and, thus, the exclusive aldosterone biosynthesis in the ZG could not be explained simply by the distribution of the enzyme. 5. We have shown in the sheep that potassium loading and acute sodium depletion stimulate the CYP11B transcript levels, which are not further increased by chronic sodium depletion. 6. The predominant CYP11B in the sheep adrenal cortex catalyses the synthesis of aldosterone from deoxycorticosterone (DOC) in vitro, is expressed throughout the adrenal cortex and the corresponding transcript levels are increased by K+ loading or sodium depletion. In short, as far as the last step of aldosterone biosynthesis is concerned, sheep are different from rats. In the rat, the CYP11B2 transcript or protein is elevated by K+ loading or sodium depletion, but not the CYP11B1 transcript or protein. 7. We propose that during severe sodium deficiency there is a switch in the aldosterone pathway to one preferentially involving 18-OH-DOC and not corticosterone.

Natriuresis and inhibition of Na+/K(+)-ATPase: modulation of response by physiological manipulation.

1. There is considerable evidence for the existence of an endogenous inhibitor of Na+/K(+)-ATPase. The exact physiological nature and role of this postulated agent remains unclear, although it would be predicted that one of its actions would be stimulation of renal sodium excretion. 2. The natriuretic effect of renal arterial infusion of ouabain is relatively slow in onset and is sustained. 3. The natriuresis is not modified by changes in sodium status, unlike the natriuretic effect of atrial natriuretic peptide. 4. The natriuretic action of ouabain is enhanced dramatically by acute volume expansion or chronic mineralocorticoid treatment, which both result in hypokalaemia, hypertension and hypervolaemia. 5. The natriuretic response to small increments in blood pressure is markedly enhanced by treatment with ouabain. 6. We hypothesize that the interaction between the inhibition of Na+/K(+)-ATPase and elevated blood pressure could result in the shedding of sodium in conditions where there are increased levels of circulating endogenous digitalis-like factors.

Hypothesis: aldosterone is synthesized by an alternative pathway during severe sodium depletion. 'A new wine in an old bottle'.

1. The last three steps of aldosterone biosynthesis, 11 beta-hydroxylation, 18-hydroxylation and 18-oxidation, have been demonstrated to be catalysed by one enzyme, which is the cytochrome P450(11 beta) (CYP11B) in cow, pig, sheep and bullfrog or cytochrome P450aldo (CYP11B2) in rat, human, mouse and hamster. 2. The related enzyme P450(11 beta) (CYP11B1) from rat, human, mouse and hamster adrenals displays 11 beta-hydroxylation and 18-hydroxylation activities, but not 18-oxidation activity in vitro. No such enzyme has been reported in the cow, pig or sheep to date. 3. Data showing the dissociation of aldosterone secretion from plasma angiotensin II (AngII) levels indicate the presence of other factor(s) that regulate aldosterone biosynthesis in response to changes in body sodium status. Thus, we propose the existence of a 'sodium status factor' that regulates aldosterone biosynthesis in addition to AngII, K+, adrenocorticotropic hormone and atrial natriuretic peptide. 4. We propose that during severe sodium deficiency there is a switch in the aldosterone pathway to a pathway using 18-hydroxy-deoxycorticosterone (18-OH-DOC) rather than corticosterone as an intermediate. This switch may be mediated via the putative 'sodium status factor'. 5. Two models of the hypothesis will be discussed in this paper: (i) a 'one-enzyme' model; and (ii) a 'two-enzyme' model. 6. The one-enzyme model proposes that P450aldo (P450(11 beta) as in the case of the cow, sheep and pig) changes its enzymatic activity during severe sodium deficiency (i.e. switching to the alternative aldosterone biosynthesis pathway). 7. The two-enzyme model proposes that, under normal circumstances, P450aldo synthesizes aldosterone from deoxycorticosterone, while during severe sodium deficiency the P450(11 beta) provides the substrate (i.e. 18-OH-DOC) for the P450aldo.

Investigation of the mineralocorticoid and hypertensinogenic activity of 18-hydroxycortisol in conscious sheep.

The increased urinary excretion of 18-hydroxycortisol (18-OHF) in patients with primary aldosteronism has raised the possibility that 18-OHF is involved in the maintenance and/or pathogenesis of the associated hypertension. This study has investigated the mineralocorticoid, glucocorticoid, and hypertensinogenic activities of 18-OHF in the conscious sheep. Infusion of 18-OHF (400 micrograms/h i.v. 5 days; n = 5) alone had no effect on blood pressure or on fluid and electrolyte balance. Infusion of a combination of five adrenal steroids (aldosterone 3 micrograms/h, cortisol 5 mg/h, corticosterone 0.5 mg/h, 11-deoxycortisol 1 mg/h and deoxycorticosterone 25 micrograms/h, i.v. 5 days; n = 5) increased blood pressure by 14 +/- 1 mmHg (p < .001), but when 18-OHF was infused together with the five adrenal steroids, no additional increase in blood pressure was observed. In another group of sheep (n = 4) 18-OHF was infused at a range of doses (5, 50, 100, 200, 500, and 1000 micrograms/h i.v.), each for 2 h, into sodium-replete and sodium-deplete, adrenalectomized sheep. 18-OHF had no effect on the urinary sodium or potassium excretion or on the salivary Na/K ratio in either group as compared with vehicle infusion. To examine the renal effects of 18-OHF, a range of doses of 18-OHF (5, 50, 100, 200, 500, and 1000 micrograms/h) were infused directly into the renal artery of conscious sheep (n = 4). 18-OHF did not affect the renal blood flow nor the urinary sodium or potassium excretion compared with vehicle infusion. In summary, we could not demonstrate any mineralocorticoid, glucocorticoid, or hypertensiongenic effects of 18-OHF in conscious sheep at a dose of 400 micrograms/h. Thus, a cautious approach to interpreting the role that 18-OHF plays in the clinical manifestations of primary aldosteronism, is necessary.

Interaction of exogenous ouabain and chronic mineralocorticoid treatment in the kidney of the conscious sheep.

1. Ouabain is known to have natriuretic effects only at high doses, and therefore if endogenously produced ouabain has a role in the regulation of sodium excretion, the renal response to ouabain must be increased substantially in certain physiological situations. The aim of this study is to determine whether treatment with the mineralocorticoid, aldosterone, potentiates that natriuretic response to ouabain. 2. Six conscious sheep received renal arterial infusion of either vehicle or aldosterone (3 micrograms/h). Forty hours after commencement of infusion ouabain was infused into the renal artery at 400 micrograms/h for 60 min. A second infusion of ouabain was administered on the 6th day of aldosterone treatment. 3. In the absence of aldosterone, the effects on sodium excretion produced by ouabain infusion at 400 micrograms/h into the renal artery were variable and not statistically significant. Ouabain infusion after 40 h of aldosterone treatment increased sodium excretion from 40 +/- 14 to 676 +/- 69 mumol/min in the second hour following cessation of ouabain infusion (P < 0.001). Ouabain infusion after 6 days of aldosterone treatment increased sodium excretion similarly. Ouabain-stimulated sodium excretion was significantly greater during aldosterone treatment compared to vehicle treatment (P < 0.05). In contrast, no enhancement of effect was observed after acute treatment with aldosterone. 4. These results demonstrate potentiation of the natriuretic response to ouabain infusion by chronic mineralocorticoid treatment and suggest a potential role of endogenous digitalis-like factor in the physiological control of sodium homeostasis.

Aldosterone secretion: a molecular perspective.

The major mineralocorticoid hormone aldosterone is secreted from the zona glomerulosa of the adrenal cortex. Aldosterone is synthesized from cholesterol via a series of hydroxylations and oxidations. The enzymes involved in these reactions are mostly members of the cytochrome P450 superfamily. The final steps of this pathway, the conversion of 11-deoxycorticosterone (DOC) to aldosterone, require conversion via the intermediates 18-hydroxy-DOC or corticosterone and 18-hydroxycorticosterone. There are significant differences between species in the number of genes that encode the P450(11beta)-related enzymes (CYP11B) involved in these steps and the zonal distribution of their expression. One enzyme is capable of 11-hydroxylation, 18-hydroxylation, and 18-oxidation of DOC to aldosterone. The genetic basis of four diseases-congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency, glucocorticoid-remediable aldosteronism, aldosterone synthase deficiency type I and type II-is explicable by mutations in these cytochrome P450(11beta)-related genes.

Functional and expression analysis of ovine steroid 11 beta-hydroxylase (cytochrome P450 11 beta).

In this study, the ovine steroid 11 beta-hydroxylase (P450(11 beta) or CYP11B) cDNA previously reported by us (1) was transfected into COS-7 cells. Using 3H-11-deoxycorticosterone (3H-DOC) as the substrate, and paper partition chromatography for separation of steroid products, the expressed enzyme was shown to catalyse the conversion of DOC to corticosterone (B), 18-hydroxy-11-deoxycorticosterone (18-OH-DOC), 18-hydroxy-corticosterone (18-OH-B), and aldosterone (ALDO). These results suggest that the expressed ovine cDNA exhibited 11 beta-hydroxylase, 18-hydroxylase and aldosterone synthesis activities. The enzymatic activity of the enzyme was further analysed by adding unlabelled steroids to compete with 3H-DOC. The conversion of 3H-DOC to 3H-ALDO was inhibited by the addition of excess DOC, B and 18-OH-DOC, indicating that all these steroids were potential substrates of the enzyme. The results also demonstrated that 18-hydroxylation could occur before 11 beta-hydroxylation with this enzyme. However, the addition of excess cold 18-OH-B had no significant effect on the level of 3H-ALDO that was synthesised. This result could imply that 18-OH-B is not an intermediate involved in the conversion of DOC to aldosterone, or, more likely, the enzyme substrate site is not accessible readily. Our results also indicated that DOC was preferred to 18-OH-DOC as a substrate for the enzyme. We have demonstrated by hybridisation histochemistry using specific oligonucleotide probes that the corresponding P450(11 beta) RNA transcript was present in all zones in the sheep adrenal cortex. In summary, we have shown that the enzyme encoded by the predominant P450(11 beta) cDNA isolated from the sheep adrenocortical cDNA library has all the enzymatic activities to biosynthesise ALDO from DOC. The corresponding transcript of this ovine P450(11 beta) cDNA was located throughout the adrenal cortex and thus the inability of the zonae fasciculata-reticularis to secrete ALDO remains to be understood.

Effect of volume expansion on the natriuretic response to ouabain infusion.

Evidence exists that an endogenous substance which inhibits (Na+,K+)-ATPase, in a similar manner to the cardiac glycosides, may have important cardiovascular and renal effects. Whilst ouabain or a closely related isomer has been reported to be present in mammalian plasma, renal effects of ouabain occur only at high concentrations. The effect of expansion of blood volume on the renal response to ouabain infusion was examined in conscious sheep. Five sheep with catheters chronically implanted into the renal artery received four treatment combinations in random order: (I) vehicle (0.15 mol l-1 NaCl) infusion; (II) 500 micrograms ouabain infused into the renal artery over 60 min; (III) 500 ml 6% dextran 70 in 0.9% saline infused intravenously, and (IV) the dextran and ouabain treatments together. Treatment with either ouabain or plasma volume expansion produced modest increases in sodium excretion and urine flow. Treatment with ouabain when combined with plasma volume expansion increased sodium excretion from 82 +/- 30 to 880 +/- 203 mumol min-1 and urine flow from 1.9 +/- 1.1 to 7.5 +/- 1.6 ml min-1. This combination of treatments results in a synergistic rather than additive response. This study indicates that under some circumstances the response of the kidney to inhibition of (Na+,K+)-ATPase can be enhanced and, if inhibition can be demonstrated to occur at physiologically relevant concentrations of endogenous digitalis-like factor, would support a possible physiological role for endogenous digitalis-like factor in the regulation of sodium homeostasis.

Whole body and renal noradrenaline release during acute infusion of endothelin-1 in conscious sheep.

1. The present study investigated in conscious sheep the response of the sympathetic nervous system to a systemic infusion of 20 nmol/h endothelin-1 (ET-1), using a tritiated-noradrenaline (NA) tracer dilution technique. 2. Mean arterial pressure increased from 79 +/- 3 mmHg to a maximal level of 102 +/- 12 mmHg by 30 min of ET-1 infusion. 3. Total and renal NA kinetics were measured during this time. Total NA spillover was not affected by infusion of ET-1. In contrast, renal NA spillover decreased from a control level of 81 +/- 5 to 30 +/- 14 ng/min (P < 0.01) after 20 min and to 27 +/- 7 ng/min (P < 0.01) after 30 min of ET-1 infusion. 4. The present findings are consistent with the proposal that a direct vasoconstrictor action of ET-1 results in a paroreflex mediated reduction in renal sympathetic vasoconstrictor activity.

Blood supply of the ovine adrenal gland and its relevance in adrenal autotransplantation.

The arterial supply and venous drainage of 62 left and 5 right ovine adrenal glands is described, and the contribution of individual arteries to successful adrenal gland autotransplantation was evaluated. Arterial flow was measured by direct collection from the draining adrenal vein. Assessment of function of the transplanted adrenal gland was made from survival of the sheep and by the cortisol response to infusion of ACTH and the aldosterone secretory response to infusion of angiotensin II or potassium. For the left adrenal, the principal arterial supply was from the renal artery in 21 (34%), a lumbar artery in 32 (52%), and the anterior mesenteric artery in 3. The total blood flow was 5.0 +/- SEM 0.4 mL/min, the flow from the renal branch 2.3 +/- 0.3 mL/min, and the principal lumbar branch 2.6 +/- 0.3 mL/min. Venous drainage from the left adrenal was via a major adrenal vein to the left renal vein, but additional tributaries to the renal vein were present in 26%. The arterial supply to the adrenal is regional and omission of a branch at transplantation could result in infarction of portion of the gland. By defining arterial supply and measuring blood flow, selection of the appropriate artery or multiple arteries can achieve an adrenal gland autotransplant survival of 90%.

Cardiovascular actions of atrial natriuretic factor in sheep with cardiac failure.

The present study examines in detail the short-term cardiovascular actions of atrial natriuretic factor (ANF) in sheep with experimental low-output cardiac failure. Five conscious sheep, surgically implanted with a ventricular pacing wire, were paced at 220 beats/min for 14 days. Most clinical symptoms of congestive heart failure (CHF) were apparent after the 14 days, characterized by low cardiac output, high venous pressure, increased total peripheral resistance, increased plasma levels of ANF, noradrenaline, arginine vasopressin and renin, and marked fluid retention. On day 14 of pacing, intravenous infusion of ANF at 100 micrograms/h for 60 min restored cardiac output to prepacing values and reduced both total peripheral resistance and right atrial pressure. These effects were sustained throughout the infusion period. No change was seen in blood pressure, plasma renin, or noradrenaline levels. These hemodynamic changes, produced by short-term infusion of ANF, contrasted with those seen in normal sheep, where there was a fall in cardiac output with increased total peripheral resistance. These changes reflect a return toward normal of the left ventricular function curve. This is the first study to report that ANF improves cardiac function in conscious sheep with CHF, primarily by a vasodilator action to reduce cardiac preload, and suggests that ANF may be useful in treating the hemodynamic effects associated with cardiac failure.

Comparison of the renal effects of urodilatin and atrial natriuretic factor: effect of changes in sodium status.

Urodilatin is an amino terminally extended form of atrial natriuretic factor (ANF) which is resistant to enzymatic cleavage by renal neutral endopeptidase (NEP: EC 3.4.24.11). The renal effects of infusion into the renal artery of equimolar doses of urodilatin or ANF have been compared following changes in Na status in conscious sheep. In all conditions urodilatin was a more potent natriuretic stimulus than was ANF and the natriuretic response to urodilatin was modulated by sodium status in the same way as the response to ANF: diminished by sodium depletion and enhanced by sodium loading. This study does not support the hypothesis that changes in NEP activity contribute to the modulation of the natriuretic response to ANF which is observed with modification of sodium status.

Sodium status affects GC-B natriuretic peptide receptor mRNA levels, but not GC-A or C receptor mRNA levels, in the sheep kidney.

1. In humans and experimental animals the natriuresis and diuresis resulting from infusion of atrial natriuretic peptide varies with the sodium status of the subject. Tissue binding studies have suggested that this may be related to changes in the renal receptors for the hormone. 2. In order to establish whether these changes are under transcriptional control, we examined the levels of mRNA for the three natriuretic peptide receptors [GC-A, GC-B and clearance (C) receptors] in renal cortex and medulla from six sodium-loaded, six sodium-depleted and four control sheep. cDNA probes specific to each receptor were generated using the polymerase chain reaction. 3. GC-B receptor mRNA levels were increased approximately two-fold in the renal cortex of sodium-depleted animals, whereas there was no influence on GC-B receptor mRNA levels in the renal medulla. There was no significant difference in mRNA levels for the GC-A and C receptors. 4. At present the role of the GC-B receptor and its natural ligand C-type natriuretic peptide in the control of renal function is unknown. The present experiments imply some intrarenal function for the GC-B receptor and its natural ligand, although the site of any such function, e.g. renal vasculature or tubules, remains unclear. In addition, we have shown that if GC-A and C receptor levels in the sheep are modulated by sodium, the regulation occurs beyond the level of gene transcription.

Differential blockade of the renal vasoconstrictor and diuretic responses to endothelin-1 by endothelin antagonist.

1. The effect of cyclo(D-Trp-D-Asp-Pro-D-Val-Leu) (or BQ123), a selective ETA receptor antagonist, on the vasoconstrictor and diuretic responses elicited by endothelin-1 (ET-1) was examined in conscious sheep with chronic indwelling renal arterial cannulae. 2. Using low dose close renal arterial infusion, ET-1 has potent effects on the kidney causing a marked decrease in effective renal plasma flow and an increase in urine output and free water clearance in the normally hydrated animal. 3. The vasoconstrictor response to renal arterial infusion of ET-1 at 5 micrograms/h was blunted by renal arterial infusion of the ETA receptor selective antagonist, BQ123 (400 micrograms/h). 4. In contrast, the effect of ET-1 on urine production and free water clearance was not affected by this dose of BQ123. 5. The differential effect of BQ123 on renal blood flow and urine production suggests that these effects of endothelin on the kidney are mediated through different receptor mechanisms.

Cardiovascular effects of long-term endothelin infusion and responses to endothelin during ACTH infusion in conscious sheep.

Infusion of endothelin-1 (ET-1) (2000 pmol/h) into conscious sheep for 6 days caused a sustained increase in mean arterial pressure (MAP) of 19 +/- 1 mm Hg. This response was mediated by the vasoconstrictor effect of ET-1 and was accompanied by a fall in cardiac output. Plasma renin concentration fell throughout the infusion and atrial natriuretic peptide was increased on day 1 of ET-1 infusion. Hematocrit dramatically increased, probably mainly due to plasma loss resulting from the ET-1-induced increased capillary hydrostatic pressure. To determine whether increased pressor responsiveness to ET-1 played a role in the rise in MAP caused by corticotropin (ACTH), the responses to bolus doses of ET-1 were evaluated before ACTH and on days 3 and 5 of ACTH infusion (5 micrograms/kg/day). ACTH increased MAP from 71 +/- 2 to 87 +/- 3 mm Hg. On the control day ET-1 (400, 1200, and 2000 pmol) increased MAP by 5 +/- 1, 18 +/- 6 and 35 +/- 11 mm Hg, respectively. No initial vasodilation occurred. The responses to all doses of ET-1 were similar during ACTH infusion. Plasma levels of ET-1 did not increase during ACTH infusion. These results demonstrate that long-term infusion of ET-1 caused a sustained increase in blood pressure. There was no evidence that the sensitivity or responsiveness to ET-1 were altered during infusion of ACTH. In conclusion, ET-1 could play a role in the pathogenesis of hypertension but does not appear to be involved in the increase in blood pressure caused by ACTH.

Effects of prednisolone and deflazacort on osteocalcin metabolism in sheep.

Glucocorticoids adversely affect bone and mineral metabolism through a number of mechanisms, including inhibition of bone formation. Deflazacort is a glucocorticoid which has been reported to be relatively "bone-sparing." We compared the effects in oophorectomized sheep of deflazacort and prednisolone on the metabolism of osteocalcin (OC), a marker of osteoblast function. An [125]OC infusion method was used to measure the OC plasma clearance rate (PCR) and OC plasma production rate (PPR). Six-day intravenous infusion of deflazacort and prednisolone (in the dose range 0.007-1.00 mg/hour) induced dose-dependent decreases in OC PPR which were of a similar pattern but significantly different magnitude (P < 0.02); deflazacort demonstrated a potency about 150% that of prednisolone. Both steroids decreased plasma OC levels on a dose-related basis but at the lower doses 0.05 mg/hour (P < 0.05) and 0.013 mg/hour (P < 0.0005), deflazacort caused greater decrements. OC PCR was significantly increased only by higher doses of deflazacort (1.00 mg/hour, 0.25 mg/hour; P < 0.05). Deflazacort and prednisolone increased both postabsorptive plasma glucose and plasma calcium levels, but there were no significant differences between their effects. We conclude that plasma OC levels and OC PPR in sheep were more sensitive to the effects of deflazacort than to prednisolone. At high doses, the depressive effect of deflazacort on plasma OC levels may have been due in part to an increased OC PCR which was not evident with prednisolone treatment. However, the agents appeared to have a similar dose-dependent hyperglycemic effect, and both caused a small dose-dependent increase in plasma calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

A compartmental model of acute stimulation of aldosterone secretion in vivo by potassium and ANG II.

Conscious sheep with an adrenal autotransplant were used to study the relationship between acute change in K+ concentration and acute change in aldosterone secretion rate (ASR). The kinetics of K+ within the adrenal circulation were shown to be consistent with distribution within a single compartment. In contrast, change in ASR during and after KCl infusion was consistent with a two-compartment model, where ASR was a sigmoidal function of concentration of K+ (or other unidentified agent) in the second, or "effect," compartment. Prior work on the relationship between acute change in angiotensin II (ANG II) concentration and acute change in ASR was extended by investigating the interaction of K+ and ANG II in the control of ASR. The results of this study indicate that acute change in ANG II concentration may cause an inhibition of the usual response of the adrenal to acute change in K+ concentration.

Two-compartment model of acute stimulation of aldosterone secretion in vivo by angiotensin II.

Sheep with a cervical adrenal autotransplant were used to establish the relationship between acute change in angiotensin II (ANG II) concentration and acute change in aldosterone secretion rate (ASR). The kinetics of 131I-labeled ANG II and unlabeled ANG II across the adrenal were consistent with distribution within a two-compartment model. ASR was found to be a linear function of the ANG II concentration predicted to occur in the second compartment, indicating that acute change in ASR is determined to a large degree by the rate of exchange of ANG II between the first and second compartments. The time required for ANG II concentration to reach 50 and 95% of steady state was estimated to be approximately 5 and 45 min, respectively. The time course for agonist distribution within the adrenal may be an important factor to consider in both the design and interpretation of experimental studies that involve the stimulation (or inhibition) of adrenocortical cells.