Epidermal growth factor-like, corneal wound healing substance in mouse tears.

We have identified the presence of a putative corneal wound healing substance in mouse tears, which has a molecular size and immunological properties similar to those of epidermal growth factor (EGF). The substance was capable of binding to EGF receptors in mouse parenchymal cells and this binding was inhibited by anti-EGF serum. The concentration of the EGF-like substance in the tears of male and female mice was estimated to be 79.3 +/- 7.0 (SD) ng/ml and 76.5 +/- 8.1 (SD) ng/ml, respectively, by EGF radioimmunoassay. Removal of the submandibular glands, which produce large amounts of EGF, reduced plasma EGF to an undetectable level and also decreased the concentration of the EGF-like substance in tears to 27.3 +/- 3.9 (SD) ng/ml in male mice and 25.8 +/- 3.7 (SD) ng/ml in female mice. Approximately 50% of sialoadenectomized (submandibular glands removed) male mice with deep corneal wounds developed severe ocular lesions or loss of sight whereas none of normal male mice with similar wounds did. Topical application of EGF to deeply wounded eyes of sialoadenectomized mice eliminated the various complications and restored the healing rate and incidence of recovery to virtually normal levels.     

Stimulation of active renin release in normal and hypertensive pregnancy

1. Active plasma renin concentration but not total renin concentration is reduced in women with pregnancy-induced hypertension compared with normotensive pregnant women. This study was conducted to determine whether women with pregnancy-induced hypertension are able to stimulate release of active renin. 2. Active plasma renin concentration was measured as the generation of angiotensin I at physiological pH in the presence of excess renin substrate, and total renin concentration was determined in the same way after trypsin activation. Inactive plasma renin concentration was calculated as the difference between total renin and active plasma renin concentrations. 3. Resting active plasma renin concentration was significantly greater in third-trimester primigravidae compared with normotensive non-pregnant women and active plasma renin and total renin concentrations rose significantly without a fall in inactive plasma renin concentration in both groups after 2 h ambulation, suggesting increased release of active plasma renin and not conversion of circulating inactive to active renin. These responses were blunted in women taking oral contraceptives. 4. Although the active plasma renin concentration was significantly reduced in third-trimester primigravidae with pregnancy-induced hypertension, total renin concentration was not significantly different compared with normotensive women of similar gestation and in both groups 30 min 60 degrees head-up tilt increased active but not inactive plasma renin concentration. 5. These studies show that in normal pregnancy active plasma renin concentration can be stimulated to a similar extent as in non-pregnant women, despite a higher resting level. This appears to be due to increased secretion of active plasma renin rather than conversion of circulating inactive to active renin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ultrafiltration of renin in the mouse kidney studied by inhibition of tubular protein reabsorption with lysine

1. In order to study the role of the kidney in the elimination of endogenous plasma renin, renin was measured in the plasma and urine of female mice. 2. The renin concentration was two orders of magnitude lower in urine than in plasma, but it increased after intraperitoneal injection of submandibular mouse renin. No correlation between the plasma renin concentration and the urinary renin concentration and renin excretion rate could be demonstrated. 3. Blockade of the tubular reabsorption of proteins by intraperitoneal injection of the basic amino acid lysine increased the urinary renin concentration, renin excretion rate and renin clearance two to three orders of magnitude, without affecting the plasma renin concentration. 4. This finding demonstrates that ultrafiltered renin is reabsorbed almost completely in the renal tubules and that the mechanism most likely is the same as for other filtered proteins. 5. The large renal renin clearance obtained after intraperitoneal lysine is in accordance with a major role of the kidneys in the elimination of renin from the circulation, by a glomerular ultrafiltration and tubular reabsorption and metabolization of renin.     

Inactive renin and aldosterone in Bartter's syndrome

Studies of plasma samples of 3 subjects with Bartter's syndrome were compared to 8 subjects with other conditions. Despite high levels of active renin initially, with low levels of inactive renin, addition of either human nephrectomized plasma or sheep substrate not only increased active renin (by at least 3-fold) but also led to the appearance of large quantities of inactive renin (10-20 times the concentration originally present, much greater than the small increase seen with other plasmas). The activated inactive renin after substrate addition possibly had a larger and more variable molecular size (42,000-48,000) than normal inactive renin (42,500-44,500). Renin substrate in Bartter's plasma was present in similar amounts and had a normal or supranormal angiotensin generation rate with exogenous human renin. Bartter's substrate had a similar molecular weight (55,000) to that found in normal human plasma. The agent in the exogenous substrate preparations causing the increase in apparent active and inactive renin was not ultrafiltrable. However, an acidification procedure that destroyed exogenous substrate also removed the renin-increasing effect. Captopril increased renin but not aldosterone, while amiloride increased aldosterone but not renin. Neither agent improved serum potassium significantly in these patients on indomethacin.     

Characterization of inactive renin ("prorenin") from renin-secreting tumors of nonrenal origin. Similarity to inactive renin from kidney and normal plasma

Inactive renin comprises well over half the total renin in normal human plasma. There is a direct relationship between active and inactive renin levels in normal and hypertensive populations, but the proportion of inactive renin varies inversely with the active renin level; as much as 98% of plasma renin is inactive in patients with low renin, whereas the proportion is consistently lower (usually 20-60%) in high-renin states. Two hypertensive patients with proven renin-secreting carcinomas of non-renal origin (pancreas and ovary) had high plasma active renin (119 and 138 ng/h per ml) and the highest inactive renin levels we have ever observed (5,200 and 14,300 ng/h per ml; normal range 3-50). The proportion of inactive renin (98-99%) far exceeded that found in other patients with high active renin levels. A third hypertensive patient with a probable renin-secreting ovarian carcinoma exhibited a similar pattern. Inactive renins isolated from plasma and tumors of these patients were biochemically similar to semipurified inactive renins from normal plasma or cadaver kidney. All were bound by Cibacron Blue-agarose, were not retained by pepstatin-Sepharose, and had greater apparent molecular weights (Mr) than the corresponding active forms. Plasma and tumor inactive renins from the three patients were similar in size (Mr 52,000-54,000), whereas normal plasma inactive renin had a slightly larger Mr than that from kidney (56,000 vs. 50,000). Inactive renin from each source was activated irreversibly by trypsin and reversibly by dialysis to pH 3.3 at 4 degrees C; the reversal process followed the kinetics of a first-order reaction in each instance. The trypsin-activated inactive renins were all identical to semipurified active renal renin in terms of pH optimum (pH 5.5-6.0) and kinetics with homologous angiotensinogen (Michaelis constants, 0.8-1.3 microM) and inhibition by pepstatin or by serial dilutions of renin-specific antibody. These results indicate that a markedly elevated plasma inactive renin level distinguishes patients with ectopic renin production from other high-renin hypertensive states. The co-production of inactive and active renin by extrarenal neoplasms provides strong presumptive evidence that inactive renin is a biosynthetic precursor of active renin. The unusually high proportion of inactive renin in plasma and tumor extracts from such patients is consistent with ineffective precursor processing by neoplastic tissue, suggesting that if activation of "prorenin" is involved in the normal regulation of active renin levels it more likely occurs in the tissue of origin (e.g., kidney) than in the circulation.     

Renin, aldosterone and renal haemodynamics in cirrhosis with ascites

The interrelationships between the renin-angiotensin-aldosterone system, renal haemodynamics and urinary sodium excretion were investigated in fifty-six non-azotaemic cirrhotics with ascites. In twelve additional patients the renal renin secretion rate was also studied. Plasma renin activity and concentration and plasma aldosterone ranged from normal to very high values. There was a significant inverse relationship between plasma aldosterone and the urinary sodium excretion. Plasma aldosterone showed a highly significant direct correlation with plasma renin activity, and plasma renin concentration was closely and directly related to the estimated renin secretion rate. Neither plasma renin activity, plasma renin concnetration nor the estimated renin secretion rate correlated with the renal plasma flow or the glomerular filtration rate. These results suggest that in non-azotaemic cirrhosis with ascites the renin-angiotensin-aldosterone system is an important factor influencing sodium excretion, increased plasma renin and aldosterone concentrations are mainly due to an increased secretion rate, and total renal perfusion is not a major factor influencing renin secretion.     

Activation of aldosterone secretion in primary aldosteronism

Angiotensin infusion evokes marked increases in aldosterone secretion in primary aldosteronism and little change in secondary aldosteronism. The low plasma renin activity of primary aldosteronism and the elevated plasma renin activity of secondary aldosteronism are thought to account for this differential response. The effect of angiotensin on aldosterone and 18-hydroxycorticosterone secretion was studied during adrenal vein catheterization in seven patients with primary aldosteronism (whose plasma renin activity had been elevated following spironolactone therapy), one hypertensive patient with normal plasma renin activity and normal aldosterone secretion, two patients with secondary aldosteronism who had elevated plasma renin activity, and one anephric patient whose plasma renin activity was 0. Adrenal venous aldosterone and 18-hydroxycorticosterone were measured before and after a ten min sub-pressor angiotensin infusion.The cells of the aldosterone-producing adenoma (APA) respond to small increases in plasma angiotensin with large increases in secretion of aldosterone and 18-hydroxycorticosterone. The dose of angiotensin capable of evoking this response from the aldosterone-producing adenoma produces little or no change in the secretion of the steroids from nontumorous glands. The augmentation of aldosterone secretion, induced by angiotensin, in primary aldosteronism is due solely to increased secretion by the adenoma and not by the contralateral zona glomerulosa. The increased sensitivity of the aldosterone-producing adenoma is characteristic of the tumor. This response is independent of fluctuations in endogenous plasma renin activity. This sensitivity is not blunted by high plasma renin activity, nor is it a function of tumor mass for the effect is observed in aldosterone-producing adenomas regardless of size. ACTH injection after angiotensin infusion resulted in a marked increase in aldosterone concentration in the effluent from the nontumorous adrenal, but was not capable of producing further increases in aldosterone concentration in the effluent from the APA. In view of this exquisite sensitivity to infused angiotensin, it may be that the small variations in endogenous plasma renin activity that have been observed in primary aldosteronism may be capable of evoking large changes in aldosterone secretion in patients with aldosterone-producing adenomas.     

Effects of furosemide and orthostasis on active and inactive renin in normal and anephric man

Abstract. We investigated active and inactive (acid-activatable) plasma renin in anephric and in normal persons. In anephric patients ( n = 15) plasma concentration of active and inactive renin was 1.15 ± 0.2 and 40.7 ± 7.1 μU/ml, respectively; angiotensin II ( n = 13) was 14.5 ± 1.9 pg/ml. Furosemide ( n = 10), 40 mg i.v., and upright posture ( n = 8) did not change active or inactive renin in the anephric state. In normal men, furosemide ( n = 9) within 15 min increased active renin from 29.9 ± 5.8 to 82.4 ± 14.8 (μ/ml ( P lt; 0.001), while inactive renin slightly but not significantly decreased from 136.3 ± 29.9 to 121.1 ± 19.2 μU/ml; orthostasis ( n = 15) within 4 h stimulated active renin ( P < 0.001) and slightly raised inactive renin ( P < 005). Both furosemide and orthostasis increased ( P < 0.001, each) the proportion of active renin in normal persons. Studies in one patient within 24 h after bilateral nephrectomy indicated half-life to be 30–60 min for active and 2–4 h for inactive renin. Thus, we detected low levels of active renin and considerable amounts of inactive renin and angiotensin II in anephric patients. Our data suggest that about 30%, of inactive renin in normal plasma is of extrarenal origin. The stimulation of active renin by furosemide and orthostasis is bound to the presence of the kidney. Our studies provide indirect evidence that both manoeuvres may stimulate the conversion of inactive to active renin within the human kidney.     

Enzymatic activity of renin in plasma of normal and uraemic subjects

Plasma renin reactivity (PRR) is the rate of angiotensin I production after addition of renin to plasma, minus endogenous renin activity. PRR is increased in plasma of patients with renal failure compared with that of normal subjects. The present study was carried out to determine if increased PRR in uraemic plasma is related to differences of endogenous active or inactive renin, endogenous renin substrate, or pH of the incubation in vitro. PRR in plasma of ten uraemic patients was greater (P less than 0.02) than that in plasma of ten normal subjects in incubations carried out at pH 7.4 and 5.7. Increased PRR was not accounted for by differences of endogenous active and inactive renin activity. After addition of renin, renin concentration (measured by direct radioimmunoassay) did not differ in normal and uraemic plasma. Renin substrate concentration, measured both indirectly and by direct radioimmunoassay, also did not differ in normal and uraemic plasma. Increased PRR in uraemic plasma is not related to alterations of renin or renin substrate concentrations. These observations are consistent with our earlier hypothesis that there is a deficiency of a renin inhibitor in uraemic plasma.     

Characterization of inactive renin from human kidney and plasma. Evidence of a renal source of circulating inactive renin.

An inactive form of renin has been isolated from human plasma. It has been suggested that this may represent renin precursor secreted from the kidney. However, early studies failed to isolate inactive renin from human renal tissue. In this investigation, rapid processing of human kidney cortex at temperatures below 4 degrees C in the presence of protease inhibitors followed by cibacron-blue affinity chromatography allowed us to extract a totally inactive form of renal renin. Furthermore, we found that in kidney inactive renin constituted from 10 to as much as 50% of the total renin concentration. Biochemical characterization of the inactive renin from plasma and from kidney indicates that they are structural homologues and, when activated, have enzymatic properties that resemble active renal renin. Renal and plasma inactive renin were found to have the following properties in common: (a) a pH optimum of activation of 3.3; (b) reversible activation by acid dialysis on return to pH 7.4, 37 degrees C; (c) pH optima of enzyme activity of 7.8 with sheep angiotensinogen and 5.5 and 6.7 (biphasic) with human angiotensinogen; (d) Michaelis-Menten constants, Km, of 0.29-0.34 microM with sheep angiotensinogen, and 0.99-1.25 microM with human angiotensinogen; (e) an antibody to human renal renin mean inhibitory titer of 1:30,000 with 1 X 10(-4) Goldblatt units of activated renal or plasma inactive renin; (f) gel filtration profiles consisting of two peaks with apparent molecular weights of 56,000 +/- 1,500 and 49,200 +/- 1,000. Activation of plasma and kidney inactive renin by acid plus renal kallikrein was not accompanied by a change in gel filtration elution patterns. To determine whether inactive renin is released by the kidney, we measured inactive renin in samples obtained simultaneously from both the renal veins and inferior vena cava below the origin of the renal veins. In eight consecutive patients, inactive renin concentration was significantly higher in renal venous blood than in inferior vena caval blood. These data indicate that human kidney contains and secretes significant quantities of inactive renin. Thus, the kidney appears to be a major source of inactive renin in human plasma.     

Mechanisms regulating the renal excretion of sodium during pregnancy

Observations were made on the relation of the renin-angiotensin-aldosterone system and renal hemodynamic function to sodium balance in 43 pregnant dogs. Daily balance studies revealed that about 30-40% of ingested sodium was retained during the last half of pregnancy; during the same period, potassium balance was also positive but to a lesser extent. For groups of pregnant dogs, plasma renin activity (n = 14) and aldosterone secretion (n = 19) were significantly higher than normal; however, in some animals one or both functions were normal even though sodium retention was present. In contrast, plasma renin substrate concentration was consistently elevated during pregnancy in seven dogs. In a group of nine dogs in which both aldosterone secretion and plasma renin activity were measured, aldosterone secretion was elevated in the three dogs with the highest values for plasma renin activity; in two of the remaining six animals aldosterone secretion was elevated but plasma renin activity was normal or only slightly increased. The sequestration of sodium and water into the uterine contents was defined quantitatively in this study but evidence was lacking to support the idea that such changes led to renin release. The glomerular filtration rate (GFR) was significantly elevated throughout pregnancy but a significant decrease from the high level of mid-pregnancy occurred during the last half of pregnancy; this decrease in GFR probably contributed to the sodium retention. Administration of a large dose of deoxycorticosterone acetate (DOCA) to dogs in late pregnancy produced marked sodium retention but "escape" from the sodium-retaining steroid occurred. The data demonstrate that although increased activity of the renin-angiotensin-aldosterone system was frequently present during pregnancy, a normal rate of aldosterone secretion occurred. This finding and the observed "escape" from DOCA suggest the existence of sodium-retaining mechanisms other than the mechanism provided by a high plasma level of aldosterone.     

The influence of potassium administration and of potassium deprivation on plasma renin in normal and hypertensive subjects

The effect of potassium administration and of dietary potassium deprivation on plasma renin activity and aldosterone excretion has been studied in 10 normal subjects and in 12 hypertensive patients maintained on a constant dietary regimen.Potassium administration reduced plasma renin activity in 18 of 28 studies of both normal and hypertensive subjects. Suppression of renin often occurred despite sodium diuresis induced by potassium administration. The renin suppression was related to induced changes in plasma potassium concentration and urinary potassium excretion.The failure of suppression of plasma renin in 10 studies could be accounted for by the smaller amounts of potassium administered to these subjects, together with a possibly overriding influence of an induced sodium diuresis.In six studies potassium deprivation invariably increased plasma renin activity even though a tendency for sodium retention often accompanied this procedure.The data indicate that both the suppression of plasma renin activity induced by potassium administration and the stimulation of renin activity which follows potassium depletion occur independently of associated changes in either aldosterone secretion or in sodium balance. However, the results do suggest that in various situations, the influence of potassium on plasma renin activity may be either amplified or preempted by changes in sodium balance.These interactions between potassium and plasma renin could be mediated by an ill-defined extrarenal pathway. But the findings are more consistent with an intrarenal action of potassium ions to modify renin release. Potassium might modify renin secretion directly by acting on the juxtaglomerular cells or by a change in its tubular reabsorption or secretion. The effects of potassium ions on renin secretion might also be mediated indirectly via an induced change in tubular sodium transport.     

Active and inactive renin in normal human plasma. Comparison between acid activation and cryoactivation.

Inactive renin in human plasma is converted to active renin in vitro by acid activation or by cryoactivation. Renin activity was measured at pH 5.5 and renin concentration at pH 7.4. The plasma renin activity before and after cryo-treatment is termed active (APRA) and total (TPRA) plasma renin activity; the plasma renin concentration before and after acid treatment active (APRC) and total (TPRC) plasma renin concentration. In this study we demonstrated that in normal subjects the proportion of active to total renin after cryo-treatment averaged 61%, which was significantly (p less than 0.001) higher than the mean percentage active renin of 34 found with the acid activation procedure. Plasma angiotensin II correlated significantly with APRA, TPRA, TPRC and plasma angiotensin I (PA I), but not with inactive renin, which suggests that inactive renin does not produce angiotensin II in vivo. Cold treatment after acid activation and acid treatment after cryoactivation did not provoke a significant change in the measured renin concentration. Our data support the view that acidification of the plasma activates more than does cryo-treatment, and that inactive renin does not contribute to plasma angiotensin II.     

Absence of activation in vitro of renin in rat plasma

1. Rat plasma was subjected at 4 degrees C to various treatments known to convert inactive renin into its active form in human plasma. 2. No statistical differences in plasma renin concentration were found when the levels after the various treatments were compared with that of untreated rat plasma. 3. It is concluded that, in contrast to human plasma, no inactive form of renin is present in rat plasma.     

Growth hormone enhances hepatic epidermal growth factor receptor concentration in mice.

The effect of growth hormone (GH) on binding of epidermal growth factor (EGF) to liver membrane preparations was investigated in hypophysectomized mice and partially GH-deficient, genetic mutant "little" (lit/lit) mice. The EGF binding of normal male mice and testosterone-treated females was higher than in normal females. Due to diminished receptor concentration, hepatic EGF binding was decreased in male and female lit/lit mice to a level that was unaffected by gender or androgen treatment. GH replacement therapy by intermittent injections and continuous infusion restored the EGF binding of hypophysectomized mice to normal male and female levels, respectively, suggesting a role for the more pulsatile GH secretion in normal males. In lit/lit mice, however, both continuous and intermittent GH resulted in EGF binding levels comparable to those in normal females. In normal males continuous GH suppressed EGF binding. In conclusion, endogenous GH secretion induces EGF receptors in mice and this effect may be modulated by sex differences in GH secretion.     

The effect of in vitro captopril and angiotensin II on plasma renin activity

Samples of plasma from ten normotensive volunteers and ten hypertensive patients were assayed for plasma renin activity before and after the addition of either captopril or captopril and angiotensin II. The study was repeated after treating portions of the same specimens with trypsin, to activate the inactive renin component. The results indicate that inactive renin is not converted to the active form by captopril in vitro, nor does the addition of angiotensin II inactivate the active form. These data are consistent with the in vivo findings that changes in active and inactive renin occur independently under conditions of challenge by captopril or angiotensin II analogues.     

Somatostatin is required for masculinization of growth hormone–regulated hepatic gene expression but not of somatic growth

Pulsatile growth hormone (GH) secretion differs between males and females and regulates the sex-specific expression of cytochrome P450s in liver. Sex steroids influence the secretory dynamics of GH, but the neuroendocrine mechanisms have not been conclusively established. Because periventricular hypothalamic somatostatin (SST) expression is greater in males than in females, we generated knockout (Smst(-/-)) mice to investigate whether SST peptides are necessary for sexually differentiated GH secretion and action. Despite marked increases in nadir and median plasma GH levels in both sexes of Smst(-/-) compared with Smst(+/+) mice, the mutant mice had growth curves identical to their sibling controls and retained a normal sexual dimorphism in weight and length. In contrast, the liver of male Smst(-/-) mice was feminized, resulting in an identical profile of GH-regulated hepatic mRNAs between male and female mutants. Male Smst(-/-) mice show higher expression of two SST receptors in the hypothalamus and pituitary than do females. These data indicate that SST is required to masculinize the ultradian GH rhythm by suppressing interpulse GH levels. In the absence of SST, male and female mice exhibit similarly altered plasma GH profiles that eliminate sexually dimorphic liver function but do not affect dimorphic growth.     

The effect of metoclopramide and haloperidol on plasma renin activity and aldosterone levels in rats

To gain further information on dopaminergic inhibition of renin release and aldosterone secretion, we studied the effect of 0.1, 1.0, or 5.0 mg metoclopramide or haloperidol/kg body weight i.p. on plasma renin activity (PRA) and aldosterone concentration in serum, and of furosemide pretreatment or dietary sodium restriction (14 days) on PRA and aldosterone responses to 1.0 and 5.0 mg haloperidol/kg b.wt. i.p. in groups of eight male Sprague-Dawley rats. Aldosterone levels in serum were increased very similarly by 0.1 and 1.0 mg metoclopramide and haloperidol/kg. Whereas PRA and aldosterone were unaffected by 5.0 mg metoclopramide/kg, both were maximally stimulated by 5.0 mg haloperidol/kg. Furosemide pretreatment increased PRA and aldosterone concentration and blunted the aldosterone response to haloperidol. PRA response to 5.0 mg haloperidol/kg was not changed. After sodium restriction, aldosterone concentration as inappropriately high and did not respond to 1.0 mg haloperidol/kg. However, PRA and aldosterone response to 5.0 mg haloperidol/kg was magnified. Our study confirms both dopaminergic inhibition of PRA and stimulation of aldosterone secretion by dopamine antagonists in rats. A feedback regulatory mechanism becomes conceivable which comprises aldosterone secretion, sodium turnover, volume homeostasis, and dopaminergic activity.     

Interrelation of the renin system and erythropoietin in rats

Evidence is presented implicating the renin-angiotensin system in the regulation of plasma erythropoietin concentration. Male and female rats were exposed to hypoxia at 0.43 atm for 8 hr. In male rats, individual erythropoietin values showed a positive correlation with renin, renin substrate, and angiotensin I after 8 hr of hypoxia. In female rats, renin was not elevated during hypoxia. However, after renin was injected subcutaneously, plasma renin values became similar to those in male rats and erythropoietin doubled. Individual erythropoietin values of the combined groups showed a positive correlation with plasma renin. A single oral dose of SQ 14225, an angiotensin I-converting enzyme inhibitor, reduced erythropoietin to undetectable levels in renin-injected female rats. Angiotensin II, in subpressor amounts, prevented the suppression of erythropoietin by SQ 14225. SQ 14225 also reduced renin substrate concentration at ambient pressure and during hypoxic exposure. The correlation coefficient between renin substrate and erythropoietin in rats given SQ 14225 to lower substrate or angiotensin II to increase substrate was 0.85; p < 0.0005. The increase in renin substrate that occurred during hypoxia in female rats given angiotensin II correlated positively with erythropoietin, r = 0.86; p < 0.0005.     

Pharmacological evidence for a role of brain serotonin in the maintenance of plasma renin activity in unanesthetized rats

To determine whether serotonin is involved in the regulation of renin secretion in unanesthetized rats, plasma renin activity was measured in animals treated with the serotonin-depleting drugs p-chlorophenylalanine and 5,7-dihydroxytryptamine, with the serotonin releasing drug p-chloroamphetamine and with the serotonin agonist quipazine. Plasma corticosterone was also measured. p-Chlorophenylalanine decreased plasma renin activity and p-chlorophenylalanine plus 5-hydroxytryptophan increased plasma renin activity. Plasma renin activity was also reduced in rats that had received intraventricular 5,7-dihydroxytryptamine after pretreatment with desmethylimipramine. p-Chlorophenylalanine and 5,7-dihydroxytryptamine did not change plasma corticosterone concentration. p-Chloroamphetamine and quipazine produced dose-dependent increases in plasma renin activity and plasma corticosterone. The increase in plasma renin activity produce by quipazine was more rapid than that produced by p-chloroamphetamine. The effects of p-chloroamphetamine on plasma renin activity and plasma corticosterone were prevented by prior administration of p-chlorophenylalanine. The renin stimulating effect of p-chloroamphetamine was unaffected by adrenalectomy. L-Tryptophan failed to increase plasma renin activity. The data support the hypothesis that in rats release of serotonin within the central nervous system increases renin secretion and corticosterone secretion and that the increase in renin is independent of the increase in corticosterone.