Diminished aldosterone responses to angiotensin II and adrenocorticotropin in hypocalcemic subjects: restoration of responsiveness with normocalcemia

ACTH-, angiotensin II (AII)-, and K+-mediated aldosterone responses in vitro are dependent on extracellular and intracellular Ca concentrations. This study examined in vivo the relationship of changes in ambient serum calcium (serum Ca) to ACTH- and AII-mediated aldosterone release in hypoparathyroid subjects. Plasma aldosterone (PA) responses to graded dose infusions of ACTH and AII were examined in hypoparathyroid (HypoPTH) patients before (n = 8) and after correction of hypocalcemia (n = 6) and compared to responses in 20 normotensive normocalcemic subjects. ACTH and AII were infused for 90 min at rates increasing from 12.5 to 50 mIU/30 min and 0.5 to 2.0 ng/kg X min, respectively. Pretreatment mean serum Ca was 6.8 +/- 0.2 (+/- SEM) mg/dl, and it rose to 9.3 +/- 0.2 mg/dl after 3-8 weeks of vitamin D administration. In the untreated HypoPTH patients, basal mean PA (5.4 +/- 1.3 ng/dl) was lower (P less than 0.01) than in the normal subjects (10.6 +/- 0.6 ng/dl) or treated HypoPTH patients (9.5 +/- 1.8 ng/dl). There was a marked reduction in PA responses to ACTH at all doses in the untreated HypoPTH patients compared to the normal subjects. With normalization of serum Ca in four patients, the mean peak PA response to ACTH (25.1 +/- 6.0 ng/dl) was not significantly different from normal (28.9 +/- 1.7 ng/dl). During graded dose AII infusion in five untreated HypoPTH patients, mean PA levels increased from 6.9 +/- 1.2 to 11.6 +/- 2.2 ng/dl; when the serum Ca was normal, the corresponding values were 8.7 +/- 1.8 and 20.2 +/- 3.61 ng/dl. There was a positive correlation (r = 0.475; P less than 0.05) between basal PA and serum Ca levels. In addition, maximum changes in mean arterial pressure in response to AII infusions were significantly greater after correction of hypocalcemia. These observations indicate that in HypoPTH patients, extracellular Ca concentrations can influence humoral aldosterone response to ACTH and AII and pressor responses to AII.     

Effect of upright posture on the aldosterone responses to dopamine, metoclopramide, angiotensin II, and adrenocorticotropin

Aldosterone secretion in man is stimulated by potassium (K), ACTH, and angiotensin II (AII) and inhibited by dopamine (DA). In normal sodium-replete supine individuals, aldosterone secretion is under maximum tonic inhibition by DA and is not inhibited further by DA administration. Sodium depletion alters plasma aldosterone responses to secretogogues. Upright posture, another physiological stimulus to aldosterone secretion, recently was demonstrated to sensitize the adrenal cortex to inhibition of aldosterone secretion by a large quantity of DA (4.0 micrograms/kg X min). The effect of upright posture on aldosterone responses to other secretogogues is unknown. In this study, we investigated the effect of upright posture on aldosterone responses to low infusion rates of DA, to the DA antagonist metoclopramide (M) and to AII and ACTH. Fourteen normal men eating a normal sodium diet were studied. In eight, PRA, plasma aldosterone (PAC), plasma cortisol (F), and serum K concentrations were determined after 4 h of upright posture and infusion of vehicle (D5W) or DA at 0.1, 0.4, and 2.0 micrograms/kg X min. Six other normal men were kept supine for 3 h and, on separate days, upright for 3 h and given iv M (10-mg bolus dose), AII (1 and 4 pmol/kg X min for 30 min), and ACTH (20 and 120 mU/h for 30 min). PAC, PRA, F, and K were measured before and after these three secretogogues were administered. In the presence of vehicle, mean PAC increased by 15.1 +/- 4.3 (+/- SEM) ng/dL after 4 h of upright posture. In the presence of DA infused at 0.1, 0.4, and 2.0 micrograms/kg X min, the PAC response to upright posture was decreased to 9.7 +/- 2.5 (P = NS), 7.5 +/- 3.9 (P less than 0.05), and 8.1 +/- 2.0 (P less than 0.05) ng/dL, respectively. This occurred without a decrease in PRA, F, or K. The stimulation of PAC 10 and 20 min after a 10-mg bolus dose of M was 9.6 +/- 3.3 and 9.3 +/- 2.6 ng/dL, respectively, in supine subjects and 8.3 +/- 2.3 and 10.8 +/- 3.4 ng/dL 10 and 20 min after the M dose in upright subjects. The responses of PAC to ACTH and AII also were unchanged after 3 h of upright posture. We conclude that upright posture sensitizes the adrenal cortex to inhibition of aldosterone secretion by DA without affecting other modifiers of aldosterone secretion.(ABSTRACT TRUNCATED AT 400 WORDS)     

Plasma adrenocorticotropin, cortisol, and aldosterone responses to corticotropin-releasing factor: modulatory effect of basal cortisol levels

Two hundred micrograms of corticotropin-releasing factor (CRF) were administered as an iv bolus injection to 10 normal subjects (5 men and 5 women). Mean plasma ACTH levels rose significantly (P less than 0.0005, by Friedman's nonparametric analysis of variance) from a basal value of 27 +/- 5 pg/ml (mean +/- SEM) to a peak value of 63 +/- 8 pg/ml 30 min after CRF administration. This ACTH response was followed by a rise in plasma mean cortisol levels (P less than 0.0005, by Friedman's test) from a baseline value of 12.3 +/- 1.4 micrograms/100 ml to a peak value of 21.0 +/- 0.7 micrograms/100 ml 60 min after CRF and a rise in mean plasma aldosterone levels from a basal value of 13 +/- 2 ng/100 ml to a peak value of 23 +/- 2 ng/100 ml. There was no significant difference between men and women in the responsiveness of ACTH, cortisol, and aldosterone to CRF administration. The individual basal cortisol levels were highly significantly and negatively correlated with the areas under the individual ACTH curves (r = -0.76; P less than 0.005, by Pearson's correlation test) and cortisol curves (r = -0.91; P less than 0.001, by Pearson's test). These data suggest a modulatory effect of physiological cortisol levels on the response of the pituitary-adrenal axis to CRF.     

Effect of bromocriptine treatment on the aldosterone response to angiotensin II and adrenocorticotropin in idiopathic hyperaldosteronism

Bromocriptine can prevent an increase in plasma aldosterone during the infusion of angiotensin II in normal subjects and during upright posture in some patients with idiopathic hyperaldosteronism. To determine if bromocriptine prevents the increase in plasma aldosterone concentration during angiotensin II infusion in idiopathic hyperaldosteronism, we infused angiotensin II in five patients with idiopathic hyperaldosteronism, before and after treatment with bromocriptine (2.5 mg, three times daily for 5 days), and measured the resulting plasma aldosterone and angiotensin II concentrations. We also determined the adrenal response to ACTH infusion before and after bromocriptine treatment in four of these patients. Bromocriptine treatment did not significantly change the plasma concentrations of aldosterone before or during the infusions of angiotensin II and ACTH. It did significantly decrease mean blood pressure and increase the plasma corticosteroid concentrations in the preinfusion periods, but it did not alter the response of blood pressure to angiotensin II or of plasma corticosteroid concentrations to the ACTH infusions.     

Dopamine selectively inhibits aldosterone responses to angiotensin II in humans

Previous studies have suggested that dopamine may have an important role as an inhibitor of aldosterone secretion in humans. Recent studies have also suggested that the adrenergic nervous system may have an important role in controlling aldosterone secretion. The present study investigated the effects of dopamine on aldosterone secretion in response to angiotensin II, with and without pretreatment with propranolol, and to adrenocorticotropic hormone, another known stimulator of aldosterone secretion. Nine normal subjects in balance at 10 mEq sodium intake received dopamine (4 micrograms/kg/min) or vehicle for 270 minutes on 2 consecutive days on three separate occasions. After 120 minutes of dopamine infusion, the subjects received a 30-minute intravenous infusion of angiotensin II (in cumulative doses of 0.5, 1, 2, 4, and 6 pmol/kg/min), angiotensin II after oral pretreatment with propranolol, or adrenocorticotropic hormone (in cumulative doses of 0.5, 1, 2, and 5 U/hr). Aldosterone responses to 2, 4, and 6 pmol/kg/min of angiotensin II (without propranolol) were greater in vehicle-treated than in dopamine-treated subjects (p less than 0.05), as was the slope of the angiotensin II-vehicle dose-response curve (0.46, p less than 0.05). Propranolol suppressed the aldosterone response to angiotensin II, but dopamine still inhibited the response. Aldosterone and cortisol secretion were stimulated equally by adrenocorticotropic hormone in dopamine-treated and vehicle-treated groups. These results suggest that dopamine selectively inhibits the aldosterone response to angiotensin II and that this response is not mediated by teh activity of dopamine at beta-adrenergic receptors.     

Role of angiotensin II in the aldosterone secretory response to adrenocorticotropin in sodium-restricted normal human subjects.

A study was performed to determine the possible role of angiotensin II (AII) in mediating the increased adrenal aldosterone response to infused alpha 1-24-ACTH, induced by sodium deprivation. Nine normal subjects, aged 18-31 yr. received 8-h infusions of 1) alpha 1-24-ACTH (0.5 U given over 8 h) while on a diet with unrestricted sodium content; 2) saralasin at 0.5 micrograms/kg/min or ACTH alone (0.5 U over 8 h) on the 7th day of a 10 meq sodium diet; and 3) ACTH and saralasin together on the 8th day while still on sodium restriction. AII was administered for the last 2 h of infusion 3. Plasma cortisol and aldosterone concentrations were measured at hourly intervals during the infusions and plasma renin activity was measured at 2 hourly intervals. ACTH infusion produced an increase in the plasma aldosterone concentration which was significantly greater during sodium restriction than when sodium intake was unlimited. This increase was not associated with an ACTH-induced rise in the plasma renin activity and was not significantly altered when ACTH was administered with saralasin. The rise in plasma cortisol concentration induced by ACTH was not significantly different when the normal subjects were on liberal and restricted sodium intakes. It is concluded that AII plays little if any acute role in increasing the stimulatory action of ACTH on aldosterone secretion during sodium restriction.     

Plasma aldosterone and corticosterone responses to adrenocorticotropin, angiotensin, potassium, and stress in spontaneously hypertensive rats

The responses of plasma aldosterone and corticosterone to ACTH, angiotensin II (AII), and potassium chloride (KCl) infusion and the aldosterone, corticosterone and PRA responses to immobilization stress were studied in 2-month-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) normotensive controls. Basal levels of plasma aldosterone and corticosterone were greater and PRA was less in the SHR than in the WKY. Aldosterone and corticosterone responses to graded AII were similar in both groups. Aldosterone and corticosterone responses to graded doses of KCl and ACTH, however, were significantly greater in SHR than in WKY normotensive rats. Plasma corticosterone, PRA, and aldosterone responses to immobilization stress were reduced in SHR compared to WKY. At 2 months of age, blood pressure was definitely elevated in SHR and was associated with low PRA and relatively high basal levels of aldosterone and corticosterone. Discordance between the renin-angiotensin system and mineralocorticoid secretion in the SHR may be due to enhanced adrenal sensitivity to factors such as ACTH and potassium. Suppressed PRA in SHR may be due, in part, to increased mineralocorticoid secretion, resulting in sodium retention and intravascular volume expansion.     

Analysis of the role of angiotensin II in mediation of adrenocorticotropin secretion

It has been suggested that ACTH secretion in response to selected stimuli may be modulated by angiotensin II (AII) via direct action at the level of the corticotrope or through central actions to facilitate CRF secretion into the hypophysial-portal circulation. These hypotheses were evaluated in the present series of experiments. Our failure to observe a significant portal to peripheral plasma immunoreactive (ir) AII gradient suggested that AII does not act as a physiologically significant ACTH secretagogue at the level of the corticotrope. Central administration of synthetic AII evoked a modest dose-related stimulation of hypothalamic irCRF secretion into the portal circulation, which was reversed by the AII receptor antagonist saralasin. Activation of a known AII-positive neuronal pathway projecting from the subfornical organ (SFO) to the hypothalamic paraventricular nuclei resulted in an elevation of hypophysial-portal plasma irCRF levels and increased circulating ACTH. Pretreatment with saralasin prevented SFO stimulation-induced irCRF secretion. These observations suggest that central AII-containing pathways may participate in mediation of ACTH secretion in response to hypovolemia or hyperosmolality by facilitating irCRF secretion. Involvement of the SFO, a circumventricular organ, in this circuit is intriguing as it provides a means of monitoring peripheral irAII concentration and then converting this humoral signal into a neural signal distributed to regions regulating drinking behavior, neurohypophysial AVP secretion, and activation of the hypothalamic-pituitary-adrenal axis.     

Intracerebroventricular atrial natriuretic peptide infusion augments the adrenocorticotropin and angiotensin II responses to hemorrhage in sheep

The central actions of atrial natriuretic peptide (ANP) in rats include inhibition of arginine vasopressin (AVP) release, and less consistently, ACTH suppression and hypotension. To explore any such inhibitory actions on basal and stimulated levels of AVP and ACTH, we have studied the effect of intracerebroventricular (ICV) infusion of ANP on the hemodynamic and hormonal response to acute hemorrhage in conscious sheep. Two groups of 5 sheep received rat ANP(101-126) by ICV infusion (0.5 microgram bolus followed by 0.5 microgram/h for 3 h, or 5 micrograms bolus followed by 5 micrograms/h for 3 h) as well as artificial cerebrospinal fluid control infusions in random order. One hour after the start of the ICV infusion, acute hemorrhage (15 ml/kg BW within 10 min) was performed. Basal levels before hemorrhage of mean arterial pressure (MAP), heart rate and plasma hormones were unaltered by either dose of ICV ANP. After hemorrhage, the fall in MAP and rise in heart rate were similar in each group. However, compared to control infusions the response to hemorrhage of ACTH (433 +/- 147 to 2,175 +/- 588 vs. control 541 +/- 103 to 893 +/- 244 ng/l; p less than 0.016) and angiotensin II (AII) (18 +/- 3 to 94 +/- 23 vs. control 18 +/- 4 to 58 +/- 8 pmol/l; p less than 0.001) were significantly greater during high-dose ANP infusion. Although peak AVP levels more than doubled those observed on the control day, the increase did not reach statistical significance (p less than 0.1053). Plasma concentration of cortisol, aldosterone, epinephrine and norepinephrine were not significantly different in control and ANP-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic angiotensin II infusion decreases renal norepinephrine overflow in conscious dogs

Sympathetic nerve activity and in particular renal sympathetic nerve activity were monitored in six conscious dogs subjected to 6 days of intravenous angiotensin (ANG II) infusion (20 ng/kg/min). This was accomplished by measurement of both arterial and renal venous plasma catecholamine concentration. During the initial 4 hours of ANG II infusion, mean arterial pressure (MAP) increased 35 +/- 8 mm Hg from a control value of 101 +/- 4 mm Hg. Although there were no significant changes in arterial plasma norepinephrine (NE) concentration at this time (control = 148 +/- 40 pg/ml), arterial plasma epinephrine (E) concentration increased threefold (control 42 +/- 15 pg/ml). After 24 hours of ANG II infusion, MAP remained elevated (132 +/- 5 mm Hg), but plasma E concentration returned to control levels. From Days 2 through 6 of ANG II infusion, MAP was elevated approximately 40 mm Hg, but there were no chronic increases in either arterial plasma E or NE concentrations. In contrast to arterial plasma catecholamine concentration, renal vein plasma NE concentration (control = 216 +/- 27 pg/ml) actually decreased during both the acute (122 +/- 12 pg/ml) and chronic (103 +/- 26 pg/ml) phases of ANG II infusion. Moreover, renal NE overflow (renal venous plasma NE concentration-arterial plasma NE concentration X effective renal plasma flow), an index of renal sympathetic nerve activity, was depressed during the chronic phase of ANG II hypertension. These results, therefore, do not support the contention that the sympathetic nervous system mediates the hypertension produced by elevated plasma levels of ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)     

Importance of endogenous angiotensin II in the cardiovascular responses to sympathetic stimulation in conscious rabbits

Pharmacological evidence indicates that angiotensin (Ang II) converting enzyme inhibitors attenuate cardiovascular responses to sympathetic stimulation. To investigate the physiological significance of this attenuation, the pressor and heart rate responses to bilateral carotid occlusion (BCO) were studied before and after administration of captopril and again during Ang II replacement in conscious, aortic nerve-sectioned rabbits with chronically implanted carotid occluders. In the control period, BCO produced increases (p less than 0.05) in mean arterial pressure (MAP) and heart rate (HR) of 37.3 +/- 3.0 mm Hg and 21.7 +/- 5.4 beats/min from baseline values of 79.1 +/- 2.5 mm Hg and 255.4 +/- 16.7 beats/min. Captopril (5 mg/kg i.v.) markedly reduced (p less than 0.05) both the pressor (10.2 +/- 2.6 mm Hg) and HR (5.0 +/- 4.0 beats/min) responses to BCO, in parallel with a decrease in plasma Ang II of 75%. Infusion of a subpressor dose of Ang II (5-25 ng/kg/min i.v.) increased plasma Ang II to precaptopril levels and fully restored (p less than 0.05) the pressor (33.0 +/- 5.7 mm Hg) and HR (19.8 +/- 7.7 beats/min) responses to BCO. In two additional series of experiments, the mechanism of the effects of captopril and Ang II were investigated. In the first series, cardiac baroreflex curves (pulse interval versus MAP) were generated by increasing or decreasing blood pressure with phenylephrine or nitroprusside (5-20 micrograms/kg/min i.v.). The slope of the linear region of the curve (2.9 msec/mm Hg) was not changed significantly by captopril treatment (3.1 msec/mm Hg) or Ang II replacement (3.2 msec/mm Hg), indicating that cardiac baroreflex sensitivity was not altered by blockade of the renin-angiotensin system. In the second series, the effect of captopril on the pressor response to exogenous norepinephrine (0.1-2.5 micrograms/kg/min i.v.) was tested. The response was reduced by less than 40%, indicating only a modest postsynaptic component to the action of captopril. These results provide physiological evidence for an important action of endogenous Ang II in facilitating the cardiovascular responses to sympathetic stimulation in conscious rabbits. This facilitation is not due to an action upon the baroreflex per se but results, at least in part, from a presynaptic action of Ang II.     

The role of beta adrenoceptors in the coronary and systemic hemodynamic responses to emotional stress in conscious dogs

The present observations were made to investigate the role of beta adrenoceptors in the hemodynamic response to stress in conscious dogs. Probes for electromagnetic flowmeter were implanted on the ascending aorta and left circumflex coronary artery and a catheter was inserted into the aortic arch, 15 days before observations were made. Emotional stress, produced by firing a gun, increased heart rate, cardiac output, and left ventricular work. The responses were reduced by propranolol, practolol, and sotalol, 0.2 and 1.0 mg. per kilogram of body weight, and abolished by alprenolol. The difference between the effect of alprenolol and the other drugs may result from the marked intrinsic sympathomimetic activity of alprenolol which increased the resting levels of heart rate, cardiac output, and left ventricular work.Emotional stress increased mean blood flow through the left circumflex coronary artery as aresult of increase in stroke coronary flow and heart rate. Propranolol, sotalol, and practolol reduced the increase in mean coronary flow produced by stress through a reduction in tachycardia; the increase in stroke coronary flow was unaltered. The decreases in mean and late diastolic coronary resistance produced by stress were not altered by these three drugs.Alprenolol, unlike the other drugs, completely abolished the increases in mean and stroke circumflex coronary flow and the decreases in coronary vascular resistance produced by stress.The present observations indicate that the dilatation of coronary arteries produced by stress does not result entirely from an increase in cardiac metabolism; they also suggest that stimulation of beta adrenoceptors in the coronary arteries plays an important role in the coronary vasodilation produced by emotional stress.     

Aldosterone responses to angiotensin II, adrenocorticotropin, and potassium in chronic experimental diabetes mellitus in rats

To investigate alterations in aldosterone secretion in diabetes mellitus, the effects of angiotensin II, ACTH, and potassium on aldosterone secretion were examined in conscious unrestrained streptozotocin-induced diabetic rats (60 mg/kg, 12 weeks before study). In chronic experimental diabetic rats where PRA, plasma aldosterone concentration, and urinary excretion of prostaglandin E2 were significantly decreased, a significant attenuated response of aldosterone secretion was demonstrated after infusion of angiotensin II, ACTH, or potassium. Yet the plasma fluorogenic corticosteroids response to ACTH in diabetic rats was not significantly different from that in control rats. After acute potassium infusion (0.30 meq/kg X min), plasma potassium levels in diabetic rats were significantly higher than in control rats, although immunoreactive insulin levels remained unchanged compared to the significant elevation in control rats. These results suggest that defects in aldosterone synthesis exist in chronic experimental diabetic rats and that potassium homeostasis is impaired during acute potassium loading. This change in potassium homeostasis may be related to both insulin and aldosterone deficiencies.     

Corticosterone and aldosterone dose-dependent responses to ACTH and angiotensin II in the duck (Anas platyrhynchos)

The effects of [1-24]ACTH, [5-Val]angiotensin II, and potassium (K+) on the secretion of corticosterone and aldosterone by tissue slices from the subcapsular (SCZ) and inner (IZ) zones of the duck adrenal gland were determined using incubation and superfusion systems. Both methods demonstrated that the release of corticosterone and aldosterone from IZ and SCZ cells was dependent on the ACTH dose concentration. The IZ cells produced more corticosterone than the SCZ cells in response to stimulation with 1-1000 ng ACTH/ml. The dose response by aldosterone from the cells of the SCZ and the IZ were comparable, but the proportion of aldosterone per total amount of steroid released was greater by cells of the SCZ (11.3%), than by cells of the IZ (3.6%). Elevating the K+ concentration in the incubation medium from 4.0 to 6.5 and 11.2 mM did not directly stimulate corticosteroid release or potentiate the stimulatory effect of ACTH. Superfusion with 10(-12) to 10(-5) M AII stimulated the release of aldosterone from the SCZ cells but had no detectable effect on the IZ and failed to stimulate corticosterone release from either the SCZ or IZ cells. The results presented here demonstrate that in the bird stimulation for the release of corticosterone and aldosterone are different. Methodology for superfusion of adrenal tissue and for the direct radioimmunoassay of aldosterone and corticosterone in the superfusate are described.     

Enhanced responses to pressor stimuli by intracerebroventricular infusions of angiotensin II in conscious rats

Effects of the intracerebroventricular (IVT) infusion of a subpressor dose (3 ng/kg/min) of angiotensin II (ang II) on the pressor responses to intravenous (IV) infusions of ang II and to IV bolus injections of norepinephrine (NE) were studied in conscious rats. This study was undertaken to determine whether activations of the brain renin-angiotensin system alter pressor responsiveness to IV infusions of ang II and IV injections of NE in the conscious state. Pressor responses to IV infusions of ang II and IV injections of NE were potentiated by the concurrent IVT infusion of the subpressor dose of ang II. Plasma renin activity (PRA), plasma corticosterone (B), and plasma prolactin concentration (PRL) were also measured before and during the IVT infusion of the subpressor (3 ng/kg/min) or the pressor (50 ng/kg/min) dose of ang II in order to determine the mechanisms for this pressor hyperresponsiveness to vasoconstrictor substances. The IVT subpressor dose of ang II increased PRA, but did not significantly change B and PRL. The IVT pressor dose of ang II decreased PRA and increased B, but did not significantly change PRL. These results suggest that the brain renin-angiotensin system plays an important role in pressor responsiveness to IV ang II and NE. Although the mechanisms are not fully understood, pressor hyperresponsiveness to IV ang II and NE by an intracerebroventricularly administered subpressor dose of ang II may be related to increased sympathetic outflow, because of the increment in PRA.     

Renal sensitivity to angiotensin II in the conscious dog

Local formation of angiotensin II (AII) within the kidney has been demonstrated. Changes in renal function induced by inhibitors of the renin-angiotensin system have been the basis for the postulate that AII may act as a paracrine substance in the kidney. We studied the renal action of chronic intrarenal infusions of AII at doses between 2 and 2000 fmol/kg X min in uninephrectomized conscious dogs monitored on 80 meq daily sodium intake. Exogenous AII was confined to the kidney, as demonstrated by the absence of systemic pressor and adrenal cortical responses during the intrarenal infusion. After 2 control days, each dose of AII was infused intrarenally for a period of 3 days. The smallest intrarenal dose of AII that caused significant antinatriuresis and antidiuresis was 20 fmol/kg X min. A significant reduction in urinary volume and sodium excretion occurred during the first 24 h of the infusion period and was proportionate to the amount of peptide infused. Renal escape from the antinatriuretic and antidiuretic effects of the peptide ensued on the second and third days of infusion. There were no significant changes in urinary potassium excretion, plasma renin activity (PRA), plasma aldosterone concentration, or blood pressure throughout the period of intrarenal AII administration. These data demonstrate dose-dependent direct antinatriuretic and antidiuretic actions of low AII concentrations. Escape from the sodium-retaining action of intrarenal AII occurred by 48 h and was independent of suppression of endogenous renin-angiotensin. These results indicate that AII alters renal function by direct intrarenal mechanisms.     

Effects of angiotensin II on the cardiac responses to sympathetic nerve stimulation in dogs

In anesthetized dogs with the left cardiac sympathetic nerves and both vagal nerves intact, angiotensin II (AII) induced a substantial, dose-dependent increase in arterial blood pressure and small increments in cardiac cycle length and ventricular contractile force. In dogs in which the cardiac sympathetic and vagal nerves had been interrupted, AII produced similar increases in blood pressure and larger increases in contractile force, but it decreased the cardiac cycle length. In both groups of dogs, AII augmented substantially the positive inotropic responses to sympathetic nerve stimulation, but it enhanced the positive chronotropic responses only slightly. However, AII did not appreciably prolong the cardiac responses to sympathetic nerve stimulation, nor did it alter significantly the cardiac responses to norepinephrine infusions. Hence, at the dosage levels used, AII probably did not inhibit the neuronal uptake of norepinephrine appreciably nor did it enhance the responsiveness of the cardiac effector sites to norepinephrine. Therefore, the potentiation of the cardiac responses to sympathetic nerve stimulation by AII in these experiments was probably achieved principally by facilitating norepinephrine release from the adrenergic nerve terminals in the heart.     

Effect of intrarenal angiotensin II blockade on renal function in conscious dogs.

The effects of intrarenal infusion of 1-sar-8-ala angiotension II (P 113) and a converting enzyme inhibitor, SQ 20881, at doses that did not affect systemic blood pressure (2.0 mug/kg per min) were studied in conscious, uninephrectomized dogs. In dogs receiving approximately equal to 5 mEq/day of sodium, intrarenal infusion of P 113 increased renal blood flow (RBF) from 219.8 +/- 32.3 to 282.7 +/- 20.0 ml/min (P less than 0.004), and with intrarenal SQ 20881 infusion from 215.3 +/- 14.2 to 278.0 +/- 22.2 ml/min (p less than 0.005). In sodium-restricted dogs (approximately equal to 5 mEq/day), glomerular filtration rate (GFR) also increased with intrarenal P 113 infusion from 57.9 +/- 5.7 to 66.3 +/- 6.6 ml/min (P less than 0.05), and with SQ 20881 infusion from 43.1 +/- 2.1 to 55.7 +/- 4.5 ml/min (P less than 0.01). Dogs on approximately equal to 5 mEq/day of sodium showed significant increases in plasma renin activity (PRA) with intrarenal infusion of the peptides, unmasking a negative feedback inhibition of renin release by angiotensin II. No increases in RBF, GFR, or PRA were seen with infusion without inhibitors, or in dogs give P 113 or SQ 20881 while on approximately equal to 80 mEq/day of sodium. In addition, angiotensin II inhibition increased sodium excretion during sodium restriction. These findings suggest that intrarenal angiotensin II is intimately involved in renal responses to sodium restriction which result in conservation of sodium and water.