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To elucidate the role of the rostral ventrolateral medulla (RVLM) in cardiovascular control through the release of central amino acid neurotransmitters, experiments were performed in Sprague-Dawley (normotensive) rats and spontaneously hypertensive rats (SHR) anesthetized with urethane by using microdialysis sampling from the RVLM for determination of amino acid neurotransmitters. The baseline release of the excitatory amino acid neurotransmitter, glutamate (GLU) from the RVLM in SHR was higher and those of the inhibitory amino acid neurotransmitters, glycine (GLY), taurine (TAU), and gamma-aminobutyric acid (GABA), were lower than in normotensive rats. Microinjection of angiotensin II (ANG II) into the RVLM caused a dose-dependent increase in mean arterial pressure (MAP) and heart rate (HR), accompanied by increased release of GLU in the RVLM. In contrast, microinjection of the ANG II type 1 receptor (AT1) antagonist CV 11974 into the RVLM reduced MAP and HR, accompanied by increased release of GLY, TAU and GABA. These changes in MAP and HR after administration of ANG II or AT1 antagonist were partially blocked by the use of the corresponding antagonist of each amino acid neurotransmitter. Furthermore, these effects were more prominently seen in SHR than in normotensive rats. These results suggest that the release of amino acid neurotransmitters mediate the cardiovascular effects of the angiotensin system in the RVLM, which may be involved in the generation of hypertension in SHR.

We evaluated the renal effects of the new angiotensin II type 1 (AT ) receptor antagonist, HR 720, in the stroke-prone spontaneously hypertensive rat. Rats were treated with either vehicle, HR 720, MK-954 (a selective AT1 receptor antagonist) or enalapril for 6 weeks. Blood pressure was decreased to a similar extent by HR 720, MK-954 and enalapril (203 +/- 4, 202 +/- 5 and 190 +/- 4 vs. 247 +/- 4 mm Hg for control). Urinary protein secretion was also decreased (5.2 +/- 0.3, 5.3 +/- 0.2 and 5.5 +/- 0.6 vs. 25.2 +/- 4.6 mg/100g/24h). The glomerular hypertensive change was improved in each drug-treated group (2.0 +/- 0.2, 3.3 +/- 0.3 and 1.6 +/- 0.1 vs. 17.6 +/- 1.5%; p < 0.0001). These results show that, in addition to its antihypertensive effect, HR 720 has a beneficial effect on renal function.

TCV-116 is an orally active, nonpeptide antagonist of angiotensin-II type-1 receptor. The angiotensin-II antagonistic potency of TCV-116 was evaluated in normal volunteers. TCV-116 was administered at single doses of 1, 2.5, and 5 mg orally on separated days. Before, and 4, 8, and 24 h after the drug administration, angiotensin-II was infused intravenously at the rate of 2.5 to 40 ng/kg/min for 5 min each. At 2.5 mg of TCV-116, the pressor response to angiotensin-II was significantly suppressed at 4 and 8 hours after drug administration. TCV-116 at 5 mg produced a reduction of basal blood pressure and a suppression of pressor response to angiotensin-II, which persisted for 24 h. Aldosterone response to exogenous angiotensin-II was suppressed to 10% at 8 h after 5 mg of TCV-116 administration and remained suppressed to 48% until 24 h. These results suggest that TCV-116 is a highly potent and long-lasting antagonist of angiotensin-II receptor in man. The renin-angiotensin system may play a role in the regulation of blood pressure even in normotensive subjects.

We investigated the underlying mechanisms of baroreflex alteration produced by intravenous angiotensin II (ANG II) by monitoring the release of amino acids from the rostral ventrolateral medulla (VLM) using a brain microdialysis technique. Reflex changes in heart rate were elicited by bolus intravenous injection of phenylephrine (2-40 micrograms/kg) before and 120 min after the initiation of administration of a subpressor dose of ANG II (5.4 pmol/kg/min) or vehicle. The slope of the regression line obtained from changes in mean arterial pressure and heart rate elicited by phenylephrine was used as an index of baroreceptor reflex sensitivity. ANG II administration for 120 min significantly attenuated the baroreflex sensitivity (from -0.59 +/- 0.10 to -0.30 +/- 0.08 bpm/mmHg). This attenuation was accompanied with an increase in the release of glutamate and glycine from the VLM (+40% and +20%, respectively) at 120 min. Glycine perfusion into this area resulted in an attenuation of baroreflex sensitivity with a magnitude similar to that obtained with infusion of a subpressor dose of ANG II, whereas glutamate perfusion caused a resetting of baroreflex. These results suggest that glycine and glutamate are involved in cardiovascular regulation in the VLM. Furthermore, the augmented releases of these amino acids may account for the underlying mechanism of ANG II-induced attenuation of baroreflex function.

1. We previously reported that angiotensin II release from the mesenteric arteries of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) increased in a time-dependent manner as a result of the isolation of the arteries and perfusion. This phenomenon appeared to be due to the withdrawal of circulating angiotensin II (AII). 2. The purpose of the present study was to test the hypothesis that vascular AII generation may be negatively regulated by circulating AII in WKY and SHR, and to clarify the role of this vascular angiotensin II in the sustained hypertension of SHR following nephrectomy. 3. The mesenteric arteries from kidney-intact and nephrectomized WKY and SHR were perfused and the amount of AII released into the perfusate was measured. The effects of the angiotensin converting enzyme inhibitor, captopril, and the effects of supplementation of renal renin and circulating angiotensins to nephrectomized rats, by blood exchange between kidney-intact and nephrectomized rats, on AII release were examined to clarify the pathway of vascular AII generation after nephrectomy. 4. Nephrectomy caused augmentation of vascular AII release both in WKY and SHR in spite of the abolishment of circulating renin. Captopril reduced this enhanced release of AII, but blood exchange did not affect it. There was no significant difference in these responses between WKY and SHR. 5. These results suggest that WKY and SHR have in common a potent pathway for production of vascular AII in response to the withdrawal of circulating AII, although this pathway is not responsible for the sustained hypertension of SHR after nephrectomy. The precise pathophysiological role of this pathway remains to be elucidated.

To investigate the role of tissue angiotensin II (Ang II) in the maintenance of hypertension after nephrectomy in spontaneously hypertensive rats (SHR), Ang II levels were measured in various tissues of both 12-week-old SHR and normotensive control, Wistar-Kyoto rats (WKY), 48 h after nephrectomy or sham operation. Ang II was determined by radioimmunoassay coupled with high performance liquid chromatography. Nephrectomy caused a decrease of plasma renin activity and plasma Ang II concentration in both SHR and WKY. Aortic Ang II levels were significantly lowered by nephrectomy only in WKY, and not in SHR. Ang II levels in hypothalamic block, brainstem and cerebellum of SHR increased after nephrectomy, whereas those of WKY were unchanged. Intracerebroventricular administration of ceronapril, an angiotensin converting enzyme inhibitor, significantly decreased sustained high blood pressure in SHR 48 h after nephrectomy compared with vehicle administration, whereas intravenous administration had no effect. These results suggest that in spite of the important role of the renal renin-angiotensin system in maintenance of high blood pressure in SHR, control mechanisms may switch to other systems after nephrectomy, and that the increased brain Ang II levels after nephrectomy may be related to these mechanisms.

The objectives of the present study were to test the hypothesis that vascular angiotensin II (AII) generation may be negatively regulated by circulating AII in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), and to clarify the role of this vascular AII in the sustained hypertension seen in SHR following nephrectomy. The mesenteric arteries from kidney-intact and nephrectomised WKY and SHR were perfused, and the level of AII released into the perfusate were measured. The effects of CV-11974, a newly developed nonpeptide AII receptor antagonist, on AII release were examined to investigate the existence of a local feedback system in the blood vessels. Nephrectomy augmented vascular AII release both in WKY and SHR despite the reduction in circulating AII. CV-11974 significantly increased AII release from the mesenteric arteries of kidney-intact rats. There were no significant differences in these responses between WKY and SHR. These results suggest that WKY and SHR share a potent pathway for producing vascular AII in response to the withdrawal of circulating AII, although this pathway is not responsible for the sustained hypertension seen in SHR after nephrectomy.

Objective: To investigate the role of vascular angiotensin II (Ang II) in the vascular thickening of one-kidney, one clip (1-K, 1C) hypertensive rats, which show normal plasma renin activity., Methods: The type 1 Ang II receptor antagonist TCV-116 (1 mg/kg per day), the angiotensin converting enzyme (ACE) inhibitor delapril (20 mg/kg per day), hydralazine (20 mg/kg per day) or vehicle were administered to four groups of 1-K, 1C rats aged 6-10 weeks. Vehicle was also given to uninephrectomized rats., Results: The aortae of 1-K, 1C rats contained significantly higher levels of Ang II than those of uninephrectomized rats and showed hypertrophy, but not hyperplasia of their medial smooth muscle cells. Hypertrophy was estimated by immunohistochemical staining of alpha-actin. Hyperplasia was estimated by DNA content and incorporation of 5-bromo-2'-deoxyuridine. The blood pressure of the 1-K, 1C rats was not affected by either TCV-116 or delapril, even at doses sufficient to induce depressor effects in spontaneously hypertensive rats. However, subdepressor doses of TCV-116 and delapril both significantly reduced the alpha-actin-stained area to 78 and 73%, respectively, of that in the 1-K, 1C rats, whereas a depressor dose of hydralazine did not affect the alpha-actin-stained area. The level of Ang II in the aorta, but not in plasma, was suppressed by delapril but not by hydralazine., Conclusions: These results suggest strongly that vascular Ang II plays a major role in the development of vascular hypertrophy, independently of plasma Ang II, bradykinin and ACE-independent pathways of Ang II generation, and in the regulation of blood pressure in this normoreninaemic hypertensive model.

Recent studies suggest the linkage of hypertension and insulin resistance. High fructose diet is known to induce hyperinsulinemia and hypertension in rats. In a previous study, however, high fructose (66%) diet failed to elevate blood pressure but increased left ventricular weight in Sprague-Dawley rats. In the present study, we investigated the precise mechanism of high fructose diet-induced changes in the cardiovascular system in rats. Intake of fructose-enriched diet for 2 weeks increased serum insulin and plasma angiotensin II levels. Urinary excretion of sodium and norepinephrine was not changed. Blood pressure measured directly through an indwelling catheter was not increased, but left ventricular weight and protein content were increased by high fructose diet. To further elucidate the role of the renin-angiotensin system, an angiotensin II type 1 receptor antagonist, TCV-116, was given orally at 1 mg/kg per day with either normal or high fructose diet. Concomitant administration of TCV-116 did not affect plasma glucose or serum insulin levels. Plasma angiotensin II was increased, but neither urinary sodium nor norepinephrine was changed by TCV-116. TCV-116 similarly decreased blood pressure in rats on normal and high fructose diets. Increase in left ventricular weight induced by high fructose diet was prevented by the concomitant administration of TCV-116. On the other hand, left ventricular weight in control rats was not changed by TCV-116. In conclusion, increased plasma angiotensin II may account for the left ventricular hypertrophy induced by high fructose diet, whereas hemodynamic change, sodium retention, and the sympathetic nervous system do not play an important role.

The pathophysiological role of angiotensin II in the development of renal sclerosis was investigated in 5/6-nephrectomized, 12-week-old male spontaneously hypertensive rats. After 1 week of a control period, nephrectomized rats received one of the following treatments for 4 weeks: the selective nonpeptide angiotensin II type 1 receptor antagonist TCV-116 (1 mg/kg per day), the angiotensin converting enzyme inhibitor delapril (30 mg/kg per day), hydralazine (15 mg/kg per day), or vehicle. Urinary protein and albumin excretions and systolic blood pressure were determined every week. Rats with reduced renal mass treated with vehicle had a poor survival rate (30%). Although TCV-116, delapril, and hydralazine treatment significantly improved the survival rate for 4 weeks, hydralazine failed to improve proteinuria and albuminuria as well as the decline in renal function compared with delapril or TCV-116. Histological examination revealed that both TCV-116 and delapril protected glomeruli from sclerosis, whereas hydralazine did not improve histological findings (5%, 7%, and 30% of glomeruli were affected, respectively). These results indicate that angiotensin II plays a dominant role through its type 1 receptor in the pathogenesis of renal deterioration by hypertension.

Angiotensin II (Ang II) has been shown to induce proliferation of cardiac myocytes. To examine the role of Ang II in left ventricular (LV) hypertrophy, isoproterenol was infused subcutaneously into 9-week-old male Wistar rats at 4.2 mg/kg/day for 7 days. Infusion of isoproterenol increased LV weight and Ang II concentrations in plasma and in LV tissue. In anephric rats, LV weight and tissue Ang II were increased similarly, but plasma Ang II was not changed by isoproterenol. Concomitant oral administration of trandolapril and isoproterenol prevented increases in both LV Ang II and LV weight. Treatment with hydralazine decreased blood pressure in a similar way as trandolapril but did not affect either LV weight or LV Ang II. Plasma Ang II was not decreased by either trandolapril or hydralazine when administered in combination with isoproterenol. These results suggest that cardiac tissue Ang II regulates myocyte growth in isoproterenol-induced LV hypertrophy, and the reduction of Ang II partly explains the prevention of cardiac hypertrophy by the converting enzyme inhibitor.

The present study was performed to examine the effect of chemical sympathectomy with guanethidine on the BP change and humoral factors in rats which received continuous and concomitant infusion of i.c.v. hypertonic NaCl with i.v. Ang II, both at subpressor doses for 7 days. Male rats were divided into 3 groups which received the following infusions using an osmotic minipump at a rate of 1 microliter/min: Group 1 (n = 11), 0.15 M NaCl i.c.v. and Ang II (5.4 pmol/kg/min) i.v.; Group 2 (n = 9), 0.8 M NaCl i.c.v. and Ang II i.v.; Group 3 (n = 5), 0.8 M NaCl i.c.v. and Ang II i.v. with daily i.p. injection of guanethidine (40 mg/kg). Significant increase in BP was observed only in Group 2 (from 103 +/- 3 mmHg to 132 +/- 5 mmHg on day 7, p less than 0.001). Addition of i.p. guanethidine to i.c.v. infusion of 0.8 M NaCl and the subpressor dose of Ang II completely prevented increase in the BP, suggesting that the presence of the intact sympathetic nervous system is necessary for the development of BP elevation in response to i.c.v. hypertonic NaCl plus i.v. Ang II. Thus, the sodium status in the central nervous system is important in the regulation of BP and is closely related to the activity of the sympathetic nervous system.

To examine the role of the tissue renin-angiotensin system in left ventricular hypertrophy, converting enzyme inhibitors were administered orally to 12-week-old male spontaneously hypertensive rats (SHR) for 4 weeks, and cardiac tissue angiotensin II was measured. Treatment with enalapril (10 mg/kg per day) and trandolapril (1 mg/kg per day) lowered systolic blood pressure, left ventricular weight and left ventricular angiotensin II content. Plasma angiotensin II concentration was increased by the treatment with enalapril whereas trandolapril did not cause any change. There was significantly positive correlation between left ventricular weight and angiotensin II content. Because angiotensin II promotes cell proliferation, these results suggest that cardiac tissue angiotensin II, rather than circulating angiotensin II, may account for the pathophysiology of left ventricular hypertrophy in SHR.

The effects of endothelin on the vascular renin-angiotensin system were examined in isolated perfused rat mesenteric arteries by measuring vascular renin activity and angiotensin II released into the perfusate. Infusion of endothelin (10(-9)M and 10(-11)M) increased the vascular renin activity and angiotensin II release. Pretreatment with nicardipine (10(-6)M), a calcium channel blocker, significantly suppressed these effects of endothelin. These results suggest that endothelin activates the vascular renin-angiotensin system via intracellular calcium metabolism. Vascular angiotensin II produced by endothelin may modulate the local effect of endothelin on the resistance vessels.

1. To characterize the renin-angiotensin-aldosterone system in elderly hypertensive patients, an angiotensin II antagonist, [Sar1,Ile8]angiotensin II, was infused into individuals 60 years old and older with and without hypertension. 2. After infusion of [Sar1,Ile8]angiotensin II in all of the elderly patients and subjects an agonistic pressor response was observed that was greater than in middle-aged hypertensive patients. 3. Pre-infusion plasma renin activity and plasma aldosterone concentration in hypertensive and normotensive elderly groups were suppressed in comparison with those in middle-aged hypertensive subjects. The increased agonistic effects of [Sar1,Ile8]angiotensin II infusion on blood pressure in the elderly are presumably due to their hyporeninaemia. 4. The angiotensin-aldosterone system in elderly essential hypertensive patients is suppressed and is presumably not responsible for their elevated blood pressures.

The effect of selective NaCl loading to the brain on the blood pressure regulation was examined in male Wistar rats. Hypertonic NaCl (0.8M, 1 microL/h) was infused for 7 days into the lateral ventricle (ICV) along with intravenous (IV) infusion of angiotensin II (AII) at a dose of 5.4 pmol/kg per minute. Although neither ICV hypertonic NaCl or IV AII infusion alone had any substantial pressor effect, concomitant administration of these resulted in a consistent and significant increase in the blood pressure on day 7 over the baseline value, amounting to 29 +/- 5 mm Hg (n = 9; P less than 0.001). Inasmuch as the increase in the BP was totally prevented by intraperitoneal injection of guanethidine (40 mg/day), hyperactivity of the sympathetic nervous system appears, at least in part, responsible for the BP elevation caused by the combination of ICV hypertonic NaCl and IV subpressor AII infusion.

[1-Sarcosine, 8-Isoleucine] angiotensin II was given to 8 patients with cirrhosis and ascites and 7 cirrhotic patients without ascites on a regular diet. The 3 ascitic patients with high plasma renin activity (PRA) gave a depressor response, but the other ascite patients with normal or low PRA gave a pressor response or no response. All the non-ascitic patients gave a pressor response. There was an inverse correlation between the PRA before infusion and the change in blood pressure induced by this compound. In the patient with the highest PRA, who had ascites of a few days' duration, a marked reduction in blood pressure was observed on infusion of this compound. These results suggest that the renin-angiotensin system might be involved in maintenance of a normal blood pressure in some patients with cirrhosis and ascites, whose ascites is presumably in an early stage.

Angiotensin II analogue (AIIA), 1-sarcosine, 8-isoleucine angiotensin II (Sar1, Ile8-AII), was given in a graded dose to patients with adrenal hypofunction of various etiologies, and the blood pressure response to AIIA was observed to investigate the role of the renin-angiotensin system for the maintenance of blood pressure in the state of adrenal insufficiency. An agonistic pressor response to AIIA was observed in the control subjects without adrenal hypofunction. In contrast with this, patients with Addison's disease showed a blood pressure fall to AIIA. When the test was repeated on the same patients after hydrocortisone replacement, these patients showed a neutral or pressor response. Three patients with adrenalectomy and hydrocortisone replacement showed a pressor response to AIIA in a supine position. When these patients were tilted, fall in blood pressure to AIIA was observed in two of them who had been on a regular diet, whereas one patient who had been on a high sodium diet showed no fall in blood pressure with this procedure. We concluded that the renin-angiotensin system plays an important role in the maintenance of normal or subnormal blood pressure in Addison's disease and in the postural change of adrenalectomized patients on hydrocortisone and regular salt intake. The response of blood pressure to AIIA may be a clue for the diagnosis of Addison's disease and the evaluation of the adequacy of replacement therapy with regard to these patients.

Among the various biological effects of angiotensin II (AII), both pressor activity and aldosterone stimulation appear to be mediated by functionally different receptors. With this in mind, we compared pressor and aldosterone-stimulating activities of AII with those of triprolyl [(Pro)3] AII and pentasarcosyl [(Sar)5] AII. In conscious male Wistar rats (Pro)3 AII and (Sar)5 AII produced 48 and 46% of the pressor activity of AII. After intravenous infusion (conscious unrestrained rats, 125 pmol/kg/min for 30 min), plasma aldosterone concentrations were not significantly different from those of control rats which were infused with saline. However, when the rats were infused with AII (125 pmol/kg/min for 30 min), plasma aldosterone concentrations increased significantly (1,306 +/- 80 pg/ml). This study indicates that (Pro)3 AII and (Sar)5 AII may prove to be useful tools to elucidate biological actions of AII.

Two angiotensin II analogues, i.e., 1-sarcosine, 8-isoleucine angiotensin II (Sar1, Ile8-AII) and 1-sarcosine, 8-alanine angiotensin II (Sar1, Ala8-AII), are now available in the clinical study. Comparative studies of the antagonistic potency and the agonistic effect of these two AII analogues were made in normal subjects on three sodium balances and in hypertensive patients with various etiologies on sodium depletion. Both AII analogues had an agonistic pressor effect in normal subjects. This effect changed with different sodium balances. In the low sodium state, this agonistic action was minimized. The agonistic pressor effect of Sar1, Ile8-AII was greater than that of Sar1, Ala8-AII in all sodium states. There was found an agonistic activity of both AII analogues not only on blood pressure, but also on renin and aldosterone secretion, and renal vasculature in normal subjects on a regular diet. The antagonistic depressor potency of both compounds was also varied by changing sodium balance, being greatest in the low sodium state. In hypertensive patients on sodium depletion, the blood pressure responses of individual patients to these two AII analogues were significantly correlated (r = 0.8, n = 20). These results indicate taht pretreatment of sodium depletion is necessary to prevent the side effect caused by the agonistic pressor action of AII analogue, and also to predict renin depency in hypertensive patients efficiently.

Two angiotensin II analogues (AIIA), 1-sarcosine, 8-isoleucine angiotensin II ([Sar, Ile]-AII) and 1-sarcosine, 8-alanine angiotensin II ([Sar, Ala]-AII), were infused in six normal volunteers on high, regular and low sodium diets. The agonist and antagonist activities of these AIIA on blood pressure (BP), plasma aldosterone concentration (PAC), creatinine clearance and plasma renin activity were examined. Both AIIA had agonistic pressor activities in subjects on high and regular sodium diets, [Sar, Ile]-AII being more potent than [Sar, Ala]-AII. Both AIIA caused similar elevation of PAC in subjects on high and regular sodium diets, and an equally fall in PAC in subjects on a low sodium diet. Both AIIA strongly antagonized the rise in BP, the increase in PAC and the reduction of Ccr induced by AII administration in subjects on all three sodium diets. The results indicate that both AIIA can be used to examine the activity of the renin-angiotensin system in patients with hypertension, and they also suggest that AII interaction with its receptors differs in different target tissues.

To examine the involvement of renin-angiotensin-aldosterone system in the etiology of oral contraceptive induced hypertension, normal women (Group I), normotensive (Group II) and hypertensive (Group III) women taking Ovulen (R) were infused with a competitive angiotensin II (AII) antagonist, [1-sarcosine, 8-isoleucine] angiotensin II. The angiotensin II antagonist was infused at a rate of 600 ng/kg/min for 30 min 1.5 hrs after intravenous injection of 40 mg of furosemide. Blood pressure was monitored and pre-infusion and post-infusion plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were determined. Pre-infusion PRA and PAC showed no significant differences among these three groups. In response to the AII antagonist infusion blood pressure rose in Groups I and II, but blood pressure responses in Group III were variable. Four out of the total 6 subjects had pressor responses and only one subject had a significant blood pressure reduction. In both Groups I and II, PRA decreased and PAC rose after infusion of the antagonist. In Group III, PRA decreased to a lesser degree and PAC showed no consistent change. These data suggest that the renin-angiotensin-aldosterone system in hypertensive women or oral contraceptives is different from that of the normotensive users. However, the pathophysiology of oral contraceptive induced hypertension is not homogenous and angiotensinogenic hypertension is uncommon.

An angiotensin II antagonist, [sacrosine1, isoleucine8] angiotensin II, was infused into thyrotoxic patients. Blood pressure was monitored before and during the infusions to investigate whether the renin-angiotensin-aldosterone system was involved in the maintenance of blood pressure in normotensive and hypertensive thyrotoxic patients. Five out of 17 normotensive patients with hyperthyroidism showed more than a 10 mmHg decrease in mean blood pressure in response to the infusion (responders), while the remaining 12 patients showed no substantial change in blood pressure (non-responders). The infusion caused little change in blood pressure in 8 hyperthyroid patients with systolic hypertension. The mean levels of serum thyroxine, triiodothyronine, plasma renin activity and plasma aldosterone concentration in the normotensive responders were significantly higher than the values in the normotensive non-responders. There were no significant differences in these laboratory values between the hypertensive patients and the normotensive non-responders except that serum triiodothyronine levels were significantly higher in the hypertensive patients. The present study indicates that increased activity of the renin-angiotensin-aldosterone system is involved in the maintenance of blood pressure in most normotensive patients with severe hyperthyroidism, while hypertension in patients with hyperthyroidism is not angiotensin II dependent.

The synthetic angiotensin II antagonist, 1-sarcosine, 8-isoleucine angiotensin II was infused in two patients with untreated Addison's disease. Blood pressure decreased following infusion of this angiotensin II antagonist. Re-infusion of the antagonist after cortisol replacement therapy for one month caused a slight increase in blood pressure. Addison's disease is one of the conditions in which the renin-angiotensin system is involved in the maintenance of blood pressure.

To elucidate whether the presence of angiotensin II immunoreactivity (ANG II-ir) in the cerebrospinal fluid (CSF) of the dog is in part due to passage of the peptide across the CSF-blood-brain barrier, [Ile5] angiotensin II (ANG II) was infused intravenously for 7 days in conscious, trained dogs at a rate of 10 micrograms/kg/day. Mean arterial pressure (MAP) and heart rate were monitored each day, and samples of arterial blood and CSF (with a catheter secured into the cisterna magna) were drawn at regular intervals for determination of catecholamine levels, ANG II-ir, and electrolyte levels. Within 2 days after ANG II infusion, MAP stabilized at 35 +/- 1 mm Hg (mean +/- SE, p less than 0.001) above control values. The hypertension was associated with bradycardia, suppressed plasma renin activity, and a fall in both plasma and CSF Na+ concentrations. These changes coincided with a considerable and sustained decrease in the levels of plasma and CSF norepinephrine. On the other hand, levels of epinephrine and K+ in the two compartments remained unchanged. Although concentration of ANG II-ir in plasma was augmented markedly (368% above control values, p less than 0.001), ANG II-ir in the CSF remained within the low values measured in the control period.(ABSTRACT TRUNCATED AT 250 WORDS)

The renin-angiotensin-aldosterone system in patients with acromegaly was evaluated by infusing [sarcosine1, isoleucine8]angiotensin II, a competitive angiotensin II antagonist, into five acromegalic patients with hypertension and three normotensive acromegalics. The drug was infused at a rate of 600 ng/kg . min for 30 min, 1 h after iv injection of 40 mg furosemide. In addition, before the infusion, plasma samples were obtained for determination of PRA and plasma aldosterone concentration. A significant pressor response to [sarcosine1, isoleucine8]angiotensin II was observed in all eight patients. Preinfusion PRA and plasma aldosterone concentration were significantly lower than in normal controls. It is concluded that in acromegaly, the renin-angiotensin-aldosterone system is suppressed and that this system is probably not involved in maintenance of the high blood pressure observed in some acromegalic patients.