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The neurohormonal contribution to high blood pressure was investigated in 9 conscious two-kidney, two-clip Goldblatt (2K2C) hypertensive dogs during evolution of the benign and malignant phases after application of bilateral renal clips (BRC). Serial measurements were taken of the plasma renin activity (PRA), plasma angiotensin I-immunoreactivity (Ang I-ir), plasma angiotensin II-ir (Ang II-ir), renin substrate (RS) catecholamines [epinephrine (Epi) and norepinephrine (NE)] and vasopressin (AVP). Immediately after BRC, the elevation of the blood pressure (86 +/- 3 to 110 +/- 3 mmHg, p less than 0.01) was associated with an increase in heart rate (93 +/- 3 to 114 +/- 9 beats/min, p less than 0.01). These hemodynamic changes were accompanied by increases in PRA, Ang I-ir, Ang II-ir, Epi, NE and AVP. The renin angiotensin system was activated throughout the 3 week period following BRC, as indicated by increases in PRA, Ang I-ir and Ang II-ir. Catecholamines were elevated immediately after BRC, followed by a return toward the control values. AVP underwent a slight but not significant elevation after BRC, which was sustained during the 3 weeks. Production of malignant hypertension was affected by occlusion of one of the adjustable renal clips 3 weeks after BRC. A marked elevation of the blood pressure was associated with significant increases in PRA, Ang I-ir, Ang II-ir, Epi, NE and AVP, compared with the pre-occlusion values. In addition, pharmacologic experiments were performed in 6 of 9 dogs. Administration of angiotensin I converting enzyme inhibitor (SQ 14225) reduced the blood pressure both in the benign and malignant phases of 2K2C renovascular hypertension, and a ganglionic blocking agent (hexamethonium) also decreased the blood pressure. However, a specific, vascular acting AVP antagonist failed to reduce the blood pressure significantly. From this study, it seems likely that severe renal ischemia caused by renal clipping caused the activation of the renin-angiotensin and the sympathetic nervous system and elevation of serum vasopressin. However, there are no apparent differences between the benign and malignant phases of renovascular hypertension, except for the marked elevation of neurohormone levels in malignant hypertension.

The role of the renin-angiotensin system in the regulation of the blood pressure of dexamethasone-treated rats (Dex) was evaluated using saralasin, an angiotensin II antagonist, and SQ 14225 (SQ) (d-3-mercapto-2-methylpropranoyl-1-proline), an angiotensin-converting enzyme inhibitor. During a 7-day period blood pressure rose 65 +/- 10 mmHg (P less than 0.001) in Dex with no significant changes in plasma renin activity. Concurrent administration of dexamethasone and SQ attenuated the elevation of blood pressure (P less than 0.05). In the conscious, freely moving state, intravenous injection of SQ (10, 30, 100 micrograms/kg) reduced blood pressure of DEX in a dose-dependent manner (P less than 0.05). Also, intravenous injection of saralasin (10 micrograms.kg-1 . min-1) reduced blood pressure significantly (P less than 0.01). Bilateral nephrectomy abolished the effects of saralasin and SQ on blood pressure in Dex. These results indicate that the elevation of blood pressure in DEX depends partially on the renin-angiotensin system.

The experiments were carried out to develop a monitoring method of fission products in the primary coolant helium of the experimental VHTR(Very High Temperature Reactor). In the experiments, the high-temperature in-pile gas loop OGL-1 (Oarai Gas Loop-l)was used to simulate a primary circuit condition of the VHTR. The monitoring system consists of a conventional wire-driving precipitator and a Ge gamma-ray spectrometer. The gross counts due to fission products in the primary circuit are measured by the precipitator, and the gamma-ray spectra of the fission products are monitored by the Ge spectrometer for identification of the fission product nuclides. It was observed that gross counts due to fission products released from coated particle fuel samples change significantly depending on the reactor power and the irradiation temperature in the manner of 10cps(12MW, 350°C), 150cps(50MW, 1100°C) and 325cps(50MW, 1350°C). Individual contributions of each fission-product nuclide to the gross count were monitored in detail and were Kr-88:Kr-85M:Kr-87:Xe-133:Xe-135:Xe-135M:Xe-137: Xe-138 = 1.00:0.40:1.70:0.181.17:1.30:1.59:2.51. The concentration of Kr-88 was 7.36 Bq/ml(1.99×10-4 ?Ci/ml) at that time. It was also determined that the gross inventory of the fission-product activities was 3.4× 1011 Bq(9.2 Ci) refered to the primary coolant of the experimental VHTR and the sensitivity of the experimental monitoring system was 9.6×10-10cps/Bq (35cps/Ci) as the equivalent activity to Kr-88.

The effects of vasoactive substances on the release of prostaglandin (PG) and thromboxane (TX) from isolated rat glomeruli were investigated. The PGE2, PGF2 alpha, 6-keto-PGF1 alpha, and TXB2 release during 60 min into Krebs-Henseleit medium was assessed by radioimmunoassay following extraction. Norepinephrine (NE) stimulated PGE2 (from 2,117 +/- 117 to 3,968 +/- 182 pg X mg protein-1 X 60 min-1, P less than 0.01) at a concentration of 10(-4)M and PGF2 alpha (from 2,748 +/- 285 to 8,535 +/- 495 pg X mg protein-1 X 60 min-1, P less than 0.01) at a concentration of 10(-5)M. However, neither angiotensin II (ANG II) nor arginine vasopressin (AVP) affected the release of PG and TXB2 at concentrations up to 10(-5)M. In the presence of 10(-5) M NE, ANG II enhanced the release of PGE2 (from 3,307 +/- 207 to 6,865 +/- 469 pg X mg protein-1 X 60 min-1., P less than 0.01) and PGF2 alpha (from 3,652 +/- 252 to 6,612 +/- 388 pg X mg protein-1 X 60 min-1, P less than 0.01) at a concentration of 10(-8)M, whereas AVP lacked any similar effect. These results indicate that catecholamine acts as a major stimulant for the release of PG from isolated glomeruli via alpha-receptors. ANG II may work in cooperation with catecholamine, but AVP appears to play little role.

Page 368 : M. Epstein and T. Saruta. “Effect of water immersion on renin-aldosterone and renal handling in normal man.” Page 368: line 10, first paragraph of materials and methods, column 2, should begin: excretory rates....

SummaryEthanol, 1 and 2%, inhibited the synthesis of aldosterone in beef adrenal tissue in vitro. The inhibition appears to occur between the conversion of corticosterone to aldosterone.

Changes in the serum creatine kinase (CK) activity and the mechanism of its release after administration of two kinds of beta-blockers to rats were studied in order to determine the mechanism of the increase in serum CK accompanying administration of beta-blockers. When pindolol or propranolol was administered at a dose of more than 10 mg/kg of body weight, the serum CK activity was increased in proportion to the dose. Also when an alpha-stimulator or an alpha, beta-stimulator such as noradrenaline and adrenaline was administered, the serum CK activity was increased. When the beta-stimulator isoproterenol or the alpha 1-blocker prazosin was administered, there was no increase in the serum CK activity. In terms of consecutive administration of a combination of beta-blockers and adrenaline, the serum CK activity was not increased by the second and succeeding administrations. As for the use of adrenaline alone, on the other hand, the serum CK activity after the second administration was equal to that after the first administration. The increase in CK activity after administration of adrenaline as the second treatment following administration of a beta-blocker as the first treatment was approximately the same as that after single administration of adrenaline. From the fact that the serum CK activity in rats was increased by administration of an alpha-stimulator and of a beta-blocker, it is possible that CK release in the blood is due to the action of alpha-receptors rather than beta-receptors. In the case of consecutive administration of a beta-blocker, the serum CK activity was not increased after the second administration. However, the serum CK activity was increased by the administration of an alpha-stimulator. This finding suggests the possibility that CK release is due to the disturbance of the balance between alpha-receptor and beta-receptor. Most of the CK isoenzymes released in the blood after administration of a beta-blocker were of the MM type.

Plasma levels of aldosterone and other mineralocorticoids were determined in six patients with Bartter's syndrome. In spite of a remarkable elevation of plasma renin activity, the plasma aldosterone and 18-hydroxycorticosterone levels varied in each patient. These levels were slightly increased in three of the six patients, almost normal in two patients, and slightly reduced in one patient. The plasma deoxycorticosterone and corticosterone levels were within the normal range in all patients. The responses of plasma aldosterone to infusion of angiotensin II were reduced in all patients. Plasma aldosterone and 18-hydroxycorticosterone significantly increased with supplement of potassium, and the responses of plasma aldosterone to infusion of angiotensin II were also improved after supplement of potassium. Our results suggest that plasma aldosterone in Bartter's syndrome is dependent on potassium balance, even though plasma renin activity is remarkably increased, and that hyperaldosteronism is not an inevitable finding in Bartter's syndrome.

Three patients receiving maintenance hemodialysis therapy for end-stage renal failure presented with spontaneous rupture of the quadriceps tendon(s). Biochemical data and the skeletal roentgenograms were compatible with secondary hyperparathyroidism. Histological examination of the excised quadriceps tendon specimens suggested that repeated minor avulsion fractures of the bone cortex at the tendon insertion site had preceded the final total tendon rupture and that osteitis fibrosa was responsible for these minor fractures. Serum alkaline phosphatase level had been increasing continuously for approximately five years prior to the tendon rupture in all three patients, indicating that uncontrolled osteitis fibrosa due to secondary hyperparathyroidism over these years preceded the tendon rupture.

Both the antihypertensive efficacy and side effects of nifedipine were investigated in hypertensive patients with impaired renal function (n = 44) in short-term (7 days) and long-term (6 months) therapeutic trials. Comparable hypotensive effects were obtained in both the short- and long-term studies (from 184 +/- 4.6/108 +/- 2.8 to 166 +/- 4.6/97 +/- 3.2 mmHg, and from 178 +/- 4.2/108 +/- 2.1 to 157 +/- 4.4/95 +/- 2.4 mmHg, respectively). In the short-term study (n = 20), the antihypertensive effect was significantly related to the pretreatment blood pressure (r = 0.51) and inversely related to the plasma renin activity (PRA) (r = -0.61; p less than 0.05). However, it was not related to age or reciprocal value of the pretreatment serum creatinine. In the long-term study (n = 24), blood-pressure-lowering effects of nifedipine were found to depend on the reciprocal value of the serum creatinine but not on PRA. The blood urea nitrogen and creatinine were not changed significantly during the observation period. Side effects occurred in 8 of the 44 patients, but severe side effects necessitating termination of administration were observed in only 2 patients. These results indicate that nifedipine is effective in both the short- and long-term treatment of hypertensives patients with impaired renal function. Impaired renal function is a key factor in the hypotensive effects of nifedipine in long-term therapy.

Carvedilol, a new beta-blocker with vasodilating activity, was given orally to 9 hypertensive inpatients with impaired renal function in a dosage regimen of 5 to 20mg once daily to evaluate its clinical efficacy and safety. Treatment with carvedilol produced a significant decrease in blood pressure from 172/101 to 150/87mm Hg (p less than 0.01), but it did not cause orthostatic hypotension. Heart rate was decreased from 74.3 to 72.8 beats/min, but the decrease was not statistically significant. Serum creatinine and BUN levels were unchanged and other laboratory parameters were within normal limits. There were no side effects in any of the patients during the trial. These results suggest that carvedilol is a useful and safe drug for the treatment of renal hypertension.

Post receptor insulin resistance has been demonstrated in insulin sensitive tissues from streptozotocin induced diabetic animals. Insulin deficiency itself or metabolic derangements of diabetes seem to contribute to this insulin resistant state. However, the mechanism is presently unknown. Using largely insulin insensitive rat thymocytes, we have studied glucose oxidation stimulated by agents that mimic insulin action but that work independently of the insulin receptor. Glucose oxidations stimulated by these agents were markedly diminished in the thymocytes from streptozotocin induced diabetic rats. These findings as well as our finding that the thymocytes from diabetic rats possess a normal complement of insulin receptor provide further evidence that post insulin receptor impairment of glucose metabolism occurs in streptozotocin diabetes. Thus although thymocytes are not sensitive to insulin, they are useful for the investigation of the impaired glucose metabolism.

The angiotensin II receptor in the rabbit, rat and human adrenal gland and that in the rabbit and rat aorta were studied by using [3H]-angiotensin II ([3H]-AII). The adrenal glands and the aorta of each species were centrifuged at 20,000Xg for 30 min, and pellets which contained 95% of binding sites were collected and diluted by a buffer [20 mM Tris-HCl buffer (pH 7.4), 120 mM NaCl, 0.2% BSA, 1 mM EDTA] and used as a membrane fraction. The binding study was done by incubating the membrane fraction and [3H]-AII. After incubation at 25 degrees C for 30 min, the binding of the membrane fraction and [3H]-AII reached the equilibrium state, and free and bound angiotensin II were separated by 0.48 micrometer filters. Protein concentration was determined according to the method of Lowry. The binding sites fulfilled the criteria of the receptor which has organ and structure specificities, high affinity and reversibility. We could thus measure angiotensin II receptor in this study correctly and concisely. The properties of the angiotensin II receptor were analysed by Scatchard plot. The number of rabbit adrenal receptors (12833 +/- 2115 x 10(-15) mol/mg.protein) (M ++/- SD) was greater than that of the rat (1780 +/- 166 x 10(-15) mol/mg.protein) and that of the human (356 +/- 124 x 10(-15) mol/mg.protein). But the dissociation constant of all species was the same. The number of aorta binding sites was less than that of the adrenal in rabbits and rats. But the dissociation constant of rabbits and rats aorta binding sites was quite similar to that of adrenal glands.

In order to study the control system of plasma aldosterone in human, we examined the effects of low salt plus upright posture, angiotensin II, ACTH and potassium upon plasma renin activity, aldosterone and cortisol in five subjects who were supposed to be normal. All of the procedures, low salt diet with below 3 g of salt and 2 hr-upright posture, 0.25 mg of Cortrosyn, angiotensin infusion to increase 20mmHG of diastolic pressure for an hour, and 30 mEq of potassium infusion stimulated plasma aldosterone significantly. Furthermore, in each subject the degrees of response to each of these stimulations were almost same. In an old woman aged 68, responses to all of stimulations were significantly lower than those in other subjects. Plasma cortisol was significantly stimulated by ACTH, but slightly reduced by potassium infusion. From these results, it is certain that plasma aldosteron levels are easily affected by a small amount of changes in angiotensin, ACTH, potassium and sodium. However, responses of aldosterone to these changes seem to be decreased in old subjects.

To clarify the significance of insulin autoantibodies (IAA) in insulin-dependent diabetes mellitus, we measured the IAA longitudinally in non-obese diabetic (NOD) mice, and in high-dose streptozotocin-induced diabetes (high-SZ) and EMC virus-induced diabetes (EMC) in mice, and compared the data with the occurrence of insulitis. The IAA were detected by the polyethylene glycol (PEG) method using 125I-(Tyr A14) human insulin. The IAA were found in 38% of NOD mice and correlated with the occurrence of insulitis. The prevalence of IAA was 0% before the appearance of insulitis, 80% at 12-14 weeks of age and 30% after 20 weeks of age in female NOD mice. In male NOD mice, IAA were found in 45% at 12-14 weeks of age and 20% after 20 weeks. In high-SZ mice, IAA were detected in several mice while insulitis was not present. In EMC-virus induced diabetic mice, IAA and lymphocytic infiltration into the islets were detected 4-14 days after EMC virus infection. These results suggest that (a) IAA are markers for islet autoimmunity in NOD mice, (b) the presence of IAA does not always reflect insulitis, (c) the presence of IAA is not sufficient for the development of overt diabetes and (d) the appearance of IAA may reflect a difference of the immune response genotype.

The intracerebroventricular (i.c.v.) injection of dopamine (50--200 micrograms/kg) produced a dose-dependent decrease in arterial blood pressure in conscious rats. This depressor effect of dopamine was attenuated by the pretreatment with metoclopramide (16.5 micrograms/kg, i.c.v.), a dopamine receptor antagonist. Metoclopramide in higher doses (50 and 150 micrograms/kg), given i.c.v., produced an increase in blood pressure. The pretreatment with dopamine (50 micrograms/kg, i.c.v.) attenuated the pressor effect of metoclopramide. Furthermore, autonomic ganglion blockade with hexamethonium (25 mg/kg, i.v.) almost completely abolished the effects of dopamine and metoclopramide, indicating that these substances were exerting their effects within the central nervous system. These results suggest that the dopaminergic system in the brain is involved in regulation of systemic blood pressure in conscious rats.

Hypertension in 17 alpha-hydroxylase deficiency was studied by comparing it with hypertension in Cushing syndrome or that in primary aldosteronism. Furthermore, the role of endogenous increases of ACTH, deoxycorticosterone, and 18 alpha-hydroxy-deoxycorticosterone upon blood pressure was studied in rats by administerating metopirone. Hypertension in 17 alpha-hydroxylase deficiency was considered to be more similar to that in primary aldosteronism from the studies on renin components, pressor responses to angiotensin II and norepinephrine, and renin responses to stimulations. Plasma catecholamines were slightly decreased in 17 alpha-hydroxylase deficiency. The hypertension was alleviated by the administeration of dexamethasone in 2 of 3 patients with 17 alpha-hydroxylase deficiency. However, in the remaining one who had an accelerated hypertension and normal renin, the hypertension was not alleviated by dexamethasone. In the animal studies, hypertension induced by metopirone was accelerated by salt loading of uni-lateral nephrectomy plus salt loading. In those rats, plasma ACTH, and deoxycorticosterone were markedly increased.

Pathologic study of a rare 11-deoxycorticosterone-producing adrenocortical tumor causing primary aldosteronismlike signs and symptoms, revealed several characteristic features as follows: (1) fairly large size with histologic features corresponding to those of benign zone glomerulosa-type aldosteronoma, (2) lack of spironolactone (S) bodies despite S administration, and (3) heavy mast cell infiltration. In order to explain this rare histology, the localization of mast cells in the adrenal glands and functioning adrenocortical tumors of 67 surgical specimens were investigated. The results of the study supported the view that detection of mast cells helps in the differentiation of mineralocorticoid-producing tumors from cortisol-producing ones, and that the observed mast cell infiltration was due, in part, to its production of 11-deoxycorticosterone.