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The antihypotensive effect of amezinium metilsulfate, a newly developed antihypotensive agent, and the drug's effect on norepinephrine, epinephrine, and atrial natriuretic peptide was investigated in nine hemodialysis patients with hypotension. Amezinium metilsulfate 10 mg once daily was administered on the day of hemodialysis for a period of 12 weeks. After treatment with amezinium, both systolic and diastolic blood pressures at 3, 4, and 5 hours after hemodialysis were significantly higher than those during a control period. The infusion volume during hemodialysis was significantly decreased with the treatment. Plasma norepinephrine, epinephrine, and atrial natriuretic peptide levels were not significantly different after therapy compared with the control period. These results confirm that amezinium metilsulfate is a safe and effective antihypotensive agent for the treatment of hypotension associated with hemodialysis.

High activity of angiotensin-converting enzyme was demonstrated in human pituitary tissue. This activity required the presence of chloride ion and was almost completely inhibited by a specific converting enzyme inhibitor captopril (10 nM), indicating that the activity measured is indeed angiotensin-converting enzyme. The specific activity of the enzyme was 1.68±1.20 nmol hippuric acid generated mg of protein −1 min −1 (means±SD, for 11 specimens). The biochemical features of the enzyme were closely related to the well-characterized human lung converting enzyme, such as molecular weight (290,000), optimum pH (8.0–8.5), the presence of glycoprotein residues, and dependence on chloride ion concentration. These results provide definitive evidence for the presence of angiotensin-converting enzyme in human pituitary tissue.

Inactive renin in the brain of spontaneously hypertensive rat was investigated. The results are as follows. Treatment with either trypsin or glandular kallikrein of the brain tissue extract caused a rapid and apparent increase in the renin activity at either 0 or 27 degrees C. The molecular weight of the active renin was estimated to be 41,000 or 50,000 daltons, while that of the trypsin-activatable inactive renin was found to be 44,000 or 57,000 daltons on a column chromatography with Sephadex G-100. The contents of the active renin was the highest in the hypothalamus, followed by the striatum, thalamus, midbrain, medulla oblongata, cerebral cortex and cerebellum, while the contents of the trypsin-activatable inactive renin was the highest in the hypothalamus, followed by the striatum, thalamus, cerebellum, midbrain, cerebral cortex and medulla oblongata. These results suggest that inactive renin(s) exist in the brain of spontaneously hypertensive rat. It seems likely that the brain renin-angiotensin system is modulated by the conversion of inactive to active renin(s), which, in turn, plays at least in part a role in the blood pressure regulation through generation of angiotensin II in spontaneously hypertensive rats.

A 17-year-old female weighing 37 kg and 140 cm in height was referred to our hospital for evaluation of dwarfism and primary amenorrhea. She was delivered with 3350 g in weight and 50 cm in height after a ten month pregnancy without complications. No abnormal findings were revealed in physical appearance except critomegaly. Episodes of nausea, vomiting and dehydration were rare throughout her childhood, but she had a tendency to salt craving. At the age of 14, her height was 140 cm. On admission, her physical development was markedly retarded for her age, except external genitalia. Diffuse pigmentations on the trunk and extremities were observed. Her blood pressure was normal (112/62 mm Hg). Serum potassium concentration was 2.9 mEq/L. Arterial-blood gas analysis revealed metabolic alkalosis. Both of renin activity (PRA) and aldosterone concentration (PAC) in plasma at rest were markedly elevated to 15.5 ng/ml/h and 107.1 ng/dl, respectively. The plasma concentrations of pregnenolone (1449 ng/dl), progesterone (178 ng/dl), 17-OH-pregnenolone (1613 ng/dl), 17-OH-progesterone (180 ng/dl), dehydroepiandrosterone (3706 ng/dl), androstendione (824.6 ng/dl) and testosterone (900 ng/dl) were high, whereas deoxycorticosterone (15.7 ng/dl), corticosterone (0.65 microgram/dl) and cortisol (6.8 micrograms/dl) were within normal limits. Urinary 17-KS excretion showed high levels between 65.7 and 109.4 mg/day, while urinary 17-OHCS excretion was normal (5.7-7.0 mg/day). Vascular response to angiotensin II (A-II) was attenuated. Distal fractional chloride reabsorption was decreased (CH2O/CH2O+CCl = 0.62, normal: 0.92 +/- 0.04). Moderate hyperplasia of the juxtaglomerular cells was demonstrated in biopsy specimen of the kidney. Cytogenetic studies showed a 46, XX chromosome constitution with translocation of the long arm of chromosome 6 to the short arm of chromosome 9. Her mother as well as younger brother and sister, whose electrolytes and arterial-blood gas analysis showed normal values, had chromosomes with the same translocation. Treatment with dexamethasone (2 mg/day) reduced every adrenal steroids to normal range, but PRA and PAC remained high levels. Furthermore, neither hypokalemic alkalosis nor vasoreactivity to exogenous A-II was improved. Indomethacin (75 mg/day) decreased urinary excretion of prostaglandin E2 from a high level of 738.4 ng/day to 433.4 ng/day and normalized metabolic alkalosis. Vascular response to A-II was moderately improved. However, serum potassium remained low.(ABSTRACT TRUNCATED AT 400 WORDS)

Relationship between blood pressure and brain renin was studied in four groups of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY); as controls (n = 5), administered captopril (n = 5), trichlormethiazide (n = 5) and atenolol (n = 5). 1) Inactive renin in the hypothalamus of captopril-administered SHR was significantly lower than that of control SHR and captopril-administered WKY. On the other hand, active renin in the hypothalamus, thalamus and striatum of captopril-administered SHR was significantly lower than that of control SHR and captopril-administered WKY. 2) Inactive renin in the hypothalamus of trichlormethiazide administered SHR was significantly lower than that of control SHR and trichlormethiazide-administered WKY. On the other hand, active renin in the hypothalamus, thalamus and midbrain of trichlormethiazide-administered SHR was significantly lower than that of control SHR and trichlormethiazide-administered WKY. 3) Inactive renin in the hypothalamus of atenolol-administered SHR was significantly lower than that of control SHR and atenolol-administered WKY. On the other hand, active renin in the hypothalamus, thalamus and midbrain of atenolol-administered SHR was significantly lower than that of control SHR and atenolol-administered WKY. These results suggest that the production and/or activation of renin in the hypothalamus, thalamus, midbrain and striatum play an important role in the initiation and/or development of hypertension of SHR by the local generation of angiotensin II.

1. There is increasing evidence which suggests that the adrenal gland contains the renin–angiotensin cycle. The localization of renin has been reported to be mainly in the zona glomerulosa rather than the fasciculata medullary portion. In the present study we have investigated extracts from aldosteronomas (n = 3), which are believed to derive from the zona glomerulosa cells. In addition, we have attempted to characterize the biochemical properties of the adrenal renin. 2. Sizable quantities of renin-like activity (32.0 ± 7.7 ng of angiotensin I generated h−1 mg−1 of protein, mean ± SEM) were detected in the extracts. This renin-like activity was inhibited by anti-renin antibody raised against pure renin (mean, 95% of the total renin-like activity), indicating that it was not due to the non-specific action of proteases such as cathepsin D. 3. The optimum pH of the tissue renin-like enzyme was 6.0 for rat plasma substrate. Differences were found, however, in the molecular mass (36000, 37000, 44000 and 48000), binding to concanavalin A and isoelectric points (4.40, 4.68 and 5.00). 4. These results confirm the existence of specific renin in aldosteronoma. Renin microheterogeneity could be evidence for local production of the enzyme.

Renin-like enzyme(s) in the brain of spontaneously hypertensive rat (SHR) were activated unequivocally by trypsin. The highest concentration of the active renin-like enzyme was localized in the hypothalamus (1.03 +/- 0.25 ng angiotensin I/mg of protein per h, mean +/- S.D.), followed by the striatum (0.51 +/- 0.21), thalamus (0.40 +/- 0.08), midbrain (0.33 +/- 0.04), medulla oblongata (0.25 +/- 0.01), cerebral cortex (0.21 +/- 0.03), and cerebellum (0.14 +/- 0.03), while the highest concentration of the inactive renin-like enzyme was localized in the hypothalamus (0.86 +/- 0.17), followed by the striatum (0.47 +/- 0.15), thalamus (0.32 +/- 0.09), cerebellum (0.29 +/- 0.04), midbrain (0.26 +/- 0.02), cerebral cortex (0.24 +/- 0.04), and medulla oblongata (0.10 +/- 0.03). The active renin-like activity in the thalamus of SHR was significantly lower than that of age- and sex-matched normotensive Wistar-Kyoto (WKY) rats. Furthermore, the inactive renin-like activity in the striatum, thalamus, cerebellum, midbrain, and medulla oblongata of SHR was significantly lower than that in the corresponding areas of WKY rats. Although the precise mechanisms underlying the conversion of inactive to active renin-like enzyme in the brain remain to be resolved, these results may offer a new aspect for the role of the brain renin-angiotensin system in the initiation and/or development of hypertension of SHR.

Readily detectable levels of renin activity were demonstrated in the human brain. This activity was inhibited by specific antibody raised against human renal renin, indicating that it was not due to the nonspecific action of proteases such as cathepsin D. The pineal gland was found to be the richest source of renin followed by the pituitary, hypothalamus and hippocampus. The substantia nigra, caudate nucleus, putamen and thalamus contained moderately high concentrations of renin. The brain renins from pineal and pituitary glands shared some biochemical features with well-known kidney renin, such as molecular weight (46, 000 daltons for pineal renin ; 37, 000-45, 000 daltons for pituitary renin), optimum pH (6.0-7.0), the presence of trypsin-activatable inactive renin, and a glycoprotein nature. However, the electro-focusing pattern of renin from pituitary tissue (pI = 4.43, 5.77) differed from that of plasma and kidney enzymes heretofore reported, a discrepancy which could be interpreted as evidence for the endogeneous synthesis of renin in the brain tissue. Furthermore, a high activity of immunoreactive renin was found in human neuroblastoma tissue. The biochemical characteristics of the neuroblastomal renin were generally similar to the known properties of kidney renin in many respects, providing evidence of the presence of the renin-angiotensin system within human neuronal cells.

Renin-like enzyme(s) in the arterial wall of the spontaneously hypertensive rat (SHR) were activated markedly by either acidic pH or treatment of proteolytic enzymes (trypsin and glandular kallikrein). The highest concentration of renin-like enzyme (active form) was localized in the renal artery (2.51 +/- 0.59 ng angiotensin I generated/mg of protein per h, mean +/- S.D.), followed by the mesenteric (1.58 +/- 0.31), the carotid (1.44 +/- 0.27) and the major aortic trunk (0.20 +/- 0.10), while the highest concentration of the inactive renin-like enzyme was localized in the major aortic trunk (0.97 +/- 0.18), followed by the carotid (0.72 +/- 0.41), the renal (0.71 +/- 0.31) and the mesenteric (0.60 +/- 0.29) arteries. In addition, the active renin-like activity from the mesenteric and the carotid arteries of SHR rats was higher significantly than that of age-matched normotensive Wistar-Kyoto (WKY) rats, despite a similar concentration of total renin-like enzyme of the corresponding arteries of both groups. These results suggest that increased interconversion of the inactive to the active renin-like enzymes in the arterial wall of SHR rats may result in local vasospasm through generation of angiotensin II, which may contribute in part at least to systemic hypertension of SHR rats.

High activity of angiotensin-converting enzyme was demonstrated in human neuroblastoma tissue. This activity required the presence of chloride ion and was almost completely inhibited by a specific converting enzyme inhibitor captopril (10 nM), indicating that the activity measured is indeed angiotensin-converting enzyme. Furthermore, the biochemical features of the enzyme were closely similar to the well-known properties of human lung converting enzyme, such as molecular weight (290,000), optimum pH (8.0-8.5), the presence of glycoprotein residues, and dependence on chloride ion concentration. These results provide definitive evidence for the presence of true angiotensin-converting enzyme in human neuroblastoma tissue.

High activity of renin was demonstrated in human prolactinoma tissue. This activity was almost completely inhibited by specific antibody raised against human renal renin, indicating that it was not due to the nonspecific action of proteases. The specific activity of renin was 5.04 ng of angiotensin I generated/mg of protein per h, comparable to that of the pituitary tissue prepared from postmortem human subjects. The biochemical properties of the prolactinoma renin were generally similar to those of well-known kidney enzyme, such as molecular mass (Mr=46, 000), optimum pH (6.0), and glycoprotein nature. However, the isoelectric points (pI) of the prolactinoma renin pI=4.90, 5.04, 5.24 and 5.41) differed somewhat from those of plasma and kidney renins reported hitherto. These results indicate that true renin can be produced in human prolactinoma tissue.

Immunoreactive renin was demonstrated in pituitary tissues of post-mortem human subjects with different diseases. The specific immunoreactive renin activity comprised the majority of the tissue renin-like activity (mean, 83%), indicating the absence of nonspecific actions of proteases such as cathepsin D. We used three pituitary specimens with high levels of the specific renin activity for further biochemical characterization of the enzyme. Small differences were found in the molecular mass (45 K, 42 K and 37 K), binding to concanavalin A-Sepharose, and isoelectric points (pI) (4.72, 4.78, 4.86, 5.06, 5.28 and 5.44). These results seem to be interpreted as evidence for the presence of specific renin in the human pituitary with microheterogeneity.