Abstract. The effect of nifedipine on CRF-41- and AVP-induced ACTH release was examined using monolayer cultured rat anterior pituitary cells and pituitary halves. Nifedipine inhibited ACTH release induced by synthetic rat CRF-41 in two systems. In pituitary halves, CRF-41 significantly stimulated both ACTH release and cyclic AMP accumulation. Nifedipine inhibited CRF-41-induced ACTH release and the inhibitory effect of nifedipine on CRF-41-induced ACTH release was accompanied by parallel decrease of cyclic AMP levels in pituitary halves. Nifedipine did not inhibit AVP-induced ACTH release in pituitary halves, and AVP did not significantly affect cyclic AMP accumulation in pituitary halves. These results suggest that CRF-41 stimulates ACTH release through the intracellular cyclic AMP system and calcium-calmodulin system which are accelerated by the influx of extracellular calcium ions. Moreover, it is suggested that the calcium required for AVP-induced ACTH release is derived primarily from intracellular rather than extracellular sources.
Kazuharu Murakami, Kozo Hashimoto and Zensuke Ota
Kazuhiro Iitake, Tokihisa Kimura, Kuniaki Matsui, Kozo Ota, Masaru Shoji, Minoru Inoue and Kaoru Yoshinaga
Abstract. Changes in plasma ADH levels and plasma aldosterone levels (PA) were studied in patients with end-stage renal disease (N = 40). The patients were divided into two groups according to their plasma renin activity (PRA) into a low renin (LR, n = 9) and a high renin group (HR, n = 31). The metabolic clearance rate (MCR) of plasma ADH was also investigated in 4 patients and 5 normal volunteers. Additionally, it was examined whether plasma ADH, aldosterone and renin were permeable through the dialysis membrane. Pre- and post-dialysis plasma ADH levels in LR were similar to those in the HR group. However, pre- and post-dialysis PA in the HR group were significantly greater than those in the LR group. Post-dialysis PRA was significantly increased in HR compared to pre-dialysis, but not in LR. Pre- and post-dialysis plasma osmolality was increased in both groups, but effective plasma osmolality (EPosm) was within the normal range. There was a significant correlation between EPosm and plasma ADH level both before and after haemodialysis, but the majority of the abnormally high values of ADH compared to the normal values was found within the normal range of EPosm. The patients exhibited high blood pressure and a rise in body weight, and haemodialysis caused a significant fall in body weight and blood pressure in both groups. MCR of ADH was significantly lower in the patients than that in normal subjects. Plasma ADH proved to be permeable through the dialysis membrane in all cases, but aldosterone in only a few cases. Renin was not permeable.
Tokihisa Kimura, Kozo Ota, Masaru Shoji, Minoru Inoue, Kazutoshi Sato, Masahiro Ohta, Tadasu Yamamoto, Yasuyuki Shimizu and Kaoru Yoshinaga
To assess whether arginine vasopressin and atrial natriuretic hormone participate in impaired urinary dilution and excretion in glucocorticoid deficiency secondary to hypopituitarism. an acute oral water load of 20 ml·kg−1 BW was undertaken in the absence and presence of an oral hydrocortisone (60 mg) treatment in patients with ACTH deficiency (N= 7) and panhypopituitarism (N = 2). Plasma arginine vasopressin and atrial natriuretic hormone and renal water handling were simultaneously determined and compared with those in similarly water-loaded normal subjects. Plasma arginine vasopressin did not fall in response to decreased blood osmolality after an acute water load in the absence of hydrocortisone; plasma atrial natriuretic hormone did not change despite blood volume expansion; and impairment in urinary dilution and excretion remained. On the other hand, in the presence of hydrocortisone, plasma arginine vasopressin fell in response to a decrease in plasma osmolality and plasma atrial natriuretic hormone increased, thereby restoring urinary dilution and excretion. These results demonstrate that the impaired arginine vasopressin response to acute water loading play an essential role in deranged renal water and electrolyte handling in the state of glucocorticoid deficiency; the impaired release of atrial natriuretic hormone also may affect these disorders.
Kozo Ota, Tokihisa Kimura, Kuniaki Matsui, Kazuhiro Iitake, Masaru Shoji, Minoru Inoue, Kazutoshi Sato, Masahiro Ohta, Tadasu Yamamoto and Kaoru Yoshinaga
To assess the central effect of hypertonic NaCl on the release of vasopressin (AVP) and methionine enkephalin-like substances into the blood and cerebrospinal fluid, and on blood pressure, ventriculocisternal perfusion (0.25 ml/min, 60 min) was performed in anesthetized dogs with artificial cerebrospinal fluid (CSF), either isotonic (300 mosmol/kg) or hypertonic (600 and 1200 mosmol/kg). The effect of central administration of a V1-AVP antagonist on the central osmotic challenge was also studied. In dogs, given 600 mosmol/kg, CSF osmolality increased with a concomitant rise in mean arterial pressure and plasma AVP concentrations. Plasma osmolality, heart rate, CSF AVP and plasma and CSF methionine enkephalin-like substances showed no significant change. In dogs, given 1200 mosmol/kg, the CSF osmolality increase was accompanied by a rise in mean arterial pressure, heart rate, plasma AVP and CSF AVP. Plasma osmolality and plasma and CSF methionine-enkephalinlike substances did not change significantly. A V1-AVP antagonist given centrally attenuated the rise in mean arterial pressure induced by osmotic challenge. In dogs, given 300 mosmol/kg, no parameters changed significantly except for a gradual fall in heart rate. These results suggest that central osmotic stimulation by hypertonic NaCl increases blood pressure, heart rate and the release of AVP, but not methionine enkepholin-like substances, into the blood and CSF, and a V1-blocker given centrally attenuates the pressor response.
Kozo Hashimoto, Shuso Suemaru, Teruhiko Hattori, Masanori Sugawara, Zensuke Ota, Shinji Takata, Kazuo Hamaya, Kenji Doi and Michel Chrétien
Abstract. A male patient with corticotropin-releasing factor (CRF) and adrenocorticotropin (ACTH)-producing syndrome is described. Soon after being referred to us the patient developed pneumonia, anaemia, oedema and respiratory distress, and died on the 24th day after admission. Autopsy and histology revealed that he had a rare type of multiple endocrine neoplasia (type 1 + paraganglioma) with a mediastinal paraganglioma, parathyroidal hyperplasia, pancreatic islet cell adenoma, duodenal multiple carcinoid tumours and adrenocortical nodular hyperplasia. It was not possible to examine the pituitary. The paraganglioma contained a large amount of immunoreactive (IR)-CRF (606 ng/g wet weight), IR-ACTH (59.4 ng/g wet weight), IR-human proopiomelanocortin n-terminal (1–76) peptide (hNT, 156.8 ng/g wet weight) and IR-β-lipotropin (β-LPH, 146.9 ng/g wet weight). The major IR-ACTH, β-LPH and IR-hNT were eluted at ACTH-(1–39), β-LPH and hNT marker positions, respectively. Big ACTH was not detected. IR-CRF eluted at the human CRF marker position on Sephadex G-75 chromatography and high performance liquid chromatography (HPLC). The IR-CRF fraction from the HPLC showed CRF bioactivity which paralleled that of synthetic human CRF in monolayer cultured rat anterior pituitary cells. Our results suggest that not only ACTH but CRF produced by the paraganglioma was responsible for the patient's Cushing's syndrome.
Kozo Ota, Tokihisa Kimura, Minoru Inoue, Takeharu Funyu, Masaru Shoji, Kazutoshi Sato, Masahiro Ohta, Tadasu Yamamoto and Keishi Abe
Ota K, Kimura T, Inoue M, Funyu T, Shoji M, Sato K, Ohta M, Yamamoto T, Abe K, Effects of V1- and V2-vasopressin (AVP) antagonists on the pressor, AVP and atrial natriuretic peptide responses to a hypertonic saline infusion in conscious anephric rats. Eur J Endocrinol 1995;133:127–32. ISSN 0804–4643
To examine the role of vasopressin (AVP) receptors in the regulation of the hemodynamics and release of atrial natriuretic peptide (ANP), and the participation of renal nerve inputs in the osmotic AVP release, hypertonic saline (HS) was infused into conscious, bilaterally nephrectomized rats with nonpeptide, selective antagonists for the V1-receptor or V2-receptor of AVP. In the control group, HS alone increased mean arterial pressure, plasma ANP and AVP, plasma volume and plasma osmolality, and decreased the heart rate. In the V1-receptor antagonist group, an increase in the mean arterial pressure and a decrease in heart rate were completely abolished and an increase in plasma ANP was attenuated. In the V2-receptor antagonist group, increases in mean arterial pressure and plasma ANP and a decrease in heart rate were attenuated. However, the ratio of the changes in heart rate to the changes in mean arterial pressure in the V2-receptor antagonist group is significantly higher than that in the control group. In both experimental groups, increases in plasma AVP, plasma volume and plasma osmolality were not different from those in the control group. These results suggest that a HS-induced increase in mean arterial pressure is mediated by the pressor effect of AVP, mainly through V1-receptors, and that the depressor effect of AVP through V2-receptors may not influence tonically HS-induced hypertension. Moreover, HS-induced increase in plasma ANP is mediated mainly by increases in plasma volume and blood pressure, but may not be affected by a direct action of AVP to the heart. Renal afferent nerve inputs may not have effects on the regulation of osmotic AVP release.
Kozo Ota, Second Department of Internal Medicine, Tohoku University School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-77, Japan
Kozo Ota, Tokihisa Kimura, Meiichi Ito, Minoru Inoue, Masaru Shoji, Susumu Shinoda, Michio Nagashima, Kuniaki Matsui, Kazuhiro Iitake and Kaoru Yoshinaga
Abstract. In order to study the effect of atrial tachycardia on the release of atrial natriuretic peptide (ANP), AVP, and methionine enkephalin (M-Enk), plasma concentrations of these peptides in the right ventricle were determined in patients with various arrhythmias (N = 10) during cardiac catheterization and incremental atrial pacing. Each pacing (100 per min, the maximum rate for 1:1 atrioventricular conduction, and 200 per min) lasted 4 to 5 min. Plasma ANP was significantly increased from 53.1 ± 12.2 in the resting condition to 168.9 ± 59.9 pmol/l at a pacing rate of 200 beats per min (P < 0.05); plasma AVP tended to decrease, but not significantly, and plasma M-Enk did not change at all. Pulse pressure in the right atrium (PPRA) and mean right atrial pressure (MRAP) tended to increase during the pacing, and at the rate of 200 beats per min PPRA was significantly higher than at the rate of 100 beats per min. Mean arterial blood pressure, plasma osmolality, and plasma sodium and potassium concentrations did not change significantly. There were significant correlations between plasma ANP and PPRA, MRAP and heart rate. These results indicate that atrial pacing stimulates ANP release with a rise in right atrial pressure, but does not influence M-Enk and AVP releases.
Kazutoshi Sato, Tokihisa Kimura, Kozo Ota, Masaru Shoji, Minoru Inoue, Masahiro Ohta, Tadasu Yamamoto, Takeharu Funyu, Kaoru Yoshinaga and Keishi Abe
To assess whether increases in circulating atrial natriuretic hormone (ANH) in response to the plasma volume expansion, besides the volume receptor-mediated mechanisms, attenuate the arginine vasopressin (AVP) response to increased plasma osmolality and whether changes in plasma AVP and ANH affect renal solute excretion under hypertonic plasma volume expansion, hypertonic saline (0.95 mol/l saline) alone, hypertonic saline with 6% dextran (6D-HS) and hypertonic saline with 9% dextran (9D-HS) were administered into anesthetized dogs. In the control study, 0.15 mol/l NaCI alone was administered. Plasma AVP and ANH and cardiovascular and renal functions were determined. Hypertonic saline and 9D-HS also were administered into the vagotomized and sham operated dogs, and the same parameters were determined. Mean blood pressure and heart rate never changed in all the groups, but central venous pressure and plasma volume increased markedly in 6D-HS and 9D-HS groups. In the control and hypertonic saline groups, central venous pressure increased slightly but plasma volume never changed. Plasma AVP increased in the order of hypertonic saline, 6D-HS and 9D-HS, but plasma ANH increased in reverse order. Vagotomy restored the AVP response to 9D-HS to 75% of its response to hypertonic saline, with a marked rise in plasma ANH. Urine sodium and potassium excretion and urine flow increased in hypertonic saline, 6D-HS and 9D-HS groups, but these increases were comparable among the groups. In the control group, these parameters never changed. These results suggest that the volume receptor-mediated vagal neural and ANH responses to the plasma volume expansion may have an effect on the suppression of the AVP response to osmotic stimuli, and increased plasma ANH release never potentiated the natriuresis under the hypertonic plasma volume expansion.