Akira Nishibe

Parathyroid Hormone–Related Protein Inhibits Endothelin-1 Production

Abstract The effect of human parathyroid hormone–related protein, a powerful vasodilator, on endothelin-1 production in cultured bovine pulmonary arterial endothelial cells was studied. Treatment with parathyroid hormone–related protein(1-34) at concentrations of 10−9 to 10−6 mol/L for 24 hours caused dose-dependent suppression of the secretion of endothelin-1, with maximal suppression at 10−7 mol/L to 74% of the control value. This inhibitory effect was completely abolished by coincubation with 100 ng/mL pertussis toxin, an inhibitor of GTP binding protein. Furthermore, addition of N G-monomethyl-l-arginine, an inhibitor of nitric oxide synthase, at 10−3 mol/L significantly blocked the suppressive effect of parathyroid hormone–related protein(1-34) on endothelin-1 secretion, and further addition of 5×10−3 mol/L l-arginine significantly attenuated the blocking effect of N G-monomethyl-l-arginine. Parathyroid hormone–related protein(1-34) at 10−7 mol/L resulted in an approximately fivefold increase in intracellular cGMP level. Northern blot analysis revealed that parathyroid hormone–related protein(1-34) inhibited both basal and thrombin-induced endothelin-1 gene expression. These findings suggest that the vasodilating property of parathyroid hormone–related protein may be mediated in part through its inhibitory effect on endothelin-1 production, which is probably mediated through nitric oxide and cGMP in endothelial cells. Thus, a feedback regulatory mechanism may exist between parathyroid hormone–related protein and endothelin-1 in the vascular wall.

Interleukin-2 modulates the responsiveness to angiotensin II in cultured vascular smooth muscle cells.

Preincubation with interleukin-2 (IL-2), a T cell-derived cytokine, enhanced the increase in intracellular Ca2+ ([Ca2+]i) induced by angiotensin II (AII) in vascular smooth muscle cells (VSMC). IL-2 itself did not affect the basal [Ca2+]i level or the maximal response of [Ca2+]i increase induced by AII. Furthermore, IL-2-induced enhancement was not observed in the absence of extracellular Ca2+, suggesting that IL-2 enhances Ca2+ influx induced by AII. IL-2 also enhanced the stimulation of DNA synthesis induced by AII, although IL-2 alone did not stimulate DNA synthesis. Genistein, an inhibitor of protein tyrosine kinases, significantly inhibited IL-2-induced enhancement of both Ca2+ influx and DNA synthesis induced by AII. A neutralizing antibody against heparin-binding epidermal growth factor-like growth factor (HB-EGF) partially inhibited IL-2-induced enhancement of DNA synthesis induced by AII. These findings suggest that autocrine HB-EGF is partially involved in the mechanism of IL-2-induced enhancement of DNA synthesis. On the other hand IL-2 stimulated both glycosaminoglycan (GAG) and prostacyclin syntheses and enhanced the stimulation of both GAG and prostacyclin syntheses induced by AII. Therefore, IL-2 may play important roles in the pathogenesis of atherosclerosis and vascular disease by modulating the responsiveness to AII in VSMC.

Comparison of effects of estriol on bone mineral density of vertebrae between elderly and postmenopausal women

Abstract: To compare the efficacy of estriol (E3) for postmenopausal and senile osteoporosis, we administered orally 1 g/day calcium lactate alone (control groups) or with 2 mg/day estriol (E3 groups) to 20 postmenopausal women aged 50–65 years and 29 elderly women aged 70–84 years, and determined their bone mineral density (BMD) of the lumbar vertebrae AP scan by dual-energy X-ray absorptiometory. Of 41 subjects who completed 10 months of treatment, 8 postmenopausal women and 12 elderly women in the E3 groups showed a significant (P < .05) increase in BMD, 5.59% ± 4.79% and 3.83% ± 7.90% of the respective basal values, while 10 postmenopausal women and 11 elderly women in the control groups showed a decrease in BMD, −4.02% ± 7.00% and −3.26% ± 4.60% of the respective basal values, after 10 months. On the other hand, genital bleeding as a side effect of E3 occurred in 6 elderly subjects at this dose. Moreover, decrease in serum level of corrected calcium was seen only in the elderly women receiving E3. Although a lower dosage of E3 may be recommended for elderly subjects, these observations suggest, first, that hormone replacement therapy with E3 has efficacy for involutional osteoporosis, and, second, that the bones in elderly women also maintain responsiveness to E3.

Hyperparathyroidism as a cause of calcification of the abdominal aorta in elderly female subjects

We evaluated serum levels of calcium-related factors and bone mineral content in 40 healthy elderly female subjects (mean age ± SD, 79 ± 7 years) as possible factors relating to calcification of the abdominal aorta. There were no significant differences in serum levels of total cholesterol, triglycerides, and estradiol between elderly female subjects with and without calcification of the abdominal aorta. Elderly female subjects with calcification of the abdominal arota, when compared to those without calcification, showed significantly reduced values of bone mineral content of the distal radius. Moreover, the elderly female subjects with calcification of the abdominal aorta showed significant increases in serum levels of parathyroid hormone and calcitonin, and significantly decreased levels of 24,25-dihydroxyvitamin D3. There were no significant differences in serum levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3. These data suggest that elevated secretion of parathyroid hormone plays an important role in the development of calcification of the abdominal aorta.

A Single-Center, Open-Label, Randomized, Parallel-Group Study Assessing the Differences Between an Angiotensin II Receptor Antagonist and an Angiotensin-Converting Enzyme Inhibitor in Hypertensive Patients with Congestive Heart Failure: The Research for Efficacy of Angiotensin II Receptor Antagonist in Hypertensive Patients with Congestive Heart Failure Study

BACKGROUND Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) have been used to treat congestive heart failure (CHF). According to a MEDLINE search, however, few studies are available on the clinical differences between ARBs and ACEIs in CHF. OBJECTIVE To examine the clinical differences between an ARB (candesartan cilexetil) and an ACEI (lisinopril) in the treatment of CHF, we investigated exercise capacity, ventricular function, and neurohormonal levels in hypertensive patients with CHF before and after treatment with these agents. METHODS Patients with symptoms of CHF (New York Heart Association functional class II-III and left ventricular ejection fraction [LVEF] ≤45%) complicated by hypertension (systolic blood pressure [BP] ≥140 mm Hg or diastolic BP ≥90 mm Hg) were eligible for this single-center, open-label, randomized, parallel-group study. They were given either the ARB or the ACEI for 24 weeks. A cardiopulmonary exercise test and echocardiography were performed. Clinical findings and cardiac events in addition to the CHF symptoms were investigated. Neurohormonal levels were measured before and after 24 weeks of treatment with the study drug. The primary end point of this study was exercise capacity, which was measured using peak oxygen consumption (VO2). RESULTS Forty-two patients with CHF were enrolled and 38 (28 men, 10 women; mean [SD] age, 69.0 [8.2] years) completed the study. None of these patients had definite progression of the CHF symptoms. In the ARB-treated patients, mean (SD) peak VO2 (mL/min/kg) and LVEF (%) increased from 14.1 (2.9) to 15.3 (3.4) and from 34.4 (9.5) to 41.8 (9.5), respectively. In the ACEI group, the peak VO2 did not change, but the LVEF (%) increased from 34.2 (10.2) to 40.4 (13.0). However, the differences between ARB and ACEI were not clarified because of the possibility of a small sample size. CONCLUSIONS Although this study was not powered to show differences in efficacy between the ARB and ACEI in this study, our findings suggest that both ARB and ACEI had beneficial effects in hypertensive patients with CHF. Some unidentified differences in hemodynamic characteristics were found between the ARB and the ACEI groups.