Tadaaki Niinobu

Reduction of risk of pneumonia associated with use of angiotensin I converting enzyme inhibitors in elderly inpatients

Pneumonia is a major direct cause of death in the elderly. Although aspiration based on a reduced cough reflex is one of the causes of pneumonia in the elderly, there are few studies of angiotensin-I converting enzyme inhibitors (ACE inhibitors), which are antihypertensive drugs that induce cough, as a factor influencing the incidence of pneumonia in institutionalized elderly subjects. To assess the effect of ACE inhibitors and dihydropiridine calcium-channel blockers on the incidence of pneumonia, we conducted a hospital-based case-control study. Cases were 55 pneumonia patients aged > or = 65 years during a 1-year period. The controls were elderly subjects, frequency matched to the cases by age and gender (n = 220). Data were collected on known risk factors and on medication for hypertension, consisting of ACE inhibitors, calcium-channel blockers, and nonantihypertensive medication. The significance of differences in risk factors was analyzed using univariate and multivariate comparisons of cases and controls. After adjustment for potential confounding factors, the relative risk estimates for pneumonia were 0.38 (95% confidence interval [CI], 0.15-0.97) and 1.84 (95% CI, 0.89-3.78) for ACE inhibitors and calcium-channel blockers, respectively, relative to nonantihypertensive medication. The preventive effect of ACE inhibitors on pneumonia was apparent in long-acting ACE inhibitor users (0.24; 95% CI, 0.07-0.88). We conclude that ACE inhibitor use is an independent factor reducing risk of pneumonia among elderly inpatients.

Decreased circulating levels of vitamin K and 25-hydroxyvitamin D in osteopenic elderly men

Changes in the circulating factors participating in involutional osteoporosis have been intensively investigated in women, but little is known about this in men. We investigated the possible participation of circulating factors including testosterone, vitamin D metabolites, and vitamins K1 and K2 in osteopenia in elderly men. In a group of 27 ambulatory men aged 74 +/- 10 years (mean +/- SD; range, 60 to 90), the bone mineral density (BMD) of the second to fourth lumbar vertebrae was measured by dual-energy x-ray absorptiometry (DXA) and expressed as a Z score, the age-adjusted BMD value for the Japanese population (mean +/- SD, 0 +/- 1). Although the plasma level of total testosterone significantly decreased with age in the group, it did not significantly correlate with the Z score. However, the plasma levels of 25-hydroxyvitamin D (25-OHD), phylloquinone, menaquinone-7 (MK-7), and albumin were significantly positively correlated with the Z score. Moreover, plasma 25-OHD and both phylloquinone and MK-7 were significantly positively correlated in the subjects. These observations suggest that depressed circulating levels of 25-OHD and vitamin K concomitantly and cooperatively participate in osteopenia in elderly men, which may reflect the etiology of the type II moiety of involutional osteoporosis.

Pranidipine Enhances the Action of Nitric Oxide Released From Endothelial Cells

Nitric oxide (NO) synthesis in vascular endothelium of patients with hypertension is altered. Calcium antagonists have been shown to improve endothelial function in hypertensive patients. Here we report that pranidipine, one of the latest long-acting calcium antagonists in the dihydropyridine group, enhances the actions of NO released from endothelial cells (ECs). Pranidipine significantly enhanced cGMP accumulation in vascular smooth muscle cells cocultured with ECs, whereas amlodipine and nifedipine had no significant effects. In addition, pranidipine also suppressed basal and thrombin-stimulated endothelin-1 production from ECs. Pranidipine also enhanced cGMP accumulation in rat aortic segments with endothelium but not in endothelium-denuded vessels. In contrast, pranidipine had no effect in the presence of N(G)-monomethyl-L-arginine, an inhibitor of NO synthesis. Pranidipine did not affect the basal expression of endothelial NO synthase in ECs. However, pranidipine upregulated the activity of superoxide dismutase in ECs. These findings suggest that pranidipine enhances NO action through inhibition of superoxide-induced NO decomposition in the vessel wall. Thus, pranidipine may be useful in the treatment of impaired endothelial function in patients with hypertension.

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.

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.