zaprinast and Body-Weight

Erectile dysfunction is common in men with chronic renal failure. Previously nitrergic and endothelium-dependent relaxation responses have been shown to be reduced in chronic renal failure rabbits. We have therefore investigated the efficacy of phosphodiesterase inhibitors on the corpora cavernosa obtained from uremic rabbits. Uremia was induced with 5/6 nephrectomy and 4 weeks later cavernosal tissue strips were isolated. The relaxant effect of phosphodiesterase 5 inhibitors, zaprinast (1-300 microM) and sildenafil (0.01-300 microM), phosphodiesterase 3 inhibitor amrinone (1-100 microM) and non-specific phosphodiesterase inhibitor papaverine (1-300 microM) were investigated on phenylephrine (10 microM)-induced tone. We found a shift in the dose-response curve of only phosphodiesterase 5 inhibitors. These results suggest that the decreased production or availability of endogenous nitric oxide in chronic renal failure animals leads to decreased efficacy of phosphodiesterase 5 inhibitors to induce relaxation.

Topics: Amrinone; Animals; Body Weight; Calcium; Creatinine; Dose-Response Relationship, Drug; Electric Stimulation; In Vitro Techniques; Isoenzymes; Kidney Failure, Chronic; Male; Muscle Relaxation; Nephrectomy; Papaverine; Parathyroid Hormone; Penis; Phosphates; Phosphodiesterase Inhibitors; Phospholipases; Piperazines; Purines; Purinones; Rabbits; Sildenafil Citrate; Sulfones; Testosterone

We have reported that denbufylline, a phosphodiesterase 4 (PDE4) inhibitor, inhibits bone loss in Walker256/S tumor-bearing rats, suggesting therapeutic potentiality of a PDE4 inhibitor in osteopenia. In the present study, effects of a new PDE4 inhibitor, 1-n-butyl-3-n-propylxanthine (XT-44), in bone were evaluated in cell cultures and animal experiments. In rat bone marrow culture, XT-44 stimulated mineralized-nodule formation, whereas it inhibited osteoclast-like cell formation in mouse bone marrow culture. In Walker256/S-bearing rats (6-week-old female Wistar Imamichi rats), rapid decrease in bone mineral density (BMD) was prominent, and oral administration of XT-44 (0.3 mg/kg, every 2 days) inhibited the decrease in BMD. In the second animal experiment, female Wistar rats (6-week-old) were sciatic neurectomized, and XT-44 was orally administered to these rats every 2 days for 4 weeks. XT-44 administration (0.3 mg/kg) recovered BMD in these neurectomized animals. Furthermore, 19-week-old, female Wistar rats were ovariectomized (OVX), and 15 weeks after surgery, these rats were orally administered XT-44 every 2 days for 8 weeks. XT-44 treatment (1 mg/kg) increased the BMD of OVX rats. These results indicate that XT-44 could be a candidate as a therapeutic drug for treating osteopenia including osteoporosis.

Topics: 1-Methyl-3-isobutylxanthine; 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Body Weight; Bone Density; Bone Diseases, Metabolic; Bone Marrow Cells; Cyclic Nucleotide Phosphodiesterases, Type 4; Denervation; Dose-Response Relationship, Drug; Female; Femur; Giant Cells; Male; Mice; Osteoblasts; Osteoclasts; Osteogenesis; Ovariectomy; Phosphodiesterase Inhibitors; Purinones; Pyrrolidinones; Rats; Rats, Wistar; Rolipram; Sciatic Nerve; Xanthines