zaprinast and denbufylline

The effects of denbufylline, a xanthine derivative with selective inhibitory activity on the phosphodiesterase (PDE) 4 isoenzyme, on bone loss in Walker 256/S-bearing rats and on mineralized nodule formation and osteoclastlike cell formation in bone marrow culture systems were examined. Serial oral administrations of denbufylline inhibited the decrease in the bone mineral density of femurs from Walker 256/S-bearing rats, without influence on the healthy rats. Denbufylline restored the bone mass and the number of osteoclasts and osteoblasts per trabecular surface in the femur metaphysis. Among PDE inhibitors, only PDE4-selective inhibitors increased the number of mineralized nodules and decreased the number of osteoclastlike cells in the in vitro bone marrow culture systems, and dibutyryl cyclic AMP mimicked these effects in the in vitro systems. These results suggest that the PDE4 isoenzyme may play an important role in bone turnover through cyclic AMP and that its inhibitors are candidates for therapeutic drugs for the bone loss diseases.

Topics: 1-Methyl-3-isobutylxanthine; 3',5'-Cyclic-AMP Phosphodiesterases; 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Animals; Bone Marrow Cells; Bone Resorption; Bucladesine; Calcification, Physiologic; Carcinoma 256, Walker; Cells, Cultured; Cyclic Nucleotide Phosphodiesterases, Type 4; Female; Mice; Milrinone; Osteoclasts; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Purinones; Pyridones; Rats; Rats, Wistar; Xanthines

Nonadrenergic, noncholinergic relaxations were elicited by field stimulation (1-16 Hz, 1 msec, 8 V for 15 sec) of guinea pig trachea desensitized with capsaicin (3 microM), pretreated with atropine (1 microM), propranolol (1 microM), indomethacin (3 microM) and treated with alpha-chymotrypsin (2 U/ml) and contracted with 3 microM histamine. The effect of the phosphodiesterase (PDE) isozyme selective inhibitors siguazodan (PDE III-selective), rolipram (PDE IV-selective), denbufylline (PDE IV-selective) and zaprinast (PDE V-selective) was examined on the relaxant responses to field stimulation and on relaxations elicited by the nitric oxide donor 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1). The response to field stimulation in the presence of alpha-chymotrypsin (the putative nitric oxide component), at all the frequencies tested, was potentiated significantly by the PDE IV inhibitors rolipram (1 and 10 microM) and denbufylline (3 and 10 microM) as were responses to SIN-1. The PDE V inhibitor zaprinast (30 microM) potentiated relaxations elicited by field stimulation at 8 and 16 Hz and also potentiated responses to SIN-1. The PDE III inhibitor siguazodan (1 microM), however, was without effect on relaxant responses to field stimulation or to SIN-1. These results suggest that the nitric oxide component of the nonadrenergic, noncholinergic relaxant response is mediated primarily via cyclic AMP whose action is inactivated by a PDE IV isozyme and also by cyclic GMP which is inactivated by a PDE V isozyme.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Atropine; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Electric Stimulation; Guanidines; Guinea Pigs; Indomethacin; Isoenzymes; Muscle Relaxation; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Propranolol; Purinones; Pyridazines; Pyrrolidinones; Receptors, Adrenergic; Receptors, Cholinergic; Rolipram; Trachea; Vasoactive Intestinal Peptide; Xanthines