ovalbumin and zaprinast

The aim of the present study was to compare the effects of selective phosphodiesterase (PDE) 3, 4 and 5 inhibitors on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs. When the sensitized guinea-pigs were orally pre-treated with the selective PDE4 inhibitor, Ro 20-1724 (30 mg/kg), and studied 48h after OA, a significant reduction (P<0.01) of the leftward shift of the dose-response curve to ACh was noted, whereas it was ineffective at the lower dose (10 mg/kg). Administration of the selective PDE3 inhibitor, milrinone (30 mg/kg) also elicited a significant reduction (P<0.01) of the airway hyperresponsiveness, whereas the PDE5 inhibitor zaprinast (30 mg/kg) was ineffective. These results show that both PDE3 and PDE4 inhibitors are able to inhibit the antigen-induced airway hyperresponsiveness in sensitized guinea-pigs and support the potential utility of selective PDE inhibitors in the treatment of asthma.

Topics: 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Acetylcholine; Analysis of Variance; Animals; Guinea Pigs; Male; Milrinone; Ovalbumin; Phosphodiesterase Inhibitors; Purinones; Respiratory Hypersensitivity

1. The effects of phosphodiesterase (PDE) inhibition and forskolin pretreatment on the contractile responses of guinea-pig urinary bladder strips to electrical field stimulation, carbachol, ATP and KCl were studied. 2. Inhibition of cyclic AMP-specific PDE4 isozymes by rolipram significantly reduced the contractile response of bladder strips to field stimulation. Rolipram also suppressed the contractile response to low concentrations of carbachol, but potentiated the response to high concentrations. The contractile response to ATP was significantly reduced by rolipram treatment, but that to KCl was unaltered. 3. Inhibition of cyclic GMP-specific PDE5 isozymes by zaprinast had no effects on the contractile response of bladder strips to field stimulation, ATP or KCl. Zaprinast suppressed the contractile responses to 1 microM carbachol and potentiated the response to high concentrations. 4. Contractile responses to field stimulation and to carbachol after pretreatment with the adenylyl cyclase activator, forskolin, were qualitatively similar to those caused by rolipram treatment. beta-Adrenoceptor blockade with propranolol partially reversed the inhibitory effects of rolipram on the response to field stimulation. 5. Rolipram significantly reduced the contractile response of bladder strips from sensitized guinea-pigs to ovalbumin challenge, but zaprinast was ineffective. PDE inhibition had similar effects on the responsiveness of control and of sensitized guinea-pig bladder strips to field stimulation, carbachol, ATP and KCl. 6. The data suggest that the contractile response of guinea-pig bladder strips can be modified by increases in cyclic AMP levels.

Topics: Animals; Carbachol; Colforsin; Cyclic AMP; Electric Stimulation; Female; Guinea Pigs; In Vitro Techniques; Muscle Contraction; Ovalbumin; Purinones; Pyrrolidinones; Rolipram; Urinary Bladder

Antigen (ovalbumin)-induced contraction of guinea-pig isolated trachea, which largely resulted from the endogenous release of peptidoleukotrienes, was strongly inhibited by the non-selective phosphodiesterase (PDE) inhibitor theophylline and, more potently, by the selective PDE type IV inhibitors rolipram and Ro 20-1724. It was also strongly inhibited by the PDE type V inhibitor zaprinast, but much less so by the PDE type III inhibitor siguazodan and milrinone. Similar results were obtained in trachea minus epithelium. In contrast to their effects vs. allergic airway smooth muscle contraction, both milrinone and siguazodan potently relaxed leukotriene C4 (LTC4)-induced contraction in isolated trachea from non-sensitized animals. In this assay, rolipram, Ro 20-1724 and zaprinast were less active compared to their effects vs. ovalbumin-induced contraction, whereas theophylline had equivalent potency in the two tests. The relative potencies of rolipram and siguazodan in relaxation of trachea were similar when added prior to or after either LTC4 or histamine. These results suggest that the higher potency of selective PDE type IV & V inhibitors compared with PDE type III inhibitors vs. ovalbumin-induced contraction is due to their greater inhibition of anaphylactic mediator release. The converse is true if we consider their bronchodilator actions, although the superior efficacy of selective PDE type III inhibitors over PDE type IV inhibitors may vary in sensitized vs. non-sensitized animals. The present results are in agreement with a previous study showing that low concentrations of a beta 2-agonist increased the relaxant effect of selective PDE type IV inhibitors in guinea-pig trachea. The present data indicate that prophylactic use of selective PDE type IV inhibitors combined with therapeutic use of low dose inhaled beta-agonist might represent an alternative to the use of antiallergic or steroid therapy in asthma.

Topics: 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Animals; Bronchoconstrictor Agents; Bronchodilator Agents; Guanidines; Guinea Pigs; Histamine Antagonists; In Vitro Techniques; Leukotriene C4; Male; Milrinone; Muscle Tonus; Ovalbumin; Phosphodiesterase Inhibitors; Purinones; Pyridazines; Pyridones; Pyrrolidinones; Rolipram; Theophylline; Trachea

A vasorelaxing peptide was purified from a peptic digest of ovalbumin, after three steps of reverse-phase HPLC. The structure of the peptide was Phe-Arg-Ala-Asp-His-Pro-Phe-Leu, which corresponded to residues 358-365 of ovalbumin. The peptide was named ovokinin. Ovokinin showed relaxing activity for a canine mesenteric artery (EC50 = 6.3 microM). The relaxing activity was blocked by the bradykinin B1 antagonist [des-Arg9] [Leu8]bradykinin, but not by the B2 antagonist Hoe 140. Ovokinin binds to B1 receptors (IC50 = 64 microM). Prostaglandin I2 was released from the artery after ovokinin stimulation as a relaxing factor. Thus, ovokinin is a weak bradykinin B1 agonist peptide derived from food proteins.

Topics: 1-Methyl-3-isobutylxanthine; Amino Acid Sequence; Animals; Bradykinin; Dinoprost; Dogs; Dose-Response Relationship, Drug; Egg Proteins; In Vitro Techniques; Mesenteric Arteries; Molecular Sequence Data; Muscle Relaxation; Muscle, Smooth, Vascular; Ovalbumin; Papaverine; Peptide Fragments; Phosphodiesterase Inhibitors; Purinones; Pyrrolidinones; Rolipram; Vasodilator Agents

1. The ability of various phosphodiesterase (PDE) inhibitors to reduce the initial and/or late response to ovalbumin (OVA) in isolated strips of guinea-pig colonic smooth muscle from sensitized animals was examined. 2. Both the initial and late responses to OVA (0.05 mg ml-1) were inhibited by the non-selective PDE inhibitor, 3-isobutyl-1-methyl-xanthine (IBMX, EC50 = 26.0 and 6.1 microM, respectively), and the selective inhibitors of low Km cyclic AMP specific PDE (PDE IV), (R)- and (S)-rolipram. The (S)-isomer (EC50 = approximately 1.0 microM for both responses) was about 10 fold less potent than the (R)-isomer (EC50 = approximately 0.1 microM for both responses). 3. Zaprinast, a selective inhibitor of the cyclic GMP-specific PDE (PDE V) inhibited only the late response (EC50 = 1.4 microM). 4. SK&F 94120, a selective inhibitor of the cyclic GMP-inhibited low Km cyclic AMP PDE (PDE III), inhibited the initial response (45.9 +/- 11.9%, P < 0.05) at the highest concentration tested (100 microM), and had no effect on the late response. 5. The results suggest that PDE inhibitors, especially PDE IV inhibitors, can attenuate the contractile response of guinea-pig colon to OVA.

Topics: 1-Methyl-3-isobutylxanthine; 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Antigens; Colon; Cyclic Nucleotide Phosphodiesterases, Type 4; Guinea Pigs; Immunization; Male; Muscle Contraction; Muscle, Smooth; Ovalbumin; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Purinones; Pyrazines; Pyrrolidinones; Rolipram