PMID- 9453467
OWN - NLM
STAT- MEDLINE
DCOM- 19980316
LR  - 20190726
IS  - 0028-1298 (Print)
IS  - 0028-1298 (Linking)
VI  - 356
IP  - 6
DP  - 1997 Dec
TI  - Bronchodilator and anti-inflammatory activities of SCA40: studies in human 
      isolated bronchus, human eosinophils, and in the guinea-pig in vivo.
PG  - 806-14
AB  - There is currently interest in the use of inhibitors of cyclic nucleotide 
      phosphodiesterases (PDE) as potential anti-asthma agents. In this study we 
      examined the effects of SCA40 (6-bromo-8-methylaminoimidazol-[1,2-a] 
      pyrazine-2-carbonitrile), a preferential inhibitor of PDE 3 also endowed with PDE 
      4 and 5 inhibitory activities, on isolated bronchus and eosinophil functions and 
      in an animal model of asthma. SCA40 (1 nM-0.1 mM) produced 
      concentration-dependent inhibition of spontaneous and stimulated tone of human 
      isolated bronchus and reached a maximal relaxation similar to that of 
      theophylline (3 mM). The potency (-log EC50 values) of SCA40 against spontaneous 
      tone (6.52 +/- 0.10) was greater than against tone raised by equieffective 
      concentrations (approximately 70%) of histamine (5.76 +/- 0.06), leukotriene C4 
      (5.44 +/- 0.11), and acetylcholine (4.98 +/- 0.09). In the presence of 
      cytochalasin B, the chemotactic peptide 
      N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP; 0.5 microM) induced 
      leukotriene C4 production in human eosinophils isolated in discontinuous 
      metrizamide gradients. The production of leukotriene C4 was inhibited by SCA40 in 
      a concentration-related fashion (-log IC50 = 6.04 +/- 0.20; n = 6). Rolipram, a 
      selective PDE 4 inhibitor, was also effective (-log IC50 = 7.29 +/- 0.32) but the 
      selective PDE 3 inhibitor SKF94120 was scarcely effective (< 10% inhibition for 
      10 microM). In ovalbumin sensitized guinea-pigs, SCA40 (1 mg kg(-1), i.p.) given 
      30 min before antigen challenge significantly inhibited the acute 
      bronchoconstriction produced by aerosol antigen (5 mg ml(-1), 30 s) (antigen 
      response was 185 +/- 13 and 91 +/- 21 cmH2O l(-1) s(-1) in control and 
      SCA40-treated animals, respectively, P < 0.05). Pretreatment with SCA40 (1 mg 
      kg(-1), i.p., 30 min pre- and 3 h post-antigen exposure) prevented airway 
      hyperreactivity to histamine which developed 24 h after exposure of conscious 
      guinea-pigs to aerosol antigen. Eosinophil lung accumulation that accompanied 
      airway hyperreactivity was also inhibited by SCA40 (from 6.15 +/- 0.86 in control 
      to 1.27 +/- 0.27 in treated animals; expressed as eosinophils x 10(6); P < 0.05). 
      SCA40 (1 mg kg(-1), i.p.) also inhibited the microvascular leakage produced after 
      inhaled antigen (5 mg ml(-1), 30 s) at all airway levels. The haemodynamic 
      effects of SCA40 (1 mg kg(-1), i.p.) consisted of a rapid decrease (peak at 5 
      min) in mean arterial blood pressure (-39.4 +/- 2.4%) and tracheal mucosal blood 
      flow (-13.5 +/- 2.0%) that slowly recovered with time. These data support 
      previous work showing that PDE inhibition results in antispasmogenic and 
      anti-inflammatory effects. SCA40 was effective in vitro and in vivo and these 
      effects are probably related to its activity as a mixed PDE inhibitor.
FAU - Cortijo, J
AU  - Cortijo J
AD  - Departamento de Farmacologia, Facultad de Medicina y Odontologia, Universitat de 
      Valencia, Spain.
FAU - Pons, R
AU  - Pons R
FAU - Dasi, F
AU  - Dasi F
FAU - Marin, N
AU  - Marin N
FAU - Martinez-Losa, M
AU  - Martinez-Losa M
FAU - Advenier, C
AU  - Advenier C
FAU - Morcillo, E J
AU  - Morcillo EJ
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Naunyn Schmiedebergs Arch Pharmacol
JT  - Naunyn-Schmiedeberg's archives of pharmacology
JID - 0326264
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Antigens)
RN  - 0 (Bronchodilator Agents)
RN  - 0 (Imidazoles)
RN  - 0 (Pyrazines)
RN  - 142744-39-6 (6-bromo-8-methylaminoimidazo(1,2-a)pyrazine-2-carbonitrile)
RN  - 2CU6TT9V48 (Leukotriene C4)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
MH  - Antigens
MH  - Bronchi/*drug effects/physiology
MH  - Bronchial Hyperreactivity/*drug therapy/etiology
MH  - Bronchodilator Agents/*pharmacology/therapeutic use
MH  - Eosinophils/*drug effects/metabolism
MH  - Guinea Pigs
MH  - Humans
MH  - Imidazoles/*pharmacology/therapeutic use
MH  - In Vitro Techniques
MH  - Leukotriene C4/biosynthesis
MH  - Muscle Relaxation
MH  - Muscle, Smooth/*drug effects/physiology
MH  - Pyrazines/*pharmacology/therapeutic use
EDAT- 1998/02/07 00:00
MHDA- 1998/02/07 00:01
CRDT- 1998/02/07 00:00
PHST- 1998/02/07 00:00 [pubmed]
PHST- 1998/02/07 00:01 [medline]
PHST- 1998/02/07 00:00 [entrez]
AID - 10.1007/pl00005121 [doi]
PST - ppublish
SO  - Naunyn Schmiedebergs Arch Pharmacol. 1997 Dec;356(6):806-14. doi: 
      10.1007/pl00005121.