Biochemical and electrical aspects of the tracheal relaxant action of AH 21-132.
In Triton X-100-skinned trachealis muscle, neither papaverine nor AH 21-132 modified responses to Ca2+. The (-)-enantiomer of AH 21-132 was more potent than the (+)-enantiomer both in relaxing intact trachealis muscle and in inhibiting tracheal cAMP phosphodiesterase (PDE). AH 21-132 (0.6 microM) potentiated forskolin in causing tracheal relaxation but did not potentiate isoprenaline, cromakalim or sodium nitrate. AH 21-132 (2 microM) potentiated all four agents in relaxing the trachea. AH 21-132 (1 microM) potentiated forskolin in increasing tissue cAMP content and, in higher concentration, itself increased tissue cAMP. Electrical effects of AH 21-132 included suppression of spontaneous slow waves and cellular hyperpolarisation. It is concluded that AH 21-132 lacks a direct depressant effect on the intracellular contractile machinery. The weight of evidence suggests that AH 21-132-induced relaxation results from inhibition of cAMP-PDE. However, in common with other PDE inhibitors. AH 21-132 increases tissue cAMP content only at concentration greater than that required to cause full relaxation.
Small
R C
RC
Smooth Muscle Research Group, Department of Physiological Sciences, University of Manchester, U.K.
Berry
J L
JL
Boyle
J P
JP
Chapman
I D
ID
Elliott
K R
KR
Foster
R W
RW
Watt
A J
AJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000200:Action Potentials / Q000187:drug effects; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D001696:Biomechanical Phenomena; D002462:Cell Membrane / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D019806:Cromakalim; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology*; D009712:Nucleotides, Cyclic / Q000378:metabolism; D010208:Papaverine / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012977:Sodium Nitrite / Q000494:pharmacology; D013237:Stereoisomerism; D014132:Trachea / Q000187:drug effects*
D001578:Benzopyrans; D009287:Naphthyridines; D009712:Nucleotides, Cyclic; D011758:Pyrroles; D019806:Cromakalim; D005576:Colforsin; C044843:AH 21-132; D010208:Papaverine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D007545:Isoproterenol; D012977:Sodium Nitrite