Further analysis of the mechanisms underlying the tracheal relaxant action of SCA40

• Published in: British journal of pharmacology 1995-01, Vol.114 (1), p.143-151
• Main Authors: Cook, S.J., Archer, K., Martin, A., Buchheit, K.H., Fozard, J.R., Müller, T., Miller, A.J., Elliott, K.R.F., Foster, R.W., Small, R.C.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; cardiac atrial muscle; charybdotoxin; Cyclic AMP - pharmacology; cyclic nucleotide phosphodiesterase; Electric Stimulation; Electrophysiology; Female; Guinea Pigs; Imidazoles - pharmacology; isoprenaline; Isoproterenol - pharmacology; K+‐rich Krebs solution; levcromakalim; Male; Medical sciences; nifedipine; Nifedipine - pharmacology; Parasympatholytics - pharmacology; Pharmacology. Drug treatments; Pyrazines - pharmacology; quinine; Quinine - pharmacology; Respiratory system; SCA40; Theophylline - pharmacology; Trachea - drug effects; Trachealis muscle
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1995.tb14918.x

1 SCA40 (1nm − 10 μm), isoprenaline (1–300 nm) and levcromakalim (100 nm − 10 μm) each produced concentration‐dependent suppression of the spontaneous tone of guinea‐pig isolated trachea. Propranolol (1 μm) markedly (approximately 150 fold) antagonized isoprenaline but did not antagonize SCA40. The tracheal relaxant action of SCA40 was unaffected by suramin (100 μm) or 8‐(p)‐sulphophenyltheophylline (8‐SPT; 140 μm). 2 An isosmolar, K+‐rich (80 mm) Krebs solution increased tracheal tone, antagonized SCA40 (approximately 60 fold), antagonized isoprenaline (approximately 20 fold) and very profoundly depressed the log concentration‐effect curve for levcromakalim. Nifedipine (1 μm) did not itself modify the relaxant actions of SCA40, isoprenaline or levcromakalim. However, nifedipine prevented the rise in tissue tone and the antagonism of SCA40 and isoprenaline induced by the K+‐rich medium. In contrast, nifedipine did not prevent the equivalent antagonism of levcromakalim. 3 Charybdotoxin (100 nm) increased tracheal tone, antagonized SCA40 (approximately 4 fold) and antagonized isoprenaline (approximately 3 fold). Nifedipine (1 μm) prevented the rise in tissue tone and the antagonism of SCA40 and isoprenaline induced by charybdotoxin. 4 Quinine (30 μm) caused little or no change in tissue tone and did not modify the relaxant action of isoprenaline. However, quinine antagonized SCA40 (approximately 2 fold). Nifedipine (1 μm) prevented the antagonism of SCA40 induced by quinine. 5 Tested on spontaneously‐beating guinea‐pig isolated atria SCA40 (1 nm − 10 μm) increased the rate of beating in a concentration‐dependent manner. Over the concentration‐range 1 μm − 10 μm, SCA40 also caused an increase in the force of atrial contraction. 6 Intracellular electrophysiological recording from guinea‐pig isolated trachealis showed that the relaxant effects of SCA40 (1 μm) were often accompanied by the suppression of spontaneous electrical slow waves but no change in resting membrane potential. When the concentration of SCA40 was raised to 10 μm, its relaxant activity was accompanied both by slow wave suppression and by plasmalemmal hyperpolarization. 7 SCA40 (10 nm − 100 μm) more potently inhibited the activity of cyclic AMP phosphodiesterase (PDE) than that of cyclic GMP PDE derived from homogenates of guinea‐pig trachealis. Theophylline (1 μm − 10 mm) also inhibited these enzymes but was less potent than SCA40 in each case and did not exhibit selectivity for inhibition of