In vitro and in vivo effects of SCA40 on guinea pig airways.
SCA40 (6-bromo-8-methylaminoimidazo [1,2-a]-pyrazine-2-carbonitrile), a compound which had been described as an opener of Ca(2+)-dependent large conductance potassium channels (BKCa channels), was investigated in comparison with salbutamol for in vitro and in vivo bronchospasmolytic effects and for the ability to reverse airways hyperreactivity in guinea pigs. SCA40 reduced the spontaneous tone of isolated guinea pig tracheal rings with a biphasic concentration-response curve (first phase: pD2 = 8.0, EMax = 29.7% of maximal effect; second phase: pD2 = 6.4, EMax = 72.6%). The salbutamol curve was monophasic (pD2 = 8.0, EMax = 100%). Total lung resistance (RL) was determined in anaesthetized, ventilated guinea pigs. Bronchoconstriction, measured as an increase in RL, was elicited in normoreactive animals by i.v. infusion of bombesin (100 ng/kg/min) or by i.v. injection of histamine (1.8-5.6 micrograms/kg). Airways hyperreactivity was induced by acute i.v. administration of pre-formed immune complexes. Intravenous bolus injections of histamine (2.4 micrograms/kg) were used to define the sensitivity of the airways prior to and after the exposure to immune complex. Following intratracheal (i.t.) administration, SCA40 reversed bombesin-induced bronchoconstriction with an ED50 of 43 micrograms/kg (EMax = 57%). The ED50 for salbutamol was 0.8 microgram/kg i.t. (EMax = 78%). Histamine-induced bronchoconstriction in hyperreactive guinea pigs was inhibited by SCA40 with an ED50 of 13 micrograms/ kg i.t. (EMax = 82%). Salbutamol completely inhibited histamine-induced bronchospasm with an ED50 of 9 ng/kg i.t. In normoreactive guinea pigs, SCA40 prevented histamine-induced bronchoconstriction with an ED50 of 100 micrograms/kg i.t.; for salbutamol the ED50 in this test was 0.48 microgram/kg i.t. Thus, for both SCA40 and salbutamol, the effects obtained at low doses in hyperreactive guinea pigs represent a true reversal of airways hyperreactivity, whereas at higher doses, anti-hyperreactive and bronchospasmolytic properties may account for the observed effects. In conclusion, SCA40 relaxes guinea pig airways smooth muscle in vitro and in vivo, and it partly reverses airways hyperreactivity. With respect to both potency and efficacy, SCA40 is markedly less active than the beta-adrenoceptor agonist salbutamol.
Buchheit
K H
KH
Sandoz Pharma Ltd., Basel, Switzerland.
Hofmann
A
A
Pfannkuche
H J
HJ
D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001839:Bombesin / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D001993:Bronchodilator Agents; D007093:Imidazoles; D011719:Pyrazines; C080660:6-bromo-8-methylaminoimidazo(1,2-a)pyrazine-2-carbonitrile; D006632:Histamine; D001839:Bombesin; D000420:Albuterol