ABSTRACT
1. A method is described whereby either the serosal (Out) or epithelial (In) sides of rat isolated tracheae were selectively perfused. Perfusion with BRL 38227 (10(-8)-5 x 10(-6) M; In/Out) of preparations with intact epithelium (+ EP) precontracted with carbachol (10(-6) M; Out/In) produced complete relaxation. Perfusion with aminophylline (10(-5)-10(-3) M; In) of + EP preparations precontracted with carbachol (10(-6) M; Out) also produced complete relaxation. 2. In preparations precontracted with carbachol (10(-6) M) epithelium removal (- EP) increased the sensitivity to the relaxant effect of BRL 38227 (In), but not BRL 38227 (Out) [- log EC50, + EP/- EP; carbachol (In), BRL 38227 (Out): 6.76 +/- 0.11 vs 6.67 +/- 0.15; carbachol (Out), BRL 38227 (In): 5.93 +/- 0.06 vs 6.25 +/- 0.07]. Removal of the epithelium increased also the sensitivity to BRL 38227 (In) of preparations precontracted with a lower concentration (5 x 10(-7) M) of carbachol (Out). [- log EC50, + EP/- EP, carbachol (Out), BRL 38227 (In): 6.19 +/- 0.14 vs 6.58 +/- 0.17]. 3. Removal of the epithelium did not affect the sensitivity to BRL 38227 (In) of preparations precontracted with a higher concentration (5 x 10(-6) M) of carbachol (Out). 4. In both + EP and - EP preparations precontracted with carbachol (10(-6) M; Out), BRL 38227 (In) had a more potent relaxant effect than aminophylline (In) (EC50, BRL 38227 vs aminophylline, + EP/- EP: 5.93 +/- 0.06 vs 3.66 +/- 0.11/6.25 +/- 0.07 vs 3.77 +/- 0.11). 5. In preparations precontracted with carbachol (10-6 M; Out), removal of the epithelium did not affect the sensitivity to aminophylline (In) but increased the degree of precontraction (Tmax) following epithelial but not serosal stimulation with carbachol.6. We conclude that BRL 38227, a K+ channel activator, is a potent relaxant of rat tracheal smooth muscle precontracted with carbachol, and that the effect can be partially inhibited by the presence of an intact tracheal epithelium, whereas the relaxant effect of aminophylline is not.
Subject(s)
Benzopyrans/pharmacology , Bronchodilator Agents/pharmacology , Muscle, Smooth/drug effects , Potassium Channels/drug effects , Pyrroles/pharmacology , Aminophylline/pharmacology , Animals , Biotransformation/drug effects , Carbachol/pharmacology , Cromakalim , Epithelium/drug effects , Epithelium/physiology , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle Relaxation/drug effects , Rats , Rats, Sprague-Dawley , Trachea/drug effectsABSTRACT
Eighty-four patients aged less than 71 years with less than 4-hour duration acute myocardial infarction (AMI) were randomized in a multicenter study to 30 U anistreplase or heparin (single injection of 6500 IU followed by 1000 IU/hr). Early reperfusion was assessed from ECG changes (50% of sum ST decrease 2 hours postdosing) and the CK release profile (CK peak less than 16 hours after onset of symptoms, CK slope greater than 10%/hr). Reperfusion rates in patients meeting at least two criteria of reperfusion were 62.5% on anistreplase versus 27.5% on heparin. On delayed angiogram (13.7 +/- 3.4 days), patency rates were 66% with anistreplase versus 47% (NS) with heparin in 76 patients. Global LVF was similar in both groups. With anistreplase, the mean lowest fibrinogen level was 0.43 +/- 0.55 g/l, plasminogen was 20 +/- 9%, and the highest F.D.P. was 1447 +/- 548 micrograms/ml. All values recovered by hour 48. In-hospital and 1-year follow-up mortality was 7.2% (three patients) with anistreplase versus 10.2% (four patients) with heparin. Bleeding occurred in 9.7% and 5.1% of the patients (NS), respectively. No intracranial hemorrhage occurred. Thus, with combined clinical criteria or reperfusion, anistreplase is twice as efficient as heparin, has a good tolerance, and is easy to use as a single injection.
