Effects of the triazolopyrimidine trapidil on force of contraction, beating frequency and phosphodiesterase I--IV activity in guinea-pig hearts.
The effects of the triazolopyrimidine trapidil (5-methyl-7-diethylamino-s-triazolo [1,5-alpha]pyrimidine, CAS 15421-84-8) on force of contraction, beating frequency and phosphodiesterase (PDE) activity were investigated in isolated preparations from guinea-pig hearts. The effects of 3-isobutyl-1-methylxanthine (IBMX), theophylline and milrinone were studied for comparison. Trapidil exerted a concentration-dependent (1000-3000 mumol(s)/l) positive inotropic effect (EC50 562.4 mumol(s)/l) in guinea-pig papillary muscles. The positive inotropic effect was accompanied by a shortening of the duration of contraction as described for IBMX, or isoprenaline. The efficacy of trapidil was lower than that of IBMX or milrinone. Both agents maximally enhanced force of contraction to a 3fold (milrinone) or even 6fold greater amount (IBMX). The potency of trapidil was almost in the same order of magnitude as that of milrinone. The positive inotropic effect of trapidil is at least partially due to a cyclic adenosine monophosphate (cAMP)-dependent mechanism because carbachol antagonized the increase in force of contraction. Trapidil concentration-dependently but nonselectively inhibited the activities of cAMP PDE isoenzymes I-IV as did theophylline or IBMX. Based on IC50 values (275 mumol(s)/l on the average) trapidil had a potency similar to that of theophylline while IBMX was about one order of magnitude more potent. Regarding the inhibition of PDE III, IBMX was 49fold and milrinone 114fold more potent than trapidil. Trapidil revealed only a marginal positive chronotropic effect. The frequency of spontaneously beating right auricles was increased by 13% at most. Trapidil did not produce any tachyarrhythmias or contractures. It is concluded that the positive inotropic effect of trapidil is mainly due to PDE inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Bethke
T
T
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Fed. Rep. of Germany.
Mehl
H
H
Meyer
W
W
Schmitz
W
W
Scholz
H
H
Thomas
K
K
Wenzlaff
H
H
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002848:Chromatography, DEAE-Cellulose; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology; D014192:Trapidil / Q000494:pharmacology*
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D013806:Theophylline; D014192:Trapidil; D020105:Milrinone; D015056:1-Methyl-3-isobutylxanthine