Effects of a stable prostacyclin analogue, FCE 22176, on isolated guinea pig trachea and atria atria

Pharmacological Research, Vol. 21, No. 4, 1989

449

EFFECTS OF A STABLE PROSTACYCLIN ANALOGUE, FCE 22176, ON ISOLATED GUINEA PIG TRACHEA AND ATRIA E. RAGAZZI, G . FROLDI, L . CAPARROTTA and G . FASSINA Department of Pharmacology, University of Padova, Largo E . Meneghetti, 2 1-35131 Padova, Italy Ktv WORDS :

prostacyclin, stereoisomers, ( - )N'-phenylisopropyladenosine, trachea, atria .

Prostacyclin (PGI,) is an unstable metabolite of arachidonic acid metabolism [ 1 ] that inhibits the aggregation of platelets [1], possesses a positive inotropic effect on heart [2] and mediates vasodilation [3] (for review : [4]) . All prostaglandins and PGI, have been demonstrated to have specific binding sites in many tissues, by using radiolabelled eicosanoid . The study of drug-receptor interaction with different compounds stereochemically related to PGI2 is a step for studying the mechanism of action of prostanoids . Modification of the sterical structure of the 5,6 double bond of the a-side chain of PGI, or PGI, analogues, may produce antagonistic molecules . In a preliminary report [5], the effects of two geometric isomers of a stable derivative of PGI, were studied on isolated tissues . Since FCE 22176 (the 5-Z stereoisomer of (+ )13, l 4didehydro-20-methylcarboprostacyclin) showed a PGI,-receptor antagonism, we performed further investigations about this stable compound . METHODS Guinea-pigs of either sex (300-500 g) were used . Tracheal chains and atria were incubated in physiological solution gassed with 95% 02-5% CO 2 at 37 ° and 29 °C, respectively . The tracheal chain contraction and relaxation were recorded isotonically at a resting tension of 0 . 5 g . The atrial contraction above the constant resting tension of 1 g was recorded isometrically . RESULTS AND DISCUSSION In isolated and spontaneously beating guinea-pig atria, FCE 22176 (0 . 1-1 [sM) showed a low intrinsic activity, but was able to antagonize the PGI 2-induced inotropic action, both in normal physiological conditions and in increased K+ concentrations (8 mm), where the effect of PGI 2 is more evident [2] . In isolated guinea-pig tracheal chains, the FCE 22176 preventive addiction (0 . 1-1 µM) produced a parallel snift to the right of the log concentration-response curve of PGI,_ [51 . 11143-6618/89/040449-02/S03 .00/0

© 1989 The Italian Pharmacological Society



450

Pharmacological Research, Vol. 21, No. 4, 1989

Since many prostaglandins are involved in tracheal tone regulation, we studied the interaction of FCE 22176 on PGFza -induced contraction in isolated trachea . The compound antagonized the PGFza concentration-response curve, but only at higher concentrations (1-10,uM) . Furthermore, the relaxant effect of PGE 2 was enhanced by FCE 22176 (1 um), probably by antagonizing other contractile prostaglandins . The interaction between FCE 22176 and adenosine was also investigated in isolated trachea . The biphasic response of a stable adenosine derivative, (- )N6phenylisopropyladenosine (PIA), was attenuated in the contractile phase and enhanced in the relaxant one (Fig . 1) . This is in agreement with our previous finding indicating that the contractile effect of PIA is mediated by products of arachidonic acid cascade ; the inhibitory effect of FCE 22176 on prostaglandin receptors can thus result in a reduced contractile effect of prostanoids released by adenosine. 40

20

0o

0

O

-20

ô

U

1 1 I 1 1 1 0.1 0.2 0.5 1 10 50 PIA (µM)

Fig . 1 . Effect of FCE 22176 on PIA concentration-response curve in isolated guinea-pig tracheal chains . IPIA; DPIA+FCE 22176 1 um ; APIA+FCE 22176 10 /tM .

In conclusion, the stable PGI 2 derivative FCE 22176 is confirmed to have an antagonistic effect on PGI 2 activity in isolated guinea-pig atria and trachea . The antagonism evidenced against other prostaglandins and PTA confirms the role of prostanoids and adenosine in tracheal tone regulation .

REFERENCES 1. Moncada S, Gryglewski R, Bunting S, Vane JR. Nature 1976 ; 263 : 663-5 . 2 . Fassina G, Tessari F, Dorigo P. Pharmacol Res Commun 1983 ; 15 : 735-49 . 3 . Moncada S, Vane JR . In : Vanhoutte PM, Lensen 1, eds. Mechanism of vasodilation. Basel : Karger, 1978 : 107-2 1 . 4 . Oliva D, Nicosia S . Pharmacol Res Commun 1987 ; 19 : 735-65 . 5 . Fassina G, Froldi G, Caparrotta L . EurJ Pharmacol1985 ; 113 : 459-60 .