The relaxing effect of BDF 9148 on the KCl-contracted aorta isolated from normo- and hyper-tensive rats

Abstract

BDF 9148, a positive cardiac inotrope, relaxes the rat isolated portal vein and the KCl-contracted rat aorta. The aims of our study were to determine the mechanism of action of BDF 9148, and to ascertain whether the relaxing effect of BDF 9148 was maintained in the presence of the hypertrophy associated with hypertension, by investigating the effects of BDF 9148 on the contractility and electrophysiology of aortae of Wistar Kyoto normo-tensive rats (WKY) and Spontaneously Hypertensive Rats (SHRs). High concentrations of veratridine contracted the quiescent rat aorta. BDF 9148 had no effect on the quiescent, but relaxed the KCl-contracted WKY and SHR aorta by a tetrodotoxin insensitive mechanism, and these relaxations decreased with age but were not greatly altered by hypertrophy. The verapamil relaxations of the KCl-contracted aorta were not altered by age or hypertrophy. The ability of KCl to depolarise the aorta was reversed by verapamil, but not by BDF 9148. On the contracted rat aorta, the relaxant responses to acetylcholine were abolished by removal of the endothelium but potentiated by IBMX (10[-6] M), and the responses to isoprenaline were inhibited by propranolol (10[-6] M) but potentiated by forskolin (10[-7] M). The relaxation responses of the KCl-contracted aorta to BDF 9148 were not altered by removal of the endothelium, or by propranolol, forskolin and IBMX. In summary, the effects of verapamil and BDF 9148 on the aorta are different, and thus it is unlikely that the relaxant responses to BDF 9148 on the aorta are due to calcium channel blocking activity. The mechanism of the relaxant effect of BDF 9148 on the aorta remains unknown, but we have shown the response is endothelium-independent, and not mediated by sodium channel opening, hyperpolarization, beta-adrenoceptors, or by stimulating adenylate cyclase or guanylate cyclase.

Reduced Effects of Isoprenaline on the Membrane Potential of Aortic Smooth Muscle from Rats Pre- and During Hypertension

“…This study con®rms that the SHR in our Auckland colony are prehypertensive at 5 weeks (Doggrell & Liang 1998;Nand & Doggrell 1999). Hypertension is apparent in SHR after 14 weeks and the gain in weight of the aorta at this time is probably indicative of hypertrophy.…”

“…We have previously described our method (Doggrell & Liang 1998). Endothelium-intact rat aortae were cut along the longitudinal axis to form a¯at sheet of length 0Á5 cm (approx.).…”

Structure, function and pharmacology of voltage-gated sodium channels

“…A major advantage of these compounds over other ion channel modulators is that they are in principle not arrhythmogenic (Doggrell et al 1995) and not vasoconstrictive since the probability of blood vessel Na + channel being in the closed state is higher than in cardiac channels. Moreover, DPI 201-106 and BDF9148 were shown to have a vasodilatatory effect (Doggrell and Liang 1998;Hof and Hof 1985) which is desirable in patients suffering from heart failure. Another possible combination of ion channel modulator actions that may be useful in the clinic would be a compound that prolongs the opening of cardiac Na + channels to induce positive inotropy and vascular K + channel opening to produce vasodilatation.…”

Synthesis of diarylmethylamines via palladium-catalyzed regioselective arylation of 1,1,3-triaryl-2-azaallyl anions

“…Molecules containing the diarylmethylamine scaffold are prevalent in biological and pharmaceutical sciences, with examples including Zyrtec, 1 Levocetirizine, 2 Meclozine, 3 Solifenacin, 4 BDF9148, 5 SNC80, 6 and ARM434 7 (Fig. 1).…”