Effects of chronic oral administration of levcromakalim on in vitro contractile responses of arterial smooth muscle

It has been shown that oral administration of 0.038–0.15 mg/kg levcromakalim elicits a dose-related antihypertensive response in spontaneously hypertensive rats (Clapham et al., Arzneim. Forsch. 41 (1991) 385). In the present study, we examined the effects of long term administration of a high dose of levcromakalim on in vitro vascular contractility. Levcromakalim (2.25 mg/kg/day) was administered to the rats for 2 weeks and the thoracic aorta was then isolated. The levcromakalim treatment markedly reduced the relaxant effect of levcromakalim itself on norepinephrine-induced contraction. Relaxant effects of sodium nitroprusside and 8-bromo-cGMP were also attenuated by the levcromakalim treatment, although the relaxant effects of verapamil and forskolin were unchanged. The levcromakalim treatment decreased the threshold concentration for KCl and norepinephrine to induce contraction. The chronic levcromakalim treatment did not affect the cGMP production due to 3-isobutyl-1-methylxanthine and/or sodium nitroprusside. The aorta isolated from spontaneous hypertensive rats did not exhibit spontaneous activity in normal solution. After treatment with levcromakalim, however, the aorta showed spontaneous rhythmic contractions. Verapamil (10 μM) completely suppressed the spontaneous activity and decreased the basal tension below the original level. Similar to the effects of chronic treatment with levcromakalim, high-K + solution (15.4 mM) augmented the contractile response to norepinephrine in the aorta of normotensive rats and induced rhythmic contractions in the aorta of spontaneously hypertensive rats. These results suggest that chronic treatment with a high dose of levcromakalim attenuates not only the effects of levcromakalim itself but also the cGMP-mediated relaxation, possibly by desensitizing the K + channel.