St. Kau et al., CHARACTERIZATION OF ATP-SENSITIVE POTASSIUM CHANNEL-BLOCKING ACTIVITYOF ZENECA ZM181,037, A EUKALEMIC DIURETIC, Pharmacology, 49(4), 1994, pp. 238-248
ZENECA ZM181,037 is a novel eukalemic diuretic from a series of 1,1-di
arylcarbin-1-01-2 amines. In contrast to the standard diuretic hydroch
lorothiazide, the blood pressure-lowering effect was not observed with
ZENECA ZM181,037 in spontaneously hypertensive rats. ZENECA ZM181,037
demonstrated a K+ channel-blocker profile. In the isolated rat aorta
stimulated with 20 mmol/l KCl, both the d- and l-enantiomer of ZENECA
ZM181,037 antagonized the relaxation of cromakalim with mean pK(B) val
ues of 6.4 and 6.7, respectively. In the isolated guinea-pig portal ve
in and urinary detrusor muscle, both enantiomers enhanced the spontane
ous myogenic activity at concentrations of 1 mu mol/l and higher, in a
ddition to antagonizing the effect of cromakalim. ZENECA ZM181,037, si
milar to glibenclamide, prevented a significant increase in Rb-86(+) b
y cromakalim in both portal vein and detrusor muscle strips; however,
ZENECA ZM181,037, dissimilar to glibenclamide and tolbutamide, did not
increase plasma glucose when given orally to dogs. Thus, ZENECA ZM181
,037 is a blocker of the ATP-sensitive K+ channel (K-ATP) in vascular
and nonvascular tissues. In view of the profound saluresis produced by
ZENECA ZM181,037, the lack of antihypertensive effect appears to resu
lt from its blocking activity on K-ATP in vascular tissues.