CHARACTERIZATION OF ATP-SENSITIVE POTASSIUM CHANNEL-BLOCKING ACTIVITY OF ZENECA ZM181,037, A EUKALEMIC DIURETIC

ZENECA ZM181,037 is a novel eukalemic diuretic from a series of 1,1-diarylcarbin-1-01-2 amines. In contrast to the standard diuretic hydrochlorothiazide, 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) values of 6.4 and 6.7, respectively. In the isolated guinea-pig portal vein and urinary detrusor muscle, both enantiomers enhanced the spontaneous myogenic activity at concentrations of 1 mu mol/l and higher, in addition to antagonizing the effect of cromakalim. ZENECA ZM181,037, similar to glibenclamide, prevented a significant increase in Rb-86(+) by 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 result from its blocking activity on K-ATP in vascular tissues.