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 pKB 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 mumol/l and higher, in addition to antagonizing the effect of cromakalim. ZENECA ZM 181,037, similar to glibenclamide, prevented a significant increase in 86Rb+ 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 (KATP) 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 KATP in vascular tissues.
Department of Pharmacology, ZENECA Inc., Wilmington, Del 19897.
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D000081:Acetamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D019806:Cromakalim; D004232:Diuretics / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology; D006168:Guinea Pigs; D006973:Hypertension / Q000188:drug therapy; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D026902:Potassium Channel Blockers; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014044:Tolbutamide / Q000008:administration & dosage / Q000494:pharmacology
D000081:Acetamides; D001578:Benzopyrans; D001786:Blood Glucose; D004232:Diuretics; D026902:Potassium Channel Blockers; D011758:Pyrroles; D019806:Cromakalim; C074456:ICI 181037; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D005905:Glyburide