Cardiovascular effects of the K-ATP channel blocker U-37883A and structurally related morpholinoguanidines.
The cardiovascular effects of the K-ATP channel blocker U-37883A and 5 related morpholinoguanidines were determined in 6 experimental preparations. In anesthetized dogs, U-37883A (0.5-8.0 mg/kg i.v.) increased mean arterial pressure (MAP; +18%) and left ventricular (LV) effective refractory period (ERP; +35%), and decreased LV contractility (-41%). Higher doses of U-37883A (16-32 mg/kg) fatally reduced MAP (-84%), heart rate (HR; -57%) and LV contractility (-72%). In anesthetized rats, U-37883A (1.0-50 mg/kg i.v.) also maximally reduced MAP, HR and LV contractility by 68, 77 and 48%, respectively. U-37883A and its analogs were diuretic in conscious rats (1.5-15 mg/kg i.v.) and blocked pinacidil in rabbit mesenteric artery (EC50 = 0.5-50 microM). In rabbit papillary muscle, 50 microM U-37883A significantly reduced force of contraction (-33%) and prolonged conduction time (+244%). Milder papillary effects were seen with the N'-OH analog U-45194A, which did not depress LV contractility in intact rats. In conscious dogs, oral U-45194A (50 mg/kg) was diuretic but reduced LV stroke volume and increased peripheral vascular resistance. These studies characterize U-37883A's systemic cardiovascular and direct myocardial effects, and identify U-45194A as a less cardiac depressant analog having U-37883A-like diuretic and functional K-ATP channel blocking activities.
Humphrey
S J
SJ
Cardiovascular Pharmacology, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan, USA.
Smith
M P
MP
Cimini
M G
MG
Buchanan
L V
LV
Gibson
J K
JK
Khan
S A
SA
Meisheri
K D
KD
D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000284:Administration, Oral; D000704:Analysis of Variance; D000827:Animal Welfare; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004232:Diuretics / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004594:Electrophysiology; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009025:Morpholines / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013318:Stroke Volume / Q000187:drug effects; D013329:Structure-Activity Relationship; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D004232:Diuretics; D006146:Guanidines; D009025:Morpholines; D015221:Potassium Channels; D014665:Vasodilator Agents; C082658:U 37883A; D020110:Pinacidil; D000255:Adenosine Triphosphate; D000218:Adamantane