Effects of the K+ channel activators, RP 52891, cromakalim and diazoxide, on the plasma insulin level, plasma renin activity and blood pressure in rats.
In normo- or hyperglycemic (i.v. infusion of 50 mg/kg/min glucose over 30 min) pithed rats, diazoxide (1 mg/kg/min i.v. over 20 min) significantly reduced plasma insulin content. By contrast, cromakalim, nicorandil or RP 52891 even at doses 40-fold higher than those producing the same hypotensive effect as diazoxide in intact anesthetized normotensive rats, failed to change insulin plasma levels. Glibenclamide (0.01-0.3 mg/kg i.v.) pretreatment antagonized dose-dependently the hypoinsulinemic activity of diazoxide with an i.v. ED50 value of 49 +/- 1 microgram/kg. In pithed rats, diazoxide increased markedly plasma renin activity. This effect was almost inhibited completely by 20 mg/kg i.v., but not at all by a 1-mg/kg i.v. dose of glibenclamide. In pentobarbital-anesthetized rats, diazoxide (0.5-2 mg/kg/min i.v. over 20 min) produced decreases in mean carotid artery blood pressure which were antagonized dose-dependently by glibenclamide (5-20 mg/kg i.v.). This sulfonylurea (20 mg/kg i.v.) also prevented the hypotensive effects of several i.v. administered K+ channel activators (cromakalim, RP 52891 and nicorandil) but not those of numerous hypotensive agents such as acetylcholine, adenosine, bradykinin, clonidine, histamine, salbutamol, dihydralazine, papaverine, platelet aggregating factor, nitroglycerin, nitroprusside, nitrendipine and diltiazem. Although glibenclamide lowered plasma glucose levels, its blocking activity vis-à-vis the hypotension evoked by cromakalim was not affected when its hypoglycemic effects were reversed with an i.v. injection of glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
Pratz
J
J
Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
Mondot
S
S
Montier
F
F
Cavero
I
I
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D019806:Cromakalim; D003981:Diazoxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010847:Picolines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011714:Pyrans / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D012083:Renin / Q000097:blood*
D000959:Antihypertensive Agents; D001578:Benzopyrans; D001786:Blood Glucose; D007328:Insulin; D010847:Picolines; D015221:Potassium Channels; D011714:Pyrans; D011758:Pyrroles; D019806:Cromakalim; C061043:aprikalim; D012083:Renin; D005947:Glucose; D003981:Diazoxide; D005905:Glyburide