K+ channel activators, acute glucose tolerance and glibenclamide-induced hypoglycaemia in the hypertensive rat.
The effects of the K+ channel activators, levcromakalim, pinacidil and diazoxide, at comparable antihypertensive doses, on acute glucose tolerance and glibenclamide-induced hypoglycaemia were examined in conscious spontaneously hypertensive rats (SHR). Levcromakalim (0.15 mg.kg-1 p.o.) and pinacidil (1.0 mg.kg-1 p.o.) caused a slight, but short-lived, impairment of glucose tolerance following oral or s.c. administration of glucose (2.0 g.kg-1). This effect, although small, was abolished by the beta-adrenoceptor blocker, propranolol (2.0 mg.kg-1 p.o.). Diazoxide (30.0 mg.kg-1 p.o.) caused a marked and sustained impairment of oral glucose tolerance and s.c. glucose tolerance, the profile of which was quantitatively and qualitatively different from levcromakalim or pinacidil and was not significantly affected by propranolol. Glibenclamide (1.0-10. mg.kg-1 p.o.) elicited a dose-related hypoglycaemic response. Levcromakalim or pinacidil had little or no significant effect on the hypoglycaemic response elicited by glibenclamide (3.0 mg.kg-1). Conversely, diazoxide both abolished and reversed glibenclamide-induced hypoglycaemia. We conclude that levcromakalim and pinacidil have only marginal and transient effects on glycaemic control in conscious SHR and that these disturbances are probably mediated indirectly via reflex activation of the sympathetic nervous system in response to blood pressure lowering. In addition, at active antihypertensive doses neither levcromakalim nor pinacidil significantly interfered with the ability of glibenclamide to reduce blood glucose concentration. Diazoxide's impairment of oral glucose tolerance, s.c. glucose tolerance and glibenclamide response confirms this drug's well known ability to activate pancreatic KATP channels.
Clapham
J C
JC
SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Trail
B K
BK
Hamilton
T C
TC
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D019806:Cromakalim; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005951:Glucose Tolerance Test; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy; D007003:Hypoglycemia / Q000139:chemically induced* / Q000378:metabolism; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR
D000959:Antihypertensive Agents; D001578:Benzopyrans; D001786:Blood Glucose; D006146:Guanidines; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D020110:Pinacidil; D003981:Diazoxide; D005905:Glyburide