Potentiation of the diabetogenic effect of streptozocin by phentolamine in the rat.

The effect of alpha- and beta-adrenoceptor blocking agents and a beta2-agonist, salbutamol, on the diabetogenic effects of streptozocin (threshold doses) was investigated in the rat. Phentolamine and salbutamol potentiated the diabetogenic effect of streptozocin but phenoxybenzamine, tolazoline, oxprenolol and propranolol were without effect. The potentiating effect of phentolamine was blocked by oxprenolol. Potentiation of the diabetogenic effect by phentolamine is not related to alpha-adrenoceptor block, vasodilatation or insulin release. But it may be related to its ability to stimulate beta-adrenoceptors.

Participation of adrenal medulla in 6-amino-nicotinamide-induced hyperglycaemia in the rat.

In fasted rats 6-aminonicotinamide (6-AN) produced delayed hyperglycaemia, the peak effect being seen by 7 h. Fasting plasma insulin concentrations were not significantly altered but liver glycogen concentrations were decreased following treatment with 6-AN. Adrenalectomy, demedullation and pretreatment with reserpine, phentolamine, nicotinamide and nicotinic acid completely blocked the hyperglycaemic response whereas guanethidine and propranolol or oxprenolol were ineffective. Catecholamine concentrations in the adrenal venous plasma were markedly increased by treatment with 6-AN, the peak effect being seen by 5 h. It is concluded that adrenal medullary release, which is slow in onset, is mainly responsible for the development of sustained hyperglycaemia in the rat.

Hyperglycemic, antihypertensive and antidiuretic properties of Go. 8288 and its comparison with diazoxide.

Hyperglycemic, antihypertensive and antidiuretic activities of Go.8288 and diazoxide were evaluated in the rat. Go.8288 and diazoxide induced hyperglycemia which was blocked by adrenalectomy and demedullation. Pretreatmnet with hydrocortisone completely restored the hyperglycemic effect of diazoxide but only partially that of Go.8288. The hyperglycemic effect of Go.8288 and diazoxide was antagonized by glibenclamide, whereas tolbutamide antagonized only diazoxide-induced hyperglycemia. Pretreatment with oxprenolol antagonized diazoxide-induced hyperglycemia but not that of Go.8288. Guanethidine antagonized the hyperglycemic effect of Go.8288 but not that of diazoxide. Go.8288 and diazoxide markedly inhibited insulin secretion in vivo. Unlike Go.8288, diazoxide further accentuated the hyperglycemic effect in the streptozotocin diabetic rat. Diazoxide significantly increased plasma FFA and plasma renin activity but Go.8288 had no effect. In the normotensive cats and dogs and renal hypertensive rats both compounds lowered arterial blood pressure. Unlike diazoxide, Go.8288 was active orally in normotensive dogs. Similar to diazoxide Go.8288 showed an antidiuretic effect in the rat. It is therefore concluded that despite some similarities, Go.8288 shows important differences in its biological profile from that of diazoxide.

Effects of glucose and some oral hypoglycemic agents upon the plasma glucose and immuno-reactive insulin (IRI) in normal and streptozotocin induced diabetic rat.

An investigation has been made to see the effect of oral hypoglycemic agants on the blood sugar (BS) and plasma Immuno-Reactive Insulin (IRI) in normal and streptozotocin diabetic rats. Plasma IRI was significantly reduced in a streptozotocin treated diabetic rat 8 weeks after streptozotocin injection. In normal rats oral administration of Sodium tolbutamide (TOL) and Glybenclamide (GLI) produced a significant fall in BS and a concurrent increase in plasma IRI, but phenformin (PHE) was without any effect on both these parameters. Unlike normal rats streptozotocin treated diabetic rats did not show lowering of BS and increase in plasma IRI following TOL and GLI. PHE, however, did produce a significant fall in BS. Oral glucose load did show a typical glucose tolerance curve and insulin release in normal rats. However, in the diabetic rats there was no significant increase in plasma IRI following glucose load. It is therefore concluded that streptozotocin treated diabetic rats differ from the maturity onset diabetic as regards the responses of TOL and GLI are concerned and this animal model can therefore be useful in differentiating the two types of oral hypoglycemic agents.

Synthesis and oral hypoglycemic properties of two 4-oxo-4,5,6,7-tetrahydroindole-3-acetic acids.

Condensation of beta-acetyl-2-hydroxy-4,4-dimethyl-6-oxo-1-cyclohexene-1-propionic acid (3) with n-butyl and isobutylamines affords the title acids 4 and 5, respectively, which show good oral hypoglycemic activity in normal rats. Acids 4 and 5, are also active in streptozocin-induced diabetic rats. Results of extensive pharmacological and acute toxicity tests are reported.