Changed sensitivity of alpha 2-adrenoceptors mediating a decrease in protein kinase inhibitor activity in the brain...

Clonidine produced an increase of cGMP content and a decrease of the endogenous type II inhibitor of protein kinase in rat hypothalamic slices. When administered to rats, the effect of clonidine on type II inhibitor activity in the hypothalamus and brain-stem depended on the dose. Low doses (10-50 micrograms X kg-1 i.p.) produced an increase, probably by stimulating presynaptic alpha 2-adrenoceptors, whereas large doses (200-1000 micrograms X kg-1 i.p.) produced a decrease of type II inhibitor activity by stimulating postsynaptic receptors. The development of vasopressin hypertension was associated with a gradual reduction of the response of the type II inhibitor to low and high doses of clonidine. In vasopressin-hypertensive rats neither small nor large doses of clonidine were able to induce changes in type II inhibitor activity suggesting subsensitivity of pre- and postsynaptic alpha 2-adrenoceptors. However, clonidine appeared to be equally effective in blocking electrically stimulated [3H]noradrenaline release from hypothalamic slices of vasopressin-hypertensive and control, normotensive rats. Reduced reactivity of postsynaptic alpha 2-adrenoceptors seems to be of great importance since treatment of vasopressin-hypertensive rats with 6-hydroxydopamine resulted in a decrease of blood pressure and reappearance of the sensitivity of postsynaptic alpha 2-adrenoceptors to clonidine.