Development of tolerance to alpha-2 adrenergic agonists in the vascular system of the rat after chronic treatment with clonidine.

The possibility of development of tolerance after chronic treatment with clonidine (CLN) was investigated in the vascular system of the rat. Rats were treated with CLN for 3 to 10 days by dissolving the drug in the drinking water at concentrations of 0.1 to 10 micrograms/ml. Pressor responses to several vasoconstrictors were examined after pithing. Rats given CLN-containing water at a concentration of 10 micrograms/ml were considered as receiving CLN at about 1 mg/kg/day and were found to be subsensitive to l-norepinephrine. Decrease in the sensitivity varied with the length of CLN treatment and the maximum decrease was attained within 5 days of the treatment. Recovery from the subsensitivity required a long deprivation time of CLN; after 10 days of treatment, 14 days of deprivation did not cause any recovery in the sensitivity. The subsensitivity also was observed in the alpha-2 adrenergic agonists, CLN and azepexole, whereas it was not detected in alpha-1 adrenergic agents, phenylephrine and methoxamine, and the nonadrenergic vasoconstrictors, angiotensin-II and Lys-vasopressin. Pressor responses to stimulation of the complete sympathetic outflow also decreased in the CLN-treated rats. These results show clearly that chronic treatment with CLN makes rat vasculature subsensitive to l-norepinephrine and suggest that this phenomenon involves specific desensitization developed in the contractile mechanisms of vascular smooth muscles mediated by alpha-2 adrenergic receptors.