Abstract
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.
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