title: Development of tolerance to alpha-2 adrenergic agonists in the vascular system of the rat after chronic treatment with clonidine.
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.
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology*; D003655:Decerebrate State; D004361:Drug Tolerance; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013564:Sympathetic Nervous System / Q000502:physiology
chemical_list: D000316:Adrenergic alpha-Agonists; D003000:Clonidine; D009638:Norepinephrine