The thermogenic actions of alpha 2-adrenoceptor agonists in reserpinized mice are mediated via a central postsynaptic alpha 2-adrenoceptor mechanism.
1. The dose-related effects of the selective alpha 2-adrenoceptor agonists clonidine, UK-14,304 and B-HT 933 on the body temperature of untreated and reserpine-treated mice were investigated. 2. In untreated mice all three agonists induced a dose-related hypothermia. The highest doses of UK-14,304 and B-HT 933, 3 and 100 mg kg-1 respectively, elicited a marked (10 degrees C) hypothermia, whereas the maximal hypothermic effect of clonidine (5.5 degrees C) was less pronounced and reached a plateau at a dose of 0.5 mg kg-1 i.p. 3. Reserpine (2.5 mg kg-1, s.c.) induced a marked hypothermia in the mouse; 18 h after injection body temperature had decreased to only slightly (0.5-1.5 degrees C) above ambient (19 degrees C). 4. All three alpha 2-agonists produced a partial dose-related reversal of reserpine-induced hypothermia; maximal thermogenic responses (9-10 degrees C increases in body temperature) were elicited by doses of 0.2, 0.5 and 16 mg kg-1 i.p. of clonidine, UK-14,304 and B-HT 933 respectively, and the log dose-response curves for all 3 agonists were bell-shaped. 5. Following intracerebroventricular administration to reserpine-treated mice, the thermogenic response to clonidine was more rapid in onset, and the agonist was 20 fold more potent than when injected i.p. 6. The selective alpha 2-adrenoceptor antagonists, idazoxan (0.05-0.5 mg kg-1), Wy 26392 (0.3-5.0 mg kg-1) and yohimbine (0.1-1.6 mg kg-1) given orally attenuated the thermogenic responses to all 3 agonists in reserpinized mice in a dose-related manner. Pretreatment with a single dose of idazoxan (0.3 mg kg-1, orally) elicited a 6 fold parallel shift to the right in the dose-response curve to clonidine. 7. The selective alpha 1-adrenoceptor antagonists, prazosin (10 mg kg-1) and indoramin (3-10 mg kg-1), and the beta-adrenoceptor antagonist, propranolol (10 mg kg-1), only partially attenuated the thermogenic responses to the alpha 2-agonists in reserpinized mice. These effects were variable and not clearly dose-related. 8. Pretreatment of reserpinized mice with the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine, markedly attenuated (60-95%) the thermogenic response to the noradrenaline uptake inhibitor, desipramine (0.13-12.5 mg kg-1, i.p.), but only slightly reduced (10-35%) that to clonidine (0.032-0.5 mg kg-1, i.p.). 9. These results suggest that alpha2-adrenoceptor agonists reverse reserpine-induced hypothermia via a central mechanism involving activation of postsynaptic alpha 2-adrenoceptors.
Bill
D J
DJ
Wyeth Research (UK) Limited, Maidenhead, Berks.
Hughes
I E
IE
Stephens
R J
RJ
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001679:Biogenic Amines / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects*; D002395:Catecholamines / Q000096:biosynthesis; D005260:Female; D007276:Injections, Intraventricular; D008781:Methyltyrosines / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D012110:Reserpine / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D019805:alpha-Methyltyrosine
D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D001679:Biogenic Amines; D002395:Catecholamines; D008781:Methyltyrosines; D011942:Receptors, Adrenergic, alpha; D019805:alpha-Methyltyrosine; D012110:Reserpine; D014446:Tyrosine 3-Monooxygenase