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Alpha2 -adrenoceptor function in arterial hypertension associated with obesity in dogs fed a high-fat diet
Michel Pelat1, Patrick Verwaerde, Marie-Antoinette Tran
1Laboratoire de Pharmacologie Médicale et Clinique, INSERM U317, Faculté de Médecine, 37 allées Jules Guesde, 31073 Toulouse cedex, France.
Objective:
To investigate the status of alpha2-adrenoceptors in a model of obesity-related arterial hypertension.
Design:
A parallel study in dogs randomly assigned to a high-fat diet (HFD group, n = 6) or normal canine food (controls, n = 6) for 9 weeks.
Methods:
Postsynaptic vascular alpha2-adrenoceptors were assessed through analysis of dose-pressor responses to clonidine [2.5, 5.0 and 15.0 microg/kg intravenously (i.v.)] after muscarinic, beta- and alpha1-adrenergic receptor blockade. Presynaptic and central alpha2-adrenoceptors were studied through measurement of changes in plasma concentrations of catecholamine induced by yohimbine (0.05 mg/kg i.v.). The number of platelet alpha2-adrenoceptors (expressed as fmol/mg protein) and the percentage in a state of high affinity were measured using [3H]RX821002.
Results:
Clonidine, when administered to dogs that were under autonomic blockade, elicited a dose-dependent increase in blood pressure. The doses of clonidine required to induce a 50% maximum increase in systolic and diastolic blood pressures remained unchanged after 9 weeks of a high-fat diet (systolic: 6.0 +/- 0.3 microg/kg at baseline and 5.6 +/- 0.2 microg/kg after 9 weeks; diastolic: 4.2 +/- 0.2 microg/kg at baseline and 3.9 +/- 0.2 microg/kg after 9 weeks). After 9 weeks of the regimen, plasma concentrations of noradrenaline were significantly greater in the HFD group than in controls (337 +/- 22 pg/ml compared with 212 +/- 37 pg/ml). The increment in plasma concentrations of noradrenaline elicited by yohimbine after 9 weeks was smaller in the HFD group than in controls (93 +/- 44% compared with 181 +/- 46%; P = 0.024). In the HFD group, the number of platelet alpha2-adrenoceptors and the percentage that were in a state of high affinity were significantly lower after 9 weeks, compared with baseline (number: 239 +/- 21 fmol/mg protein at baseline and 95 +/- 7 fmol/mg protein after 9 weeks; high-affinity: 30 +/- 3% at baseline and 21 +/- 4% after 9 weeks; P < 0.05).
Conclusions:
These results suggest that presynaptic or central alpha2-adrenoceptor function, or both, is specifically impaired after 9 weeks of a high-fat diet. These modifications may account for the development of arterial hypertension in this model.