Prospective role of α2A/2B/2C-adrenoceptor subtypes in the modulation of cardioaccelerator sympathetic tone in an experimental model of diabetes

Abstract

Abnormalities in the cardiac sympathetic innervation and tone, as well as in the noradrenergic system are associated, among other peripheral complications, with diabetes mellitus. Furthermore, B-HT 933, an agonist at α2-adrenoceptors, induces a greater cardiac sympathetic inhibition in diabetic rats than in normoglycaemic rats. Accordingly, this pharmacological study analysed the specific involvement of the α2A/2B/2C adrenoceptor subtypes mediating inhibition of the cardioaccelerator sympathetic tone (i.e. cardiac sympathetic inhibition) in an experimental model of diabetes induced by streptozotocin (STZ). Fifty male Wistar rats were consecutively: injected i.p. with STZ to cause diabetes; pithed after four weeks; and primed for electrical preganglionic stimulation (spinal C7-T1 segment) to selectively produce increases in heart rate. These responses were evaluated after i.v. bolus injections of relatively selective α2A-, α2B- and α2C-adrenoceptor antagonists (or vehicles) during an i.v. continuous infusion of B-HT 933 or vehicle. B-HT 933 produced a significant inhibition of the sympathetic tachycardic responses, which was: (i) unaffected after the vehicles saline or dimethyl sulfoxide (DMSO); (ii) partially attenuated after blocking doses of the antagonists BRL44408 (α2A) or JP-1302 (α2C); and (iii) abolished after blocking doses of the antagonist imiloxan (α2B). These findings in diabetic pithed rats indicate that the modulation of the cardioaccelerator sympathetic tone predominantly involves the α2B-adrenoceptor subtype and, to a lesser degree, the α2A- and α2C-adrenoceptor subtypes. Hence, blockade of the sympatho-inhibitory α2B-adrenoceptor subtype (absent in normoglycaemic rats) could denote a novel pharmacological strategy for the therapy of some cardiac disorders during the early stages of diabetes.