Differential cardiac sympatho-inhibitory responses produced by the agonists B-HT 933, quinpirole and immepip in normoglycaemic and diabetic pithed rats

Abstract

This study compared the cardiac sympatho-inhibitory responses produced by agonists at α₂ -adrenergic (B-HT 933), dopamine D₂ -like (quinpirole) and histamine H₃ /H₄ (immepip) receptors between normoglycaemic and streptozotocin-pretreated (diabetic) pithed rats. Intravenous (i.v.) continuous infusions of B-HT 933, quinpirole or immepip were used in normoglycaemic and diabetic pithed rats to analyse their sympatho-inhibitory effects on the electrically-stimulated cardioaccelerator sympathetic outflow. Both in normoglycaemic and diabetic animals, B-HT 933 (until 100 μg/kg per minute) and quinpirole (until 10 μg/kg per minute) inhibited the tachycardic responses to electrical sympathetic stimulation, but not those to i.v. bolus of exogenous noradrenaline. These sympatho-inhibitory responses were more pronounced in diabetic than in normoglycaemic animals. Accordingly, the areas under the curve for 100 μg/kg per minute B-HT 933 and 10 μg/kg per minute quinpirole in diabetic rats (1065 ± 70 and 920 ± 35, respectively) were significantly smaller (P < .05) than those in normoglycaemic rats (1220 ± 45 and 1360 ± 42, respectively). In contrast, immepip infusions produced cardiac sympatho-inhibition in normoglycaemic (until 10 μg/kg per minute), but not in diabetic (until 100 μg/kg per minute) animals. Our results suggest that in diabetic pithed rats: (i) the more pronounced cardiac sympatho-inhibition to B-HT 933 and quinpirole may be probably due to up-regulation of α₂ -adrenergic and dopamine D₂ -like receptors, respectively; (ii) the histamine H₃ /H₄ receptors do not seem to play a sympatho-inhibitory role; and (iii) there is a differential participation of α₂ -adrenergic and dopamine D₂ -like receptors, which may certainly represent therapeutic targets for the treatment of diabetic complications such as cardiovascular autonomic neuropathy.

Keywords: D2-like receptors; Gi/o-protein coupled receptors; H3/H4 receptors; cardioaccelerator sympathetic outflow; diabetes; sympatho-inhibition; α2-Adrenoceptors.