Functional and autoradiographic characterization of dopamine D2-like receptors in the guinea pig heart

Abstract

Dopamine receptors include the D1- (D1and D5subtypes) and D2-like (D2, D3, and D4subtypes) families. D1-like receptors are positively and D2-like receptors negatively coupled to the adenylyl cyclase. Dopamine D2-like (D4subtype) receptors have been identified in human and rat hearts. However the presence of D2and D3receptor subtypes is unclear. Furthermore, their role in cardiac functions is unknown. By autoradiographic studies of guinea pig hearts, we identified D3and D4receptors, using the selective radioligands [3H]-7-OH-DPAT and [3H]emonapride (YM-09151-2 plus raclopride). Western blot analysis confirmed D3and D4receptors in the right and left ventricle of the same species. Selective agonists of D3and D4receptors (±)-7-OH-DPAT and PD 168 077 (10–9to 10–5M, respectively) induced a significant negative chronotropic and inotropic effect in the isolated guinea pig heart preparation. Negative inotropic effect induced by PD 168 077 was associated with an inhibition in cyclase activity. No changes in cyclase activity were found with (±)-7-OH-DPAT. The aim of this study is to support the presence of D3and D4receptors in the heart. Although our results suggest that D3and D4receptors are functionally active in the heart, we need additional information with an antagonist and an agonist of improved potency and selectivity to understand the respective roles of D3and D4receptors in the cardiac functions.Key words: Dopamine receptors (D2, D3, D4subtypes), autoradiography, Western blot, cAMP, heart.