Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice

Abstract

Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and by interacting with vasoactive hormones/humoral factors, such as aldosterone, angiotensin, catecholamines, endothelin, oxytocin, prolactin pro-opiomelancortin, reactive oxygen species, renin, and vasopressin. Dopamine receptors are classified into D(1)-like (D(1) and D(5)) and D(2)-like (D(2), D(3), and D(4)) subtypes based on their structure and pharmacology. In recent years, mice deficient in one or more of the five dopamine receptor subtypes have been generated, leading to a better understanding of the physiological role of each of the dopamine receptor subtypes. This review summarizes the results from studies of various dopamine receptor mutant mice on the role of individual dopamine receptor subtypes and their interactions with other G protein-coupled receptors in the regulation of blood pressure.

Fig. 1

D₂ and D₅ receptors affect blood pressure by inhibition of the central sympathetic nervous system. D₅ receptors are present in the prefrontal cortex, which projects to several brain areas involved with cardiovascular regulation, including the lateral hypothalamic area and ventrolateral medulla. D₅ and D₂ receptors affect blood pressure by decreasing the central sympathetic nervous system, although the detailed mechanisms remain to be determined. The dotted lines indicate inhibitory effects, whereas the solid lines indicate stimulatory effects.

Fig. 2

Dopamine receptors and cardiovascular function. Each of the dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms specific for the subtype. The major dopamine receptor that regulates blood pressure may be the D₁ receptor, which synergies with the D₃ receptor to regulate sodium transport in the Kidney and intestines directly or indirectly by the inhibitory effect of D₁ and D₃ receptors on angiotensin II (ANG II) type 1 (AT₁) receptor expression and/or interactions during conditions of modest sodium excess. D₄ receptors help in this process. Furthermore, D₃ receptors can inhibit renin secretion; D₂ receptors aid in the excretion of sodium by decreasing aldosterone secretion and by inhibiting the vasconstrictor effect of endothelin type B (ET_B) receptors. D₂ and D₅ receptors negatively regulate the sympathetic nervous system. UNaV, urinary excretion of sodium.