Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice

Abstract

Abnormalities of the DR gene (DRD2) play a role in the pathogenesis of human essential hypertension; variants of the DRD2 have been reported to be associated with hypertension. Disruption of Drd2 (D) in mice increases blood pressure. The hypertension of D mice has been related, in part, to increased sympathetic activity, renal oxidative stress, and renal endothelin B receptor (ETBR) expression. We tested in D mice the effect of etamicastat, a reversible peripheral inhibitor of dopamine-β-hydroxylase that reduces the biosynthesis of norepinephrine from dopamine and decreases sympathetic nerve activity. Blood pressure was measured in anesthetized D mice treated with etamicastat by gavage, (10 mg/kg), conscious D mice, and D littermates, and mice with the DR selectively silenced in the kidney, treated with etamicastat in the drinking water (10 mg/kg per day). Tissue and urinary catecholamines and renal expression of selected G protein-coupled receptors, enzymes related to the production of reactive oxygen species, and sodium transporters were also measured. Etamicastat decreased blood pressure both in anesthetized and conscious D mice and mice with renal-selective silencing of DR to levels similar or close to those measured in D littermates. Etamicastat decreased cardiac and renal norepinephrine and increased cardiac and urinary dopamine levels in D mice. It also normalized the increased renal protein expressions of ETBR, NADPH oxidase isoenzymes, and urinary 8-isoprostane, as well as renal NHE3 and NCC, and increased the renal expression of DR but not DR in D mice. In conclusion, etamicastat is effective in normalizing the increased blood pressure and some of the abnormal renal biochemical alterations of D mice.

Dopamine Receptors and the Kidney: An Overview of Health- and Pharmacological-Targeted Implications

“…Stimulation of the D3 receptor increases the expression of the ETBR protein in the renal proximal tubules. D2 receptors also interfere in the expression of the ETBR, with consequent regulation of blood pressure as a function of expression levels [ 111 ]. Other known interactions of dopamine receptors are with insulin and its receptors [ 112 ] and cholecystokinin receptors [ 113 ].…”

The Role of the Renal Dopaminergic System and Oxidative Stress in the Pathogenesis of Hypertension

“…The D 2 R-short is presumed to be an autoreceptor (presynaptic) while the D 2 R-long is postsynaptic [ 197 ]. The D 2 R controls the renal synthesis of dopamine [ 198 , 199 ], presumably by the D 2 R-long, which is the isoform expressed in the kidney [ 200 ].…”

“…In the rat renal proximal convoluted tubule, the dopamine-mediated inhibition of Na + /K + -ATPase activity is markedly attenuated [ 205 ] in the presence of D 1 -like receptor (SCH23390) [ 206 ] or D 2 R and D 3 R antagonist (S-sulpiride) [ 207 ]. The D 2 R probably negatively regulates NHE3 and NCC expressions because their renal expressions are increased in Drd2 −/− mice [ 199 ]. Between the WKY rat and SHR, there are no noticeable differences in the expression and allocation of renal D 2 R other than that D 2 R is expressed in the glomeruli of WKY but not SHR [ 208 ].…”

“…Drd2 siRNA-renal-selective deletion of Drd2 also increases blood pressure but salt sensitivity was not tested [ 147 , 193 ]. As with the D 1 R, the D 2 R regulates ROS production by inhibiting pro-oxidant systems and enabling antioxidant systems [ 199 , 209 , 210 ] ( Figure 3 ).…”

“…One of the mechanisms that allows D 2 R to regulate blood pressure is by decreasing oxidative stress in the kidney; germline deletion of Drd2 in mice increases the renal activity of NADPH oxidase and expressions of NOX1, NOX2, and NOX4 and urinary excretion of isoprostane, a product of the non-enzymatic oxidation of arachidonic acid, and decreases the renal expression of the antioxidant enzymes, heme oxygenase 2 (HO-2), paraoxonase 2 (PON2), and sestrin2 but not heme oxygenase-1 (HO-1) [ 81 , 82 , 83 , 199 , 209 , 210 , 211 , 212 ]. Apocynin, a reduced NADPH oxidase inhibitor, or hemin, an inducer of HO-1, normalized the blood pressure of Drd2 −/− mice [ 210 ].…”