Aberrant D1 and D3 Dopamine Receptor Transregulation in Hypertension

ABSTRACT—Dopamine plays a role in the regulation of blood pressure by inhibition of sodium transport in renal proximal tubules (RPTs) and relaxation of vascular smooth muscles. Because dopamine receptors can regulate and interact with each other, we studied the interaction of D1 and D3 receptors in immortalized RPT cells and mesenteric arteries from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs), and in human coronary artery smooth muscle cells (CASMCs). In WKY rats, the D1-like agonist, fenoldopam, increased D3 receptor protein in a time-dependent and concentration-dependent manner (EC50=4.5×10 M, t1/2=15.8 hours). In SHRs, fenoldopam (10 M) actually decreased the expression of D3 receptors. D1 and D3 receptor co-immunoprecipitation was increased by fenoldopam (10 M/24 h) in WKY rats but not in SHRs. The effects of fenoldopam in CASMCs were similar as those in WKY RPT cells (ie, fenoldopam increased D1 and D3 receptor proteins). Both D3 (PD128907, Emax=80%±6%, pED50=5±0.1) and D1-like receptor (fenoldopam, Emax=81%±8%, pED50=5±0.2, n=12) agonists relaxed mesenteric arterial rings. Co-stimulation of D1 and D3 receptors led to additive vasorelaxation in WKY rats, but not in SHRs. D1 and D3 receptors interact differently in WKY and SHRs. Altered interactions between D1 and D3 receptors may play a role in the pathogenesis of genetic hypertension, including human hypertension, because these receptors also interact in human vascular smooth muscle cells.