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 D1and D3receptors 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 D3receptor protein in a time-dependent and concentration-dependent manner (EC50=4.5×10−9M, t1/2=15.8 hours). In SHRs, fenoldopam (10−5M) actually decreased the expression of D3receptors. D1and D3receptor co-immunoprecipitation was increased by fenoldopam (10−7M/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 D1and D3receptor 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 D1and D3receptors led to additive vasorelaxation in WKY rats, but not in SHRs. D1and D3receptors interact differently in WKY and SHRs. Altered interactions between D1and D3receptors may play a role in the pathogenesis of genetic hypertension, including human hypertension, because these receptors also interact in human vascular smooth muscle cells.