Disruption of Subtype 2 Dopamine Receptor (D2-R) Causes Hypotension Independently of Its Action on Sympatetic Nerve System
D2-R, known to be involved in the pre-synaptic sympathetic inhibition, is also postulated to be present in the cardiovascular system and to modulate blood pressure via local dopaminergic system. In the present study, we investigated the localization of D2-R and the effects of the targeted disruption of both D2-long and D2 -short receptor genes on sympathetic activity and blood pressure. The male homozygous littermates at ages of 6-16 week (KO mice) and the age-matched wild type (WT) control mice were used. We assessed systemic sympathetic activity by 24-h urine norepinephrine (NE) excretion and local sympathetic activity by tissue content of NE in the heart and kidney. RT-PCR revealed that the D2-R mRNA was expressed in the heart, the aorta and the kidney as well as in the brain only in WT mice. Urinary NE excretion (KO vs. WT: 8.67± 1.71 vs. 7.78± 0.64 micro-g/day)was not different between KO and WT mice. Renal (KO vs. WT: 390±42 vs.535±155 pg/mg protein,p<0.05)but not cardiac (718±75 vs.697± 193pg/mg protein) content of NE was significantly decreased in KO than in WT mice, reflecting the depletion of stored NE in the renal sympathetic neurons. Conscious systolic tail-cuff blood pressure (KO vs. WT: 102±3.3 vs. 106.6±5.1 mmHg at 16 week, n= 10, p<0.001) and direct mean arterial blood pressure under anesthesia(86±13 vs. 101.4±10, n=5, p<0.05) were significantly lower in KO mice than in WT mice. Heart rate (563±31 vs.549±41), food and water consumption, and 24-hour urine sodium excretion (368±44 vs.359±36 microEq/day)were not different between the KO and WT mice. These results indicate that (1) D2-R is expressed in the cardiovascular system, (2) D2-R in the kidney is involved in the renal sympathetic control, but (3) disruption of D2-R causes hypotension independently of its effects on sympathetic activity.