Adenosine A1-receptor knockout mice have a decreased blood pressure response to low-dose ANG II infusion

Abstract

Adenosine, acting on A1-receptors (A1-AR) in the nephron, increases sodium reabsorption, and also increases renal vascular resistance (RVR), via A1-ARs in the afferent arteriole. ANG II increases blood pressure and RVR, and it stimulates adenosine release in the kidney. We tested the hypothesis that ANG II-infused hypertension is potentiated by A1-ARs' influence on Na+reabsorption. Mean arterial pressure (MAP) was measured by radiotelemetry in A1-AR knockout mice (KO) and their wild-type (WT) controls, before and during ANG II (400 ng·kg−1·min−1) infusion. Baseline MAP was not different between groups. ANG II increased MAP in both groups, but on day 12, MAP was lower in A1-AR KO mice (KO: 128 ± 3 vs. 139 ± 3 mmHg, P < 0.01). Heart rates were significantly different during days 11–14 of ANG II. Basal sodium excretion was not different (KO: 0.15 ± 0.03 vs. WT: 0.13 ± 0.04 mmol/day, not significant) but was higher in KO mice 12 days after ANG II despite a lower MAP (KO: 0.22 ± 0.03 vs. WT: 0.11 ± 0.02 mmol/day, P < 0.05). Phosphate excretion was also higher in A1-AR KO mice on day 12. Renal expression of the sodium-dependent phosphate transporter and the Na+/glucose cotransporter were lower in the KO mice during ANG II treatment, but the expression of the sodium hydrogen exchanger isoform 3 was not different. These results indicate that the increase in blood pressure seen in A1-AR KO mice is lower than that seen in WT mice but was increased by ANG II nonetheless. The presence of A1-ARs during a low dose of ANG II-infusion limits Na+and phosphate excretion. This study suggests that A1-AR antagonists might be an effective antihypertensive agent during ANG II and volume-dependent hypertension.