The Effect of EGF Inhibition on Diurnal Variation of Blood Pressure in Mice

There are 78 million adults in the United States, who have hypertension also known as the “silent killer” because most individuals are unaware of their diagnosis. High blood pressure (BP) is a serious medical condition that serves as risk factor for cardiovascular disease (CVD), diabetes, and chronic kidney disease (CKD). Blood pressure normally declines about 10% during sleep. This nocturnal decline in blood pressure is called “dipping”. Studies have demonstrated that an attenuated decline in nocturnal blood pressure (“non‐dipping”) is associated with increased cardiovascular risks. Investigations by our group and others have demonstrated an effect of the epidermal growth factor (EGF) on sodium transport proteins and blood pressure. However, an association between EGF and “dipping” has not been described. We hypothesized that the inhibition of EGF will attenuate the sleep time (daytime for mice) decline of BP in mice. Using radio‐telemetry, in five male mice ages 6–7 weeks old, we collected the systolic blood pressure (SBP) measurements over 24‐hours daily for two weeks. These animals received a low Na+ diet (0.4% Na chow) for 6 days and high Na+ diet (4% Na chow) for 8 days. Only the experimental (E) group (n=3) received gefitinib (an EGF receptor tyrosine kinase inhibitor) at a regimen of 100 mg/kg/d given orally while the control (C) group (n=2) received a placebo. The change in SBP for sleep (9am–9pm) versus awake (9pm–9am), while receiving low salt diet (0.4% Na chow), showed the experimental group had less of a decrease in their SBP compared to the control group (E group: −9.7 ± 0.016 vs. C group: −14.4 ± 0.34 mmHg, p<0.001). The change (delta, Δ) in SBP was 4.7 mmHg, p<0.001 where the control group had a greater decrease in their SBP. When increasing the dietary Na+ intake by giving the high salt diet (4% Na+ chow), once again the experimental group demonstrated an attenuation of their ability to lower their SBP during sleep time compared to the control group (E group: −7.3 ± 0.18 vs. C group: −13.5 ± 0.38 mmHg, p<0.001). Here the Δ is 6.1 mmHg, p<0.001, which shows that the control group maintained a greater decrease in their resting SBP compared to the experimental group. Overall, our results suggest that inhibition of EGF leads to decreased dipping in SBP regardless of the dietary Na+ intake. This effect is greater with high Na+ in the diet. Our data is the first to suggest that EGF may play a role in the nocturnal dipping of blood pressure. This could have potential implications for hypertension‐related cardiovascular disease. Support or Funding Information NIH T32:5T32DK007656‐28 (King‐Medina) and VA Merit Awards: I01BX002322‐01 (Hoover)