Abstract P063: Pressor Response To Acute Stress Is Regulated By Histamine In Humanized Sickle Cell Mice

Abstract

Acute psychosocial stress has been linked to the onset of vaso-occlusive pain crises in patients with sickle cell disease (SCD), however mechanistic insight is lacking. Studies suggest that histamine is a stress-responsive factor and promotes inflammation. In SCD, histamine levels are elevated in association with vaso-occulsive crisis, however, the impact of acute stress is unknown. We hypothesized that acute stress in a humanized SCD mouse model stimulates the histamine pathway, inflammatory mediator release, and a pressor response. Acute stress was induced using cage switch stress (CSS) in male humanized SCD (HbSS) or control (HbAA) mice (n=6-8/group) with blood pressure (BP) monitored by radiotelemetry and mice terminated at baseline (BL, no CSS) and 30 min post-CSS for plasma measurements. Plasma histamine was unchanged in HbAA mice but was elevated in HbSS in response to CSS (nM; HbAA: 90.2±21.3; 104.3±10.2; HbSS: 91.1±13.6; 174.3±19.2*, *p<0.01 vs genotype BL). HbSS mice have significantly higher IL-6 levels at BL and post-CSS (ug/mL; HbAA: 20±4, 23±7; HbSS: 37±8, 65±5*, p genotype =0.0001, *p<0.05 vs genotype BL). Significant stress-by-genotype effects were found for E-selectin (ug/mL; BL vs CSS: HbAA: 7.9±0.9, 6.4±0.8; HbSS: 10±0.7, 13±1.4*, *p genotype <0.001) and P-selectin (ug/mL; BL vs CSS: HbAA: 29±2.7, 25±2.1; HbSS: 33±3.0, 42±4.1*, *p genotype <0.01). The peak mean arterial pressure response to CSS was blunted in HbSS versus HbAA mice and was driven by lower diastolic BP (DBP), not systolic BP. Mice were treated with H1 and H2 receptor antagonists, diphenhydramine and cimetidine, to examine the histamine pathway in the BP response to CSS. Following H1/H2 receptor antagonism, the CSS-induced peak DBP response was similar in HbAA mice, but was elevated in HbSS mice (change in BP, mmHg; vehicle vs H1/H2 blockade: HbAA: 32±2, 30±1; HbSS: 23±2, 31±2*, *p<0.05 vs genotype vehicle). These data reveal that acute stress stimulates histamine release and inflammatory mediators in HbSS mice but not HbAA. Further, the stress-induced DBP response is dependent on the histamine H1/H2 pathway in HbSS mice. These data identify that in SCD the histamine pathway may be stress-responsive and represents a link between acute stress and vaso-occlusive crises.