Hypertensive Response to Acute Stress Is Attenuated in Interleukin-6 Knockout Mice

Abstract

Abstract-This study tested the hypothesis that the inflammatory cytokine, interleukin-6, contributes to the hypertensive response to acute psychosocial stress, caused by switching male mice to a cage previously occupied by a different male mouse. Male C57BL6 (WT) and interleukin-6 (IL-6) knockout (KO) mice were implanted with biotelemetry devices to monitor mean arterial pressure, heart rate, and motor activity in the unrestrained state. Baseline mean arterial pressure was 98Ϯ1 and 103Ϯ1 for WT and IL-6 KO mice. Cage switch increased mean arterial pressure by 42Ϯ2 mm Hg in WT mice, but this was blunted significantly in KO mice (31Ϯ3 mm Hg peak increase). Area under the curve for the first 90 minutes also was significantly less. Heart rate and motor activity increased similarly, and there also were no differences in the increases in plasma renin activity or plasma norepinephrine concentration between WT and KO mice. Thus, the acute hypertensive response to psychosocial stress depends significantly on IL-6, and the effect appears to be specific for blood pressure rather than to a global impairment in the response to stress. However, because perfusion of the isolated mesenteric bed with phenylephrine and chronic infusion of angiotensin II caused similar responses in WT and IL-6 KO mice, it is clear that future studies are needed to determine to what extent the acute blood pressure effect of IL-6 is stress-specific.

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

“…Baseline mean arterial pressure during the 3 hours before CSS did not differ between genotypes (flox versus VEETKO, 106.4±2.0 versus 100.2±2.7 mm Hg; P =0.099; flox, n=7; VEETKO, n=9). CSS induced a rapid increase in systolic, diastolic, and mean arterial pressures in flox mice, with a maximum increase of ≈40 mm Hg, a magnitude consistent with previously published reports in control mice 3, 25. In contrast, the pressor response in the 10 minutes following CSS was significantly blunted in VEETKO mice (Figure 1A through 1C).…”

“…We hypothesized that psychosocial stress‐induced ET‐1 contributes to the rapid increase in blood pressure via activation of the endothelin A (ET A ) receptor and is derived from the endothelium. To test this hypothesis, we conducted experiments using vascular endothelium‐specific ET ‐1 knockout mice (VEETKO) and control mice that were homozygous for the floxed allele (flox) male mice exposed to cage switch stress (CSS), an established experimental model of acute psychosocial stress 3, 25…”

Classic Interleukin-6 Receptor Signaling and Interleukin-6 trans-Signaling Differentially Control Angiotensin II-Dependent Hypertension, Cardiac Signal Transducer and Activator of Transcription-3 Activation, and Vascular Hypertrophy in Vivo

“…26 In contrast to our findings, deletion of IL-6 did not influence the pressor response to high-dose Ang II on a normal salt diet. 27 Here, considerably lower Ang II doses that are still sufficient to generate pressor responses were used, and it was found that deletion of IL-6 was fully sufficient to prevent BP eleva- Ϫ/Ϫ aortic rings after preincubation with 1 mol/L Ang II (n ϭ 8).…”

IL-6 microinjected in the nucleus tractus solitarii attenuates cardiac baroreceptor reflex function in rats

“…Because psychosocial stress or ANG II-induced hypertension was attenuated in animals deficient of IL-6 (5,16,17), this cytokine acting within the NTS may play an important role under these conditions. Moreover, the lower gene expression profile of IL-6 in the NTS of the SHR found in our previous study (34) may be secondary to the hypertensive condition, acting as a compensatory mechanism for the attenuated cardiac baroreceptor reflex gain.…”