Abstract Title

Improvement in Blood Pressure and Renal Injury Following Vagal Nerve Stimulation

RAD Assignment Number

313

Presenter Name

Charles Maloy

Abstract

Purpose:

The concept that autoimmunity and its subsequent inflammation could play a role in the pathogenesis of hypertension and its end-organ damage has recently been supported by many studies. Recent studies have proposed a novel pathway, the cholinergic anti-inflammatory pathway, which may combat this inflammation and prevent the subsequent damage. Stimulation of the vagus nerve has been shown to reduce inflammation via this pathway. Systemic Lupus Erythematosus (SLE), an autoimmune disease with a high prevalence of hypertension, provides an appropriate model to test whether stimulation of this pathway can combat chronic inflammation and hypertension. We tested the hypothesis that pharmacological stimulation of the vagus nerve reduces blood pressure and improves renal injury and function in SLE mice (NZBWF1).

Methods:

Starting at 30 weeks of age, female SLE and control (NZW) mice were treated twice per week over four weeks with CNI­1493 (Semapimod hydrochloride; 8 mg/kg, IP), which has been shown to stimulate the vagus nerve. Saline was used as the vehicle treatment. After treatment, a catheter was placed in the carotid artery to measure mean arterial pressure. Renal blood flow (mL/min*g kidney weight) was measured using a flow probe and renal vascular resistance was calculated (mmHg*min*g kidney weight/mL) as indices of renal function.

Results:

Mean arterial pressure (mmHg) was higher in SLE mice compared to controls (143±11 vs. 116±4; p=0.003; n=3­ 5/group). Treatment with CNI­1493 attenuated the development of hypertension in the SLE mice (130 ± 4), but did not alter mean arterial pressure in controls (119 ± 5). Renal injury in the form of albuminuria (albumin excretion rate; μg/day) was increased in SLE mice compared to controls (4409±2519 vs. 4 ± 1; p=0.002; n =3­6/group). Albumin excretion rate was diminished in CNI­ 1493­treated SLE mice (420±410; p = 0.008). CNI­1493 ­treated SLE mice had higher renal blood flow (3.0 vs. 2.5±0.1mL/min*g; n=1­ 2/group) and lower renal vascular resistance (21.9 vs. 23.9±1mmHg*min*g/mL; n=1­2/group) compared to SLE mice treated with saline.

Conclusion:

These data suggest that stimulation of the vagus nerve may protect the kidney and prevent SLE hypertension; however, future studies are warranted to determine how this occurs. Taken together, our findings suggest that the vagally­mediated cholinergic anti­inflammatory pathway plays a mechanistic role in the development hypertension in the setting of chronic inflammation.

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Improvement in Blood Pressure and Renal Injury Following Vagal Nerve Stimulation

Purpose:

The concept that autoimmunity and its subsequent inflammation could play a role in the pathogenesis of hypertension and its end-organ damage has recently been supported by many studies. Recent studies have proposed a novel pathway, the cholinergic anti-inflammatory pathway, which may combat this inflammation and prevent the subsequent damage. Stimulation of the vagus nerve has been shown to reduce inflammation via this pathway. Systemic Lupus Erythematosus (SLE), an autoimmune disease with a high prevalence of hypertension, provides an appropriate model to test whether stimulation of this pathway can combat chronic inflammation and hypertension. We tested the hypothesis that pharmacological stimulation of the vagus nerve reduces blood pressure and improves renal injury and function in SLE mice (NZBWF1).

Methods:

Starting at 30 weeks of age, female SLE and control (NZW) mice were treated twice per week over four weeks with CNI­1493 (Semapimod hydrochloride; 8 mg/kg, IP), which has been shown to stimulate the vagus nerve. Saline was used as the vehicle treatment. After treatment, a catheter was placed in the carotid artery to measure mean arterial pressure. Renal blood flow (mL/min*g kidney weight) was measured using a flow probe and renal vascular resistance was calculated (mmHg*min*g kidney weight/mL) as indices of renal function.

Results:

Mean arterial pressure (mmHg) was higher in SLE mice compared to controls (143±11 vs. 116±4; p=0.003; n=3­ 5/group). Treatment with CNI­1493 attenuated the development of hypertension in the SLE mice (130 ± 4), but did not alter mean arterial pressure in controls (119 ± 5). Renal injury in the form of albuminuria (albumin excretion rate; μg/day) was increased in SLE mice compared to controls (4409±2519 vs. 4 ± 1; p=0.002; n =3­6/group). Albumin excretion rate was diminished in CNI­ 1493­treated SLE mice (420±410; p = 0.008). CNI­1493 ­treated SLE mice had higher renal blood flow (3.0 vs. 2.5±0.1mL/min*g; n=1­ 2/group) and lower renal vascular resistance (21.9 vs. 23.9±1mmHg*min*g/mL; n=1­2/group) compared to SLE mice treated with saline.

Conclusion:

These data suggest that stimulation of the vagus nerve may protect the kidney and prevent SLE hypertension; however, future studies are warranted to determine how this occurs. Taken together, our findings suggest that the vagally­mediated cholinergic anti­inflammatory pathway plays a mechanistic role in the development hypertension in the setting of chronic inflammation.