Abstract P073: Long-term Augmentation Of Acetylcholine Bioavailability Halts The Progression Of Lupus Hypertension

Abstract

Renal inflammation promotes hypertension in systemic lupus erythematosus (SLE). Our recent studies suggest that renal inflammation is regulated by the vagally-mediated cholinergic anti-inflammatory pathway, and that vagal tone is reduced in SLE mice. We found that augmenting central bioavailability of acetylcholine via the acetylcholinesterase inhibitor, galantamine, increases vagal tone and reduces renal inflammation and mean arterial pressure (MAP) in SLE mice after two weeks. However, the long-term efficacy and therapeutic potential of galantamine are unknown. Thus, we hypothesized that chronic galantamine administration would effectively halt the progression of SLE hypertension and renal injury. Starting at 20 weeks of age, female SLE ( NZBWF1 ) and control ( NZW ) mice received galantamine hydrobromide (3 mg/kg/day, SQ) or vehicle continuously for 16 weeks via osmotic minipump. At 35 weeks, mice were placed in metabolic cages for urine collection, carotid catheters were implanted to assess MAP in conscious mice, and tissues were harvested. MAP (mmHg, n=4-6) was higher in SLE mice than controls (161.9±9.9 vs. 128.3±0.9, p=0.001) and long-term galantamine treatment prevented further increases in MAP in SLE mice (161.9±9.9 vs. 138.3±4.9, p= 0.01). Survival rate was lower in SLE mice compared to controls (50% vs. 100%) and galantamine improved survival to 70% in SLE mice. Eighty percent (4 of 5) of SLE mice had urinary albumin over 300 mg/dL and chronic galantamine lowered the prevalence to 57% (4 of 7); no controls had albuminuria. There was no difference in CD3+CD4+ T cells amongst groups, but the percentage of renal CD3+CD8+ T cells was increased in SLE mice compared to controls (29.7±2.2 vs. 12.8±0.79, p<0.0001, n=4-7) and galantamine reduced this percentage in SLE mice (29.7±2.2 vs. 22.9±1.2, p=0.0261). Taken together, our data indicate chronic augmentation of central acetylcholine bioavailability is protective against SLE hypertension since it improves survival rate, decreases renal injury and alters cytotoxic renal immune cell populations. These data further support acetylcholinesterase inhibition as a novel therapeutic option for hypertension associated with autoimmunity.