Abstract P395: Clozapine Treatment For Schizophrenia May Cause Salt-sensitive Hypertension By Reducing The Expression Of The Renal Dopamine D4 Receptor

Abstract

Clozapine (CLZ) is the most effective antipsychotic for treatment-resistant schizophrenia which affects approximately 24 million people worldwide. Schizophrenics are 3-4 times more likely to die from cardiovascular disease due to increased incidence of hypertension. CLZ is a high affinity antagonist for the dopamine type 4 receptor (D 4 R). Studies have shown that germline deletion of D 4 R in mice caused hypertension, and CLZ administered subcutaneously in mice induced hypertension. Since the proximal tubule (PT) regulates about 75% of excreted Na + we cultured renal proximal tubule cells excreted in the urine (uRPTCs) from individuals treated with and without clozapine and previously found that CLZ decreased D 4 R recruitment to cell surface and increased reactive oxygen species in healthy controls (HC). Recently, western blot analysis showed D 4 R expression was reduced in CLZ treated patients (CLZ 0.85±0.08 n=12 vs HC 1.09±0.09 n=11, p<0.05 t-test). The total D 4 R protein was also decreased under CLZ treatment in RPTCs from HC. This suggests that the reduction in D 4 R occurred in PTs when treated with CLZ in-vivo but this was a durable effect still measurable through the process of culturing the cells, and is replicated in-vitro using healthy control cells. In In-vivo CLZ treated patient cells, D 4 R expression is not further reduced when treated in-vitro. Moreover, the natriuretic dopamine D1 receptor (D 1 R) was significantly increased under ClZ treatment of uRPTCs from HC, but not RPTCs from CLZ treated patients (VEH 0.37±0.07 vs CLZ 0.5±0.08 n=11, p<0.05 paired t-test; CLZ/VEH, HC 1.51±0.18 n=11 vs CLZ 0.99±0.01 n=12, p<0.05 t-test). Interestingly, high salt (HS) treatment on these uRPTCs showed a similar trend with CLZ treatment (VEH 0.33±0.06 vs CLZ 0.47±0.08, n=10, p<0.05 paired t-test; HS/VEH, HC 1.55±0.29 n=11 vs CLZ 0.99±0.01 n=12, p<0.05 t-test), indicating these CLZ treated patients may have a blunted dopamine response to excess sodium and therefore develop salt sensitive hypertension. In Summary, CLZ induced hypertension in these schizophrenia patients may be caused by a disrupted dopaminergic system. Further investigations also need to be done including response of sodium transporters and modulation of the renin-angiotensin system.