Abstract P760: Plasma Kallikrein Contributes to Intracerebral Hemorrhage and Hypertension in Stroke-Prone Spontaneously Hypertensive Rats

Introduction: Hypertension is a leading risk factor for spontaneous intracerebral hemorrhage. Plasma Kallikrein (PKa) has been implicated in contributing to hemorrhage following thrombolytic therapy, however, its role in spontaneous intracerebral hemorrhage is currently not available. This report investigates the role of PKa on hemorrhage and hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). Methods: SHRSP were fed with a high salt containing stroke-prone diet to increase blood pressure and induce spontaneous intracerebral hemorrhage. The roles of PKa on blood pressure, intracerebral hemorrhage, and survival in SHRSP were examined in rats receiving a PKa inhibitor (BPCCB) or plasma prekallikrein antisense oligonucleotide (PK ASO) compared with rats receiving control ASO. Effects on PKa on the proteolytic cleavage of atrial natriuretic peptide (ANP) were analyzed by tandem mass spectrometry. Results: PKa activity in plasma was increased by 29% in SHRSP on high salt diet compared with control rats. Cleaved kininogen, a substrate for PKa, was 2-fold greater in SHRSP plasma during stroke compared with SHRSP without stroke symptoms. Systemic administration of BPCCB or PK ASO to SHRSP reduced intracerebral hemorrhage (Fig. 1A) and blood pressure (Fig. 1B), and improved neurological function and survival when compared with rats receiving control ASO. Since PKa inhibition was associated with reduced blood pressure in hypertensive rats, we investigated the effects of PKa on the cleavage of ANP. Incubation of PKa with ANP resulted in the generation fragment ANP 5-28 , which displayed reduced effects on blood pressure lowering compared with full length ANP. Conclusions: PKa contributes to increased blood pressure in SHRSP, which is associated with intracerebral hemorrhage and reduced survival. PKa-mediated cleavage of ANP reduces its blood pressure lowering effects and thereby may contribute to hypertension-induced intracerebral hemorrhage.