Pravastatin normalises peripheral cardiac sympathetic hyperactivity in the spontaneously hypertensive rat

摘要

Hypertension is associated with heightened cardiac sympathetic drive whilst statins reduce angiotensin II (ATII) signalling, superoxide anion production and increase nitric oxide bioavailability, events that can potentially reduce peripheral cardiac sympathetic neurotransmission. We therefore investigated whether pravastatin alters peripheral cardiac sympathetic control in the spontaneously hypertensive rat (SHR). SHRs (16–18 weeks) had significantly (p < 0.05) enhanced atrial ³H-norepinephrine (³H-NE) release to field stimulation compared to normotensive WKYs. 2-week pravastatin supplementation significantly reduced ³H-NE release to levels observed in the WKY. In-vivo, pravastatin lowered resting heart rate (HR) in the SHR despite not affecting arterial blood pressure or serum cholesterol. In SHR atria/right stellate ganglion preparations, the HR response to stellate stimulation (1, 3, and 5 Hz) was also significantly reduced by pravastatin whilst the HR response to exogenous NE (0.025–5 μmol) remained similar. The nitric oxide synthase (NOS) inhibitor l-NAME (1 mmol/l) increased ³H-NE release by similar amounts in atria from supplemented and non-supplemented SHRs, whilst Western blotting showed no difference in protein levels of nNOS, eNOS, guanylyl cyclase, or the NADPH oxidase subunits Gp91 and P40phox. Pravastatin significantly reduced cardiac ATII levels and angiotensin converting enzyme 1 and 2 expressions whilst protein levels of the ATII receptor (ATR1) remained unchanged in the SHR. Immunohistochemistry co-localised ATR1 with tyrosine hydroxylase positive neurons in the stellate ganglion. The ATR1 antagonist Losartan (5 μmol) equalised release of ³H-NE to comparable levels in supplemented and non-supplemented SHRs. These results suggest 2-week pravastatin treatment reduces cardiac ATII, and prevents its facilitatory effect on NE release thus normalising cardiac sympathetic hyper-responsiveness in SHRs.