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  • Title: Intrathecal Administration of Losartan Reduces Directly Recorded Cardiac Sympathetic Nerve Activity in Ovine Heart Failure.
    Author: Leversha S, Allen AM, May CN, Ramchandra R.
    Journal: Hypertension; 2019 Oct; 74(4):896-902. PubMed ID: 31378100.
    Abstract:
    Early and preferential activation of cardiac sympathetic nerve activity (CSNA) is one of the strongest prognostic markers of heart failure (HF) in patients. Our previous studies have implicated central angiotensin mechanisms as playing a critical role in generating this increase in cardiac sympathetic drive. However, it is unclear if inhibition of AT1R (angiotensin type-1 receptors) in different neural groups in the sympathetic pathway to the heart, such as the sympathetic preganglionic neurons in the intermediolateral column of the spinal cord, can reduce cardiac sympathetic drive. We hypothesized that in HF, localized intrathecal administration of the AT1R antagonist losartan, specifically into the T1-2 subarachnoid space, would decrease CSNA. In normal conscious sheep, intrathecal infusion of Ang II (angiotensin II; 3.0 nmol/mL per hour), significantly increased mean arterial pressure and CSNA; this effect was abolished by prior administration of losartan (1 mg/h). In an ovine rapid ventricular pacing model of HF, the resting levels of heart rate and CSNA were significantly elevated compared with normals. Intrathecal infusion of losartan (1 mg/h) in HF significantly reduced CSNA and heart rate but did not change arterial pressure. The AT1R binding density in the spinal cord was also elevated in the HF group. Our data suggest that AT1Rs within the spinal cord are responsible, in part, for the increased CSNA in HF and may represent a target for the selective reduction of CSNA in HF.
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