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Rho Kinase Inhibition Lowers Sympathetic Nerve Activity in Conscious Rabbits with Chronic Heart Failure
Author(s) -
Haack Karla Kristine Vincent,
Gao Lie,
Curry Pamela,
Zucker Irving H
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.703.7
Subject(s) - medicine , heart failure , cannula , heart rate , endocrinology , saline , sympathetic nervous system , cardiology , anesthesia , blood pressure , surgery
Rho‐Associated protein kinase (RhoK) is a serine/threonine kinase that is involved in calcium sensitization and vascular smooth muscle cell contraction. Recent work has implicated RhoK overactivation in cardiovascular diseases. Furthermore, the RhoK pathway in the brain stem has been shown to contribute to blood pressure regulation via the sympathetic nervous system (SNS). It has been extensively shown that a hallmark of chronic heart failure (CHF) is increased SNS activation. We investigated the effect of central RhoK blockade on renal sympathetic nerve activity (RSNA) in a pacing rabbit model of CHF. Briefly, we induced CHF in a rabbit model by placement of left ventricular pacing leads, and pacing at 360–380 BPM for 1–2 weeks. CHF was confirmed by echocardiography, and characterized by a reduction in ejection fraction to ~45%. Nerve recording electrodes were then implanted on the renal nervealong with an intracerebroventricular cannula and osmotic minipump containing sterile saline or 1.5 mg/kg/mL fasudil (Fas, a RhoK inhibitor) in saline at a rate of 1 μL/h. After 3 days, infusion with Fas lowered resting heart rate by 25 ± 2.1 BPM (p<0.03) and significantly reduced RSNA frequency (Fas: 13.1±4.7 Hz vs Veh: 39.1 ± 5.2 Hz; p<0.02). Change in RSNA in response to oropharyngeal smoke was increased in CHF Fas animals (93 ± 18%) vs CHF Veh treated animals (45 ± 9%) (p<0.03). These data suggest that central RhoK activation may contribute to sympatho‐excitation in the setting of CHF. Supported by PO‐1 HL62222.