Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) regulates renal O(2) consumption. This mechanism is impaired in heart and kidney of dogs with heart failure (CHF). Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, increases eNOS expression in the endothelium. Therefore, we studied whether simvastatin treatment could restore the regulation of renal O(2) consumption by stimulators of NO production in dogs with CHF. Renal O(2) consumption was measured after stimulation of NO production with bradykinin, ramiprilat, or amlodipine or the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Simvastatin delayed the time to euthanasia in dogs with CHF (35 +/- 1.0 vs. 29 +/- 1.2 days; P < 0.01). In normal dogs, bradykinin (10(-4) M), ramiprilat (10(-4) M), amlodipine (10(-5) M), and SNAP (10(-4) M) significantly reduced O(2) consumption in the renal cortex (-31.8 +/- 0.9, -30.3 +/- 1.1, -30.1 +/- 2.0, -46.9 +/- 1.0%) and renal medulla (-29.7 +/- 2.1, -33.0 +/- 2.7, -30.8 +/- 2.2, -46.8 +/- 1.1%). Responses to bradykinin, ramiprilat, and amlodipine were significantly attenuated in CHF but were partially or completely restored by simvastatin. Responses to SNAP were unaffected. These data demonstrate that treatment with simvastatin improves renal production of NO in CHF, restoring the normal regulation of renal O(2) consumption by NO.
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PMID:Simvastatin reverses impaired regulation of renal oxygen consumption in congestive heart failure. 1159 37

Inhibitors of hydroxymethylglutaryl-CoA reductase or statins have been shown to alleviate endothelial dysfunction. Their effects on constitutive nitric oxide synthase in the central nervous system may hypothetically affect the autonomic balance in sympathoexcitatory states, such as chronic heart failure (CHF). To address this issue, simvastatin (SIM) (0.3, 1.5, or 3 mg. kg-1. day-1 po) was given to rabbits with pacing-induced CHF over a 3-wk period. Normal and CHF vehicle-treated rabbits served as controls. Autonomic balance was assessed by measuring heart rate variability, including power spectral analysis (PSA). In addition, changes in resting heart rate were assessed before and after vagal and sympathetic autonomic blockade by atropine and metoprolol, respectively. The SD for all intervals was 8.9 +/- 0.7 ms in normal, 4.9 +/- 0.6 ms in CHF (P < 0.01), 3.8 +/- 0.6 ms in CHF with 0.3 mg. kg-1. day-1 SIM (P < 0.001), 5.7 +/- 0.9 in CHF with 1.5 mg. kg-1. day-1 SIM (P < 0.05), and 7.2 +/- 0.5 in CHF with 3.0 mg. kg-1. day-1 SIM. Similarly, total power was 40.5 +/- 6.3 ms2 in normal, 10.1 +/- 3.0 ms2 in CHF (P < 0.01), 6.0 +/- 1.6 ms2 in CHF with 0.3 mg. kg-1. day-1 SIM (P < 0.01), 13.2 +/- 3.9 ms2 in CHF with 1.5 mg. kg-1. day-1 SIM (P < 0.05), and 22.0 +/- 3.0 ms2 in CHF with 3.0 mg. kg-1. day-1 SIM. Both PSA data for low (0.625-0.1875 Hz) and high frequencies (0.1875-0.5625 Hz) showed recovery in CHF animals on medium and high SIM doses without changes in the low-to-high-frequency ratio. SIM beneficially affects autonomic tone in CHF as seen by the reversal of depressed HRV and total power of PSA. These data have important implications for the treatment of patients with autonomic imbalance.
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PMID:Statin therapy restores sympathovagal balance in experimental heart failure. 1271 69

Our previous study demonstrated that oral treatment with simvastatin (SIM) suppressed renal sympathetic nerve activity (RSNA) in the rabbits with chronic heart failure (CHF). The purpose of this experiment was to determine the effects of direct application of SIM to the central nervous system on RSNA and its relevant mechanisms. Experiments were carried out on 21 male New Zealand White rabbits with pacing-induced CHF. The CHF rabbits received infusion of vehicle, SIM, or SIM + N(omega)-nitro-L-arginine methyl ester into the lateral cerebral ventricle via osmotic minipump for 7 days. We found that 1) in CHF rabbits, intracerebroventricular infusion of SIM significantly suppressed basal RSNA (1st day 69.5 +/- 8.9% maximum; 7th day 26.0 +/- 6.0% maximum; P < 0.05, n = 7) and enhanced arterial baroreflex function starting from the 2nd day and lasting through the following 5 days; 2) statin treatment significantly up-regulated neuronal nitric-oxide synthase (nNOS) protein expression in the rostral ventrolateral medulla (RVLM) (control, n = 6, 0.12 +/- 0.04; SIM-treated, n = 7, 0.31 +/- 0.05. P < 0.05); 3) in CATH.a neurons, incubation with SIM significantly up-regulated the nNOS mRNA expression, which was blocked by coincubation with mevalonate, farnesyl-pyrophosphate, or geranylgeranyl-pyrophosphate; and 4) incubation with Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide] significantly up-regulated nNOS mRNA expression in these neurons. These results suggest that central treatment with SIM decreased sympathetic outflow in CHF rabbits via up-regulation of nNOS expression in RVLM, which may be due to the inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase and a decrease in Rho kinase by SIM.
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PMID:Simvastatin inhibits central sympathetic outflow in heart failure by a nitric-oxide synthase mechanism. 1844 Dec 51

Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) reduce plasma cholesterol and improve endothelium-dependent vasodilation, inflammation and oxidative stress. A 'pleiotropic' property of statins receiving less attention is their effect on the autonomic nervous system. Increased central sympathetic outflow and diminished cardiac vagal tone are disturbances characteristic of a range of cardiovascular conditions for which statins are now prescribed routinely to reduce cardiovascular events: following myocardial infarction, and in hypertension, chronic kidney disease, heart failure and diabetes. The purpose of the present review is to synthesize contemporary evidence that statins can improve autonomic circulatory regulation. In experimental preparations, high-dose lipophilic statins have been shown to reduce adrenergic outflow by attenuating oxidative stress in central brain regions involved in sympathetic and parasympathetic discharge induction and modulation. In patients with hypertension, chronic kidney disease and heart failure, lipophilic statins, such as simvastatin or atorvastatin, have been shown to reduce MNSA (muscle sympathetic nerve activity) by 12-30%. Reports concerning the effect of statin therapy on HRV (heart rate variability) are less consistent. Because of their implications for BP (blood pressure) control, insulin sensitivity, arrhythmogenesis and sudden cardiac death, these autonomic nervous system actions should be considered additional mechanisms by which statins lower cardiovascular risk.
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PMID:Statins and the autonomic nervous system. 2427 67