Radiofrequency Renal Denervation Protects the Ischemic Heart via Inhibition of GRK2 and Increased Nitric Oxide Signaling

Abstract

Rationale:Catheter-based renal denervation (RDN) is currently under development for the treatment of resistant hypertension and is thought to reduce blood pressure via interruption of sympathetic pathways that modulate cardiovascular function. The sympathetic nervous system also plays a critical role in the pathogenesis of acute myocardial infarction and heart failure.Objective:We examined whether treatment with radiofrequency (RF)-RDN would protect the heart against subsequent myocardial ischemia/reperfusion injury via direct effects on the myocardium.Methods and Results:Spontaneously hypertensive rats received either bilateral RF-RDN or sham-RDN. At 4 weeks after RF-RDN (n=14) or sham-RDN (n=14) treatment, spontaneously hypertensive rats were subjected to 30 minutes of transient coronary artery occlusion and 24 hours –7 days reperfusion. Four weeks after RF-RDN, myocardial oxidative stress was markedly attenuated, and transcription and translation of antioxidants, superoxide dismutase 1 and glutathione peroxidase-1, were significantly upregulated compared with sham-RDN spontaneously hypertensive rats. RF-RDN also inhibited myocardial G protein–coupled receptor kinase 2 pathological signaling and enhanced myocardial endothelial nitric oxide synthase function and nitric oxide signaling. RF-RDN therapy resulted in a significant reduction in myocardial infarct size per area at risk compared with sham-RDN (26.8 versus 43.9%; P<0.01) at 24 hours postreperfusion and significantly improved left ventricular function at 7 days after myocardial ischemia/reperfusion.Conclusions:RF-RDN reduced oxidative stress, inhibited G protein–coupled receptor kinase 2 signaling, increased nitric oxide bioavailability, and ameliorated myocardial reperfusion injury in the setting of severe hypertension. These findings provide new insights into the remote cardioprotective effects of RF-RDN acting directly on cardiac myocytes to attenuate cell death and protect against ischemic injury.

Renal Denervation Improves the Baroreflex and GABA System in Chronic Kidney Disease-induced Hypertension

“…Recently, catheter-based RD to treat patients with CKD was shown to inhibit sympathoexcitatory reflexes, and the interruption of these afferent reflexes led to a reduction in systemic sympathetic tone6. Other potential effects of RD have been reported, including improvements in LVH3435, an antiarrhythmic effect including atrial fibrillation36, and myocardial reperfusion injury37. Our study further showed that RD ameliorated the baroreflex and partially improved the renal function and LVH.…”

Combined Angiotensin Receptor–Neprilysin Inhibitors Improve Cardiac and Vascular Function Via Increased NO Bioavailability in Heart Failure

“…Nitrite content of plasma and myocardial specimens was made using an ENO‐30 ion chromatography system with a PC‐PAK precolumn and an NO‐PAK separation column (Eicom), as previously described . The mobile phase was composed of 10% methanol with 0.15 mol/L NaCl‐NH 4 Cl and 0.5 g/L tetrasodium EDTA supplied at a flow of 0.33 mL/min.…”

David Polhemus

“…This alternative strategy is not drug based but could, in fact, replace or supplement current therapies. The first half of this work was published in Circulation Research in 2016 4,5 ; we're finalizing the second half now and plan to submit it soon for publication.…”