Verhandlungen der Royal Society of Medicine Dermatologische Abteilung: Sitzung vom 20. Januar 1910

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Effects of Renal Denervation on Sympathetic Activation, Blood Pressure, and Glucose Metabolism in Patients with Resistant Hypertension

Increased central sympathetic drive is a hallmark of several important clinical conditions including essential hypertension, heart failure, chronic kidney disease, and insulin resistance. Afferent signaling from the kidneys has been identified as an important contributor to elevated central sympathetic drive and increased sympathetic outflow to the kidney and other organs is crucially involved in cardiovascular control. While the resultant effects on renal hemodynamic parameters, sodium and water retention, and renin release are particularly relevant for both acute and long term regulation of blood pressure, increased sympathetic outflow to other vascular beds may facilitate further adverse consequences of sustained sympathetic activation such as insulin resistance, which is commonly associated with hypertension. Recent clinical studies using catheter-based radiofrequency ablation technology to achieve functional renal denervation in patients with resistant hypertension have identified the renal nerves as therapeutic target and have helped to further expose the sympathetic link between hypertension and insulin resistance. Initial data from two clinical trials and several smaller mechanistic clinical studies indicate that this novel approach may indeed provide a safe and effective treatment alternative for resistant hypertension and some of its adverse consequences

Effect of Arteriovenous Anastomosis on Blood Pressure Reduction in Patients With Isolated Systolic Hypertension Compared With Combined Hypertension

Background: Options for interventional therapy to lower blood pressure (BP) in patients with treatment‐resistant hypertension include renal denervation and the creation of an arteriovenous anastomosis using the ROX coupler. It has been shown that BP response after renal denervation is greater in patients with combined hypertension (CH) than in patients with isolated systolic hypertension (ISH). We analyzed the effect of ROX coupler implantation in patients with CH as compared with ISH. Methods and Results: The randomized, controlled, prospective ROX Control Hypertension Study included patients with true treatment‐resistant hypertension (office systolic BP ≥140 mm Hg, average daytime ambulatory BP ≥135/85 mm Hg, and treatment with ≥3 antihypertensive drugs including a diuretic). In a post hoc analysis, we stratified patients with CH (n=31) and ISH (n=11). Baseline office systolic BP (177±18 mm Hg versus 169±17 mm Hg, P=0.163) and 24‐hour ambulatory systolic BP (159±16 mm Hg versus 154±11 mm Hg, P=0.463) did not differ between patients with CH and those with ISH. ROX coupler implementation resulted in a significant reduction in office systolic BP (CH: −29±21 mm Hg versus ISH: −22±31 mm Hg, P=0.445) and 24‐hour ambulatory systolic BP (CH: −14±20 mm Hg versus ISH: −13±15 mm Hg, P=0.672), without significant differences between the two groups. The responder rate (office systolic BP reduction ≥10 mm Hg) after 6 months was not different (CH: 81% versus ISH: 82%, P=0.932). Conclusions: Our data suggest that creation of an arteriovenous anastomosis using the ROX coupler system leads to a similar reduction of office and 24‐hour ambulatory systolic BP in patients with combined and isolated systolic hypertension. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01642498

Porphyrin Binding to Gun4 protein, Facilitated by a Flexible Loop, Controls Metabolite Flow through the Chlorophyll Biosynthetic Pathway

In oxygenic phototrophs, chlorophylls, hemes and bilins are synthesized by a common branched pathway. Given the phototoxic nature of tetrapyrroles, this pathway must be tightly regulated and an important regulatory role is attributed to Mgchelatase enzyme at the branching between the heme and chlorophyll pathway. Gun4 is a porphyrin-binding protein known to stimulate in vitro the Mg-chelatase activity but how the Gun4-porphyrin complex acts in the cell was unknown. To address this issue we first performed simulations to determine the porphyrin-docking mechanism to the cyanobacterial Gun4 structure. After correcting crystallographic loop contacts, we determined the binding site for Mgprotoporphyrin IX. It revealed that the orientation of 6/7 loop is critical for the binding and the magnesium ion held within the porphyrin is coordinated by Asn211 residue. We also identified the basis for stronger binding in the Gun4-1 variant and for weaker binding in the W192A mutant. The W192A-Gun4 was further characterized in Mg-chelatase assay showing that tight porphyrin-binding in Gun4 facilitates its interaction with the Mg-chelatase ChlH subunit. Finally, we introduced the W192A mutation into Synechocystis 6803 cells and show that the Gun4-porphyrin complex is important for the accumulation of ChlH and for channeling metabolites into the chlorophyll biosynthetic pathway.This work was supported by project P501/12/G055 of the Czech Science Foundation, and by the National Programme of Sustainability I (LO1416) and by ERC 2009-Adg25027-PELE (to V.G). J.K. was supported by project Algain (EE2.3.30.0059). N.B.P.A., P.A.D., A.A.B. and C.N.H. thank the Biotechnology and Biological Sciences Research Council (BBSRC) U.K. for funding, under award numbers BB/G021546/1 and BB/M000265/1. CNH was also supported by an Advanced Award 338895 from the European Research Council.Peer ReviewedPostprint (author's final draft