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- The Renal Subanalysis of ASCEND-HF: The End of Nesiritide as a Cardio-Renal Therapeutic? [JOURNAL ARTICLE]
- Circulation 2014 Jul 29.
Over the last three decades there has been a remarkable explosion in our understanding of the natriuretic peptide system. Prior to 1980, only 1 entry can be found in Medline under the search term "natriuretic peptide" while currently there are >22,500. Through this impressive literature, the concept of the natriuretic peptide as an ideal cardio-renal therapeutics emerged with reports of improvement in renal function, neurohormonal activation, fibrosis, and natriuresis amongst other benefits with these agents.(1) As a result, the development of recombinant b-type natriuretic peptide (nesiritide) brought tremendous optimism regarding its potential role in acute decompensated heart failure (ADHF). The drug was approved in 2001 based on a 489 patient trial that did not actually evaluate its cardio-renal effects, but rather demonstrated efficacy via its actions as a vasodilator.(2) This took the form of a 2 mmHg greater reduction in pulmonary capillary wedge pressure with no additional relief of dyspnea compared to nitroglycerin, but significant superiority over placebo. However, presumably due to the great enthusiasm for the mechanism of the drug, sales soared to $390 million by 2004 despite the absence of any large studies showing positive clinical outcomes and even some human data indicating an absence of positive cardio-renal effects.(3, 4) The widespread enthusiasm for nesiritide ended rather abruptly in 2005 after publication of two meta-analyses by Sackner-Bernstein et al demonstrating a 52% increased risk for worsening renal function (WRF, defined as a >0.5 mg/dl increase in creatinine) and an 80% increased risk for death with nesiritide.(5, 6.)
- Effect of Arginase Inhibition on Ischemia-Reperfusion Injury in Patients with Coronary Artery Disease with and without Diabetes Mellitus. [JOURNAL ARTICLE]
- PLoS One 2014; 9(7):e103260.
Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD) and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes (Clinical trial registration number: NCT02009527).Male patients with CAD (n = 12) or CAD + type 2 diabetes (n = 12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (Nω-hydroxy-nor-L-arginine, 0.1 mg/min) or saline.The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.7±5.2% to 7.9±4.0% during saline administration (P<0.05). Nω-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.3±4.3% at baseline vs. 11.5±3.6% at reperfusion). Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P<0.01). Endothelium-independent vasodilatation did not differ between the occasions.Inhibition of arginase protects against endothelial dysfunction caused by ischemia-reperfusion in patients with CAD. Arginase inhibition may thereby be a promising therapeutic strategy in the treatment of ischemia-reperfusion injury.
- Reduced vasodilator function following acute resistance exercise in obese women. [Journal Article]
- Front Physiol 2014.:253.
Obesity contributes to stress induced impairments in endothelium-dependent vasodilation (EDV), a precursor to atherosclerosis. Since obesity is associated with inflammation and oxidative stress, we sought to determine if a single bout of strenuous weight lifting (SWL) reduces EDV among sedentary obese adults. Participants included 9 obese (OB) (BMI 30.0-40.0 kg/m(2)) and 8 lean (LN) (BMI 18.5-24.9 kg/m(2)) sedentary young women. All participants underwent a single bout of SWL using a progressive leg-press protocol. Brachial artery flow-mediated dilation (FMD) (an index of EDV) was determined using ultrasonography before and after SWL. Sublingual nitroglycerin (NTG) was used to determine brachial artery endothelium-independent vasodilation following SWL. Brachial artery FMD was significantly reduced in OB and LN women (LN: 6.4 ± 1.6%, p = 0.22) after SWL. There was no difference in the magnitude of change pre- and post-SWL between groups (OB: -2.4 ± 0.6% and LN: -2.2 ± 1.6%, p = 0.84). Dilation to NTG was lower in OB (21.6 ± 1.3%) compared to LN women (27.6 ± 2.1%, p = 0.02) and associated with body weight (r = -0.70, p = 0.01). These data suggest that EDV is reduced in woman after acute resistance exercise. Dilations to NTG were lower in obese compared to lean woman and associated with body weight suggesting that changes in sensitivity of blood vessels to NO occurs during obesity. These findings may be important for understanding vascular risk following acute exercise in obesity.
- Worsening of coronary spasm during the perioperative period: A case report. [Journal Article]
- World J Cardiol 2014 Jul 26; 6(7):685-8.
We present the case of a 65-year-old male with vasospastic angina (VSA) whose condition worsened during the perioperative period. He had been diagnosed with VSA 10 years prior. He was treated with two types of vasodilators and had not experienced any chest symptoms for 5 years. At this juncture, he underwent surgery for relapsed maxillary sublingual carcinoma. He had taken two vasodilators one day prior to surgery. Intravenous infusion of nitroglycerin (NTG) was initiated immediately before the surgery and continued the following day. Instead of stopping NTG, a dermal isosorbide dinitrate tape was applied on post-operative day 1. Two days later, a complete atrioventricular block with pulseless electrical activity appeared. After cardiopulmonary resuscitation, emergent coronary angiography showed severe coronary spasm in both the left and right coronary arteries. Intracoronary infusion of nitroglycerin and epinephrine with percutaneous cardiopulmonary support relieved the coronary spasm. During the perioperative period, several factors can trigger coronary vasospasm, including the discontinuation of vasodilators. Thus, surgeons, anesthetists, and cardiologists should watch for coronary vasospasm during this period and for worsening coronary spasm when discontinuing vasodilators in patients at risk for VSA.
- Repeated daily dosing with sildenafil provides sustained protection from endothelial dysfunction caused by ischemia and reperfusion: A Human In Vivo Study. [JOURNAL ARTICLE]
- Am J Physiol Heart Circ Physiol 2014 Jul 25.
Background. Sildenafil and nitroglycerin (GTN) are effective pharmacologic preconditioning agents, protecting from the adverse effects of ischemia and reperfusion (IR). Objectives. To determine whether repeated, daily administration of sildenafil or GTN provides sustained preconditioning from IR in the human forearm vasculature. Methods. Thirty-six healthy volunteers participated in this investigator blind, randomized, placebo- controlled trial. Subjects received transdermal GTN (0.6mg/hr, 2hrs/day), sildenafil (50mg once daily) or placebo. Twenty-four hours after the first dose of medication, subjects underwent assessment of flow- mediated dilation (FMD) before and after IR (15 min of upper arm ischemia followed by 15 min of reperfusion). Subjects continued their study medication for 7 days at which point FMD measurements were repeated before and after IR. Venous blood samples were obtained for determination of myeloperoxidase, P-selectin and myoglobin before and after each IR episode. Results. Twenty-four hours after the first dose, both sildenafil and GTN (but not placebo) provided protection from the adverse effects of IR. After 7 days of repeated daily doses, and 24 hours after the last dose, FMD was significantly blunted after IR in the placebo and GTN groups. In contrast, repeated daily administration of sildenafil provided continued protection from the adverse effects of IR on endothelial function. There was no significant change in plasma levels of myeloperoxidase, P-selectin or myoglobin at any time point. Conclusions. For the first time in humans, the present study establishes that sildenafil, but not GTN, provides sustained pharmacologic preconditioning of the endothelium and protection from the adverse IR effects on vascular function.
- Denture-related stomatitis is associated with endothelial dysfunction. [Journal Article]
- Biomed Res Int 2014.:474016.
Oral inflammation, such as periodontitis, can lead to endothelial dysfunction, accelerated atherosclerosis, and vascular dysfunction. The relationship between vascular dysfunction and other common forms of oral infections such as denture-related stomatitis (DRS) is unknown. Similar risk factors predispose to both conditions including smoking, diabetes, age, and obesity. Accordingly, we aimed to investigate endothelial function and major vascular disease risk factors in 44 consecutive patients with dentures with clinical and microbiological features of DRS (n = 20) and without DRS (n = 24). While there was a tendency for higher occurrence of diabetes and smoking, groups did not differ significantly in respect to major vascular disease risk factors. Groups did not differ in main ambulatory blood pressure, total cholesterol, or even CRP. Importantly, flow mediated dilatation (FMD) was significantly lower in DRS than in non-DRS subjects, while nitroglycerin induced vasorelaxation (NMD) or intima-media thickness (IMT) was similar. Interestingly, while triglyceride levels were normal in both groups, they were higher in DRS subjects, although they did not correlate with either FMD or NMD.
Conclusions.Denture related stomatitis is associated with endothelial dysfunction in elderly patients with dentures. This is in part related to the fact that diabetes and smoking increase risk of both DRS and cardiovascular disease.
- Enhanced Bacterial Tumor Delivery by Modulating the EPR Effect and Therapeutic Potential of Lactobacillus casei. [JOURNAL ARTICLE]
- J Pharm Sci 2014 Jul 16.
Bacteria of micrometer size could accumulate in tumor based on enhanced permeability and retention (EPR) effect. We report here Lactobacillus casei (L. casei), a nonpathogenic facultatively anaerobic bacterium, preferentially accumulated in tumor tissues after intravenously (i.v.) injection; at 24 h, live bacteria were found more in the tumor, whereas the bacteria in normal tissues including the liver and spleen were cleared rapidly. The tumor-selective accumulation and growth of L. casei is probably due to the EPR effect and the hypoxic tumor environment. Moreover, the bacterial tumor delivery was significantly increased by a nitric oxide (NO) donor nitroglycerin (NG, 10-70 times) and an angiotensin II converting enzyme inhibitor, enalapril (6-18 times). Consequently significant suppression of tumor growth was found in a colon cancer C26 model, and more remarkable antitumor effect was achieved when L. casei was combined with NG, probably by modulating the host nonspecific immune responses; tumor necrosis factor-α significantly increased in tumor after the treatment, as well as NO synthase activity and myleoperoxidase activity. These findings suggest the potential of L. casei as a candidate for targeted bacterial antitumor therapy, especially in combine with NG or other vascular mediators. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
- Testing a conceptual model on early opening of the microcirculation in severe sepsis and septic shock: A randomised, controlled pilot study. [JOURNAL ARTICLE]
- Eur J Anaesthesiol 2014 Jul 16.
Organ failure in severe sepsis and septic shock may be caused by microcirculatory failure.The objective of this study is to test a conceptual model of microcirculatory failure by using a resuscitation strategy targeting early opening of the constricted microcirculation with active vasodilatation.A prospective, randomised controlled pilot study.Single-centre mixed medical and surgical tertiary ICU.Ninety severe sepsis and septic shock patients randomised to early opening microcirculation resuscitation group or standard resuscitation group.Standard resuscitation group: fluids, noradrenaline, dobutamine and hydrocortisone were given to achieve a mean arterial pressure (MAP) of more than 60 mmHg, cardiac index more than 2.5 l min m and ScvO2 more than 70%. Microcirculation resuscitation group: nitroglycerin, enoximone, dopamine and dexamethasone targeting a microvascular flow index (MFI), measured by sublingual side-stream dark field imaging, more than 2.5.A decrease in organ failure score (SOFA) on day four of ICU treatment.Data from 37 microcirculation resuscitation and 28 standard resuscitation patients were analysed. In the microcirculation resuscitation group, MFI of more than 2.5 was achieved after a mean ± SD of 7.0 ± 4.6 h. The microcirculation resuscitation group received more fluids, and noradrenaline was equally prescribed in both groups. Per protocol, the decrease in SOFA score at day 4 was not different between groups (P = 0.64). There was a significant reduction in SOFA score in both groups compared with admission (1.2 and 1.6 in microcirculation resuscitation and standard resuscitation groups, respectively; P = 0.028 and P = 0.045).Early opening of the microcirculation in patients with severe sepsis and septic shock using nitroglycerin, enoximone, dopamine and corticosteroids did not result in a faster reduction in organ failure than standard resuscitation.Clinicaltrials.gov identifier NCT00484133.
- Evaluation of Statin Therapy on Endothelial Function in Hypercholesterolemic Rabbits by Automatic Measurement of Arterial Wall Movement Using Ultrasound Images. [JOURNAL ARTICLE]
- Ultrasound Med Biol 2014 Jul 10.
The aim of this study was to evaluate arterial endothelial function, assessed as acetylcholine-mediated dilation (AMD), in a hypercholesterolemic atherosclerotic rabbit model to investigate the effects of atorvastatin in the atherosclerotic process, using a new computerized analysis model and ultrasound images. Twenty-seven rabbits were fed a high-cholesterol (2%) diet for 6 wk and then divided into three groups for an additional 9 wk: Group A received regular chow food, group B received a 2% cholesterol-rich diet plus atorvastatin drug, and group C received regular chow food plus atorvastatin. Ultrasound examinations of endothelial function of the rabbit abdominal aorta artery were performed immediately after the 6 weeks (0 wk) and then 3, 6 and 9 wk after that. For off-line analysis, a computerized analysis method for evaluating instantaneous changes in the wall of the rabbit abdominal aorta was used. As parameters of improvement resulting from treatment, endothelium-dependent acetylcholine-induced dilation and endothelium-independent nitroglycerin-induced dilation were evaluated in treated rabbits. Differences among groups were tested using analysis of variance. On histopathology, intima-media thickness decreased after treatment in all groups. There were no significant differences in arterial diameter and blood velocity changes among treated rabbits at 0, 3, 6 and 9 wk of treatment in all groups, except in end-diastolic velocity, radial strain percentage, pulse index and resistance index in group C. In group A, AMD did not significantly improve after 3, 6 and 9 wk, as compared with 0 wk. Atorvastatin treatment significantly increased AMD (18%) at 3 wk in group B, compared with week 0. AMD significantly increased after 3 (26%), 6 (124%) and 9 (182%) wk in group C, compared with 0 wk. It is concluded that the new automatic method enables accurate and repeated evaluation of endothelial function during the progression and regression of atherosclerosis. Also, the results obtained in this study indicate that short-term administration of atorvastatin can improve endothelial function in cholesterol-fed rabbits.
- sGC-cGMP Signaling: Target for Anticancer Therapy. [JOURNAL ARTICLE]
- Adv Exp Med Biol 2014.:5-13.
The biologic endogenous production of cGMP was reported in the 1960s and followed by the demonstration of guanylyl cyclase activity and the isoforms of soluble and membrane-bound guanylyl cyclases. During the same period, cGMP specific phosphodiesterases also was discovered. Murad's lab established link between the endothelium derived relaxation factor (EDRF) and elevated cGMP concentration in the vascular system. October 12, 1998, the Nobel Assembly awarded the Nobel Prize in Medicine or Physiology to scientists Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning nitric oxide (NO) as a signaling molecule in the cardiovascular system. In contrast with the short research history of the enzymatic synthesis of NO, the introduction of nitrate-containing compounds for medicinal purposes marked its 150th anniversary in 1997. Glyceryl trinitrate (nitroglycerin; GTN) is the first compound of this category. Alfred Nobel (the founder of the Nobel Prize) himself had suffered from angina pectoris and was prescribed nitroglycerin for his chest pain while he refused to take due to the induction of headaches. Almost a century after its first chemical use, research in the nitric oxide and 3',5'-cyclic guanosine monophosphate (NO/cGMP) pathway has dramatically expanded and the role of NO/cGMP in physiology and pathology has been extensively studied. Soluble guanylyl cyclase (sGC) is the receptor for NO. The α1β1 heterodimer is the predominant isoform of sGC that is obligatory for catalytic activity. NO binds to the ferrous (Fe(2+)) heme at histidine 105 of the β1 subunit and leads to an increase in sGC activity and cGMP production of at least 200-fold. In this chapter, we reviewed the studies of sGC-cGMP signaling in cell proliferation; introduced our work of targeting sGC-cGMP signaling for cancer therapy; and explored the role of sGC-cGMP signaling in the chromatin-microenvironment.