- Sex-Related Differences in Reactivity of Cerebral Arterioles during Moderate Exercise Training. [JOURNAL ARTICLE]
- Microcirculation 2016 Aug 26.
Our goals were to determine the influence of sex on reactivity of cerebral arterioles and whether moderate exercise training (MExT) could influence sex-related differences in reactivity of cerebral arterioles.Responses of cerebral arterioles were measured in Sedentary (Sed) and MExT adult male and female Sprague-Dawley rats to eNOS-dependent (ADP); nNOS-dependent (NMDA) and NOS-independent (nitroglycerin) agonists before and following L-NMMA. In addition, protein expression for eNOS and nNOS was determined.NOS-dependent vasodilation was enhanced in Sed and MExT female rats compared to their male counterparts. L-NMMA produced a greater decrease in baseline diameter of arterioles in females compared to males, and produced less inhibition of NOS-dependent vasodilation in females. Expression of eNOS protein was significantly increased in Sed female when compared to Sed male rats, nNOS protein was similar in Sed males and females, but increased in MExT females.The findings from this study indicate that while NOS-dependent vascular reactivity is increased in females, MExT does not alter vasodilation in males or females. These studies provide insights into the influence of sex and MExT on the cerebral microcirculation and may have implications regarding mechanisms that protect the brain in females compared to males. This article is protected by copyright. All rights reserved.
- Peripheral Sensory Neurons Expressing Melanopsin Respond to Light. [Journal Article]
- Front Neural Circuits 2016.:60.
The ability of light to cause pain is paradoxical. The retina detects light but is devoid of nociceptors while the trigeminal sensory ganglia (TG) contain nociceptors but not photoreceptors. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to mediate light-induced pain but recent evidence raises the possibility of an alternative light responsive pathway independent of the retina and optic nerve. Here, we show that melanopsin is expressed in both human and mouse TG neurons. In mice, they represent 3% of small TG neurons that are preferentially localized in the ophthalmic branch of the trigeminal nerve and are likely nociceptive C fibers and high-threshold mechanoreceptor Aδ fibers based on a strong size-function association. These isolated neurons respond to blue light stimuli with a delayed onset and sustained firing, similar to the melanopsin-dependent intrinsic photosensitivity observed in ipRGCs. Mice with severe bilateral optic nerve crush exhibit no light-induced responses including behavioral light aversion until treated with nitroglycerin, an inducer of migraine in people and migraine-like symptoms in mice. With nitroglycerin, these same mice with optic nerve crush exhibit significant light aversion. Furthermore, this retained light aversion remains dependent on melanopsin-expressing neurons. Our results demonstrate a novel light-responsive neural function independent of the optic nerve that may originate in the peripheral nervous system to provide the first direct mechanism for an alternative light detection pathway that influences motivated behavior.
- Effect of nitroglycerin administration on cardio-ankle vascular index. [Journal Article]
- Vasc Health Risk Manag 2016.:313-9.
The purpose of this study was to clarify the difference between effects of nitroglycerin (NTG) on the functional stiffness in patients with and without coronary artery disease (CAD) using a newly developed stiffness index, cardio-ankle vascular index (CAVI).The two subject groups in this study were normal controls (n=31) and CAD patients (n=25). The normal controls had no medical history and were not on regular medications. On the other hand, the CAD patients had received various treatments like antihypertensive drugs, hypoglycemic agents, and statins. This study was conducted in CAD patients under medications. After a single sublingual administration of NTG 0.3 mg, CAVI, blood pressure (BP), and heart rate (HR) were measured every 5 minutes for 20 minutes. Comparisons of each parameter before and after taking NTG were evaluated for statistical significance using analysis of variance and post hoc tests. Tukey-Kramer test was used for post hoc comparisons.In the normal controls, CAVI significantly decreased from baseline after 5, 10, and 15 minutes (from 6.5±0.9 to 5.2±0.9, 5.5±0.9, and 5.7±0.9, respectively). Systolic BP and HR were not significantly changed. Diastolic BP significantly decreased from baseline after 5 and 10 minutes (from 72±8 to 64±9 and 63±9 mmHg, respectively). On the other hand, CAVI, HR, and diastolic BP were not changed significantly in CAD patients. Systolic BP was significantly decreased from baseline after 5, 10, and 15 minutes (from 147±16 to 131±14, 129±12, and 129±13 mmHg, respectively). In the comparison of the two groups, ΔCAVI was not significantly different between the normal controls and CAD patients (-1.4±0.7 vs -1.4±0.9, -1.1±0.7 vs -1.4±1.0, -0.8±0.7 vs -1.2±1.0, and -0.5±0.7 vs -1.1±1.0 at 5, 10, 15, and 20 minutes, respectively). ΔHR was not significantly different between the two groups. ΔSystolic BP in the CAD patients was significantly higher than in the normal controls at 5, 10, 15, and 20 minutes (normal controls vs CAD; -3±7 vs -10±11, -3±5 vs -10±11, -3±6 vs -13±10, and -1±6 vs -11±10 mmHg, respectively). ΔDiastolic BP in the normal controls was significantly higher than in the CAD patients at 5 and 10 minutes (normal controls vs CAD; -8±6 vs -4±4 and -9±4 vs -6±5 mmHg, respectively).After NTG administration, the stiffness of the arteries from the origin of the aorta to the ankle as measured by CAVI decreased in both the normal controls and CAD patients, indicating that the response of arterial smooth muscle cells to nitric oxide is preserved even in CAD patients under medication.
- Heart Rate reduction by IVabradine for improvement of ENDothELial function in patients with coronary artery disease: the RIVENDEL study. [JOURNAL ARTICLE]
- Clin Res Cardiol 2016 Aug 12.
Data from experimental studies suggest that the f current-inhibitor ivabradine may reduce oxidative stress and improve endothelial function. We aimed to evaluate the effect of ivabradine on endothelial function in patients with coronary artery disease (CAD) after complete revascularization with percutaneous coronary angioplasty (PCI).At least 30 days after PCI, 70 patients were randomized (T0) to receive ivabradine 5 mg twice daily (ivabradine group, n = 36) or to continue with standard medical therapy (control group, n = 34). After 4 weeks (T1), ivabradine dose was adjusted up to 7.5 mg twice daily in patients with heart rate (HR) at rest >60 bpm, and thereafter continued for additional 4 weeks (T2). At all timings, brachial artery reactivity was assessed by flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD). No significant differences were observed at T0 between ivabradine and control groups in terms of HR (68.0 ± 6.4 vs. 67.6 ± 6.4 bpm; p = 0.803), FMD (8.7 ± 4.9 vs. 8.0 ± 5.5 %; p = 0.577) and NMD (12.7 ± 6.7 vs. 13.3 ± 6.2 %; p = 0.715). Over the study period, a significant reduction of HR (65.2 ± 5.9 bpm at T1, 62.2 ± 5.7 bpm at T2; p < 0.001), and improvement of FMD (12.2 ± 6.2 % at T1, 15.0 ± 7.7 % at T2; p < 0.001) and NMD (16.6 ± 10.4 % at T1, 17.7 ± 10.8 at T2; p < 0.001) were observed in the ivabradine group, while no significant changes were observed in the control group. In the ivabradine group, a moderate negative correlation was observed between the HR variation and FMD variation from T1 to T3 (r = -0.448; p = 0.006).In patients with CAD undergoing complete revascularization with PCI, addition of ivabradine to the standard medical therapy produces a significant improvement in endothelial function. This effect seems to be related to HR reduction. ClinicalTrials.gov number, NCT02681978.
- [OP.1C.03] REGIONAL VASCULAR STIFFNESS IN RESPONSE TO NITROGLYCERIN AND THEIR IMPACT ON ARTERIAL STIFFNESS GRADIENT. [Journal Article]
- J Hypertens 2016 Sep.:e8.
In dialysis patients, we have shown that aortic-brachial stiffness gradient outperforms cf-PWV for the prediction of mortality. We hypothesized that arterial stiffness gradient increases after administration of vasodilatory drugs. The aim of this study is to examine the impact of nitroglycerin (GTN) on arterial stiffness gradient using aortic-brachial (AB-PWV ratio) and aortic-femoral PWV ratios (AF-PWV ratio) in non-dialysis subjects.This cross-sectional study was conducted in 35 adult patients. The mean age was 66 ± 10, 77% were men, 17% and 14% of the subjects had diabetes and cardiovascular disease. Aortic, brachial and femoral stiffness were respectively measured by determination of carotid-femoral (cf-PWV), carotid-radial (cr-PWV) and femoral-dorsalis pedis pulse wave velocity (fd-PWV), at baseline and 5 minutes post-GTN 0.4 mg s.l.. Direct distance measures were used to determine PWV. AB-PWV ratio and AF-PWV ratio were respectively obtained by dividing cf-PWV by cr-PWV or fd-PWV. Generalized estimating equations were used to evaluate the impact of GTN on changes of regional stiffness (cf-PWV, cr-PWV and fd-PWV) and arterial stiffness gradients (AB-PWV ratio and AF-PWV ratio) after adjustments for mean blood pressure (MBP).At baseline, cf-PWV, cr-PWV and fd-PWV were, respectively, 11.8 ± 2.1 m/s, 9.0 ± 1.4 m/s and 8.2 ± 1.6 m/s resulting in an AB-PWV ratio of 1.34 ± 0.28 and an AF-PWV ratio of 1.50 ± 0.41. After GTN, there was a decrease in MBP of 2.1 mmHg (p = 0.016), without any changes in cf-PWV (11.8 ± 2.3 m/s). However, there were a significant reduction in cr-PWV by 0.54 m/s (p < 0.001) and fd-PWV by 1.20 m/s (p < 0.001), which resulted in a significant increase in AB- and AF-PWV ratios by 0.10 (p = 0.001) and by 0.24 (p < 0.001), respectively. Adjustments for MBP did not affect the effect size nor the significance of changes in AB- and AF-PWV ratios.The present study shows that aortic-brachial and aortic-femoral stiffness gradients are adversely affected by GTN administration. The differential impact of various anti-hypertensive drugs on the vascular stiffness gradient needs to be further studied.
- Nitrates for the prevention of cardiac morbidity and mortality in patients undergoing non-cardiac surgery. [REVIEW, JOURNAL ARTICLE]
- Cochrane Database Syst Rev 2016 Aug 4.:CD010726.
Cardiac complications are not uncommon in patients undergoing non-cardiac surgery, especially in patients with coronary artery disease (CAD) or at high risk of CAD. Perioperative cardiac complications can lead to mortality and morbidity, as well as higher costs for patient care. Nitrates, which are among the most commonly used cardiovascular drugs, perform the function of decreasing cardiac preload while improving cardiac blood perfusion. Sometimes, nitrates are administered to patients undergoing non-cardiac surgery to reduce the incidence of cardiac complications, especially for patients with CAD. However, their effects on patients' relevant outcomes remain controversial.• To assess effects of nitrates as compared with other interventions or placebo in reducing cardiac risk (such as death caused by cardiac factors, angina pectoris, acute myocardial infarction, acute heart failure and cardiac arrhythmia) in patients undergoing non-cardiac surgery.• To identify the influence of different routes and dosages of nitrates on patient outcomes.We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Chinese BioMedical Database until June 2014. We also searched relevant conference abstracts of important anaesthesiology or cardiology scientific meetings, the database of ongoing trials and Google Scholar.We reran the search in January 2016. We added three potential new studies of interest to the list of 'Studies awaiting classification' and will incorporate them into our formal review findings for the review update.We included randomized controlled trials (RCTs) comparing nitrates versus no treatment, placebo or other pharmacological interventions in participants (15 years of age and older) undergoing non-cardiac surgery under any type of anaesthesia.We used standard methodological procedures as expected by Cochrane. Two review authors selected trials, extracted data from included studies and assessed risk of bias. We resolved differences by discussion and, when necessary, sought help and suggestions from a third review author. We used a random-effects model for data analysis.We included 27 randomized controlled trials (RCTs) (8244 participants analysed). Investigators reported 12 different comparisons of three different nitrates (nitroglycerin, isosorbide dinitrate and nicorandil) versus no treatment, placebo or other pharmacological interventions. All participants were older than 15 years of age. More than half of the trials used general anaesthesia. Surgical procedures in most trials were at low to moderate risk for perioperative cardiac complications. Only two comparisons including three studies reported the primary outcome - all-cause mortality up to 30 days post operation. Researchers reported other morbidity outcomes and adverse events in a variable and heterogeneous way, resulting in limited available data for inclusion in the meta-analysis. We determined that the overall methodological quality of included studies was fair to low, in accordance with risk of bias in most domains.In summary, we found no difference in the primary outcome - all-cause mortality up to 30 days post operation - when nitroglycerin was compared with no treatment (one study, 60 participants, 0/30 vs 1/30; (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.01 to 7.87, very low-quality evidence based on GRADE criteria) or with placebo (two studies, 89 participants, 1/45 vs 0/44; RR 2.81, 95% CI 0.12 to 63.83, very low-quality evidence). Regarding our secondary outcomes, we noted no statistically significant differences in angina pectoris, acute myocardial infarction, acute heart failure, cardiac arrhythmia or cardiac arrest in any comparisons. In comparisons versus nitroglycerin, although more events of cardiac ischaemia were observed in participants receiving no treatment or placebo, we found no statistically significant differences in any comparisons, except the comparison of nicorandil versus placebo. One study revealed a potential dose-dependent protective effect of nicorandil for cardiac ischaemia.Adverse events were reported in a heterogeneous way among the comparisons. In general, more participants treated with nitrates had hypotension, tachycardia and headache, but investigators reported no statistically significant differences between groups in any comparisons.This systematic review suggests that nitroglycerin or isosorbide dinitrate is not associated with improvement in mortality and cardiac complications among patients undergoing non-cardiac surgery. Limited evidence suggests that nicorandil may reduce the risk of cardiac ischaemia in participants undergoing non-cardiac surgery. Additional studies are needed to consolidate the evidence.However, the data included in many of the analyses in this review are sparse - that is, adequate data are few - resulting in very low power to detect differences between nitrates and comparators. Thus, a more objective conclusion would state that available evidence is insufficient to show whether nitrates are associated with improvement in mortality and cardiac complications among patients undergoing non-cardiac surgery.Over the past decade, no high-quality studies have focused on association of cardiac mortality and morbidity with use of nitrates during non-cardiac surgery. This review underlines the need for well-designed trials in this field.
- Suspected Arterial Vasospasm in Femoro-Femoral Veno-Arterial Extracorporeal Life Support. [JOURNAL ARTICLE]
- ASAIO J 2016 Jul 26.
Extracorporeal life support (ECLS) is increasingly used worldwide in patients with life-threatening hemodynamic and / or respiratory conditions. The femoral veno-arterial cannulation, whether percutaneous or surgical, is the simplest and quickest method, yet a number of vascular complications may occur. We present 2 cases in which, despite a well-placed reperfusion cannula in the superior femoral artery, apparent limb ischemia of the cannulated limb developed rapidly after ECLS implantation and was suspected to be due to arterial vasospasm. Both cases were successfully managed with the injection of a vasodilator cocktail of verapamil, nitroglycerin and lidocain directly in the reperfusion cannula.
- One Minute of Marijuana Secondhand Smoke Exposure Substantially Impairs Vascular Endothelial Function. [Journal Article]
- J Am Heart Assoc 2016 Aug; 5(8)
Despite public awareness that tobacco secondhand smoke (SHS) is harmful, many people still assume that marijuana SHS is benign. Debates about whether smoke-free laws should include marijuana are becoming increasingly widespread as marijuana is legalized and the cannabis industry grows. Lack of evidence for marijuana SHS causing acute cardiovascular harm is frequently mistaken for evidence that it is harmless, despite chemical and physical similarity between marijuana and tobacco smoke. We investigated whether brief exposure to marijuana SHS causes acute vascular endothelial dysfunction.We measured endothelial function as femoral artery flow-mediated dilation (FMD) in rats before and after exposure to marijuana SHS at levels similar to real-world tobacco SHS conditions. One minute of exposure to marijuana SHS impaired FMD to a comparable extent as impairment from equal concentrations of tobacco SHS, but recovery was considerably slower for marijuana. Exposure to marijuana SHS directly caused cannabinoid-independent vasodilation that subsided within 25 minutes, whereas FMD remained impaired for at least 90 minutes. Impairment occurred even when marijuana lacked cannabinoids and rolling paper was omitted. Endothelium-independent vasodilation by nitroglycerin administration was not impaired. FMD was not impaired by exposure to chamber air.One minute of exposure to marijuana SHS substantially impairs endothelial function in rats for at least 90 minutes, considerably longer than comparable impairment by tobacco SHS. Impairment of FMD does not require cannabinoids, nicotine, or rolling paper smoke. Our findings in rats suggest that SHS can exert similar adverse cardiovascular effects regardless of whether it is from tobacco or marijuana.