Differential expression of components of the CGRP-receptor family in human coronary and human middle meningeal arteries: functional implications.

BACKGROUND: Different responses in human coronary arteries (HCA) and human middle meningeal arteries (HMMA) were observed for some of the novel CGRP receptor antagonists, the gepants, for inhibiting CGRP-induced relaxation. These differences could be explained by the presence of different receptor populations in the two vascular beds. Here, we aim to elucidate which receptors are involved in the relaxation to calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2) in HCA and HMMA. METHODS: RNA was isolated from homogenized human arteries (23 HCAs; 12 F, 11 M, age 50 ± 3 years and 26 HMMAs; 14 F, 12 M, age 51 ± 3 years) and qPCR was performed for different receptor subunits. Additionally, relaxation responses to CGRP, AM or AM2 of the human arteries were quantified using a Mulvany myograph system, in the presence or absence of the adrenomedullin 1 receptor antagonist AM22-52 and/or olcegepant. RESULTS: Calcitonin-like receptor (CLR) mRNA was expressed equally in both vascular beds, while calcitonin receptor (CTR) and receptor activity-modifying protein 3 (RAMP3) expression was low and could not be detected in all samples. RAMP1 expression was similar in HCA and HMMA, while RAMP2 expression was higher in HMMA. Moreover, receptor component protein (RCP) expression was higher in HMMA than in HCA. Functional experiments showed that olcegepant inhibits relaxation to all three agonists in both vascular beds. In HCA, antagonist AM22-52 did not inhibit relaxation to any of the agonists, while a trend for blocking relaxation to AM and AM2 could be observed in HMMA. CONCLUSION: Based on the combined results from receptor subunit mRNA expression and the functional responses in both vascular tissues, relaxation of HCA is mainly mediated via the canonical CGRP receptor (CLR-RAMP1), while relaxation of HMMA can be mediated via both the canonical CGRP receptor and the adrenomedullin 1 receptor (CLR-RAMP2). Future research should investigate whether RAMP2 predominance over RAMP1 in the meningeal vasculature results in altered migraine susceptibility or in a different response to anti-migraine medication in these patients. Moreover, the exact role of RCP in CGRP receptor signalling should be elucidated in future research.

LDHB-deficient brain exhibits resistance to ischemic neuronal cell death due to increased vasodilation.

Ischemic stroke triggers a cascade of metabolic and inflammatory events leading to neuronal death, particularly in the hippocampus. Here, we investigate the role of lactate metabolism in ischemic resistance using LDHB-deficient mice, which exhibit impaired lactate utilization. Contrary to expectations of severe neuronal damage due to metabolic defects, LDHB-deficient mice displayed significantly increased neuronal survival following ischemic insult. Magnetic resonance spectroscopy revealed elevated lactate levels in LDHB-deficient brains, which correlated with enhanced vasodilation of the posterior communicating artery (PComA) and increased extracellular PGE2 levels. These findings suggest that elevated lactate inhibits PGE2 reabsorption, promoting vasodilation and neuronal protection. Our results highlight lactate's potential role in neuroprotection and its therapeutic promise for ischemic stroke.

Concentration-dependent microvascular responses to repeated iontophoresis of acetylcholine.

BACKGROUND: Iontophoresis studies face challenges due to the unknown absolute drug dose delivered and the possible effect of the current used in drug delivery on the microvessels, known as current-induced vasodilation. This study aimed to investigate how various concentrations of acetylcholine (ACh), delivered through transdermal iontophoresis using repeated current pulses, impact the recovery profile of the microvascular response. METHODS: The study included fifteen healthy volunteers, and microvascular responses to five concentrations of iontophorised ACh (ranging from 0.0055 mM to 55 mM) and sterile water were assessed at six forearm skin sites using polarized reflectance spectroscopy. Iontophoresis at each concentration involved three consecutive pulses separated 8 recovery periods. RESULTS: Current-induced responses were more pronounced for lower concentrations of ACh and for sterile water. With repeated pulses, lower concentrations of ACh exhibited a recovery profile more akin to higher concentrations. PERSPECTIVE: Through repeated iontophoresis of ACh, microvascular responses exhibit variation based on the drug concentration and the number of pulses administered. These variations are likely attributed to changes in skin conductivity and permeability.

Preparation and Vasodilation Mechanism of Angiotensin-I-Converting Enzyme Inhibitory Peptide from Ulva prolifera Protein.

Ulva prolifera, a type of green algae that can be consumed, was utilized in the production of an angiotensin-I converting enzyme (ACE) inhibitory peptide. The protein from the algae was isolated and subsequently hydrolyzed using a neutral protease. The resulting hydrolysate underwent several processes including Sephadex-G100 filtration chromatography, ultrafiltration, HPLC-Q-TOF-MS analysis, ADMET screening, UV spectrum detection test, molecular docking, and molecular dynamic simulation. Then, the ACE inhibitory peptide named KAF (IC50, 0.63 ± 0.26 µM) was identified. The effectiveness of this peptide in inhibiting ACE can be primarily attributed to two conventional hydrogen bonds. Additionally, it could activate endothelial nitric oxide synthase (eNOS) activity to promote the generation of nitric oxide (NO). Additionally, KAF primarily increased the intracellular calcium (Ca2+) level by acting on L-type Ca2+ channel (LTCC) and the ryanodine receptor (RyR) in the endoplasmic reticulum, and completed the activation of eNOS under the mediation of protein kinase B (Akt) signaling pathway. Our study has confirmed that KAF has the potential to be processed into pharmaceutical candidate functions on vasoconstriction.

CGS-21680 defers cisplatin-induced AKI-CKD transition in C57/BL6 mice.

Acute kidney injury (AKI), with a high mortality and morbidity, is known as a risk factor for developing progressive chronic kidney disease (CKD). Targeting transition of AKI to CKD displays an excellent therapeutic potential. This study aims at investigating the role of CGS-21680, selective A2AR agonist, in deferring Cis-induced AKI-CKD transition. The AKI-CKD transition model was induced in C57/BL6 mice by repeated low doses of Cis (2.5 mg/kg i.p for 5 consecutive days in two cycles with a recovery phase of 16 days between two cycles). CGS-21680 was administered daily for 6 weeks (0.1 mg/kg, i.p). Urine, blood, and kidney were collected at three different time points to track the disease progression. CGS-21680 administration preserved kidney function and attenuated tubular damage as evidenced by hematoxylin-eosin (H&E) histopathology. CGS-21680 significantly restored oxidative status as reflected by reduced malondialdehyde (MDA) content and increased total antioxidant capacity (TAC). CGS-21680 showed anti-inflammatory effect as indicated by decreased TNF-α and iNOS. Additionally, CGS-21680 ameliorated endothelial dysfunction and enhanced renal vasodilation as evidenced by upregulation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) expression and down regulation of endothelin-1 (ET-1) and its receptor endothelin-A (ET-A) receptor expression. CGS-21680 also attenuated renal fibrosis as reflected by the reduction of percentage of fibrosis in Masson's trichome-stained renal sections and down regulation of transforming growth factor beta1 (TGF-ß1) protein expression in IHC-stained renal sections. In conclusion, CGS-21680 could defer Cis-induced AKI-CKD transition via its vasodilatory, antioxidant, anti-inflammatory, and anti-fibrotic effects.

Investigation of synergistic interaction of sinensetin, eupatorin, and 3'-hydroxy-5,6,7,4'-tetramethoxyflavone in vasodilation efficacy.

Modern medicines often follow a "single-compound, single-target" paradigm, which may not be effective against complex diseases with multifactorial causes. Medicinal plants, such as Orthosiphon stamineus-widely used in Southeast Asia for its significant vasodilatory and antihypertensive properties-offer an alternative. These effects are largely attributed to the synergistic actions of sinensetin, eupatorin, and 3'-hydroxy-5,6,7,4'- tetramethoxyflavone (TMF). The present study was designed to explore the interactions among these compounds and their collective impact on vasodilation. The current investigation utilized in vitro aortic ring assays and an orthogonal stimulus-response compatibility approach to unveil the synergistic interactions of sinensetin, eupatorin, and TMF in specific combination ratios within compatibility groups. The current results showed that G2, G7, G27, and G28 achieved vasodilatory efficacies exceeding 100%, with recorded efficacies of 190%, 148%, 117.6%, and 116.25%, respectively. Conversely, formulation F1 exhibited only additive effects with an efficacy of 88.02%. The dose-response study revealed G28 exhibited the strongest concentration-dependent vasodilatory responses, with a maximum response (RMAX) of 119.05 ± 3.29% and an EC50 of 6.78 ± 0.70 µg/mL. Conversely, G2, despite showing the highest efficacy in the orthogonal stimulus-response compatibility study, demonstrated a lower vasodilatory effect, with RMAX R and EC50 recorded at 85.78 ± 12.67% and 15.32 ± 3.07 µg/mL, respectively. These findings highlight the complexities of compound interactions in plants and underscore the potential of botanical medicines as comprehensive healthcare solutions for multifactorial diseases.

Lipid emulsion attenuates vasodilation by decreasing intracellular calcium and nitric oxide in vascular endothelial cells.

Lipid emulsion (LE), a widely used parenteral nutrition, exhibits a well-documented ability to reverse the vasodilatory effects induced by acetylcholine in blood vessels. However, the specific mechanisms underlying this action are not yet fully understood. This study aimed to elucidate the mechanism by which LE reverses vasodilation in vitro through dose-response curve experiments, calcium imaging, and fluorescence assays. The results revealed a significant attenuation of acetylcholine (Ach)-induced vasodilation in rat thoracic aortic rings following LE exposure. In human aortic endothelial cells, pretreatment with LE significantly suppressed ATP-induced calcium elevation. This suppression persisted even after elimination of extracellular calcium with a calcium chelator. Moreover, LE pre-exposure reduced the intracellular calcium concentration ([Ca2+]i) elevation in endothelial cells following cyclopiazonic acid (CPA) treatment, suggesting enhanced endoplasmic reticulum (ER) calcium reuptake. Additionally, nitric oxide (NO) fluorescence assays showed a decrease in NO production upon ATP stimulation post-LE pretreatment of endothelial cells. Taken together, these results indicate that the reversal of vasodilation by LE may involve enhanced ER calcium uptake, leading to a reduction in intracellular calcium concentration and suppression of NO (key vasodilatory agent) synthesis.

Impaired Peripheral Vascular Function Following Ischemic Stroke in Mice: Potential Insights into Blood Pressure Variations in the Post-Stroke Patient.

High systolic blood pressure and increased blood pressure variability after the onset of ischemic stroke are associated with poor clinical outcomes. One of the key determinants of blood pressure is arteriolar size, determined by vascular smooth muscle tone and vasodilatory and vasoconstrictor substances that are released by the endothelium. The aim of this study is to outline alterations in vasomotor function in isolated peripheral arteries following ischemic stroke. The reactivity of thoracic aortic segments from male C57BL/6 mice to dilators and constrictors was quantified using wire myography. Acetylcholine-induced endothelium-dependent vasodilation was impaired after ischemic stroke (LogIC50 Sham = -7.499, LogIC50 Stroke = -7.350, p = 0.0132, n = 19, 31 respectively). The vasodilatory responses to SNP were identical in the isolated aortas in the sham and stroke groups. Phenylephrine-induced vasoconstriction was impaired in the aortas isolated from the stroke animals in comparison to their sham treatment counterparts (Sham LogEC50= -6.652 vs. Stroke LogEC50 = -6.475, p < 0.001). Our study demonstrates that 24 h post-ischemic stroke, peripheral vascular responses are impaired in remote arteries. The aortas from the stroke animals exhibited reduced vasoconstrictor and endothelium-dependent vasodilator responses, while the endothelium-independent vasodilatory responses were preserved. Since both the vasodilatory and vasoconstrictor responses of peripheral arteries are impaired following ischemic stroke, our findings might explain increased blood pressure variability following ischemic stroke.

Association between endothelial function and skin advanced glycation end-products (AGEs) accumulation in a sample of predominantly young and healthy adults.

BACKGROUND: In populations with chronic disease, skin autofluorescence (SAF), a measure of long-term fluorescent advanced glycation end-products (AGEs) accumulation in body tissues, has been associated with vascular endothelial function, measured using flow-mediated dilation (FMD). The primary aim of this study was to quantify the relationship between endothelial function and tissue accumulation of AGEs in adults from the general population to determine whether SAF could be used as a marker to predict early impairment of the endothelium. METHODS: A cross-sectional study was conducted with 125 participants (median age: 28.5 y, IQR: 24.4-36.0; 54% women). Endothelial function was measured by fasting FMD. Skin AGEs were measured as SAF using an AGE Reader. Participant anthropometry, blood pressure, and blood biomarkers were also measured. Associations were evaluated using multivariable regression analysis and were adjusted for significant covariates. RESULTS: FMD was inversely correlated with SAF (ρ = -0.50, P < 0.001) and chronological age (ρ = -0.51, P < 0.001). In the multivariable analysis, SAF, chronological age, and male sex were independently associated with reduced FMD (B [95% CI]; -2.60 [-4.40, -0.80]; -0.10 [-0.16, -0.03]; 1.40 [0.14, 2.67], respectively), with the multivariable model adjusted R2 = 0.31, P < 0.001. CONCLUSIONS: Higher skin AGE levels, as measured by SAF, were associated with lower FMD values, in a predominantly young, healthy population. Additionally, older age and male participants exhibited significantly lower FMD values, corresponding with compromised endothelial function. These results suggest that SAF, a simple and inexpensive marker, could be used to predict endothelial impairment before the emergence of any structural artery pathophysiology or classic cardiovascular disease risk markers. TRIAL REGISTRATION: The study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000821897) and concurrently entered into the WHO International Clinical Trials Registry Platform under the same ID number.

Impairment of microvascular endothelial Kir2.1 channels contributes to endothelial dysfunction in human hypertension.

Hypertension is associated with decreased endothelial function through reduced contributions of nitric oxide (NO). We previously discovered that flow-induced NO production in resistance arteries of mice and humans critically depends on endothelial inwardly rectifying K+ (Kir2.1) channels. The goal of this study was to establish whether these channels contribute to the impairment of endothelial function, measured by flow-induced vasodilation (FIV) in peripheral resistance arteries of humans with hypertension. We measured FIV in vessels isolated from subcutaneous fat biopsies from 32 subjects: normotensive [n = 19; 30.6 ± 9.8 yr old; systolic blood pressure (SBP): 115.2 ± 7 mmHg; diastolic blood pressure (DBP): 75.3 ± 5.7 mmHg] and hypertensive (n = 13; 45.3 ± 15.3 yr old; SBP: 146.1 ± 15.2 mmHg; DBP: 94.4 ± 6.9 mmHg). Consistent with previous studies, we find that FIV is impaired in hypertensive adults as demonstrated by a significant reduction in FIV when compared with the normotensive adults. Furthermore, our data suggest that the impairment of FIV in hypertensive adults is partially attributed to a reduction in Kir2.1-dependent vasodilation. Specifically, we show that blocking Kir2.1 with ML133 or functionally downregulating Kir2.1 with endothelial-specific adenoviral vector containing dominant-negative Kir2.1 (dnKir2.1) result in a significant reduction in FIV in normotensive subjects but with a smaller effect in hypertensive adults. The Kir2.1-dependent vasodilation was negatively correlated to both SBP and DBP, indicating that the Kir2.1 contribution to FIV decreases as blood pressure increases. In addition, we show that exposing vessels from normotensive adults to acute high-pressure results in loss of Kir2.1 contribution, as high pressure impairs vasodilation. No effect is seen when these vessels were incubated with dnKir2.1. Overexpressing wtKir2.1 in the endothelium resulted in some improvement in vasodilation in arteries from all participants, with a greater recovery in hypertensive adults. Our data suggest that hypertension-induced suppression of Kir2.1 is an important mechanism underlying endothelial dysfunction in hypertension.NEW & NOTEWORTHY Impairment of endothelial function under high blood pressure is linked to the loss of inwardly rectifying K+ (Kir2.1) channels activity in human resistance arteries, leading to a reduction in flow-induced vasodilation and possibly leading to a vicious cycle between elevation of blood pressure, and further impairment of Kir2.1 function and flow-induced vasodilation.

Peripheral venous dilation using flow-mediated dilation response: A randomized crossover study.

BACKGROUND: Venodilation is crucial in enhancing the success rate of peripheral intravenous cannulation. Flow-mediated dilation (FMD) is a vasodilatory response initiated by temporary ischemia followed by reperfusion. This crossover study aimed to test the hypothesis that FMD induces dilation of the peripheral veins of the forearm. METHODS: Fifteen healthy volunteers underwent the FMD and control conditions in a randomized order. FMD involved a 5-min occlusion of blood flow in the brachial artery, followed by reperfusion, achieved by inflating and deflating a cuff placed on the upper arm. The control condition involved participants remaining at rest. The primary outcome measure was a change in the cross-sectional area of the cephalic vein post-intervention. The secondary outcomes included changes in venous diameter and perfusion index (PI). RESULTS: FMD significantly increased the cross-sectional area of the cephalic vein compared with the control condition (relative change to baseline: 37.7% (31.4) vs 2.2% (11.7)), with a mean difference of 35.4% (95% confidence interval (CI): 16.4-54.5, p = 0.001). Both longitudinal and transverse diameters were significantly expanded with FMD compared to the control (relative change to baseline: 15.7% (15.4) vs 2.6% (3.6), p = 0.004; 18.9% (15.6) vs -0.0 (10.2), p = 0.003, respectively). Additionally, PI significantly increased with FMD compared with the control (relative change to baseline: 77.8% (56.9) vs 14.6% (36.0)), with a mean difference of 63.2% (95% CI: 31.2-95.2, p = 0.001). CONCLUSION: FMD application induced dilation of the cephalic vein of the forearm. The findings suggest that FMD is an effective technique for dilating the venous area and potentially improving the success rate of peripheral intravenous cannulation.

A 3-D whole-body human thermoregulatory model to simulate cold-induced vasodilation in the hands and feet.

The cold-induced vasodilation (CIVD) response of the human body to Arctic-like environments helps delay or prevent cold injuries to peripheral regions, such as the hands and feet. To more comprehensively predict the thermal responses of these body regions to cold stress, here we extended our previously developed and validated anatomically accurate three-dimensional whole-body thermoregulatory human model by incorporating a new phenomenological formulation of the CIVD mechanism. In this formulation, we modulated the cyclic vasodilation and vasoconstriction flow of warm blood from the body core to the peripheral regions solely by determining the heat-transfer exchange between the skin and the surrounding environment, and deactivated it when the core body temperature decreased to 36.5 °C. In total, we calibrated and validated the model using eight distinct studies involving 153 unique male subjects exposed to 10 diverse experimental conditions, including cold-air exposure of the whole body as well as air exposure and cold-water immersion of the hand or the foot. With CIVD incorporated, the model predictions generally yielded root mean square errors (RMSEs) of <3.0 °C for skin temperature, which represented a reduction of up to 3.6 °C compared to when we did not consider CIVD. Similarly, the incorporation of CIVD increased the fraction of predictions within two standard errors of the measured data by up to 63 %. The model predictions yielded RMSEs for core body temperature of <0.2 °C. The model can be used to provide guidelines to reduce the risk of cold-related injuries during prolonged exposures to very-cold environments.

Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome.

The transcriptional response to hypoxia is temporally regulated, yet the molecular underpinnings and physiological implications are unknown. We examined the roles of hepatic Bmal1 and Hif1α in the circadian response to hypoxia in mice. We found that the majority of the transcriptional response to hypoxia is dependent on either Bmal1 or Hif1α, through shared and distinct roles that are daytime determined. We further show that hypoxia-inducible factor (HIF)1α accumulation upon hypoxia is temporally regulated and Bmal1 dependent. Unexpectedly, mice lacking both hepatic Bmal1 and Hif1α are hypoxemic and exhibit increased mortality upon hypoxic exposure in a daytime-dependent manner. These mice display mild liver dysfunction with pulmonary vasodilation likely due to extracellular signaling regulated kinase (ERK) activation, endothelial nitric oxide synthase, and nitric oxide accumulation in lungs, suggestive of hepatopulmonary syndrome. Our findings indicate that hepatic BMAL1 and HIF1α are key time-dependent regulators of the hypoxic response and can provide molecular insights into the pathophysiology of hepatopulmonary syndrome.

Targeting endothelial KCa channels in vivo restores arterial and endothelial function in type 2 diabetic rats.

OBJECTIVE: This study tested the hypothesis that administration of the KCa channel activator SKA-31 restores endothelium-dependent vasodilation in vivo in Type 2 Diabetic (T2D) rats. BACKGROUND: Acute treatment of isolated resistance arteries from T2D rats and humans with SKA-31 significantly improved endothelium-dependent vasodilation. However, it is unknown whether these in situ actions translate to intact vascular beds in vivo. METHODS: Male Sprague Dawley (SD) and T2D Goto-Kakizaki (GK) rats (26-32 weeks of age) were injected intraperitoneally with either drug vehicle or 10 mg/kg SKA-31. Doppler ultrasound imaging was used to record reactive hyperemia/flow-mediated dilation (FMD) in the femoral artery following release of an occlusion cuff on the distal hind limb, along with diameter changes in the left main coronary artery in response to inhaled isoflurane (2 % â†’ 5 %). RESULTS: Vehicle treated SD rats exhibited a robust and reversible FMD response, the magnitude and time course of which did not differ in SD rats treated with SKA-31. In contrast, only a weak FMD response was observed in vehicle-treated T2D GK rats, whereas prior SKA-31 administration restored FMD to the level observed in control SD rats. Exposure of SD rats to 5 % isoflurane caused robust coronary artery dilation, which was not altered by prior treatment with SKA-31. In T2D GK rats, 5 % isoflurane inhalation alone did not increase coronary artery diameter, however, a strong vasodilatory response was observed following SKA-31 treatment. SKA-31 administration did not modify intrinsic heart rate responses in either protocol. CONCLUSIONS: Enhancement of KCa channel activity in vivo restores endothelium-dependent vasodilation in T2D rats that exhibit peripheral endothelial dysfunction.

New device for assessment of endothelial function: plethysmographic flow-mediated vasodilation (pFMD).

Measurement of flow-mediated vasodilation (FMD) in the brachial artery by using ultrasound is a well-established technique for evaluating endothelial function. To make the measurement quicker and simpler than the measurements of conventional ultrasound FMD (uFMD), we have developed a new noninvasive method, plethysmographic FMD (pFMD), to assess vascular response to reactive hyperemia in the brachial artery. The aim of this study was to determine the accuracy of measurement of pFMD in comparison to that of measurement of conventional uFMD. This study was a multi-center, cross-sectional study. We compared pFMD by a new device using cuff pressure and volume with conventional uFMD using ultrasound in 50 men (mean age, 41 ± 9 years). pFMD significantly correlated with conventional uFMD (ß = 0.59, P < 0.001). In Bland-Altman plot analysis of pFMD and conventional uFMD, the mean difference of pFMD and conventional uFMD was 0.78%, and limits of agreement (mean difference ±2 standard deviations of the difference) ranged from -4.53% to 6.11%. We demonstrated validity of the new method for measurement of pFMD, which can automate the evaluation of endothelial function in a short time. Measurement of pFMD is simpler than measurement of conventional uFMD and may have reduced artificial bias compared to that of conventional uFMD measurement (URL for Clinical Trial: https://ethics.hiroshima-u.ac.jp/site/wp-content/uploads/2022/12/eki_giji20221213.pdf . Registration Number for Clinical Trial: E2022-0131).

Pulmonary vasodilation during cardiopulmonary resuscitation - A randomized, controlled porcine study.

BACKGROUND: During resuscitation pulmonary artery pressure (PAP) increases. This reduces left ventricular filling, leading to decreased blood flow. Inhaled nitric oxide (iNO) produces selective pulmonary vasodilation. We hypothesized that iNO would lower PAP during resuscitation resulting in increased survival. METHODS: 30 pigs (40 kg) were subjected to cardiac arrest for 9.5 min after myocardial ischemia induced by coronary artery occlusion of the left anterior descending artery and ventricular fibrillation. During resuscitation, the pigs were randomized to 40 ppm iNO or placebo. The primary outcome was return of spontaneous circulation (ROSC). Pigs achieving ROSC underwent 4-hours intensive care. RESULTS: The ROSC rate was 9/14 (64%) in the control group and 11/16 (69%) in the iNO group (OR 1.2 95%CI [0.3;5.6], p > 0.99). There was no difference in diastolic aorta pressure/PAP ratio (mean difference -0.99 [95% CI: -2.33-0.36], p = 0.14). Mean pulmonary artery pressure was lower in the iNO group 60 and 120 min after ROSC (mean difference: -12.18 mmHg [95%CI: -16.94; -7.43] p < 0.01 and -5.43 [95%CI: -10.39; -0.46] p = 0.03). Troponin I levels in the iNO group were significantly higher 60 and 120 min after ROSC (mean difference: 266105 ng/l [95%CI: 6356; 525855] p = 0.045 and 420049 ng/l [95%CI: 136779; 703320], p = 0.004). The area at risk of the heart was 33% (SD 1) in controls and 34% (SD 1) in the iNO group. The infarct size divided by the area at risk was 55% (SD 3) in controls and 86% (SD 1) in the iNO group, p = 0.01. CONCLUSION: Application of iNO did not improve the rate of ROSC or hemodynamic function but increased myocardial injury.

Sex differences in CGRP-induced vasodilation of human middle meningeal arteries but not human coronary arteries: implications for migraine.

BACKGROUND: Migraine prevalence and levels of calcitonin gene-related peptide (CGRP), a peptide involved in migraine pathophysiology, differ between men and women, and appear to be affected by changes in sex hormones. The present study investigated the sex-specific responses to CGRP in human isolated arteries. METHODS: CGRP-induced relaxation of 62 (28 men and 34 women) human isolated middle meningeal arteries (HMMA) and 139 (69 men and 70 women) human isolated coronary arteries (HCA) was compared between men and women in groups <50 years and ≥50 years of age as a proxy for pre- and postmenopausal status in women, as well as matched-age groups for men. RESULTS: In HCA, no differences were observed between male and female tissue, or between the different age groups. However, in HMMA, the maximum response was significantly smaller and CGRP was less potent in females <50 compared with males <50 years of age. No differences were observed between the older age groups. CONCLUSIONS: Sex differences were observed for CGRP-induced relaxation of HMMA, but not HCA. These differences could arise from differential receptor expression in the vascular beds combined with the effect of sex hormones on CGRP and subsequent receptor desensitization.

Association between peripheral endothelial function and myocardial perfusion in patients with coronary artery disease.

Aims: Endothelial dysfunction is a systemic disorder and risk factor for atherosclerosis. Our aim was to assess whether there is a relation between peripheral endothelial function and myocardial perfusion in patients with coronary artery disease (CAD). Methods and results: We prospectively studied 54 patients, who had a positive result for obstructive CAD in coronary CT angiography. Myocardial perfusion (15O)H2O positron emission tomography was imaged at rest and during adenosine-induced maximal vasodilation. Peripheral endothelial function was assessed by measuring flow-mediated dilation (FMD) with ultrasound from the left brachial artery. There was a statistically significant correlation between FMD and global hyperaemic myocardial blood flow (MBF; r = 0.308, P = 0.023). The correlation remained statistically significant when controlling for gender, height, and diastolic blood pressure at rest (r = 0.367, P = 0.008). Receiver operating character analysis, however, yielded an area under curve of only 0.559 (P = 0.492) when FMD was used to predict reduced MBF (below 2.3 mL/g/min). Patients with significantly decreased MBF (n = 14) underwent invasive coronary angiography. FMD showed an inverse correlation with the severity of the most significant stenosis (r = -0.687, P = 0.007). Conclusion: Peripheral endothelial function is related with hyperaemic MBF and with the severity of CAD in invasive coronary angiography. Due to insufficient sensitivity and specificity in the identification of reduced MBF, FMD is not suitable for clinical practice at the individual level. However, it works at the population level as a research tool when assessing endothelial dysfunction in patients with CAD.

Change in Pd/Pa: Clinical Implications for Predicting Future Cardiac Events at Deferred Coronary Lesions.

BACKGROUND: Cardiovascular events still occur at intermediate stenosis with fractional flow reserve (FFR) ≥0.81, underscoring the additional measure to evaluate this residual risk. A reduction in distal coronary artery pressure/aortic pressure (Pd/Pa) from baseline to hyperemia (ie, change in Pd/Pa) reflects lipidic burden within vessel walls. We hypothesized that this physiological measure might stratify the risk of future cardiac events at deferrable lesions. METHODS: Lesion- (899 intermediate lesions) and patient-based (899 deferred patients) analyses in those with FFR ≥0.81 were conducted to investigate the association between change in Pd/Pa and target lesion failure (TLF) and major adverse cardiac events at 7 years, respectively. RESULTS: The occurrence of TLF and major adverse cardiac events was 6.7% and 13.4%, respectively. The incidence of target lesion-related nonfatal myocardial infarction was 0.6%. Lesions with TLF had a greater change in Pd/Pa (0.11±0.03 versus 0.09±0.04; P=0.002), larger diameter stenosis (51.0±9.2% versus 46.4±12.4%; P=0.048), and smaller FFR (0.84 [0.82-0.87] versus 0.86 [0.83-0.90]; P=0.02). Change in Pd/Pa (per 0.01 increase) predicted TLF (odds ratio, 1.16 [95% CI, 1.05-1.28]; P=0.002) and major adverse cardiac event (odds ratio, 1.08 [95% CI, 1.01-1.16]; P=0.03). Lesions with change in Pd/Pa ≥0.10 had 2.94- and 1.85-fold greater likelihood of TLF (95% CI, 1.30-6.69; P=0.01) and major adverse cardiac event (95% CI, 1.08-3.17; P=0.03), respectively. Lesions with FFR ≤0.85 had a substantially higher likelihood of TLF when there is a change in Pd/Pa ≥0.10 (12.4% versus 2.9%; hazard ratio, 3.60 [95% CI, 1.01-12.80]; P=0.04). However, change in Pd/Pa did not affect TLF risk in lesions with FFR ≥0.86 (3.8% versus 3.7%; hazard ratio, 0.56 [95% CI, 0.06-5.62]; P=0.62). CONCLUSIONS: Despite deferrable FFR values, lesions and patients with a change in Pd/Pa ≥0.10 had higher cardiovascular risk. Change in Pd/Pa might help stratify lesion- and patient-level risks of future cardiac events in those with FFR ≥0.81.

Lipid Emulsions Inhibit Labetalol-Induced Vasodilation in the Isolated Rat Aorta.

Lipid emulsions are used as adjuvant drugs to alleviate intractable cardiovascular collapse induced by drug toxicity. We aimed to examine the effect of lipid emulsions on labetalol-induced vasodilation and the underlying mechanism in the isolated rat aorta. We studied the effects of endothelial denudation, NW-nitro-l-arginine methyl ester (l-NAME), calmidazolium, methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), and lipid emulsions on labetalol-induced vasodilation. We also evaluated the effects of lipid emulsions on cyclic guanosine monophosphate (cGMP) formation, endothelial nitric oxide synthase (eNOS) phosphorylation, and endothelial calcium levels induced by labetalol. Labetalol-induced vasodilation was higher in endothelium-intact aortas than that in endothelium-denuded aortas. l-NAME, calmidazolium, methylene blue, and ODQ inhibited labetalol-induced vasodilation in endothelium-intact aortas. Lipid emulsions inhibited labetalol-induced vasodilation in endothelium-intact and endothelium-denuded aortas. l-NAME, ODQ, and lipid emulsions inhibited labetalol-induced cGMP formation in endothelium-intact aortas. Lipid emulsions reversed the stimulatory and inhibitory eNOS (Ser1177 and Thr495) phosphorylation induced by labetalol in human umbilical vein endothelial cells and inhibited the labetalol-induced endothelial calcium increase. Moreover, it decreased labetalol concentration. These results suggest that lipid emulsions inhibit vasodilation induced by toxic doses of labetalol, which is mediated by the inhibition of endothelial nitric oxide release and reduction of labetalol concentration.