Differential effects of glucose on agonist-induced relaxations in human mesenteric and subcutaneous arteries

BACKGROUND AND PURPOSE: Acute periods of hyperglycaemia are strongly associated with vascular disorder, yet the specific effects of high glucose on human blood vessel function are not fully understood. In this study we (1) characterized the endothelial-dependent relaxation of two similarly sized but anatomically distinct human arteries to two different agonists and (2) determined how these responses are modified by acute exposure to high glucose. EXPERIMENTAL APPROACH: Ring segments of human mesenteric and subcutaneous arteries were mounted in a wire myograph. Relaxations to acetylcholine and bradykinin were determined in a control (5 mM) and high glucose (20 mM) environment over a 2 and 6 h incubation period. KEY RESULTS: Bradykinin-induced relaxation in both sets of vessels was mediated entirely by EDHF whilst that generated by acetylcholine, though principally generated by EDHF, also had contribution from prostacyclin and possibly nitric oxide in mesenteric and subcutaneous vessels, respectively. A 2-h incubation of high glucose impaired bradykinin-induced relaxation of subcutaneous vessels whilst, in contrast, the relaxation generated by bradykinin in mesenteric vessels was enhanced at the same time point. High glucose significantly augmented the relaxation generated by acetylcholine in mesenteric and subcutaneous vessels at a 2 and 6 h incubation point, respectively. CONCLUSIONS AND IMPLICATIONS: Short periods of high glucose exert a variable influence on endothelial function in human isolated blood vessels that is dependent on factors of time, agonist-used and vessel studied. This has implications for how we view the effects of acute hyperglycaemia found in patients with diabetes mellitus as well as other conditions.     

CGRP function-blocking antibodies inhibit neurogenic vasodilatation without affecting heart rate or arterial blood pressure in the rat

Background and purpose:

Calcitonin gene-related peptide (CGRP) receptor antagonists effectively abort migraine headache and inhibit neurogenic vasodilatation in humans as well as rat models. Monoclonal antibodies typically have long half-lives, and we investigated whether or not function-blocking CGRP antibodies would inhibit neurogenic vasodilatation with a long duration of action and therefore be a possible approach to preventive therapy of migraine. During chronic treatment with anti-CGRP antibodies, we measured cardiovascular function, which might be a safety concern of CGRP inhibition.

Experimental approach:

We used two rat blood flow models that measure electrically stimulated vasodilatation in the skin or in the middle meningeal artery (MMA). These vasomotor responses are largely dependent on the neurogenic release of CGRP from sensory afferents. To assess cardiovascular function during chronic systemic anti-CGRP antibody treatment, we measured heart rate and blood pressure in conscious rats.

Key results:

Treatment with anti-CGRP antibodies inhibited skin vasodilatation or the increase in MMA diameter to a similar magnitude as treatment with CGRP receptor antagonists. Although CGRP antibody treatment had a slower onset of action than the CGRP receptor antagonists, the inhibition was still evident 1 week after dosing. Chronic treatment with anti-CGRP antibodies had no detectable effects on heart rate or blood pressure.

Conclusions and implications:

We showed for the first time that anti-CGRP antibodies exert a long lasting inhibition of neurogenic vasodilatation in two different rat models of arterial blood flow. We have provided strong preclinical evidence that anti-CGRP antibody may be a suitable drug candidate for the preventive treatment of migraine.     

Prostaglandin inhibition causes an increase in reactive hyperaemia after ischaemic exercise in human forearm

The hypothesis that prostaglandins contribute to the reactive hyperaemia after 5 min of ischaemia or 5 min of ischaemic exercise was investigated in six men by inhibiting prostaglandin production with ibuprofen (1800 mg) and indomethacin (225 mg) over 24 h before testing. Blood flow was measured continuously in the baseline and after ischaemia by combined pulsed and echo Doppler as the product of velocity and cross-sectional area. After 5 min of ischaemia, there were no differences in blood flow between placebo and the two drug conditions, except at 5 and 10 s when flow with indomethacin was greater than both placebo and ibuprofen. After 5 min of ischaemic exercise, blood flow was significantly greater as a consequence of increased vascular conductance in each of ibuprofen and indomethacin than placebo from 5 until 90 s of recovery. We conclude that prostaglandin inhibition had little or no effect on reactive hyperaemia after 5 min of circulatory occlusion alone, but that blood flow after ischaemic exercise was elevated due to increased vascular conductance when prostaglandin synthesis was inhibited.     

Hepatopulmonary syndrome: An update

Hepatopulmonary syndrome (HPS) is characterized by defects in oxygenation caused by intra-pulmonary vasodilation occurring because of chronic liver disease, portal hypertension, or congenital portosystemic shunts. Clinical implications of portal hypertension are very well-known, however, awareness of its effect on multiple organs such as the lungs are less known. The presence of HPS in chronic liver disease is associated with increased mortality. Medical therapies available for HPS have not been proven effective and definitive treatment for HPS is mainly liver transplantation (LT). LT improves mortality for patients with HPS drastically. This article provides a review on the definition, clinical presentation, diagnosis, and management of HPS.     

Asthma causes inflammation of human pulmonary arteries and decreases vasodilatation induced by prostaglandin I2 analogs

Objective: Asthma is a chronic inflammatory disease associated with increased cardiovascular events. This study assesses the presence of inflammation and the vascular reactivity of pulmonary arteries in patients with acute asthma. Methods: Rings of human pulmonary arteries obtained from non-asthmatic and asthmatic patients were set up in organ bath for vascular tone monitoring. Reactivity was induced by vasoconstrictor and vasodilator agents. Protein expression of inflammatory markers was detected by western blot. Prostanoid releases and cyclic adenosine monophosphate (cAMP) levels were quantified using specific enzymatic kits. Results: Protein expression of cluster of differentiation 68, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and cyclooxygenase-2 was significantly increased in arteries obtained from asthmatic patients. These effects were accompanied by an alteration of vasodilatation induced by iloprost and treprostinil, a decrease in cAMP levels and an increase in prostaglandin (PG) E₂ and PGI₂ synthesis. The use of forskolin (50 µmol/L) has restored the vasodilatation and cAMP release. No difference was observed between the two groups in reactivity induced by norepinephrine, angiotensin II, PGE₂, KCl, sodium nitroprusside, and acetylcholine. Conclusion: Acute asthma causes inflammation of pulmonary arteries and decreases vasodilation induced by PGI₂ analogs through the impairment of cAMP pathway.     

EDHF: spreading the influence of the endothelium

Our view of the endothelium was transformed around 30 years ago, from one of an inert barrier to that of a key endocrine organ central to cardiovascular function. This dramatic change followed the discoveries that endothelial cells (ECs) elaborate the vasodilators prostacyclin and nitric oxide. The key to these discoveries was the use of the quintessentially pharmacological technique of bioassay. Bioassay also revealed endothelium-derived hyperpolarizing factor (EDHF), particularly important in small arteries and influencing blood pressure and flow distribution. The basic idea of EDHF as a diffusible factor causing smooth muscle hyperpolarization (and thus vasodilatation) has evolved into one of a complex pathway activated by endothelial Ca(2+) opening two Ca(2+) -sensitive K(+) -channels, K(Ca)2.3 and K(Ca)3.1. Combined application of apamin and charybdotoxin blocked EDHF responses, revealing the critical role of these channels as iberiotoxin was unable to substitute for charybdotoxin. We showed these channels are arranged in endothelial microdomains, particularly within projections towards the adjacent smooth muscle, and close to interendothelial gap junctions. Activation of K(Ca) channels hyperpolarizes ECs, and K(+) efflux through them can act as a diffusible 'EDHF' stimulating Na(+) /K(+) -ATPase and inwardly rectifying K-channels. In parallel, hyperpolarizing current can spread from the endothelium to the smooth muscle through myoendothelial gap junctions upon endothelial projections. The resulting radial hyperpolarization mobilized by EDHF is complemented by spread of hyperpolarization along arteries and arterioles, effecting distant dilatation dependent on the endothelium. So the complexity of the endothelium still continues to amaze and, as knowledge evolves, provides considerable potential for novel approaches to modulate blood pressure.     

XbaI polymorphism of the estrogen receptor alpha gene influences the effect of raloxifene on the endothelial function

Objectives

Cardiovascular disease is the leading cause of death in postmenopausal women and estrogen deficiency may be an important factor in its development. The selective estrogen receptor modulator, raloxifene, exerts a part of its actions through the estrogen receptor alpha (ESR1) activation. We explored if polymorphisms of the ESR1 modify the effects of 6 months raloxifene treatment on endothelial function.

Methods

A total of 53 postmenopausal women, mean age 59.7 ± 6.2, finished the prospective clinical trial. The PvuII, XbaI, and P325P polymorphisms of the ESR1 gene were analyzed. In all subjects endothelium-dependent flow mediated dilatation (FMD) and cell adhesion molecules (CAM) ICAM-1, VCAM-1 and E-selectin were measured before and after 6 months of raloxifene treatment.

Results

There was no difference in FMD between the ESR1 genotypes, at baseline. After raloxifene treatment, the FMD was significantly greater in subjects with XX genotype of XbaI polymorphism compared to xx (p = 0.03) and borderline greater when compared to Xx genotype (p = 0.053). The FMD increased significantly with raloxifene treatment in women with Xx genotype of XbaI and Pp genotype of PvuII polymorphisms (p = 0.027 and p = 0.034, respectively). The P325P polymorphism did not influence the FMD after raloxifene. None of the ESR1 gene polymorphisms had any impact on the levels of CAM before or after the treatment. When analysing the whole group, a significant decrease in E-selectin (p < 0.001) and a small increase in ICAM-1 levels (p = 0.029) was observed with raloxifene treatment, but no influence on VCAM-1 levels or FMD overall was seen.

Conclusion

Our data suggest that XbaI and possibly PvuII polymorphisms of the ESR1 gene influence the impact of raloxifene treatment on endothelial function. This effect could be of pharmacogenomic and clinical importance.     

Endothelial Function is Not Changed during Short-Term Withdrawal of Thyroxine in Patients with Differentiated Thyroid Cancer and Low Cardiovascular Risk

Purpose

The incidence of differentiated thyroid cancer is increasing in young adults and females in Korea. Some of them experience short-term hypothyroidism in preparation for radioiodine (RAI) therapy, which can have a deleterious effect on the cardiovascular system. However, it is not clear if short-term hypothyroidism induces endothelial dysfunction in patients with low cardiovascular risk. Therefore, the aim of this study was to investigate whether short-term hypothyroidism is associated with endothelial dysfunction in patients with low cardiovascular risk.

Materials and Methods

To evaluate the effect of short-term hypothyroidism on endothelial function in this group, we recruited fifteen female patients with low cardiovascular risk. We analyzed clinical, biochemical, and cardiovascular parameters at four time points: the last day on levothyroxine (LT4) at their usual thyroid-stimulating hormone (TSH)-suppressive doses (P1), 7 days (P2) & 4 weeks (P3) after withdrawal of LT4, and 8 weeks (P4) after replacement of the previous dose of LT4. A high resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperemia, and after sublingual nitroglycerin.

Results

During short-term hypothyroidism (P3), serum concentrations of total cholesterol and low-density lipoprotein (LDL)-cholesterol were increased (p < 0.001 for each period). In spite of having worsened lipid states, serum high sensitivity C-reactive protein or flow-mediated vasodilatation, which is one of the surrogate markers of the endothelial function, did not change during short-term hypothyroidism.

Conclusion

Short-term hypothyroidism induced worsening of metabolic parameters, but not enough to induce the endothelial dysfunction in patients with low cardiovascular risk.     

Intertester reliability of brachial artery flow-mediated vasodilation using upper and lower arm occlusion in healthy subjects

The assessment of endothelial function as brachial artery flow-mediated vasodilatation is a widely used technique that determines the effect of risk factor intervention and may have the potential to predict the clinical benefit of antiatherogenic therapy. Previous studies suggest that flow-mediated dilation is greater using the upper-arm occlusion technique, but no data are available to compare intertester reliability between technicians. This study was undertaken to compare the amount of hyperemia between upper and lower occlusion techniques and to determine reproducibility between testers. Nineteen healthy adults, ages 25 to 50, were included in the study. Brachial artery vasodilatation was measured 1 and 3 minutes post cuff deflation and was compared with the baseline and expressed as a percent change. There was a tester effect in the percent change in diameter across all measurements. The results of this study reveal inconsistencies between testers when using a blood pressure cuff to induce hyperemia for the assessment of endothelial function through brachial artery flow-mediated vasodilation. However, upper arm as compared to lower arm blood pressure cuff occlusion results in significantly greater hyperemia and vasodilatation, even though there was a difference in measurements between testers.     

Exenatide induces an increase in vasodilatory and a decrease in vasoconstrictive mediators

In view of the known vasodilatory effects of glucagon‐like peptide‐1 and exenatide, we investigated the effects of exenatide on vasoactive factors. We analysed blood samples and mononuclear cells (MNCs) from a previous study, collected after a single dose and 12 weeks of exenatide or placebo treatment in a series of 24 patients with type 2 diabetes mellitus. After exenatide treatment, plasma concentrations of atrial natriuretic peptide, cyclic guanyl monophosphate (cGMP) and cyclic adenyl monophosphate increased significantly at 12 weeks. Plasma cGMP and adenylate cyclase expression in MNCs increased significantly after a single dose. Angiotensinogen concentration fell significantly 2 hours after a single dose and at 12 weeks, while renin and angiotensin II levels fell significantly only after a single dose and not after 12 weeks of treatment. Exenatide also suppressed the plasma concentration of transforming growth factor‐β and the expression of P311 in MNCs at 12 weeks. Thus, exenatide induces an increase in a series of vasodilators, while suppressing the renin‐angiotensin system. These changes may contribute to the overall vasodilatory effect of exenatide.