Charlotte Boydens

Adipose Tissue as Regulator of Vascular Tone

Adipokines secreted by visceral, subcutaneous, and perivascular adipocytes are involved in the regulation of vascular tone by acting as circulatory hormones (leptin, adiponectin, omentin, visfatin, angiotensin II, resistin, tumor necrosis factor-α, interleukin-6, apelin) and/or via local paracrine factors (perivascular adipocyte-derived relaxing and contractile factors). Vascular tone regulation by adipokines is compromised in obesitas and obesity-related disorders. Hypoxia created in growing adipose tissue dysregulates synthesis of vasoactive adipokines in favor of harmful proinflammatory adipokines, while the levels of the cardioprotective adipokines adiponectin and omentin decrease. Considering the potential of the role of adipokines in obesity-related vascular diseases, strategies to counter these diseases by targeting the adipokines are discussed.

Treatment of erectile dysfunction: new targets and strategies from recent research.

In recent years, research on penile erection has increasingly been centered on the molecular mechanisms involved. Major progress has been made in the field and at present a whole number of neurotransmitters, chemical effectors, growth factors, second-messenger molecules, ions, intercellular proteins, and hormones have been characterized as components of the complex process of erection. This knowledge has led to the discovery of several new therapeutic targets and multiple medical approaches for the treatment of erectile dysfunction (ED). This review focuses on the progress made in this field within the last few years.

Divergent molecular mechanisms underlay CO- and CORM-2-induced relaxation of corpora cavernosa

INTRODUCTION Similar to nitric oxide (NO), the principal mediator of penile erection, carbon monoxide (CO) possesses vasodilator capacities. However, whether CO could be a therapeutic target for treating erectile dysfunction (ED) is unexplored. The danger associated with systemic administration of CO has led to the development of CO-releasing molecules (CORMs), releasing CO in a local, safe and controlled way. These CORMs have shown positive outcomes in cardiovascular studies. More knowledge on the (patho)physiological functions of CO in erectile function and the potential therapeutic role of CORMs is required. AIM The present study aims the assessment of the effect of CO and CO donor CORM-2 on the corporal tension and the underlying molecular mechanisms. METHODS Organ bath studies were performed measuring isometric tension on isolated mice corpora cavernosa (CC) strips. Responses to CO (10-300 µmol/L) and CORM-2 (10-100 µmol/L) were measured in the presence/absence of activators/inhibitors of different molecular pathways. MAIN OUTCOME MEASURES CO and CORM-2 relax corporal strips concentration dependently, although the molecular mechanisms behind the corporal relaxation seem to differ completely. RESULTS CO induces corporal relaxation by activating soluble guanylyl cyclase (sGC), increasing cyclic guanosine monophosphate (cGMP) concentrations. The molecular mechanism involved in CORM-2-induced corporal relaxation is not related to sGC activation and remains obscure. CONCLUSIONS Both CO and CORM-2 induce corporal relaxation, although the underlying molecular mechanisms show no resemblance. That CO induces corporal relaxation through a mechanism similar to that of NO could be of importance as it indirectly offers the possibility that endogenous CO might serve as a backup system for insufficient NO availability in cases of ED. Whether CORM-2 possesses the same capacity remains questionable and requires further research.

Relaxant and Antioxidant Capacity of the Red Wine Polyphenols, Resveratrol and Quercetin, on Isolated Mice Corpora Cavernosa

INTRODUCTION The red wine polyphenols resveratrol and quercetin are known for their vasorelaxant and antioxidant capacity, which is assumed to rely on the activation of the nitric oxide (NO)/soluble guanylyl cyclase (sGC) pathway. Vasodilators as well as antioxidants can regulate penile erection and be beneficial for the treatment of erectile dysfunction (ED). AIMS The goal of this study was to evaluate the NO/sGC dependency of the relaxant effect of resveratrol and quercetin on mice aorta and corpora cavernosa (CC), as well as to explore their influence on oxidative stress-induced ED. METHODS Isolated mice aorta and CC were mounted for isometric tension recordings into organ baths. Cumulative concentration-response curves were constructed for resveratrol and quercetin in the absence/presence of inhibitors of the NO/sGC pathway. In addition, in CC the effect of resveratrol and quercetin was studied on NO-mediated relaxations using acetylcholine (Ach), sodium nitroprusside (SNP), and electrical field stimulation (EFS). In certain experiments, corporal tissues were exposed to oxidative stress using palmitic acid (PA, 0.5 mM). MAIN OUTCOME MEASURES Corporal responses to resveratrol and quercetin were measured in the presence/absence of inhibitors of different molecular pathways. The effect of resveratrol and quercetin incubation on Ach-, SNP-, or EFS-mediated responses was explored in the presence/absence of PA. RESULTS While both polyphenols are potent vasodilators of mice aorta, only resveratrol relaxes mice CC. The relaxation response to resveratrol on aorta was diminished in sGCα1 (-/-) mice, but not on CC. The polyphenols did not influence Ach-, SNP-, or EFS-mediated relaxations as such. Resveratrol, but not quercetin, was able to significantly reverse PA-induced decrease of EFS relaxations. CONCLUSION The red wine compound resveratrol, but not quercetin, relaxes isolated mice CC concentration-dependently through mechanisms independent of the NO/sGC pathway. Resveratrol is a more potent antioxidant than quercetin, being able to restore decreased neuronal NO responses in mice CC.

Ruthenium-based nitric oxide-donating and carbon monoxide-donating molecules

Over the past few years, the use of metallocomplexes for medical purposes has considerably grown. Because of its favourable characteristics, ruthenium has taken a significant place in this expanding field of research. Several ruthenium‐containing metal compounds have been developed as delivery agents of physiological important molecules such as nitric oxide (NO) and carbon monoxide (CO).

Ferulic acid-4-O-sulfate rather than ferulic acid relaxes arteries and lowers blood pressure in mice ☆ ☆☆

Consumption of foods rich in ferulic acid (FA) such as wholegrain cereals, or FA precursors such as chlorogenic acids in coffee, is inversely correlated with risk of cardiovascular disease and type 2 diabetes. As a result of digestion and phase II metabolism in the gut and liver, FA is converted predominantly into ferulic acid-4-O-sulfate (FA-sul), an abundant plasma metabolite. Although FA-sul is the main metabolite, very little has been reported regarding its bioactivities. We have compared the ex vivo vasorelaxing effect of FA and FA-sul (10-7-3.10-5M) on isolated mouse arteries mounted in tissue myographs. FA-sul, but not FA, elicited a concentration-dependent vasorelaxation of saphenous and femoral arteries and aortae. The FA-sul-mediated vasorelaxation was blunted by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a soluble guanylate cyclase (sGC) inhibitor. The role of sGC was confirmed in femoral arteries isolated from sGCα1(-/-) knockout mice. Furthermore, 4-aminopyridine, a specific inhibitor of voltage-dependent potassium channels, significantly decreased FA-sul-mediated effects. In anesthetized mice, intravenous injection of FA-sul decreased mean arterial pressure, whereas FA had no effect, confirming the results obtained ex vivo. FA-sul is probably one of the major metabolites accounting for the blood pressure-lowering effects associated with FA consumption.

The influence of ruthenium on vascular tone

Over the past few years, ruthenium has been under attention for development of organometallic drugs with various therapeutic applications. Because of its favourable characteristics, ruthenium is perfectly suitable for drug design. Ruthenium‐containing complexes exert a wide range of biological effects. However, so far, the influence of ruthenium itself on vascular tone has never been studied.

NO‐Donating Oximes Relax Corpora Cavernosa Through Mechanisms Other than Those Involved in Arterial Relaxation

INTRODUCTION Erectile dysfunction (ED), as well as many cardiovascular diseases, is associated with impaired nitric oxide (NO) bioavailability. Recently, oxime derivatives have emerged as vasodilators due to their NO-donating capacities. However, whether these oximes offer therapeutic perspectives as an alternative NO delivery strategy for the treatment of ED is unexplored. AIMS This study aims to analyze the influence of formaldoxime (FAL), formamidoxime (FAM), and cinnamaldoxime (CAOx) on corporal tension and to elucidate the underlying molecular mechanisms. METHODS Organ bath studies were carried out measuring isometric tension on isolated mice corpora cavernosa (CC), thoracic aorta, and femoral artery. After contraction with norepinephrine (NOR), cumulative concentration-response curves of FAL, FAM, and CAOx (100 nmol/L-1 mmol/L) were performed. MAIN OUTCOME MEASURES FAL-/FAM-induced relaxations were evaluated in the absence/presence of various inhibitors of different molecular pathways. RESULTS FAL, FAM, and CAOx relax isolated CC as well as aorta and femoral artery from mice. ODQ (soluble guanylyl cyclase-inhibitor), diphenyliodonium chloride (nonselective flavoprotein inhibitor), and 7-ethoxyresorufin (inhibitor of CYP450 1A1 and NADPH-dependent reductases) substantially blocked the FAL-/FAM-induced relaxation in the arteries but not in CC. Only a small inhibition of the FAM response in CC was observed with ODQ. CONCLUSIONS This study shows for the first time that NO-donating oximes relax mice CC. Therefore, oximes are a new group of molecules with potential for the treatment of ED. However, the underlying mechanism(s) of the FAL-/FAM-induced corporal relaxation clearly differ(s) from the one(s) involved in arterial vasorelaxation.

The Retinal Relaxing Factor: Update on an Enigmatic Regulator of the Retinal Circulation

The retinal circulation is regulated by different local factors and might include the retinal relaxing factor (RRF). This factor is found to be continuously released by the retina and relaxes smooth muscle cells. This review describes the current knowledge about the RRF. Despite many research efforts, the cellular source, identity, mechanism, and physiological role of the RRF remain largely unknown. Thus far, it seems that the RRF is a hydrophilic, thermostable, diffusible chemical messenger, which characteristics do not correspond with most well-known endogenous vasorelaxants. The RRF-induced relaxation seems to rely on activation of the inward rectifier K+ channels and the Rho kinase Ca2+ sensitization mechanism. Voltage-dependent K+ channels and plasma membrane Ca2+-ATPase might also be involved, whereas the involvement of cyclooxygenase is still a point of discussion. Furthermore, it appears that the RRF is involved in other relaxation pathways, namely those of hypoxia, adenosine, and adenosine triphosphate, hydrogen sulfide, γ-aminobutyric acid, and dorzolamide.

Vasorelaxing Effect of Resveratrol on Bovine Retinal Arteries

PURPOSE Resveratrol is a red wine polyphenol that causes vasorelaxation, which could be of interest in the treatment or prevention of eye diseases with an impaired blood flow. In this study, the vasorelaxant capacity of resveratrol (cis and trans) on bovine retinal arteries, its vasorelaxing mechanism, and its influence on the relaxation induced by the retinal relaxing factor (RRF) were examined. METHODS Isolated bovine retinal arteries were mounted into wire myographs for isometric tension measurements. Concentration-response curves of cis- and trans-resveratrol and concentration-response curves of resveratrol in the absence or presence of the endothelium or different inhibitors were constructed. Relaxations elicited by the RRF with and without resveratrol incubation were also compared. RESULTS Both resveratrol isomers caused a similar strong concentration-dependent relaxation. Removal of the endothelium or blocking endothelium-dependent pathways did not change the relaxation. Also, K+ channel blockers did not reduce the relaxation, except the 120 mM K+ Krebs Ringer bicarbonate solution. Phorbol 12-myristate 13-acetate and phorbol 12,13-dibutyrate blocked the relaxation partially and so did the inhibition of heme oxygenase-1. Blocking adenylyl cyclase, AMP-activated protein kinase, estrogen receptors, sirtuin 1, or sarco/endoplasmic reticulum Ca2+ ATPase did not have an effect. The relaxation caused by the RRF was not altered by resveratrol incubation. CONCLUSIONS Cis- and trans-resveratrol relax bovine retinal arteries similarly and concentration dependently. The main relaxation mechanism remains unclear, but K+ channels, carbon monoxide, and the myosin phosphatase pathway may be involved. Resveratrol does not have an influence on the RRF.