Factors influencing the soluble guanylate cyclase heme redox state in blood vessels.

Soluble guanylate cyclase (sGC) plays an important role in maintaining vascular homeostasis, as an acceptor for the biological messenger nitric oxide (NO). However, only reduced sGC (with a ferrous heme) can be activated by NO; oxidized (ferric heme) and apo (absent heme) sGC cannot. In addition, the proportions of reduced, oxidized, and apo sGC change under pathological conditions.

Soluble Guanylate Cyclase-Mediated Relaxation in Aortas from Rats with Renovascular Hypertension.

Soluble guanylate cyclase (sGC) plays an important role in nitric oxide (NO)-mediated regulation of vascular tone; however, NO bioavailability is often reduced in diseased blood vessels. Accumulating evidence suggests that a shift of sGC from the NO-sensitive form to the NO-insensitive form could be an underlying cause contributing to this reduction. Herein, we investigated the impact of renovascular hypertension on NO-sensitive and NO-insensitive sGC-mediated relaxation in rat aortas.

Alteration of the soluble guanylate cyclase system in coronary arteries of high cholesterol diet-fed rabbits.

This study aimed to investigate how atherosclerosis affects the soluble guanylate cyclase (sGC) system in coronary arteries. Rabbits were fed a normal diet for 12 weeks (N group) or a diet containing high cholesterol (1%) for 4 weeks (S-HC group) and 12 weeks (L-HC group). Cholesterol deposition in the intima of coronary arteries was observed in the S-HC group, but the formation of an atherosclerotic plaque was not observed.

Impact of cigarette smoking on nitric oxide-sensitive and nitric oxide-insensitive soluble guanylate cyclase-mediated vascular tone regulation.

Cigarette smoking induces vascular endothelial dysfunction characterized by impaired nitric oxide (NO) bioavailability. There are two types of soluble guanylate cyclase (sGC), which is a cellular target of NO: NO-sensitive reduced form (the heme moiety with a ferrous iron) and NO-insensitive oxidized (the heme moiety with a ferric iron)/heme-free form. This study investigated the influence of cigarette smoking on NO-sensitive and NO-insensitive sGC-mediated vascular tone regulation in organ chamber experiments with isolated rat and human arteries.

Chronological Change of Vascular Reactivity to cGMP Generators in the Balloon-Injured Rat Carotid Artery.

Background/aims: Soluble guanylate cyclase (sGC) exists as reduced, oxidized, and heme-free forms. Currently, it is unclear whether endovascular mechanical stenosis has an impact on vascular tone control by drugs targeting sGC, namely cGMP generators.

Methods: Pharmacological responses to acidified sodium nitrite (reduced sGC stimulant) and BAY 60-2770 (oxidized/heme-free sGC stimulant) were studied in balloon-injured rat carotid arteries at several time points.

Segmental Difference in Vasoreactivity of the Human Right Gastroepiploic Artery.

Background: The gastroepiploic artery (GEA) plays an important role in the era of multiple arterial revascularization, but spasm is a major matter of concern. The internal thoracic artery has been shown to have a strong tendency to spasm in its distal bifurcating part, whereas the segmental difference in vasoreactivity of the GEA has never been performed.

Methods and results: The full length of the GEA obtained from 21 patients undergoing a total gastrectomy was divided into 3 sections: proximal (5 cm from the origin), middle, and distal (5 cm from the end).

Responsiveness of internal thoracic arteries to nitroglycerin in patients with renal failure.

Nitroglycerin is commonly used as an antispasmodic for treating spasm of coronary artery bypass grafts. This study investigated whether the presence of renal failure affects reactivity to nitroglycerin in internal thoracic arteries obtained from patients undergoing coronary bypass surgery. The patients were divided into three groups according to estimated glomerular filtration rate (eGFR, mL/min/1.

N-3 Polyunsaturated Fatty Acids Decrease the Protein Expression of Soluble Epoxide Hydrolase via Oxidative Stress-Induced P38 Kinase in Rat Endothelial Cells.

-3 polyunsaturated fatty acids (PUFAs) improve endothelial function. The arachidonic acid-derived metabolites (epoxyeicosatrienoic acids (EETs)) are part of the endothelial hyperpolarization factor and are vasodilators independent of nitric oxide. However, little is known regarding the regulation of EET concentration by docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in blood vessels.

Impact of type 2 diabetes on vascular reactivity to cGMP generators in human internal thoracic arteries.

Objective: The balance between nitric oxide (NO)-sensitive and -insensitive forms of soluble guanylate cyclase (sGC) has been demonstrated to be disrupted in certain lifestyle-related diseases. However, it remains unclear whether type 2 diabetes results in a shift of sGC to the NO-insensitive form. This study addressed this issue in the human blood vessel.

Responsiveness of Coronary Arteries to Nitroglycerin under Hypoxia: The Importance of the Endothelium.

Background/aims: Nitroglycerin is widely used as a coronary vasodilator in the treatment of ischemic heart diseases. This study investigated the influence of hypoxia on nitroglycerin-induced relaxation in endothelium-intact and -denuded rabbit, monkey, and porcine coronary arteries.

Methods: Helically cut strips of coronary arteries were suspended in organ chambers, and isometric tension was recorded.

Suppression of Graft Spasm by the Particulate Guanylyl Cyclase Activator in Coronary Bypass Surgery.

Background: Spasm of arterial grafts is still a clinical problem in coronary artery bypass surgery. The present study was designed to examine the effect of particulate guanylyl cyclase activator (carperitide) as an antispastic agent in internal thoracic artery and gastroepiploic artery grafts.

Methods: Isolated arterial grafts taken during surgery were studied in organ bath in three ways: the relaxing effect of carperitide on vasoconstrictor-induced precontraction; the inhibitory effect of pretreatment with carperitide on subsequent vasoconstrictor-induced contraction; and the effect of carperitide and nitroglycerin on increase of intracellular cyclic guanosine monophosphate levels.

Endothelial dysfunction of internal thoracic artery graft in patients with chronic kidney disease.

Objectives: The present study was designed to evaluate the association between chronic kidney disease and the endothelial function of internal thoracic artery (ITA) grafts in patients undergoing coronary bypass surgery. An isometric tension study was performed in ITA strips obtained during surgery. Concentration-response curves for acetylcholine (ACh) and sodium nitroprusside were constructed in ITA strips partially precontracted with phenylephrine under the inhibition of cyclooxygenase.

Soluble guanylate cyclase redox state under oxidative stress conditions in isolated monkey coronary arteries.

Coronary artery disease is associated with oxidative stress due to the excessive generation of free radicals in the vascular wall. This study investigated the impact of tert-butyl hydroperoxide (t-BuOOH), a peroxyl radical generator, on the redox state of soluble guanylate cyclase (sGC) in isolated monkey coronary arteries. Helically cut strips of endothelium-intact monkey coronary arteries treated with the nitric oxide synthase inhibitor N-nitro-L-arginine (10 mol/L) were exposed for approximately 60 min to either no drug or t-BuOOH (100 mol/L) in the presence and absence of -tocopherol (300 mol/L).

Cigarette smoking impairs nitric oxide-mediated cerebral blood flow increase: Implications for Alzheimer's disease.

Cerebral blood flow is mainly regulated by nitrergic (parasympathetic, postganglionic) nerves and nitric oxide (NO) liberated from endothelial cells in response to shear stress and stretch of vasculature, whereas sympathetic vasoconstrictor control is quite weak. On the other hand, peripheral vascular resistance and blood flow are mainly controlled by adrenergic vasoconstrictor nerves; endothelium-derived NO and nitrergic nerves play some roles as vasodilator factors. Cigarette smoking impairs NO synthesis in cerebral vascular endothelial cells and nitrergic nerves leading to interference with cerebral blood flow and glucose metabolism in the brain.

Hyperhomocysteinemia impairs regional blood flow: involvements of endothelial and neuronal nitric oxide.

Increasing evidence support the idea that hyperhomocysteinemia (HHcy) is responsible for pathogenesis underlying cerebral, coronary, renal, and other vascular circulatory disorders and for hypertension. Impaired synthesis of nitric oxide (NO) in the endothelium or increased production of asymmetric dimethylarginine and activated oxygen species are involved in the impairment of vasodilator effects of NO. Impaired circulation in the brain derived from reduced synthesis and actions of NO would be an important triggering factor to dementia and Alzheimer's disease.

Aging does not affect soluble guanylate cyclase redox state in mouse aortas.

Aging is associated with endothelial dysfunction, defined as a reduction in nitric oxide (NO) bioavailability. Although the redox state of the NO acceptor soluble guanylate cyclase (sGC) is another determinant factor for its bioavailability and is disturbed by reactive oxygen species (ROS) known to be increased with age, it is unclear whether aging actually has an impact on vascular sGC redox equilibrium. Therefore, this study investigated this issue using two different types of compounds, the sGC stimulator BAY 41-2272 and the sGC activator BAY 60-2770.

MicroRNA-494 plays a role in fiber type-specific skeletal myogenesis in human induced pluripotent stem cells.

Mitochondrial oxidative capacity in skeletal muscle is known to decrease in diabetic patients, and sarcopenia is a risk factor for diabetes, particularly in elderly people. We previously revealed that microRNA (miR)-494 inhibits mitochondrial biogenesis during myogenic differentiation in murine C2C12 cells and others reported that exercise regulates miR-494 levels in obese sedentary individuals with increased risk of type 2 diabetes. In this study, to investigate the therapeutic potential of miR-494, we first investigated the role of miR-494 during human skeletal myogenesis.

Duality of n-3 Polyunsaturated Fatty Acids on Mcp-1 Expression in Vascular Smooth Muscle: A Potential Role of 4-Hydroxy Hexenal.

N-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have protective effects against atherosclerosis. Monocyte chemotactic protein (MCP)-1 is a major inflammatory mediator in the progression of atherosclerosis. However, little is known about the regulation of MCP-1 by DHA and EPA in vessels and vascular smooth muscle cells (VSMCs).

Effects of hydrogen peroxide on relaxation through the NO/sGC/cGMP pathway in isolated rat iliac arteries.

The production of reactive oxygen species, including hydrogen peroxide (H(2)O(2)), is increased in diseased blood vessels. Although H(2)O(2) leads to impairment of the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP signaling pathway, it is not clear whether this reactive molecule affects the redox state of sGC, a key determinant of NO bioavailability. To clarify this issue, mechanical responses of endothelium-denuded rat external iliac arteries to BAY 41-2272 (sGC stimulator), BAY 60-2770 (sGC activator), nitroglycerin (NO donor), acidified NaNO(2) (exogenous NO) and 8-Br-cGMP (cGMP analog) were studied under exposure to H(2)O(2).

Effects of peroxynitrite on relaxation through the NO/sGC/cGMP pathway in isolated rat iliac arteries.

Background/aims: The present study investigated the mechanism by which peroxynitrite impairs vascular function through the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP pathway.

Methods: Mechanical responses of rat external iliac arteries without endothelium were studied under exposure to peroxynitrite. cGMP concentrations were determined by enzyme immunoassay.

Vasorelaxing effects of the soluble guanylyl cyclase activator BAY 60-2770 in nitrate-tolerant monkey and canine coronary arteries.

Nitrate tolerance is an important problem in the treatment of ischemic heart diseases. The present study investigated whether or not a soluble guanylyl cyclase (sGC) activator can be used as a coronary vasodilator under nitrate-tolerant conditions. Helically cut strips of endothelium-denuded monkey and canine coronary arteries were suspended in organ chambers for isometric tension recording.

Recent advances in research on nitrergic nerve-mediated vasodilatation.

Cerebral vascular resistance and blood flow were widely considered to be regulated solely by tonic innervation of vasoconstrictor adrenergic nerves. However, pieces of evidence suggesting that parasympathetic nitrergic nerve activation elicits vasodilatation in dog and monkey cerebral arteries were found in 1990. Nitric oxide (NO) as a neurotransmitter liberated from parasympathetic postganglionic neurons decreases cerebral vascular tone and resistance and increases cerebral blood flow, which overcome vasoconstrictor responses to norepinephrine liberated from adrenergic nerves.

Different influences of extracellular and intracellular superoxide on relaxation through the NO/sGC/cGMP pathway in isolated rat iliac arteries.

Superoxide production is increased in diseased blood vessels, which is considered to lead to impairment of the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP pathway. To investigate the respective influence of extracellular and intracellular superoxide on vascular function through the NO/sGC/cGMP pathway, mechanical responses of rat external iliac arteries without endothelium were studied under exposure to a superoxide-generating agent, pyrogallol, or menadione. Exposure to pyrogallol impaired the relaxation induced by acidified NaNO2 (exogenous NO) but not that by nitroglycerin (organic nitrate), BAY 41-2272 (sGC stimulator), BAY 60-2770 (sGC activator), or 8-Br-cGMP (cGMP analog).

Noninvasive metabolic syndrome model using an extremely small minipig, the microminipig.

Metabolic syndrome (MetS) induces serious complications; therefore, we developed a noninvasive MetS model using an extremely small minipig, the Microminipig. For 8 weeks, Microminipigs were administrated a high-fat and high-cholesterol diet (HFCD) for atherosclerosis and N(G)-nitro-l-arginine methyl ester (l-NAME) for inhibiting nitric oxide synthase. HFCD significantly increased serum low-density lipoprotein levels, l-NAME increased blood pressure and cardiac hypertrophy, and HFCD-induced aortal arteriosclerosis was accelerated by l-NAME administration.