Penile erection and cardiovascular function: effects and pathophysiology.

Penile erection (PE) is a hemodynamic event that results from a neuroendocrine process, and it is influenced by the cardiovascular status of the patient. However, it may also modulate an individual's cardiovascular events. The present study provides the mechanisms involved in the association of PE and cardiovascular function. Erection upsurges the cardiac rate, blood pressure, and oxygen uptake. Sex-enhancing strategies, such as phosphodiesterase inhibitors, alprostadil, and testosterone also promote vasodilatation and cardiac performance, thus preventing myocardial infarction. More so, drugs that are used in the treatment of hypertensive heart diseases (such as angiotensin system inhibitors and ß-blockers) facilitate vasodilatation and PE. These associations have been linked with nitric oxide- and testosterone-dependent enhancing effects on the vascular endothelium. In addition, impaired cardiovascular function may negatively impact PE; therefore, impaired PE may be a pointer to cardiovascular pathology. Hence, evaluation of the cardiovascular status of an individual with erectile dysfunction (ED) is essential. Also, employing strategies that are used in maintaining optimal cardiac function may be useful in the management of ED.

Can nutrients act as signals under abiotic stress?

Plant cells are in constant communication to coordinate development processes and environmental reactions. Under stressful conditions, such communication allows the plant cells to adjust their activities and development. This is due to intercellular signaling events which involve several components. In plant development, cell-to-cell signaling is ensured by mobile signals hormones, hydrogen peroxide (H2O2), nitric oxide (NO), or hydrogen sulfide (H2S), as well as several transcription factors and small RNAs. Mineral nutrients, including macro and microelements, are determinant factors for plant growth and development and are, currently, recognized as potential signal molecules. This review aims to highlight the role of nutrients, particularly calcium, potassium, magnesium, nitrogen, phosphorus, and iron as signaling components with special attention to the mechanism of response against stress conditions.

Nitric oxide-mediated vasodilation in human bone.

OBJECTIVE: Regulation of blood flow to bone is critical but poorly understood, particularly in humans. This study aims to determine whether nitric oxide (NO), a major regulator of vascular tone to other tissues, contributes also to the regulation of blood flow to bone. METHODS: In young healthy adults (n = 16, 8F, 8M), we characterized NO-mediated vasodilation in the tibia in response to sublingual nitroglycerin and contrasted it to lower leg. Blood flow responses were assessed in supine individuals by continuously measuring tibial total hemoglobin (tHb) via near-infrared spectroscopy and lower leg blood flow (LBF) as popliteal flow velocity via Doppler ultrasound in the same leg. RESULTS: LBF increased by Δ9.73 ± 0.66 cm/s and peaked 4.4 min after NO administration and declined slowly but remained elevated (Δ3.63 ± 0.60 cm/s) at 10 min. In contrast, time to peak response was longer and smaller in magnitude in the tibia as tHb increased Δ2.08 ± 0.22 µM and peaked 5.3 min after NO administration and declined quickly but remained elevated (Δ0.87±0.22 µM) at 10 min (p = .01). CONCLUSIONS: In young adults, the tibial vasculature demonstrates robust NO-mediated vasodilation, but tHb is delayed and diminishes faster compared to LBF, predominately reflective of skeletal muscle responses. Thus, NO-mediated vasodilation in bone may be characteristically different from other vascular beds.

Insights on the functional dualism of nitric oxide in the hallmarks of cancer.

Nitric oxide (NO), a gaseous radical, governs a variety of physiological and pathological processes, including cancer, pro-inflammatory signalling, and vasodilation. The family of nitric oxide synthases (NOS), which comprises the constitutive forms, nNOS and eNOS, and the inducible form, iNOS, produces NO enzymatically. Additionally, NO can be generated non-enzymatically from the nitrate-nitrite-NO pathway. The anti- and pro-oxidant properties of NO and its functional dualism in cancer is due to its highly reactive nature. Numerous malignancies have NOS expression, which interferes with the tumour microenvironment to modulate the tumour's growth in both favourable and unfavourable ways. NO regulates a number of mechanisms in the tumour microenvironment, including metabolism, cell cycle, DNA repair, angiogenesis, and apoptosis/necrosis, depending on its concentration and spatiotemporal profile. This review focuses on the bi-modal impact of nitric oxide on the alteration of a few cancer hallmarks.

An in vitro analog of learning that food is inedible in Aplysia: decreased responses to a transmitter signaling food after pairing with transmitters signaling failed swallowing.

An in vitro analog of learning that a food is inedible provided insight into mechanisms underlying the learning. Aplysia learn to stop responding to a food when they attempt but fail to swallow it. Pairing a cholinergic agonist with an NO donor or histamine in the Aplysia cerebral ganglion produced significant decreases in fictive feeding in response to the cholinergic agonist alone. Acetylcholine (ACh) is the transmitter of chemoreceptors sensing food touching the lips. Nitric oxide (NO) and histamine (HA) signal failed attempts to swallow food. Reduced responses to the cholinergic agonist after pairing with NO or HA indicate that learning partially arises via a decreased response to ACh in the cerebral ganglion.

Endothelial Dysfunction in Superior Mesenteric Arteries Isolated from Adenine-Induced Renal Failure in Model Rats.

Endothelial dysfunction-a hallmark of chronic kidney disease (CKD)-is one of the major risk factors for cardiovascular diseases (CVD). Imbalances in endothelium-derived relaxing factors (EDRFs) and contracting factors (EDCFs) specific to endothelial dysfunction in CKD are yet to be studied. Therefore, using adenine-treated rats-a CKD rat model-we investigated the responsiveness of superior mesenteric artery (SMA) endothelium to acetylcholine (ACh) stimulation under different experimental conditions. Nine-week-old male Wistar rats were treated daily with adenine (200 and 600 mg/kg body weight) by oral gavage, for 10 d; the two groups were named adenine-200 (200 mg/kg body weight) and adenine-600 (600 mg/kg body weight). The systolic blood pressure (measured 1-, 8-, and 15 d post-treatment) was significantly increased in the adenine-600 group compared with that in the control group; whereas that in the adenine-200 group showed only a slight increase. Moreover, in the adenine-600 group the serum creatinine and blood urea nitrogen (BUN) levels (measured at 18 d post-treatment) were significantly elevated when compared with those in control or adenine-200 groups. The ACh-mediated relaxation was slightly reduced in the adenine-200 group. The ACh- and sodium nitroprusside (SNP)-mediated relaxations were impaired in the adenine-600 group. Although no ACh-mediated contraction was observed in the presence of a nitric oxide (NO) synthase inhibitor, ACh-induced endothelium-derived hyperpolarizing factor-mediated relaxation was largely impaired in the adenine-600 mg/kg group. This study revealed that in the SMA of adenine-induced CKD model rats, EDCF signaling remained unaltered while the NO and EDHF signaling were impaired.

Acute nitric oxide synthase inhibition induces greater increases in blood pressure in female versus male Wistar Kyoto rats.

Nitric oxide (NO) contributes to blood pressure (BP) regulation via its vasodilatory and anti-inflammatory properties. We and others previously reported sex differences in BP in normotensive and hypertensive rat models where females have lower BP than age-matched males. As females are known to have greater NO bioavailability than age-matched males, the current study was designed to test the hypothesis that anesthetized female normotensive Wistar Kyoto rats (WKY) are more responsive to acute NOS inhibition-induced increases in BP compared to male WKY. Twelve-week-old male and female WKY were randomized to infusion of the nonspecific NOS inhibitor NG -nitro-L-arginine methyl ester (L-NAME, 1 mg/kg/min) or selective NOS1 inhibition with vinyl-L-NIO (VNIO, 0.5 mg/kg/min) for 60 min. Mean arterial BP, glomerular filtration rate (GFR), urine volume, and electrolyte excretion were assessed before, and during L-NAME or VNIO infusion. L-NAME and VNIO significantly increased BP in both sexes; however, the increase in BP with L-NAME infusion was greater in females versus males compared to baseline BP values. Acute infusion of neither L-NAME nor VNIO for 60 min altered GFR in either sex. However, urine volume, sodium, chloride and potassium excretion levels increased comparably in male and female WKY with L-NAME and VNIO infusion. Our findings suggest sex differences in BP responses to acute non-isoform-specific NOS inhibition in WKY, with females being more responsive to L-NAME-induced elevations in BP relative to male WKY. However, sex differences in the BP response did not coincide with sex differences in renal hemodynamic responses to acute NOS inhibition.

Nitric Oxide Function and Nitric Oxide Synthase Evolution in Aquatic Chordates.

Nitric oxide (NO) is a key signaling molecule in almost all organisms and is active in a variety of physiological and pathological processes. Our understanding of the peculiarities and functions of this simple gas has increased considerably by extending studies to non-mammal vertebrates and invertebrates. In this review, we report the nitric oxide synthase (Nos) genes so far characterized in chordates and provide an extensive, detailed, and comparative analysis of the function of NO in the aquatic chordates tunicates, cephalochordates, teleost fishes, and amphibians. This comprehensive set of data adds new elements to our understanding of Nos evolution, from the single gene commonly found in invertebrates to the three genes present in vertebrates.

Relaxation of thoracic aorta and pulmonary artery rings of marmosets (Callithrix spp.) by endothelium-derived 6-nitrodopamine.

6-Nitrodopamine is a novel catecholamine released by vascular tissues, heart, and vas deferens. The aim of this study was to investigate whether 6-nitrodopamine is released from the thoracic aorta and pulmonary artery rings of marmosets (Callithrix spp.) and to evaluate the relaxing and anti-contractile actions of this catecholamine. Release of 6-nitrodopamine, dopamine, noradrenaline, and adrenaline was assessed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The relaxations induced by 6-nitrodopamine and by the selective dopamine D2 receptor antagonist L-741,626 were evaluated on U-46619 (3 nM)-pre-contracted vessels. The effects of 6-nitrodopamine and L-741,626 on the contractions induced by electric-field stimulation (EFS), dopamine, noradrenaline, and adrenaline were also investigated. Both aorta and pulmonary artery rings exhibited endothelium-dependent release of 6-nitrodopamine, which was significantly reduced by the NO synthesis inhibitor L-NAME. Addition of 6-nitrodopamine or L-741,626 caused concentration-dependent relaxations of both vascular tissues, which were almost abolished by endothelium removal, whereas L-NAME and the soluble guanylate cyclase inhibitor ODQ had no effect on 6-nitrodopamine-induced relaxations. Additionally, pre-incubation with 6-nitrodopamine antagonized the dopamine-induced contractions, without affecting the noradrenaline- and adrenaline-induced contractions. Pre-incubation with L-741,626 antagonized the contractions induced by all catecholamines. The EFS-induced contractions were significantly increased by L-NAME, but unaffected by ODQ. Immunohistochemical assays showed no immunostaining of the neural tissue markers S-100 and calretinin in either vascular tissue. The results indicated that 6-nitrodopamine is the major catecholamine released by marmoset vascular tissues, and it acts as a potent and selective antagonist of dopamine D2-like receptors. 6-nitrodopamine release may be the major mechanism by which NO causes vasodilatation.

Contribution of sensory nerves to cutaneous reactive hyperaemia in non-Hispanic Black and White young adults.

NEW FINDINGS: What is the central question of this study? Does cutaneous sensory nerve-mediated vasodilatation differ between non-Hispanic Black and White young adults? What is the main finding and its importance? The magnitude of cutaneous reactive hyperaemia is lower in non-Hispanic Black relative to non-Hispanic White young adults, but the overall sensory nerve contribution is the same, suggesting that sensory nerve function is similar in both non-Hispanic Black and White young adults. ABSTRACT: The aim of this study was to assess cutaneous sensory nerve function, independent of nitric oxide, in non-Hispanic Black and White young adults. We tested the hypothesis that cutaneous reactive hyperaemia and sensory nerve-mediated vasodilatation would be lower in non-Hispanic Black young adults relative to non-Hispanic White young adults. Twenty-four participants who self-identified as non-Hispanic Black (n = 12) or non-Hispanic White (n = 12) were recruited. All participants underwent three bouts of reactive hyperaemia. An index of skin blood flow was measured continuously using laser-Doppler flowmetry at a control site and at a site treated with topical 4% lignocaine to inhibit sensory nerve function. Peak reactive hyperaemia was lower in non-Hispanic Black relative to non-Hispanic White participants (P < 0.001). Total reactive hyperaemia was lower in non-Hispanic Black [mean (SD); control, 4085 (955)%CVCmax  s; lignocaine, 2127 (639) percent maximal cutaneous vascular conductance * seconds, %CVCmax  s] relative to non-Hispanic White [control: 6820 (1179)%CVCmax  s; lignocaine, 3573 (712)%CVCmax  s] participants (P < 0.001 for both sites). There was no difference between groups for the calculated contribution of sensory nerves to either the peak [non-Hispanic Black, 25 (14)%; non-Hispanic White, 19 (13)%] or total reactive hyperaemic response [non-Hispanic Black, 48 (10)%; non-Hispanic White, 47 (10)%]. These data suggest that cutaneous reactive hyperaemia is lower in non-Hispanic Black young adults, but the sensory nerve contribution is similar in non-Hispanic Black and White young adults.

Control of tissue oxygenation by S-nitrosohemoglobin in human subjects.

S-Nitrosohemoglobin (SNO-Hb) is unique among vasodilators in coupling blood flow to tissue oxygen requirements, thus fulfilling an essential function of the microcirculation. However, this essential physiology has not been tested clinically. Reactive hyperemia following limb ischemia/occlusion is a standard clinical test of microcirculatory function, which has been ascribed to endothelial nitric oxide (NO). However, endothelial NO does not control blood flow governing tissue oxygenation, presenting a major quandary. Here we show in mice and humans that reactive hyperemic responses (i.e., reoxygenation rates following brief ischemia/occlusion) are in fact dependent on SNO-Hb. First, mice deficient in SNO-Hb (i.e., carrying C93A mutant Hb refractory to S-nitrosylation) showed blunted muscle reoxygenation rates and persistent limb ischemia during reactive hyperemia testing. Second, in a diverse group of humans-including healthy subjects and patients with various microcirculatory disorders-strong correlations were found between limb reoxygenation rates following occlusion and both arterial SNO-Hb levels (n = 25; P = 0.042) and SNO-Hb/total HbNO ratios (n = 25; P = 0.009). Secondary analyses showed that patients with peripheral artery disease had significantly reduced SNO-Hb levels and blunted limb reoxygenation rates compared with healthy controls (n = 8 to 11/group; P < 0.05). Low SNO-Hb levels were also observed in sickle cell disease, where occlusive hyperemic testing was deemed contraindicated. Altogether, our findings provide both genetic and clinical support for the role of red blood cells in a standard test of microvascular function. Our results also suggest that SNO-Hb is a biomarker and mediator of blood flow governing tissue oxygenation. Thus, increases in SNO-Hb may improve tissue oxygenation in patients with microcirculatory disorders.

Nitric oxide deficiency is a primary driver of hypertension.

Hypertension remains a global health crisis. High blood pressure is the number one modifiable risk factor in the onset and progression of cardiovascular disease. Despite many different classes of drug therapies approved for hypertension, the use of polypharmacy and recommendations on lifestyle modification, many patients still suffer from uncontrolled or unmanaged hypertension. Nitric oxide is a naturally produced vasodilator that controls and regulates vascular tone and therefore controls and regulates blood pressure. Research over the past 40 years reveals that loss of nitric oxide production, termed endothelial dysfunction, is the earliest event in the development of hypertension. Strategies aimed at preventing the loss of nitric oxide production and/or therapeutic strategies designed to restore nitric oxide production will likely have a positive effect on patients' health and lead to better management of blood pressure. This review article will focus on the loss of nitric oxide production as the primary contributor to hypertension and also discuss safe and clinically proven strategies to restore nitric oxide production and recapitulate nitric oxide based signaling in humans.

The role of nitric oxide in the dorsomedial periaqueductal gray (dmPAG) column in cardiovascular responses in urethane-anesthetized male rats.

BACKGROUND: The dorsomedial periaqueductal gray (dmPAG) is a mesencephalic area and has numerous functions including cardiovascular regulation. Because nitric oxide (NO) is present in the dmPAG, here we investigate, the probable cardiovascular effect of NO in the dmPAG. METHODS: Five groups (n = 6 for each group) were used as follows: (1) control; (2) L-NAME (NG -nitro-L-arginine methyl ester, a NO synthase inhibitor, 90 nmol); (3) L-arginine (L-Arg, a precursor for NO, 60 nmol); (4) Sodium nitroprusside (SNP, a NO donor, 27 nmol); and (5) L-Arg + L-NAME. The cardiovascular parameters were recorded by a Power Lab device after cannulation of the femoral artery. Drugs were injected using a stereotaxic instrument. The changes (∆) in systolic blood pressure (SBP), mean arterial pressure (MAP), and heart rate (HR) were calculated at different times and compared to the control group. RESULTS: Microinjection of L-NAME significantly increased ∆SBP, ∆MAP, and ∆HR more than saline (from p < 0.05 to p < 0.001). L-Arg only significantly increased ∆HR (p < 0.05). In the L-Arg + L-NAME group, the above parameters also significantly increased (from p < 0.01 to p < 0.05) but not as significantly as with L-NAME alone. Microinjection of SNP significantly decreased ∆SBP and ∆MAP more than in the control and L-NAME groups (from p < 0.01 to p < 0.001), but ∆HR did not change significantly. CONCLUSION: The results indicated that NO in dmPAG has an inhibitory effect on cardiovascular responses in anesthetized rats.

Pulmonary hypertension in the newborn- etiology and pathogenesis.

A disruption in the well-orchestrated fetal-to-neonatal cardiopulmonary transition at birth results in the clinical conundrum of severe hypoxemic respiratory failure associated with elevated pulmonary vascular resistance (PVR), referred to as persistent pulmonary hypertension of the newborn (PPHN). In the past three decades, the advent of surfactant, newer modalities of ventilation, inhaled nitric oxide, other pulmonary vasodilators, and finally extracorporeal membrane oxygenation (ECMO) have made giant strides in improving the outcomes of infants with PPHN. However, death or the need for ECMO occurs in 10-20% of term infants with PPHN. Better understanding of the etiopathogenesis of PPHN can lead to physiology-driven management strategies. This manuscript reviews the fetal circulation, cardiopulmonary transition at birth, etiology, and pathophysiology of PPHN.

NO, CO and H2S: A trinacrium of bioactive gases in the brain.

Oxygen and carbon dioxide are time honored gases that have direct bearing on almost all life forms, but over the past thirty years, and in large part due to the Nobel Prize Award in Medicine for the elucidation of nitric oxide (NO) as a bioactive gas, the research and medical communities now recognize other gases as critical for survival. In addition to NO, hydrogen sulfide (H2S) and carbon monoxide (CO) have emerged as a triumvirate or Trinacrium of gases with analogous importance and that serve important homeostatic functions. Perhaps, one of the most intriguing aspects of these gases is the functional interaction between them, which is intimately linked by the enzyme systems that produce them. Despite the need to better understand NO, H2S and CO biology, the notion that these are environmental pollutants remains ever present. For this reason, incorporating the concept of hormesis becomes imperative and must be included in discussions when considering developing new therapeutics that involve these gases. While there is now an enormous literature base for each of these gasotransmitters, we provide here an overview of their respective physiologic roles in the brain.

[A novel approach to treating erectile dysfunction with a light-controlled nitric oxide donor].

It has long been known that nitric oxide (NO) is involved in the initiation and maintenance of erection. For this reason, NO supplementation has been considered a useful target for the treatment of erectile dysfunction (ED), and many studies have been conducted. However, to date, no compounds have been launched for a variety of reasons. One of the reasons is the systemic adverse reactions. In order to solve this problem, we focused on light-controlled NO donors and investigate their potential application in ED treatment. Light-controlled NO donors have three main characteristics: first, they release NO only at the site of light irradiation, second, they release NO only during the time of light irradiation, and third, the amount of NO released can be controlled according to the light intensity. These features suggest that light-responsive NO donors may be useful for ED therapy. Our group has been working on the development of light-controlled NO donors, and has so far developed the blue light-controlled NO donor "NOBL-1", the yellowish-green light-controlled NO donor "NO-Rosa", and the red light-controlled NO donor "NORD-1". Our recent studies have shown that NORD-1 and red light can enhance the erectile response in rats at the in vivo level. Next, we examined the effects of NORD-1 and red light using a neurogenic ED model, which is believed to be less effective than existing ED drugs. The results showed that red light irradiation after NORD-1 administration enhanced the erectile response and improved ED in the neurogenic ED model. These results suggest that NORD-1, a light-controlled NO donor, and red light can enhance the erectile response in rats and may have potential as an ED drug. Although optimization of the compound is essential, it is expected that a new therapeutic approach called photobiotherapy for ED will be developed in the future.

Protective Effect of L-Arginine in an Animal Model of Alzheimer's Disease Induced by Intra-Hippocampal Injection of AlCl3.

Background and Objective: Aluminum chloride (AlCl3) can impair spatial memory recovery. We investigated the protective effect of L-arginine, a precursor of nitric oxide (NO), on memory retrieval in an Alzheimer's animal model induced by AlCl3 at intra-hippocampal CA1 using a seeking behavior practice. Materials and Methods: Wistar rats were deeply anesthetized and cannulated at CA1 (AP: -3.8 mm, L: ±2.2 mm, V: 3 mm), and received once AlCl3 (1-200 µg/rat, intra-CA1), on day of cannulation under stereotaxic device. After a week of recovery, they experienced the novelty task with a three-stage paradigm and injected L-arginine (0.05-25 µg/rat) intra-CA1, pretesting. L-NAME, the neuronal NO synthase inhibitor was administered before L-arginine effective doses in the test stage. Also, a reference group exclusively received beta-amyloid 2 µg/rat. Control group solely received saline. Finally, after euthanasia of rat, the hippocampal sample was collected on ice and evaluated by immunohistochemical marking and specific staining. Results: AlCl3 caused novelty-seeking behavior without meaningful change in animal locomotor activity. ßA (2 µg/rat, intra-CA1) affected the rat's grooming, causing it to stop further in the new side. Pretest injection of L-arginine restored behavior in AlCl3-treated rats; however, this effect was stopped by L-NAME pretreatment, indicating NO involvement. CA1 did not show necrotic change due to AlCl3 exposure; however, neurofibrillary tangles were accumulated in the region. Conclusions: Prophylaxis with L-arginine probably due to NO has a protective role against the dangerous effect of AlCl3 on the function of neurons in the cortical hippocampus.

Crosstalk between Melatonin and Reactive Oxygen Species in Plant Abiotic Stress Responses: An Update.

Melatonin acts as a multifunctional molecule that takes part in various physiological processes, especially in the protection against abiotic stresses, such as salinity, drought, heat, cold, heavy metals, etc. These stresses typically elicit reactive oxygen species (ROS) accumulation. Excessive ROS induce oxidative stress and decrease crop growth and productivity. Significant advances in melatonin initiate a complex antioxidant system that modulates ROS homeostasis in plants. Numerous evidences further reveal that melatonin often cooperates with other signaling molecules, such as ROS, nitric oxide (NO), and hydrogen sulfide (H2S). The interaction among melatonin, NO, H2S, and ROS orchestrates the responses to abiotic stresses via signaling networks, thus conferring the plant tolerance. In this review, we summarize the roles of melatonin in establishing redox homeostasis through the antioxidant system and the current progress of complex interactions among melatonin, NO, H2S, and ROS in higher plant responses to abiotic stresses. We further highlight the vital role of respiratory burst oxidase homologs (RBOHs) during these processes. The complicated integration that occurs between ROS and melatonin in plants is also discussed.

Methotrexate mediates the integrity of intestinal stem cells partly through nitric oxide-dependent Wnt/ß-catenin signaling in methotrexate-induced rat ileal mucositis.

This study aimed to elucidate the role of nitric oxide (NO) in intestinal stem cells in methotrexate-induced ileal mucositis in rats. Methotrexate induced the mRNA expressions of the Wnt/ß-catenin target genes Wnt3a, Sox9, and Lgr5 and the Wnt-antagonist gene sFRP-1 and the protein expressions of Lgr5 and sFRP-1. Methotrexate also induced Lgr5+ cells and lysozyme+ cells. A non-selective NO inhibitor inhibited the methotrexate induction of Wnt/ß-catenin target genes and Lgr5+ cells but enhanced that of sFRP-1 expression. Thus, methotrexate mediates the integrity of intestinal stem cells partly through NO-dependent Wnt/ß-catenin signaling and may enhance tolerability to methotrexate-induced injury.