Vascular Nitric Oxide Synthesis Research Articles

Tactics of managing a cardiac patient with comorbidity: promising opportunities for correction of endothelial dysfunction

Background. Arterial hypertension (AH) and heart diseases are the leading causes of morbidity, mortality and the number of visits to the doctor. Cardiac patients are characterized by the frequent polymorbidity. The cardiovascular continuum, which predicts the course of events from atherosclerosis to the final stages of cardiovascular diseases (CVD), includes the following pathogenetic links: oxidative stress, inflammation and endothelial dysfunction (ED).
 Objective. To describe the management of a cardiac patient with comorbidity and promising options for the ED correction.
 Materials and methods. Analysis of the literature on this issue.
 Results and discussion. The previous paradigm of CVD development involved damage to target organs due to hypertension. Instead, according to the current paradigm, CVD are the result of the vascular dysfunction. The recently proposed paradigm indicates that all CVD are based on ED. Nitric oxide (NO) is the main molecule necessary for the proper functioning of the endothelium. NO takes part in the relaxation of blood vessels and smooth muscles, regulates the synthesis and secretion of a number of hormones, controls platelet activity and the interaction of leukocytes with vascular walls, participates in antipathogenic reactions of the immune system. ED is known to be a predictor of complications and poorer survival in patients with coronary heart disease. Dysfunctional endothelium promotes vasoconstriction, oxidation, inflammation and thrombosis. To improve the condition of the endothelium, it is advisable to increase the NO content. The increase in NO content can be the result of angiotensin-converting enzyme inhibitors, calcium channel blockers, sartans, statins, estrogens, antioxidants, and aspirin intake, as well as exercise. L-arginine is the substrate for the NO formation in human body. Potential mechanisms of L-arginine effect in AH include improvement of endothelial function, increase of vascular NO synthesis, decrease of endothelin-1 and angiotensin II activity, modulation of renal hemodynamics and reduction of oxidative stress. L-arginine therapy (9 g per day for 4 weeks) reduced systolic blood pressure by 4 mm Hg and diastolic – by 2.6 mm Hg. L-arginine also has a beneficial effect on the metabolic profile via increasing insulin sensitivity. The use of L-arginine is well studied in patients with chronic heart failure (HF) with preserved ejection fraction. In this category of patients, such treatment leads to an increase in glomerular filtration rate, improvement of endothelium-dependent vasodilation, reduction of the functional class of HF. The ESPEN guidelines on parenteral nutrition state that the use of L-arginine has both NO-dependent and NO-independent effects. The latter include the synthesis of creatine, proline and polyamines; stimulation of insulin and growth hormone secretion. Administration of L-arginine in combination with L-carnitine helps to eliminate the advanced glycation end products and to increase the rate of glomerular filtration.
 Conclusions. 1. The cardiovascular continuum includes such elements as oxidative stress, inflammation and endothelial dysfunction. 2. NO is the main molecule necessary for the proper functioning of the endothelium. 3. L-arginine is the substrate for the NO formation in human body. L-arginine also helps to improve endothelial function, to reduce the activity of endothelin-1 and angiotensin II, to modulate renal hemodynamics and to reduce oxidative stress. 4. L-arginine also has a beneficial effect on the metabolic profile via increasing insulin sensitivity. 5. In patients with chronic HF with preserved ejection fraction, treatment with L-arginine leads to an increase in glomerular filtration rate, improvement of endothelium-dependent vasodilation, reduction of the functional class of HF.

Inhibition of Dimethylarginine Dimethylaminohydrolase 1 Improves the Outcome of Sepsis in Pregnant Mice.

Sepsis is one of the most important causes of maternal mortality. In our previous work, we established a polymicrobial sepsis (cecal ligation and puncture [CLP]) model in murine pregnancy and found that pregnant mice had a greater susceptibility to septic shock. In this model, mortality seemed to be associated with the development of early hemodynamic dysfunction and although circulating cytokine levels were similar, "off target" lung inflammatory cell numbers were greater in pregnant mice.Here, we have used the same CLP model to test the hypothesis that inhibiting the metabolism of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine would improve the outcome of sepsis in pregnancy. We used a dimethylarginine dimethylaminohydrolase 1-selective inhibitor (L-257), which reduces vascular nitric oxide synthesis without impairing immune cell function, in combination with a broad-spectrum antibiotic (Imipenem) and studied the outcome of septic shock in pregnant mice. Treatments were administered 3 h after CLP and samples were taken 3 h later. Both Imipenem and L-257 treatment alone slightly improved mortality rates from 13% (NaCl) to 20% (Imipenem) and 33% (L-257), whereas the combination of Imipenem and L-257 significantly improved survival to 50%. Imipenem and L-257 together prevented cardiovascular collapse and improved both organ function and bacterial killing, but did not reduce lung inflammatory cell numbers and actually increased lung cytokine levels.These data suggest that conventional management in combination with selective inhibition of DDAH1 may have therapeutic potential in the management of sepsis in pregnancy.

Compensatory Vasodilator Mechanisms in the Ophthalmic Artery of Endothelial Nitric Oxide Synthase Gene Knockout Mice

Nitric oxide (NO) generated by endothelial nitric oxide synthase (eNOS) plays an important role in the maintenance of ocular vascular homeostasis. Therefore, perturbations in vascular NO synthesis have been implicated in the pathogenesis of several ocular diseases. We recently reported that eNOS contributes significantly to vasodilation of the mouse ophthalmic artery. Interestingly, dilatory responses were also retained in eNOS gene-deficient mice (eNOS−/−), indicating inherent endothelial adaptive mechanism(s) that act as back-up systems in chronic absence of eNOS to preserve vasorelaxation. Thus, this study endeavoured to identify the compensatory mechanism(s) in the ophthalmic artery of eNOS−/− mice employing isolated arterial segments and pharmacological inhibitors in vitro. Endothelium removal virtually abolished acetylcholine (ACh)-induced vasodilation, suggesting an obligatory involvement of the endothelium in cholinergic control of vascular tone. However, non-NOS and non-cyclooxygenase components compensate for eNOS deficiency via endothelium-derived hyperpolarizing factors (EDHFs). Notably, arachidonic acid-derived metabolites of the 12-lipoxygenase pathway were key mediators in activating the inwardly rectifying potassium channels to compensate for chronic lack of eNOS. Conclusively, endothelium-dependent cholinergic responses of the ophthalmic artery in the eNOS−/− mice are largely preserved and, this vascular bed has the ability to compensate for the loss of normal vasodilator responses solely via EDHFs.

L-Leucine and NO-mediated cardiovascular function.

Reduced availability of nitric oxide (NO) in the vasculature is a major factor contributing to the impaired action of insulin on blood flow and, therefore, insulin resistance in obese and diabetic subjects. Available evidence shows that vascular insulin resistance plays an important role in the pathogenesis of cardiovascular disease, the leading cause of death in developed nations. Interestingly, increased concentrations of L-leucine in the plasma occur in obese humans and other animals with vascular dysfunction. Among branched-chain amino acids, L-leucine is unique in inhibiting NO synthesis from L-arginine in endothelial cells and may modulate cardiovascular homeostasis in insulin resistance. Results of recent studies indicate that L-leucine is an activator of glutamine:fructose-6-phosphate aminotransferase (GFAT), which is the first and a rate-controlling enzyme in the synthesis of glucosamine (an inhibitor of endothelial NO synthesis). Through stimulating the mammalian target of rapamycin signaling pathway and thus protein synthesis, L-leucine may enhance GFAT protein expression, thereby inhibiting NO synthesis in endothelial cells. We propose that reducing circulating levels of L-leucine or endothelial GFAT activity may provide a potentially novel strategy for preventing and/or treating cardiovascular disease in obese and diabetic subjects. Such means may include dietary supplementation with either α-ketoglutarate to enhance the catabolism of L-leucine in the small intestine and other tissues or with N-ethyl-L-glutamine to inhibit GFAT activity in endothelial cells. Preventing leucine-induced activation of GFAT by nutritional supplements or pharmaceutical drugs may contribute to improved cardiovascular function by enhancing vascular NO synthesis.

Körperliche Aktivität und endotheliale Dysfunktion bei Typ-2-Diabetikern: über die Rolle von Stickstoffmonoxid und oxidativem Stress

Type 2 diabetic patients have an increased level of systemic free radicals, which severely restrict the bioavailability of endothelium-derived nitric oxide (NO) and thus contribute to the development of an endothelial dysfunction. This review analyses the influence of physical training on molecular development mechanisms of the endothelial dysfunction and determines the significance of regular physical exercise for the endothelial function in type 2 diabetic patients. Systematic training reinforces the endogenic antioxidative capacity and results in a reduction in oxidative stress. Training - also combined with a change in diet - furthermore reduces hyperglycaemic blood sugar levels, thus curbing a major source of free radicals in diabetes. Moreover, physical exercise enhances vascular NO synthesis through an increased availability/activity of endothelial NO synthases (eNOS). Endurance, as well as resistance training with submaximal intensity or a combination of both forms of training is suitable to effectively improve the endothelial function in type 2 diabetic patients in the long term.

Chronic hyperglicemia and nitric oxide bioavailability play a pivotal role in pro-atherogenic vascular modifications

Diabetes is associated with accelerated atherosclerosis and macrovascular complications are a major cause of morbidity and mortality in this disease. Although our understanding of vascular pathology has lately greatly improved, the mechanism(s) underlying enhanced atherosclerosis in diabetes remain unclear. Endothelial cell dysfunction is emerging as a key component in the pathophysiology of cardiovascular abnormalities associated with diabetes. Although it has been established that endothelium plays a critical role in overall homeostasis of the vessels, vascular smooth muscle cells (vSMC) in the arterial intima have a relevant part in the development of atherosclerosis in diabetes. However, high glucose induced alterations in vSMC behaviour are not fully characterized. Several studies have reported that impaired nitric oxide (NO) synthesis and/or actions are often present in diabetes and endothelial dysfunction. Furthermore, although endothelial cells are by far the main site of vascular NO synthesis, vSMC do express nitric oxyde synthases (NOSs) and NO synthesis in vSMC might be important in vessel's function. Although it is known that vSMC contribute to vascular pathology in diabetes by their change from a quiescent state to an activated proliferative and migratory phenotype (termed phenotypic modulation), whether this altered phenotypic modulation might also involve alterations in the nitrergic systems is still controversial. Our recent data indicate that, in vivo, chronic hyperglycemia might induce an increased number of vSMC proliferative clones which persist in culture and are associated with increased eNOS expression and activity. However, upregulation of eNOS and increased NO synthesis occur in the presence of a marked concomitant increase of O(2-) production. Since NO bioavailabilty might not be increased in high glucose stimulated vSMC, it is tempting to hypothesize that the proliferative phenotype observed in cells from diabetic rats is associated with a redox imbalance responsible quenching and/or trapping of NO, with the consequent loss of its biological activity. This might provide new insight on the mechanisms responsible for accelerated atherosclerosis in diabetes.

Effect of chronic social stress on nitric oxide synthesis and vascular function in rats with family history of hypertension

Genetic predisposition and psychosocial stress are known risk factors in the aetiology of hypertension. The aim of this study was to investigate the as yet unknown role of nitric oxide (NO) in mechanisms of social stress-induced hypertension in rats with a family history of hypertension. Male adult rats used in the study were offspring of normotensive (Wistar) dams and spontaneously hypertensive sires. The rats were exposed to 6-week crowding stress (5 rats/cage, 200 cm 2/rat). Control rats were kept four per cage (480 cm 2/rat). Blood pressure was determined non-invasively on the tail. Basal blood pressure of all rats was 131 ± 2 mm Hg. Crowding stress increased significantly blood pressure ( p < 0.02 vs. basal value). Crowding had no influence on NO synthase activity in the left ventricle, adrenal glands and kidney. However, crowding stress reduced significantly NO synthase activity in the aorta by 37% ( p < 0.01 vs. control). Acetylcholine-induced relaxation and noradrenaline-induced vasoconstriction of the femoral artery were reduced in stressed rats by 58% ( p < 0.001) and 41% ( p < 0.003), respectively. On balance then, the results indicate that chronic social stress produced by crowding was associated with reduced vascular NO synthesis and altered vascular function in adult borderline hypertensive rats of normotensive mothers.

Increased eNO and pulmonary iNOS expression in eNOS null mice.

Nitric oxide (NO) is a major regulatory molecule of the cardiovascular system; however, measurement of vascular NO synthesis in vivo represents a major challenge. NO stemming from the lower respiratory tract has been used as a marker of vascular endothelial function. Experimental evidence for this concept is lacking. Therefore, the aim of the present study was to investigate this relationship. Lower respiratory tract exhaled NO concentration, together with systemic and pulmonary artery pressure, was measured in endothelial nitric oxide synthase (NOS) (eNOS) null mice (eNOS-/-). Similar studies were performed in inducible NOS (iNOS) null mice (iNOS-/-). Defective endothelial NO synthesis in eNOS-/- mice (evidenced by systemic and pulmonary hypertension) was associated with augmented exhaled NO levels (12.5 +/- 1.9 versus 9.8 +/- 1.2 parts per billion (ppb), eNOS-/- versus wild type), whereas normal endothelial NO synthesis in iNOS-/- mice was associated with decreased exhaled NO levels (4.3 +/- 1.5 ppb). Augmented exhaled NO levels in eNOS-/- mice were associated with upregulation of iNOS expression in the lung. These results indicate that inducible nitric oxide synthase is a major determinant of gaseous nitric oxide production in the lung, and lower respiratory tract exhaled nitric oxide does not always represent a marker of vascular endothelial nitric oxide synthesis.

Nitric oxide does not mediate the vasodilation of early human pregnancy

Background: In early pregnancy, a substantial drop in arterial blood pressure occurs, that might be attributed to enhanced vascular nitric oxide synthesis. We investigated whether nitric oxide mediates the vasodilation that occurs in early human pregnancy. Methods: Resting and stimulated forearm vascular resistance were measured (venous occlusion plethysmograph) in six women at 10 ± 3 weeks of uncomplicated pregnancy and in the same women 7 ± 5 weeks after elective termination of pregnancy. Forearm vascular resistance was also measured in six non-pregnant, healthy controls. Results: Resting forearm vascular resistance was similar during pregnancy (33 ± 16 arbitrary units (AU)), after pregnancy (31 ± 10 AU) and in controls (41 ± 13 AU, P > 0.05). The decreases in forearm vascular resistance to intrabrachial infusions of acetylcholine (2 and 20 pg/min), serotonin (10 and 100 ng/min) and sodium nitroprusside (1 and 2.5 gg/min) were similar in all groups. The nitric oxide synthase inhibitor N G-monomethyl-L-arginine (16 pmol/min) produced similar increases in vascular resistance in pregnant women (38 ± 17 AU), after pregnancy (36 ± 14 AU) and in control subjects (42 ± 8 AU, P = NS). Conclusions: These results indicate that neither basal nor stimulated nitric oxide levels are altered in the forearm circulation during first trimester pregnancy.

Bactericidal/permeability-increasing protein inhibits endotoxin-induced vascular nitric oxide synthesis.

Endotoxin (lipopolysaccharide, LPS) up-regulates inducible nitric oxide synthase (iNOS) in blood vessels during septic shock. This promotes the production of nitric oxide (NO), leading to dilation of the vessels. The aim of the study was to investigate the effects of the LPS-binding endogenous antibiotic bactericidal/permeability-increasing protein (BPI) on the action of LPS on the blood vessels wall and to identify possible influence on underlying NO-related mechanisms. Isolated segments of rat thoracic aorta and cultured primary smooth muscle cells were incubated for 5-48 h in the presence of the following combinations of compounds: (a) LPS; (b) interleukin-1beta (IL-1beta); (c) BPI; (d) BPI + LPS; (e) BPI + IL-1beta or (f) neither BPI, LPS nor IL-1beta (control). After incubation of intact segments, we measured smooth muscle contraction in response to phenylephrine and accumulation of the NO end products nitrate and nitrite in surrounding medium. Western blot was used to assess the levels of inducible nitric oxide synthase (iNOS) in cultured cells. Both LPS and IL-1beta decreased contractility and increased NO production, as well as iNOS. Co-incubation with BPI attenuated all the effects of LPS but only the effects of prolonged exposure to IL-1beta in cultured cells. We conclude that BPI attenuates the LPS-induced changes in vascular reactivity by inhibiting the expression of iNOS resulting in decreased NO formation and restored responsiveness to vasoconstrictors. The data suggest that BPI can prevent circulatory disturbances during Gram-negative sepsis.

The pressor effect of NO synthase inhibition correlates to pre-existing systolic BP in the rat

A number of studies have found that the vasopressor effect of nitric oxide (NO) synthase inhibition is small following treatment with hypotensive agents but is enhanced after hypertensive agents, and have implicated NO in the mechanism of action of these drugs. We investigated the hypothesis that the rate of vascular NO synthesis is directly related to blood pressure. The vasopressor effect of 10 mg/kg of l-nitro- l-arginine methyl ester ( l-NAME) was studied in relation to changes in BP induced by a variety of treatments in both pentobarbital sodium anesthetized and pithed rats. BP reductions were induced by blood withdrawal, surgery and pithing. BP increases were made by injecting 10 and 15 μg/kg boluses of phenylephrine or by injecting 5% albumin solution. Pithing decreased baseline BP and attenuated the vasopressor effect of l-NAME while phenylephrine increased both BP levels and the hypertensive effect of l-NAME. Volume expansion with 5% albumin solution increased both BP and the vasopressor effect of l-NAME. Both surgery (abdominal incision) and withdrawal of 1 ml blood reduced BP and attenuated the pressor effect of l-NAME. When the results of all these studies were combined, systolic BP was found to correlate strongly with the vasopressor effect of l-NAME ( R 2=0.73, P<0.0001). Diastolic BP correlated less well with l-NAME ( R 2=0.36, P<0.0003). The results suggest that shear stress generated by blood flow during the systole releases NO, and lowers BP. The pressor effect of NO synthase inhibition is closely related to pre-existing systolic BP.

Vascular nitric oxide, sex hormone replacement, and fish oil may help to prevent Alzheimer's disease by suppressing synthesis of acute-phase cytokines

The neurodegenerative plaques of Alzheimer's disease (AD) are characterized by a self-sustaining acute-phase reaction in which both interleukin-1 (IL-1) and interleukin-6 (IL-6) are up-regulated. The fact that IL-6 is detectable in early stage diffuse plaques encourages the speculation that the acute-phase process is crucial to the pathogenesis of AD. The epidemiological association of AD with estrogen deficiency, as well as with various disorders characterized by vascular endotheliopathy, suggest a protective role for vascular nitric oxide (NO). NO has an autocrine anti-inflammatory impact on endothelium, owing in part to antagonism of NF-κB activity; since induction of IL-6 is dependent on NF-κB, this may explain recent evidence that NOinhibits macrophage IL-6 production. It is reasonable to postulate that, analogously, cerebrovascular NOdecreases IL-6 production in the brain. Vascular NO may also have direct neuroprotective activity. Estrogen, in addition to promoting vascular NO synthesis, can block IL-6 production by a more direct mechanism in cells expressing estrogen receptors; since such receptors have been reported in brain glia and astrocytes, estrogen has the potential to limit brain IL-1 activity. Testosterone likewise can inhibit IL-6 induction in androgen-responsive cells, which may include brain glia and astrocytes. Since fish oil and γ linolenic acid (GLA) suppress IL-1 production by stimulated monocytes, they conceivably could exert this effect in the brain as well; the comparatively low prevalence of AD in elderly Japanese is intriguing in this regard. These considerations suggest that a healthy cerebrovascular endothelium, sex hormone activity, and dietary fish oil/GLA may slow or prevent AD onset by dampening acute-phase mechanisms in the brain.

Impaired aerobic capacity in hypercholesterolemic mice: partial reversal by exercise training.

The present study assessed whether impaired aerobic capacity previously observed in hypercholesterolemic mice is reversible by exercise training. Seventy-two 8-wk-old female C57BL/6J wild-type (+, n = 42) and apolipoprotein E-deficient (-, n = 30) mice were assigned to the following eight interventions: normal chow, sedentary (E+, n = 17; E-, n = 8) or exercised (E+ex, n = 13; E-ex, n = 7) and high-fat chow, sedentary (E+chol, n = 6; E-chol, n = 8) or exercised (E+chol-ex, n = 6; E-chol-ex, n = 7). Mice were trained on a treadmill 2 x 1 h/day, 6 days/wk, for 4 wk. Cholesterol levels correlated inversely with maximum oxygen uptake (r = -0.35; P < 0. 02), which was blunted in all hypercholesterolemic sedentary groups (all P < 0.05). Maximum oxygen uptake improved in all training groups but failed to match E+ex (all P < 0.05). Vascular reactivity and nitric oxide (NO) synthesis correlated with anaerobic threshold (r = 0.36; P < 0.025) and maximal distance run (r = 0.59; P < 0.007). We conclude that genetically induced hypercholesterolemia impairs aerobic capacity. This adverse impact of hypercholesterolemia on aerobic capacity may be related to its impairment of vascular NO synthesis and/or vascular smooth muscle sensitivity to nitrovasodilators. Aerobic capacity is improved to the same degree by exercise training in normal and genetically hypercholesterolemic mice, although there remains a persistent difference between these groups after training.

ATP: the red blood cell link to NO and local control of the pulmonary circulation

Recently, we reported that rabbit red blood cells (RBCs) were required for the expression of nitric oxide (NO) activity on pulmonary vascular resistance (PVR) in rabbit lungs. Here, we investigate the hypothesis that RBCs participate in the regulation of PVR via release of ATP in response to mechanical deformation that, in turn, evokes vascular NO synthesis. We found that rabbit and human RBCs, but not dog RBCs, release ATP in response to mechanical deformation. To determine the contribution of this ATP to NO synthesis and PVR, we compared the effects of human and dog RBCs on pressure-flow relationships in isolated rabbit lungs. In the presence of human RBCs, NG-nitro-L-arginine methyl ester (100 microM) produced a shift in the pressure-flow relationship consistent with a reduction in vascular caliber. NG-nitro-L-arginine methyl ester had no effect in lungs perfused with dog RBCs. These results suggest a unique mechanism for the control of PVR in rabbits and humans whereby release of ATP by RBCs in response to mechanical deformation leads to stimulation of NO synthesis that, in turn, modulates the PVR.

Inhibition of nitric oxide synthesis in rats during pregnancy produces signs similar to those of preeclampsia

Preeclampsia is associated with hypertension, fetal growth retardation, and proteinuria. We hypothesized that impaired vascular nitric oxide synthesis during pregnancy may be an important causal factor in preeclampsia. An inhibitor of nitric oxide synthase, L-nitro-arginine methyl ester, or a nitric oxide donor, nitroglycerin, was infused subcutaneously to rats at a constant rate from day 17 of gestation. Systolic blood pressure, day of spontaneous delivery, weight, and mortality rate of pups were recorded. Systolic blood pressures in rats infused with L-nitro-arginine methyl ester at daily doses of both 25 and 50 mg were significantly elevated compared with controls. This treatment also caused a substantial decrease in the weight of pups, with an increase in mortality rate, without affecting the gestational length. These effects were dose dependent. Nitroglycerin infusion, on the other hand, affected neither the weight and mortality rate of the pups nor the length of gestation. Infusion of an inhibitor of nitric oxide synthesis during pregnancy causes hypertension and fetal growth retardation, without affecting gestational length. These signs are similar to those of preeclampsia and indicate that an alteration in nitric oxide synthesis may be one of the factors responsible for this disorder. Treatment with nitric oxide inhibitors may be used in an animal model for preeclampsia, to test various therapeutic strategies.

Direct coronary and cerebral vascular responses to dexmedetomidine. Significance of endogenous nitric oxide synthesis.

Dexmedetomidine activates alpha 2-adrenergic receptors in the central nervous system and in the peripheral vasculature. In vivo dexmedetomidine has been found to cause alterations in coronary and cerebral blood flows and arterial pressure by stimulation of vascular smooth muscle alpha 2 receptors. The direct vasoconstrictor effects of alpha 2-adrenergic agonists may be opposed by release of endothelium-derived relaxing factor believed to be nitric oxide. A functional endothelium was demonstrated recently in canine coronary collateral vessels. The objective of the current study was to assess the direct effect of dexmedetomidine on isolated canine proximal and distal coronary arteries, coronary collateral vessels, and middle cerebral arteries. Responses were measured in tissue baths in the presence of indomethacin 10(-5) M and in the absence and presence of NG nitro-l-arginine methyl ester (L-NAME), an inhibitor of vascular nitric oxide synthesis. Dexmedetomidine (3 x 10(-8) to 3 x 10(-3.9) M) caused constriction (3.9, 5.5, 72.8, and 2.3% for proximal and distal coronary arteries, middle cerebral arteries, and coronary collateral vessels, respectively, expressed as a percentage of KCl-induced contraction) in all vessels. This constriction was enhanced by the presence of L-NAME in all vessels except cerebral arteries. The selective alpha 2-adrenergic antagonist atipamezole (10(-4) M) abolished the response to low but not high concentrations of dexmedetomidine in middle cerebral arteries, proximal coronary arteries, and coronary collateral vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Development and mechanism of a specific supersensitivity to nitrovasodilators after inhibition of vascular nitric oxide synthesis in vivo.

The mechanism of the increased sensitivity to nitrovasodilators after removal of endothelial nitric oxide (NO) was investigated in vitro and in vivo. The vasoconstrictor potency of phenylephrine and the force of contraction of rat isolated aortic rings were significantly enhanced after endothelium removal or treatment with inhibitors of endothelial NO synthase. Furthermore, these procedures led to a significant decrease in the basal levels of cGMP in the vascular rings. Moreover, the potency of glyceryl trinitrate (n3Gro) and sodium nitroprusside (SNP) as relaxing agents and the ability of SNP to induce increases in cGMP in aortic rings were significantly enhanced in those rings denuded of endothelium or treated with the inhibitors. These procedures did not affect the vasodilator actions of isoprenaline or 8-bromo-cGMP. In the anesthetized rat, treatment with the inhibitors enhanced significantly the hypotensive responses to n3Gro without affecting those to isoprenaline. These data indicate that the removal of the basal NO-mediated vasodilator tone in the cardiovascular system leads, at the level of the soluble guanylate cyclase, to a specific supersensitivity to nitrovasodilators in vivo. The existence of such a phenomenon has important implications for understanding the local physiological control of blood flow, its pathological disturbances, and the mechanism of action of nitrovasodilators.

Modulation of vascular nitric oxide synthesis by physiological Ca ++ concentrations

Modulation of vascular nitric oxide synthesis by physiological Ca ++ concentrations