Efficacy of fenbendazole and ivermectin in treating gastrointestinal nematode infections in an Ontario cow-calf herd.

The objective of this randomized clinical trial was to compare performance of cow-calf pairs in southern Ontario treated with fenbendazole or ivermectin, or not treated, for gastrointestinal nematode infections. Treatments were administered to 128 cow-calf pairs over 2 years. Weights, body condition score, and fecal egg counts (FEC) were collected at treatment and at 28-day intervals. Treating calves with an anthelmintic was significantly advantageous compared with not treating, and there was no significant difference between treatment with fenbendazole or ivermectin. Neither treatment nor calf FEC had a significant effect on calf weaning weight. This could be the result of time of treatment, low initial FEC, or lack of power. Treatment affected cow FEC (P = 0.003). Cows in the ivermectin groups had the lowest FEC (P < 0.05), but because FEC were all low, biological significance is questionable. Additional work is needed to provide recommendations on when an anthelmintic should be used.

Efficacité du fenbendazole et de l'ivermectin pour traiter les infections à nématodes gastrointestinaux dans un troupeau de vaches-veaux en Ontario. L'objectif de cet essai clinique randomisé était de comparer les performances de paires de vaches-veaux dans le sud de l'Ontario traitées avec du fenbendazole ou de l'ivermectin, ou non-traitées, pour des infections à nématodes gastro-intestinaux. Les traitements furent administrés à 128 paires de vaches-veaux sur une période de 2 ans. Le poids, le pointage de l'état corporel, et le dénombrement des oeufs dans les fèces (FEC) furent colligés au moment du traitement et à des intervalles de 28 jours. Traiter des veaux avec un anthelmintique était significativement avantageux comparativement à ne pas les traiter, et il n'y avait pas de différence significative entre un traitement au fenbendazole ou à l'ivermectin. Ni l'un ou l'autre des traitements ou les FEC n'avaient un effet significatif sur le poids au sevrage des veaux. Ceci pourrait être dû au moment du traitement, un FEC initial peu élevé, ou un manque de puissance. Les traitements ont affecté les FEC des vaches (P = 0,003). Les vaches dans le groupe ivermectin avaient les plus bas FEC (P < 0,05), mais étant donné que tous les FEC étaient bas, la signification biologique est questionnable. Du travail supplémentaire est requis pour fournir des recommandations sur le moment où un anthelmintique devrait être utilisé.(Traduit par Dr Serge Messier).

Community-based assessment and rehabilitation of hearing loss: A scoping review.

Although the World Health Organization (WHO) recommends the use of a Community-Based Rehabilitation (CBR) model, little is known about how CBR has been applied in the hearing healthcare setting. The purpose of this scoping review was to identify and describe studies on Community-Based Hearing Rehabilitation (CBHR) programs within the applied context. The review was conducted in September 2020 with updated searches in November 2021 according to the Joanna Briggs Institute (JBI) methodology and reported using the guidelines and checklist for Preferred Reporting Items for Systematic Reviews and Meta Analyses-Extension for Scoping Reviews (PRISMA-ScR). Fifty-nine peer-reviewed research articles were included in the review. A narrative synthesis was conducted to map out the types of CBHR programs. Studies were classified into audiological themes: awareness, screening and assessment of hearing in newborn/infants, children and adults, training of community health workers, rehabilitation, cost-effectiveness and describing the service delivery models. Further categorisation was made based on CBR aspect matrices for each study. Most of the studies come from high-income countries in North America and Europe. CBHR studies predominantly focused on creating awareness, training and hearing screenings and/or assessments in communities and evaluating effectiveness in providing knowledge and access to hearing health services in rural or underserved communities. Further work is needed to examine the outcomes and effectiveness of CBHR using controlled studies. Moreover, more work is needed in low- and middle-income countries where the application of CBHR is critical for increased access and affordability.

Role of endothelium-derived nitric oxide in the regulation of cardiac oxygen metabolism: implications in health and disease.

Endothelium-derived NO is considered to be primarily an important determinant of vascular tone and platelet activity; however, the modulation of myocardial metabolism by NO may be one of its most important roles. This modulation may be critical for the regulation of tissue metabolism. Several physiological processes act in concert to make endothelial NO synthase-derived NO potentially important in the regulation of mitochondrial respiration in cardiac tissue, including (1) the nature of the capillary network in the myocardium, (2) the diffusion distance for NO, (3) the low toxicity of NO at physiological (nanomolar) concentrations, (4) the fact that low PO(2) in tissue facilitates the action of NO on cytochrome oxidase, and (5) the formation of oxygen free radicals. A decrease in NO production is involved in the pathophysiological modifications that occur in heart failure and diabetes, disease states associated with altered cardiac metabolism that contributes to the evolution of the disease process. In contrast, several drugs (eg, angiotensin-converting enzyme inhibitors, amlodipine, and statins) can restore or maintain endogenous production of NO by endothelial cells, and this mechanism may explain part of their therapeutic efficiency. Thus, the purpose of this review is to critically evaluate the role of NO in the control of mitochondrial respiration, with special emphasis on its effect on cardiac metabolism.

Myocardial glucose uptake is regulated by nitric oxide via endothelial nitric oxide synthase in Langendorff mouse heart.

Although the role of nitric oxide (NO) in the modulation of vascular tone has been studied and well understood, its potential role in the control of myocardial metabolism is only recently evident. Several lines of evidence indicate that NO regulates myocardial glucose metabolism; however, the details and mechanisms responsible are still unknown. The aim of this study was to further define the role of NO in the control of myocardial glucose metabolism and the nitric oxide synthase (NOS) isoform responsible using transgenic animals lacking endothelial NOS (ecNOS). In the present study, we examined the regulation of myocardial glucose uptake using isometrically contracting Langendorff-perfused hearts from normal mice (C57BL/6J), mice with defects in the expression of ecNOS [ecNOS (-/-)], and its heterozygote [ecNOS (+/-)], and wild-type mice [ecNOS (+/+)] (n=6, respectively). In hearts from normal mice, little myocardial glucose uptake was observed. This myocardial glucose uptake increased significantly in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME). Similarly, in the hearts from ecNOS (-/-), glucose uptake was much greater than in normal mice, whereas myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice was not different from normal mice. In addition, myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice increased significantly in the presence of L-NAME. At a workload of 800 g. beats/min, L-NAME increased glucose uptake from 0.1+/-0.1 to 3+/-0.4 microg/min x mg in ecNOS (+/-) mice and from 0.2+/-0.1 to 2.7+/-0.7 microg/min x mg in ecNOS (+/+) mice. Furthermore, in the hearts from ecNOS (-/-) mice, 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a cGMP analog or S-nitroso-N-acetylpenicillamine (SNAP), a NO donor essentially shut off glucose uptake, and in hearts from ecNOS (+/-) mice, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), an inhibitor of cGMP, increased the glucose uptake significantly. These results indicate clearly that cardiac NO production regulates myocardial glucose uptake via a cGMP-dependent mechanism and strongly suggest that ecNOS plays a pivotal role in this regulation. These findings may be important in the understanding of the pathogenesis of the diseases such as ischemic heart disease, heart failure, diabetes mellitus, hypertension, and hypercholesterolemia, in which NO synthesis is altered and substrate utilization by the heart changes.

Nitric oxide modulates mitochondrial respiration in failing human heart.

Background-Our objective for this study was to investigate whether nitric oxide (NO) modulates tissue respiration in the failing human myocardium. Methods and Results-Left ventricular free wall and right ventricular tissue samples were taken from 14 failing explanted human hearts at the time of transplantation. Tissue oxygen consumption was measured with a Clark-type oxygen electrode in an airtight stirred bath containing Krebs solution buffered with HEPES at 37 degrees C (pH 7.4). Rate of decrease in oxygen concentration was expressed as a percentage of the baseline, and results of the highest dose are indicated. Bradykinin (10(-4) mol/L, -21+/-5%), amlodipine (10(-5) mol/L, -14+/-5%), the ACE inhibitor ramiprilat (10(-4) mol/L, -21+/-2%), and the neutral endopeptidase inhibitor thiorphan (10(-4) mol/L, -16+/-5%) all caused concentration-dependent decreases in tissue oxygen consumption. Responses to bradykinin (-2+/-6%), amlodipine (-2+/-4%), ramiprilat (-5+/-6%), and thiorphan (-4+/-7%) were significantly attenuated after NO synthase blockade with N-nitro-L-arginine methyl ester (10(-4) mol/L; all P<0.05). NO-releasing compounds S-nitroso-N-acetyl-penicillamine (10(-4) mol/L, -34+/-5%) and nitroglycerin (10(-4) mol/L, -21+/-5%), also decreased tissue oxygen consumption in a concentration-dependent manner. However, the reduction in tissue oxygen consumption in response to S-nitroso-N-acetyl-penicillamine (-35+/-7%) or nitroglycerin (-16+/-5%) was not significantly affected by N-nitro-L-arginine methyl ester. Conclusions-These results indicate that the modulation of oxygen consumption by both endogenous and exogenous NO is preserved in the failing human myocardium and that the inhibition of kinin degradation plays an important role in the regulation of mitochondrial respiration.

Potential role of eNOS in the therapeutic control of myocardial oxygen consumption by ACE inhibitors and amlodipine.

OBJECTIVES: Our aim was to investigate the potential therapeutic role of endothelial nitric oxide synthase (eNOS) in the modulation of cardiac O(2) consumption induced by the angiotensin converting enzyme (ACE) inhibitor ramiprilat and amlodipine. METHODS: Three different groups of mice were used; wild type, wild type in the presence of N-nitro-L-arginine methyl ester (L-NAME, 10(-4) mol/l) or genetically altered mice lacking the eNOS gene (eNOS -/-). Myocardial O(2) consumption was measured using a Clark-type O(2) electrode in an air-tight stirred bath. Concentration-response curves to ramiprilat (RAM), amlodipine (AMLO), diltiazem (DIL), carbachol (CCL), substance P (SP) and S-nitroso-N-acetyl-penicillamine (SNAP) were performed. The rate of decrease in O(2) concentration was expressed as a percentage of the baseline. RESULTS: Baseline O(2) consumption was not different between the three groups of mice. In tissues from wild type mice, RAM (10(-5) mol/l), AMLO (10(-5) mol/l), DIL (10(-4) mol/l), CCL (10(-4) mol/l), SP (10(-7) mol/l) and SNAP (10(-4) mol/l) reduced myocardial O(2) consumption by -32+/-4, -27+/-10, -20+/-6, -25+/-2, -22+/-4 and -42+/-4%, respectively. The responses to RAM, AMLO, CCL and SP were absent in tissues taken from eNOS -/- mice (-7.1+/-4.3, -5.0+/-6.0, -5.2+/-5.1 and -0.4+/-0.2%, respectively). In addition, L-NAME significantly (P<0.05) inhibited the reduction in O(2) consumption induced by RAM (-9.8+/-4.4%), AMLO (-1.0+/-6.0%), CCL (-8.8+/-3.7%) and SP (-6.6+/-4.9%) in cardiac tissues from wild type mice. In contrast, NO-independent responses to the calcium channel antagonist, DIL, and responses to the NO donor, SNAP, were not affected in cardiac tissues taken from eNOS -/- (DIL: -20+/-4%; SNAP: -46+/-6%) or L-NAME-treated (DIL: -17+/-2%; SNAP: -33+/-5%) mice. CONCLUSIONS: These results suggest that endogenous endothelial NO synthase derived NO serves an important role in the regulation of myocardial O(2) consumption. This action may contribute to the therapeutic action of ACE inhibitors and amlodipine.

Estrogen maintains nitric oxide synthesis in arterioles of female hypertensive rats.

We hypothesized that in female spontaneously hypertensive rats (SHR), estrogen moderates the dysfunction of arterioles by preserving nitric oxide synthesis. To this end, we conducted experiments on isolated gracilis muscle arterioles (approximately 55 microns in diameter) of 12-week-old (SHR divided into four groups: females (fSHR), ovariectomized females (fSHR-OV), ovariectomized females with estrogen replacement (fSHR-OV+ES, 50 micrograms/kg SC 17 beta-estradiol benzoate every 48 hours), and males (mSHR). Arteriolar diameter in the presence of perfusion pressures of 60, 80, 100, and 120 mm Hg were obtained, and diameter changes were measured (at 80 mm Hg) in response to various concentrations of substance P (10(-9) to 5 x 10(-8) mol/L), sodium nitroprusside (10(-8) to 10(-6) mol/L), and A23187 (5 x 10(-8) to 10(-6) mol/L). The pressure-induced diameter of mSHR and fSHR-OV arterioles was significantly less (by approximately 10%) than that of fSHR and fSHR-OV+ES arterioles. N omega-nitro-L-arginine (10(-4) mol/L), a nitric oxide synthase inhibitor, elicited a significant decrease in basal arteriolar diameter of fSHR (by approximately 19%) and fSHR-OV+ES (by approximately 17%), thereby eliminating the differences in tone among the various groups. Dilations of fSHR and fSHR-OV+ES arterioles to substance P were significantly greater (by 140% at a concentration of 5 x 10(-8) mol/L) than those of mSHR and fSHR-OV arterioles, whereas dilations to sodium nitroprusside were not different among the groups. A23187 (a nitric oxide releaser) elicited dilations in arterioles of fSHR (5.9 +/- 1.5%, 13.0 +/- 1.8%, and 19.2 +/- 2.1%) and fSHR-OV+ES (4.3 +/- 1.0%, 10.3 +/- 2.4%, and 15.0 +/- 4.0%) but constrictions in those of mSHR (-7.5 +/- 1.6%, -25.3 +/- 39%, and -36.9 +/- 4.1%) and fSHR-OV (-2.6 +/- 1.7%, 7.4 +/- 3.3%, and -11.5 +/- 6.1%). We conclude that estrogen in fSHR is responsible for the preservation of nitric oxide synthesis in skeletal muscle arterioles, resulting in a greater modulation of pressure-induced myogenic tone than in mSHR and maintenance of nitric oxide-mediated dilations.

Estrogen preserves regulation of shear stress by nitric oxide in arterioles of female hypertensive rats.

Previously we found that flow-induced arteriolar dilation in male spontaneously hypertensive rats (SHR) is significantly impaired, due to the absence of the nitric oxide (NO)-mediated portion of the response, resulting in an elevation of maintained wall shear stress. Since estrogen has been shown to affect NO-mediated responses, we hypothesized that in female SHR (fSHR) the NO-mediated portion of flow-induced responses is preserved. Gracilis muscle arterioles (approximately 45 to 55 microm) from 12-week-old fSHR, ovariectomized fSHR (OV fSHR), or ovariectomized and supplemented with estrogen fSHR (OVE fSHR) were isolated, cannulated, and pressurized at 80 mm Hg of perfusion pressure. Arteriolar dilations elicited by step increases in perfusate flow from 0 to 25 microL/min were significantly less (by approximately 30%) in OV fSHR compared with fSHR and OVE fSHR (delta19.4+/-1.5 versus 26.0+/-0.9 and 26.8+/-2.0 microm, respectively at maximum flow rate). Inhibition of prostaglandin synthesis with indomethacin elicited a approximately 50% reduction in flow-dependent dilation in all three groups of rats. N(omega)-nitro-L-arginine (L-NNA) significantly inhibited flow-induced responses in arterioles of fSHR and OVE fSHR (by approximately 50%) but not in those of OV fSHR. Constrictions to norepinephrine (10(-7)-3 x 10(-7) mol/L) were significantly greater (up to approximately 40%) in arterioles of OV fSHR compared with those of fSHR and OVE fSHR; these differences, however, were abolished in the presence of L-NNA. In conclusion, estrogen seems to preserve the NO-mediated portion of flow/shear stress-induced dilation in female hypertensive rats resulting in a lower maintained wall shear stress in female than in male SHR. The lower wall shear stress may contribute to the mechanisms by which estrogen lowers systemic blood pressure and the incidence of cardiovascular diseases in women.

Nitroglycerin and nitroprusside increase coronary blood flow in dogs by a mechanism independent of prostaglandin release.

The hypothesis that local release of vasodilator prostaglandins mediates, in part, the decrease in coronary resistance after nitroglycerin (NG) administration was tested. NG (60 micrograms/min) and nitroprusside (NP) (30 micrograms/min) were infused for 10 minutes into the left circumflex coronary artery of 9 open-chest, chloralose-anesthetized dogs before and after blockade of prostaglandin synthesis with indomethacin (5 mg/kg). Also, to eliminate the effects of reflex tachycardia on the responses to NG and NP, these experiments were repeated in 6 dogs with heart rate held constant by pacing. NG infusion into dogs without pacing resulted in a maximal increase in coronary blood flow of 55% and after 8 minutes of infusion an increase of 20%, from a baseline of 57 ml/min. NP infusion resulted in a maximal increase in blood flow of 89% and after 8 minutes an increase of 71%, from a baseline of 64 ml/min. In dogs with heart rate held constant, NG infusion caused a maximal increase in coronary artery blood flow of 132% and after 8 minutes of infusion an increase of 18%, from a baseline of 48 ml/min; NP infusion resulted in increase from 51 ml/min of 132% and 62%, respectively. In neither group of dogs did indomethacin significantly change the increases in coronary blood flow or decreases in coronary resistance to NG or NP. Thus, both NG and NP, when infused into the coronary artery of dogs, cause increases in coronary blood flow and decreases in coronary resistance by a mechanism which is independent of prostaglandin release.

Angiotensin-converting enzyme inhibitors promote nitric oxide production in coronary microvessels from failing explanted human hearts.

We have previously shown that nitric oxide (NO) release by the coronary circulation in the failing and nonfailing human heart is, in part, regulated by local kinin production in coronary microvessels. Angiotensin-converting enzyme (ACE) also known as kininase II, inactivates kinins. ACE inhibitors prevent kinin breakdown by ACE, thereby increasing the concentration of bradykinin (BK) and related kinins. The goal of this study was to determine if kinins contribute to the therapeutic action of ACE inhibitors. Six hearts from end-stage heart failure patients were harvested at the time of orthotopic cardiac transplantation. Microvessels were prepared as previously described, and nitrite production, a metabolic product of NO in vitro, was determined by the Griess reaction. Microvessels were incubated in the presence of kininogen and bradykinin, and with the ACE inhibitors ramiprilat, enalaprilat, or captopril. All caused dose-dependent increases in nitrite. For instance, ramiprilat increased nitrite from 76 +/- 5.6 to 155 +/- 15 pmol/min per mg wet weight. Nitrite production in response to ACE inhibition was blocked by N-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, and icatibant (HOE 140), a B2-kinin receptor-specific antagonist. Furthermore, NO production was prevented by 3 different serine protease inhibitors, which block kallikrein, the enzyme responsible for conversion of kininogen to kinins. Our results indicate that ACE/kininase inhibitors increase NO production by the coronary microvasculature in the failing human heart, through increased available active kinins. The therapeutic action of ACE inhibition in the failing human heart may result in part from increased NO production by coronary microvessels.

Amlodipine promotes kinin-mediated nitric oxide production in coronary microvessels of failing human hearts.

Recently, we found that amlodipine can release nitric oxide (NO) from canine coronary microvessels, which raises the question of whether amlodipine can also promote coronary NO production in failing human hearts. The goal of this study was to define the effect of amlodipine on NO production in failing human hearts and to determine the role of kinins in the control of NO production induced by amlodipine. Six explanted human hearts with end-stage heart failure were obtained immediately at transplant surgery. Coronary microvessels were isolated as previously described, and nitrite, the stable metabolite of NO in aqueous solution, was measured using the Griess Reaction. Amlodipine (10(-10) to 10(-5) mol/L) significantly increased nitrite production in coronary microvessels in a dose-dependent manner. The increase in nitrite in response to the highest dose of amlodipine (79%) was similar in magnitude to either that of the angiotensin-converting enzyme inhibitor ramiprilat (74%) or the neutral endopeptidase inhibitors phosphoramidon (61%) and thiorphan (72%). Interestingly, the increase in nitrite production induced by amlodipine was entirely abolished by N(omega)-nitro-L-arginine methyl ester and also HOE-140 (a bradykinin-2 antagonist) and dichloroisocoumarin (a serine protease inhibitor that blocks kallikrein activity). These results indicate that amlodipine can promote coronary NO production in failing human hearts and that this effect is dependent on a kinin-mediated mechanism.

Mechanisms of reflex bradycardia and hypotension by metabolites of arachidonic acid in the cat.

In the cat, intravenous injections of arachidonic acid or prostaglandin (PG)F2 alpha caused significant reductions in mean arterial pressure and heart rate which were eliminated or significantly lessened, respectively, by previous administration of indomethacin. The bradycardia to intravenous prostacyclin (PGI2) was unaffected by indomethacin. In cats with bilateral ligation of the carotid arteries to eliminate competition between systemic baroreflexes and cardiopulmonary reflexes, PGI2, PGF2 alpha and arachidonic acid caused significantly greater hypotension and bradycardia than in cats with intact carotid baroreflexes. The bradycardia to PGI2, PGF2 alpha and arachidonic acid was eliminated by bilateral vagal section or atropine. PGE1, PGE2 and nitroprusside caused dose-related falls in mean arterial pressure and a small tachycardia. In a small group of cats (7 of 67) nitroprusside also caused a reduction in heart rate which was eliminated by indomethacin. We conclude that the reflex bradycardia to PGF2 alpha, like that to arachidonic acid is, at least in part, the result of the stimulation of synthesis of another prostaglandin, most likely PGI2.

Neural regulation of coronary vascular resistance: role of nitric oxide in reflex cholinergic coronary vasodilation in normal and pathophysiologic states.

A number of reflexes participate in the control of coronary vascular resistance through activation of the sympathetic or parasympathetic nervous system. Classically, activation of vagal efferent fibers to the heart results in vasodilation due to the release of acetylcholine and activation of muscarinic receptors. Recently, we have found that activation of a number of reflexes in conscious dogs, the Bezold-Jarisch reflex and the carotid chemoreflex in particular, results in cholinergic coronary vasodilation which is blocked by an inhibitor of nitric oxide synthesis, nitro-L-arginine. After the development of pacing-induced heart failure, the cholinergic dilation subsequent to activation of the Bezold-Jarisch or carotid chemoreflex is essentially abolished, since coronary blood vessels no longer produce nitric oxide. In contrast, after brief exercise training, there is a potentiation of Bezold-Jarisch reflex-induced coronary vasodilation since exercise upregulates nitric oxide production by coronary blood vessels. Since the Bezold-Jarisch reflex may be important as a compensatory mechanism during acute myocardial infarction, and the carotid chemoreflex is the acute mechanisms responsible for ameliorating systemic hypoxemia, the role of nitric oxide in reflex cholinergic coronary vasodilation may be essential in the compensatory vascular adjustments evoked by these and other reflexes.

Short-term daily exercise activity enhances endothelial NO synthesis in skeletal muscle arterioles of rats.

We aimed to test the hypothesis that as a consequence of short-term daily bouts of exercise the control of arteriolar smooth muscle by endothelium is altered. Rats ran on a treadmill once a day, 5 days/wk, for 2-4 wk (with gradually increasing intensity, up to 26 min at 22 m/min at a 1% grade by the beginning of the 3rd wk and up to 38 min at 28 m/min at a 2% grade by the beginning of the 4th wk) while a control group remained sedentary (SED). Cannulated and pressurized arterioles of rat gracilis muscle developed spontaneous myogenic tone, which was slightly enhanced in exercised (EX) compared with SED rat arterioles. At 80 mmHg pressure, the passive (Ca(2+)-free solution) and active diameters of SED and EX rat arterioles were 105.4 +/- 3.8 and 55.1 +/- 2.3 microns and 107.1 +/- 3.4 and 50.2 +/- 2.2 microns, respectively. Dose-dependent dilations to sodium nitroprusside (10(-8)-10(-6) M) and constrictions to norepinephrine (10(-8)-10(-6) M) were not affected in EX arterioles, whereas dilations to adenosine (10(-6)-10(-4) M) were significantly reduced. In contrast, dose-dependent dilations to acetylcholine (ACh; 5 x 10(-9)-10(-7) M) and L-arginine [precursor of nitric oxide (NO); 10(-4)-10(-3) M] were significantly enhanced (by 33-78 and 57-75%, respectively) in arterioles of EX compared with those of SED rats. Responses of arterioles to sodium nitrite were not different in SED and EX groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperosmolality dilates rat skeletal muscle arterioles: role of endothelial K(ATP) channels and daily exercise.

The purpose of this study was to investigate the mechanism underlying arteriolar responses to hyperosmolality and to determine the effects of daily exercise on this response. Dilator responses were measured in isolated, cannulated, and pressurized skeletal muscle arterioles. Osmolality was increased from approximately 290 to 330 mosmol/kgH(2)O by adding glucose, sucrose, or mannitol to the superfusion solution. All three compounds elicited similar changes in vessel diameter, suggesting that this response was due to changes in osmolality. Responses to glucose were abolished by endothelium removal but were not altered in endothelium-intact vessels by superfusion with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine or the cyclooxygenase inhibitor indomethacin. In endothelium-intact arterioles, responses to glucose superfusion with the ATP-sensitive potassium (K(ATP)) channel inhibitor glibenclamide; however, intraluminal perfusion with glibenclamide nearly abolished the responses to glucose and mannitol. Intraluminal administration of glucose elicited a significantly greater dilation than extraluminal glucose. The response to intraluminal glucose was also inhibited by intraluminal glibenclamide. Four weeks of daily exercise did not significantly alter the responses to hyperosmolality in gracilis or soleus muscle arterioles. These data demonstrate that physiological increases in intraluminal osmolality dilate rat skeletal muscle arterioles via activation of endothelial K(ATP) channels; however, this endothelium-dependent response is not augmented by daily exercise.

Effect of estrogen on flow-induced dilation in NO deficiency: role of prostaglandins and EDHF.

To investigate the role of estrogen in flow-induced dilation (FiD) in nitric oxide (NO) deficiency, FiD was examined in isolated gracilis arterioles of ovariectomized (OVX) and OVX rats with estrogen replacement (OVE). Both groups of rats were treated chronically with N(omega)-nitro-L-arginine methyl ester. Plasma concentration of NO(2)/NO(3) was reduced in both groups. Plasma concentration of estradiol was lower in OVX than in OVE rats. FiD was similar in vessels of the two groups; calculated wall shear stress and basal tone were significantly greater in OVX vs. OVE rats. Indomethacin did not affect FiD in vessels from OVE rats but abolished dilation in vessels from OVX rats. Valeryl salicylate or NS-398 inhibited FiD by approximately 50%, whereas their simultaneous administration eliminated the response in arterioles from OVX rats. In vessels from OVE rats, miconazole or charybdotoxin eliminated FiD. Thus, in NO deficiency, prostaglandins derived from both cyclooxygenase isoforms mediate FiD in gracilis arterioles of OVX rats. Estrogen replacement switches the mediation, showing dependence on endothelium-derived hyperpolarizing factor in the arterioles of OVE rats.

Nitric oxide and prostaglandins mediate vasodilation to 5,6-EET in rabbit lung.

We have previously found that 5,6-EET (epoxyeicosatrienoic acid)(50 nM) significantly dilates the vascular bed(42%) of the isolated, constantly perfused rabbit lung, which has been constricted with U46619(5-8 pM). We studied the role of EDRF-NO and prostaglandins in the 5,6-EET-induced vascular relaxation. Dilation to 5,6-EET was evident only when the pulmonary vascular tone was increased. L-NNA (N omega-nitro-L-arginine, 10(-4) M), an inhibitor of NO synthase(NOS); U46619(5-10 pM), a thromboxane mimetic; and L-NNA + INDO(indomethacin, 10(-5) M), a cyclooxygenase inhibitor, all increased the pressure of pulmonary artery(PPa) from baseline, to a peak range of 28-38mmHg(32.75 [symbol: see text] 2.2), whereas INDO alone increased Ppa only by 10mmHg. L-NNA + INDO,L-NNA alone, and INDO + U46619 attenuated the 5,6-EET relaxing effect by 100%, 88% and 64.5%, respectively. In the presence of L-NNA and 5,6-EET, SNAP(S-nitroso-N-acetyl-D,L-penicillamine, 10(-6) M), a NO donor, reduced Ppa by 75%. We conclude that the mechanism of vasodilation to 5,6-EET in the rabbit pulmonary circulation is via both EDRF-NO and PG pathways and that the vasodilation is largely EDRF-NO dependent.

Role of nitric oxide in the control of mitochondrial function.

In summary, NO is capable of decreasing mitochondrial respiration in a variety of mammalian tissues. This effect is mediated primarily via binding of NO to the O2 binding site of cytochrome oxidase. This highly sensitive interaction presumably reflects a remnant homology between cytochrome oxidase and bacterial nitrate reductase. This effect has been demonstrated at physiologic levels of NO, highlighting the role for NO in the tonic control of cellular respiration. As this inhibition is dependent upon the levels figure: see text[ of NO and O2 in the tissue, various states of NO production and oxygen supply dictate the ultimate respiratory rate of the mitochondria. Furthermore, deviation from a physiologic NO: O2 may lead to an exacerbation of pathologic states, such as congestive heart failure and septic shock. Thus, NO may play a crucial role in the control of cellular respiration, providing an additional mechanism of action for this biologically diverse molecule that is distinct yet inseparable from its dilator effect on blood vessels.