Biomedical subjects

Ulf Simonsen

Publications and source records attributed to Ulf Simonsen.

At least 19 recordsLinked to original sources

PubMed2006

Contribution of both Ca2+ entry and Ca2+ sensitization to the alpha1-adrenergic vasoconstriction of rat penile small arteries.

Sympathetic adrenergic nerves maintain the flaccid state of the penis through the tonic release of norepinephrine that contracts trabecular and arterial smooth muscle. Simultaneous measurements of intracellular Ca(2+) concentration ([Ca(2+)](i)) and tension and experiments with alpha-toxin-permeabilized arteries were performed in branches of the rat dorsal penile artery to investigate the intracellular Ca(2+) signaling pathways underlying alpha(1)-adrenergic vasoconstriction. Phenylephrine increased both [Ca(2+)](i) and tension, these increases being abolished by extracellular Ca(2+) removal and reduced by about 50% by the L-type Ca(2+) channel blocker nifedipine (0.3 microM). Non-L-type Ca(2+) entry through store-operated channels was studied by inhibiting the sarcoplasmic reticulum Ca(2+)-ATPase with cyclopiazonic acid (CPA). CPA (30 microM) induced variable phasic contractions that were abolished by extracellular Ca(2+) removal and by the store-operated channels antagonist 2-aminoethoxydiphenyl borate (2-APB, 50 microM) and largely inhibited by nifedipine (0.3 microM). CPA induced a sustained increase in [Ca(2+)](i) that was reduced in a Ca(2+)-free medium. Under conditions of L-type channels blockade, Ca(2+) readmission after store depletion with CPA evoked a sustained and marked elevation in [Ca(2+)](i) not coupled to contraction. 2-APB (50 microM) inhibited the rise in [Ca(2+)](i) evoked by CPA and the nifedipine-insensitive increases in both [Ca(2+)](i) and contraction elicited by phenylephrine. In alpha-toxin-permeabilized penile arteries, activation of G proteins with guanosine 5'-O-(3-thiotriphosphate) and of the alpha(1)-adrenoceptor with phenylephrine both enhanced the myofilament sensitivity to Ca(2+). This Ca(2+) sensitization was reduced by selective inhibitors of PKC, tyrosine kinase (TK), and Rho kinase (RhoK) by 43%, 67%, and 82%, respectively. As a whole, the present data suggest the alpha(1)-adrenergic vasoconstriction in penile small arteries involves Ca(2+) entry through both L-type and 2-APB-sensitive receptor-operated channels, as well as Ca(2+) sensitization mechanisms mediated by PKC, TK, and RhoK. A capacitative Ca(2+) entry coupled to noncontractile functions of the smooth muscle cell is also demonstrated.

Adrenergic alpha-1 Receptor Agonists↗

PubMed2006

Combination of Ca2+ -activated K+ channel blockers inhibits acetylcholine-evoked nitric oxide release in rat superior mesenteric artery.

BACKGROUND AND PURPOSE: The present study investigated whether calcium-activated K+ channels are involved in acetylcholine-evoked nitric oxide (NO) release and relaxation. EXPERIMENTAL APPROACH: Simultaneous measurements of NO concentration and relaxation were performed in rat superior mesenteric artery and endothelial cell membrane potential and intracellular calcium ([Ca2+]i) were measured. KEY RESULTS: A combination of apamin plus charybotoxin, which are, respectively, blockers of small-conductance and of intermediate- and large-conductance Ca2+ -activated K channels abolished acetylcholine (10 microM)-evoked hyperpolarization of endothelial cell membrane potential. Acetylcholine-evoked NO release was reduced by 68% in high K+ (80 mM) and by 85% in the presence of apamin plus charybdotoxin. In noradrenaline-contracted arteries, asymmetric dimethylarginine (ADMA), an inhibitor of NO synthase inhibited acetylcholine-evoked NO release and relaxation. However, only further addition of oxyhaemoglobin or apamin plus charybdotoxin eliminated the residual acetylcholine-evoked NO release and relaxation. Removal of extracellular calcium or an inhibitor of calcium influx channels, SKF96365, abolished acetylcholine-evoked increase in NO concentration and [Ca2+]i. Cyclopiazonic acid (CPA, 30 microM), an inhibitor of sarcoplasmic Ca2+ -ATPase, caused a sustained NO release in the presence, but only a transient increase in the absence, of extracellular calcium. Incubation with apamin and charybdotoxin did not change acetylcholine or CPA-induced increases in [Ca2+]i, but inhibited the sustained NO release induced by CPA. CONCLUSIONS AND IMPLICATIONS: Acetylcholine increases endothelial cell [Ca2+]i by release of stored calcium and calcium influx resulting in activation of apamin and charybdotoxin-sensitive K channels, hyperpolarization and release of NO in the rat superior mesenteric artery.

Acetylcholine↗

PubMed2006

Neuropeptide Y2 receptors are involved in enhanced neurogenic vasoconstriction in spontaneously hypertensive rats.

1. The present study addressed the role of neuropeptide (NPY) Y2 receptors in neurogenic contraction of mesenteric resistance arteries from female spontaneously hypertensive rats (SHR). Arteries were suspended in microvascular myographs, electrical field stimulation (EFS) was performed, and protein evaluated by Western blotting and immunohistochemistry. 2. In vasopressin-activated endothelium-intact arteries, NPY and fragments with selectivity for Y1 receptors, [Leu31,Pro34]NPY, Y2 receptors, NPY(13-36), and rat pancreatic polypeptide evoked more pronounced contractions in segments from SHR than in Wistar Kyoto (WKY) arteries, even in the presence of the Y1 receptor antagonist, BIBP3226 (0.3 microM, (R)-N(2)-(diphenacetyl)-N-[(4-hydroxyphenyl)methyl]D-arginineamide). 3. In the presence of prazosin and during vasopressin activation, EFS-evoked contractions were larger in arteries from SHR compared to WKY. EFS contractions were enhanced by the Y2 receptor selective antagonist BIIE0246TF (0.5 microM, (S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b,e]azepin-11-y1]-1-piperazinyl]-2-oxoethyl]cyclo-pentyl-N-[2-[1,2-dihydro-3,5 (4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide), reduced by BIBP3226, and abolished by the combination of BIBP3226 and BIIE0246TF. 4. Immunoblotting showed NPY Y1 and Y2 receptor expression to be similar in arteries from WKY and SHR, although a specific Y2 receptor band at 80 kDa was detected only in arteries from WKY. 5. Immunoreaction for NPY was enhanced in arteries from SHR. In contrast to arteries from WKY, BIIE0246TF increased NPY immunoreactivity in EFS-stimulated arteries from SHR. 6. The present results suggest that postjunctional neuropeptide Y1 and Y2 receptors contribute to neurogenic contraction of mesenteric small arteries. Moreover, both enhanced NPY content and altered neuropeptide Y1 and Y2 receptor activation apparently contribute to the enhanced neurogenic contraction of arteries from SHR.

Animals↗

PubMed2006

Vascular reactivity and endothelial NOS activity in rat thoracic aorta during and after hyperbaric oxygen exposure.

Accumulating evidence suggests that hyperbaric oxygen (HBO) stimulates neuronal nitric oxide (NO) synthase (NOS) activity, but the influence on endothelial NOS (eNOS) activity and vascular NO bioavailability remains unclear. We used a bioassay employing rat aortic rings to evaluate vascular NO bioavailability. HBO exposure to 2.8 atm absolute (ATA) in vitro decreased ACh relaxation. This effect remained unchanged, despite treatment with SOD-polyethylene glycol and catalase-polyethylene glycol, suggesting that the reduction in endothelium-derived NO bioavailability was independent of superoxide production. In vitro HBO induced contraction of resting aortic rings with and without endothelium, and these contractions were reduced by the NOS inhibitor N(omega)-nitro-l-arginine. In addition, in vitro HBO attenuated the vascular contraction produced by norepinephrine, and this effect was reversed by N(omega)-nitro-l-arginine, but not by endothelial denudation. These findings indicate stimulation of extraendothelial NO production during HBO exposure. A radiochemical assay was used to assess NOS activity in rat aortic endothelial cells. Catalytic activity of eNOS in cell homogenates was not decreased by HBO, and in vivo HBO exposure to 2.8 ATA was without effect on eNOS activity and/or vascular NO bioavailability in vitro. We conclude that HBO reduces endothelium-derived NO bioavailability independent of superoxide production, and this effect seems to be unrelated to a decrease in eNOS catalytic activity. In addition, HBO increases the resting tone of rat aortic rings and attenuates the contractile response to norepinephrine by endothelium-independent mechanisms that involve extraendothelial NO production.

Animals↗

PubMed2006

Enhanced neuropeptide Y immunoreactivity and vasoconstriction in mesenteric small arteries from the early non-obese diabetic mouse.

The present study investigated whether sympathetic neurotransmission is altered at an early stage of diabetes in mesenteric small arteries isolated from female non-obese diabetic (NOD) and control animals without diabetes from the same mouse strain. The NOD diabetic mice had increased plasma glucose and hypertension. Confocal microscopy showed distribution of nerve terminals was similar, but immunoreaction intensity for neuropeptide Y (NPY) and tyrosine hydroxylase was higher in small arteries from NOD diabetic compared with NOD control mice. In the presence of prazosin and activated with vasopressin, electrical field stimulation evoked contractions which were more pronounced in mesenteric arteries from NOD diabetic versus NOD control mice and inhibited by the NPY Y(1) receptor antagonist, BIBP 3226. NPY concentration-response curves were leftward shifted in arteries from NOD diabetic versus NOD control both in arteries with and without endothelium, but not in the presence of the BIBP 3226. The present findings suggest that enhanced NPY content and vasoconstriction to NPY by activation of NPY Y(1) receptors in arteries from diabetic mice may contribute to the enhanced sympathetic nerve activity and vascular resistance in female non-obese early diabetic animals.

Animals↗

PubMed2006

Intracellular smooth muscle [Ca2+] in acetylcholine and nitric oxide-mediated relaxation of human small arteries.

In human resistance arteries the role of intracellular calcium during receptor agonist and nitric oxide (NO)-mediated vasorelaxation is almost unknown. We examined changes in smooth muscle calcium concentration ([Ca2+]i) caused by acetylcholine and the NO donor S-nitroso-N-acetylpenicillamine (SNAP) in isolated human subcutaneous small arteries. In arteries constricted with 50 mM KCl, acetylcholine and SNAP induced relaxation without any change in [Ca2+]i, whereas in noradrenaline constricted vessels, both acetylcholine and to a lesser degree also SNAP-mediated relaxation were associated with a decrease in [Ca2+]i. Furthermore incubation with SNAP (1 microM) induced a rightward shift in the [Ca2+]i-force relationship. These results suggest that relaxation mediated by endothelium derived hyperpolarizing factors (EDHF) is associated with reduction in [Ca2+]i, whereas NO-mediated relaxation can take place without changes in [Ca2+]i. This finding seems to be, at least partly, due to NO-mediated desensitization of the contractile apparatus to calcium.

Acetylcholine↗

PubMed2006

Blunted non-nitric oxide vasodilatory neurotransmission in penile arteries from renal hypertensive rats.

The present study was designed to explore whether there are any effects on neurogenic responses in penile small arteries during the development of hypertension in a one-kidney, one-clip (1K1C) model, a non-renin-dependent model of renovascular hypertension. Five weeks after surgery, male Sprague-Dawley rats were given vehicle, bendroflumethiazide (7.5 mg/kg/day), or L-arginine (2 g/kg/day) in their drinking water for five weeks. Experiments were performed on penile small artery rings (150-200 microm) mounted on microvascular myographs for electrical field stimulation (EFS), and erectile tissue was processed for immunohistochemistry. Maximal neurogenic contractions were unmodified in penile preparations. Relaxations induced by EFS were reduced in the presence of ADMA. In 1K1C rats, neurogenic vasorelaxation mediated by nitric oxide (NO) was unaltered, while relaxation resistant to NO synthase inhibition was blunted. L-arginine and bendroflumethiazide lowered blood pressure in 1K1C rats, but vasodilation was still blunted in the penile arteries. Immunoreactivity for factor VIII and neuronal NO synthase was unaltered in penile arteries from 1K1C animals. Endothelium-dependent vasorelaxation evoked by acetylcholine was also blunted in preparations from 1K1C rats, while exogenous NO relaxation was unaffected. Plasma concentrations and urinary excretion of ADMA did not differ among the experimental animals. Our findings indicate that the reduced release of a non-NO vasodilatory neurotransmitter accounts for the impaired neurogenic vasodilation of the penile arteries. Although ADMA inhibits penile vasorelaxation, it is unlikely to affect erectile function in 1K1C rats.

Acetylcholine↗

PubMed2006

Size of myocardial infarction induced by ischaemia/reperfusion is unaltered in rats with metabolic syndrome.

Obesity is associated with metabolic syndrome and increased incidence of and mortality from myocardial infarction. The aim of the present study was to develop an animal model with metabolic syndrome and examine how that influences size of myocardial infarcts induced by occlusion and reperfusion of the left anterior descending coronary artery. Sprague-Dawley rats (n = 105) were fed either LF (low-fat) or MHF (moderately high-fat) diets for 13 weeks before coronary occlusion for 45 min, followed by reperfusion for 60 min. Compared with LF-fed and lean MHF-fed rats, obese MHF-fed rats developed metabolic disturbances similar to those seen in the metabolic syndrome, including being overweight by 24% (compared with lean MHF-fed rats), having 74% more visceral fat (compared with LF-fed rats), 15% higher blood pressure (compared with LF-fed rats), 116% higher plasma insulin (compared with lean MHF-fed rats), 10% higher fasting plasma glucose (compared with LF-fed rats), 35% higher non-fasting plasma glucose (compared with lean MHF-fed rats), 36% higher plasma leptin (compared with lean MHF-fed rats) and a tendency to lower plasma adiponectin and higher plasma non-esterified fatty acids. Infarct size was similar in the three groups of rats (36+/-14, 42+/-18 and 41+/-14% in obese MHF-fed, lean MHF-fed and LF-fed rats respectively). In conclusion, rats fed a MHF diet developed metabolic syndrome, but this did not influence myocardial infarct size.

Adiponectin↗

PubMed2005

Adenosine concentration in the porcine coronary artery wall and A2A receptor involvement in hypoxia-induced vasodilatation.

We tested whether hypoxia-induced coronary artery dilatation could be mediated by an increase in adenosine concentration within the coronary artery wall or by an increase in adenosine sensitivity. Porcine left anterior descendent coronary arteries, precontracted with prostaglandin F(2alpha) (10(-5) M), were mounted in a pressure myograph and microdialysis catheters were inserted into the tunica media. Dialysate adenosine concentrations were analysed by HPLC. Glucose, lactate and pyruvate were measured by an automated spectrophotometric kinetic enzymatic analyser. The exchange fraction of [(14)C]adenosine over the microdialysis membrane increased from 0.32 +/- 0.02 to 0.46 +/- 0.02 (n = 4, P < 0.01) during the study period. At baseline, interstitial adenosine was in the region of 10 nM which is significantly less than previously found myocardial concentrations. Hypoxia (P(O(2)) 30 mmHg for 60 min, n = 5) increased coronary diameters by 20.0 +/- 2.6% (versus continuous oxygenation -3.1 +/- 2.4%, n = 6, P < 0.001) but interstitial adenosine concentration fell. Blockade of adenosine deaminase (with erythro-9-(2-hydroxy-3-nonyl-)-adenine, 5 microM), adenosine kinase (with iodotubericidine, 10 microM) and adenosine transport (with n-nitrobenzylthioinosine, 1 microM) increased interstitial adenosine but the increase was unrelated to hypoxia or diameter. A coronary dilatation similar to that during hypoxia could be obtained with 30 microM of adenosine in the organ bath and the resulting interstitial adenosine concentrations (n = 5) were 20 times higher than the adenosine concentration measured during hypoxia. Adenosine concentration-response experiments showed vasodilatation to be more pronounced during hypoxia (n = 9) than during normoxia (n = 9, P < 0.001) and the A(2A) receptor antagonist ZM241385 (20 nM, n = 5), attenuated hypoxia-induced vasodilatation while the selective A(2B) receptor antagonist MRS1754 (20 nM, n = 4), had no effect. The lactate/pyruvate ratio was significantly increased in hypoxic arteries but did not correlate with adenosine concentration. We conclude that hypoxia-induced coronary artery dilatation is not mediated by increased adenosine produced within the artery wall but might be facilitated by increased adenosine sensitivity at the A(2A) receptor level.

Acetamides↗

PubMed2005

Physiologically relevant measurements of nitric oxide in cardiovascular research using electrochemical microsensors.

Nitric oxide (NO) plays an important role in the regulation of blood flow. Pharmacological tools and a series of other techniques have been developed for studying the NO/L-arginine pathway, but it has proved difficult to make a quantitative link between effect and tissue NO concentration. NO microsensors have been applied with success for the measurement of NO in suspensions of mitochondria and cells, such as platelets and leukocytes, and in cell cultures, which together with other interventions or measurements are particularly useful for the examination of cell signalling related to the NO/L-arginine pathway. In isolated vascular segments, studies using the NO microsensor have defined the relationship between NO concentration and relaxation and revealed residual NO release in the presence of NO synthase inhibitors. Moreover, simultaneous measurements of NO concentration and vasorelaxation in isometric preparations have shown that agonist-induced relaxation is L-arginine dependent and NO release is reduced in hypertension. By placing NO microsensors in catheters, it is possible to measure NO in the living animal and man. This approach has been applied for the measurements of NO concentration in relation to increases in flow, erection, in conditions of hypoxia, and in endotoxemia. However, further methodological development of NO microsensors is necessary to avoid the influence of changes in temperature, pH and oxygen on the measurements.

Arginine↗

PubMed2005

Dual impact of a nitric oxide donor, GEA 3175, in human pulmonary smooth muscle.

Nitric oxide (NO) donors could constitute an alternative to inhaled NO as treatment in some patients with pulmonary hypertension. Therefore, the present study investigated the relaxation mechanisms of a novel NO donor, 3-(3-chloro-2-methylphenyl)-5-[[4-methylphenyl)sulphonyl]amino]-)hydroxide (GEA 3175) in segments of human pulmonary arteries and bronchioles, which were mounted in microvascular myographs. GEA 3175 induced concentration-dependent relaxations and was more potent in pulmonary arteries than in bronchioles. A blocker of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), and iberiotoxin, a blocker of large-conductance calcium-activated K channels, both reduced relaxations induced by GEA 3175 in pulmonary arteries and bronchioles. Combining of ODQ and iberiotoxin did not produce additional inhibition. GEA 3175 relaxation is mediated through guanylyl cyclase-dependent mechanisms followed by activation of large-conductance calcium-activated K(+) channels. The dilatation of both pulmonary small arteries and airways by GEA 3175 seems advantageous, if it is considered administered as inhalation therapy for pulmonary hypertension.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2005

Lack of synergistic effect of molsidomine and sildenafil on development of pulmonary hypertension in chronic hypoxic rats.

The present study addressed whether combined treatment with a phosphodiesterase type 5 inhibitor, sildenafil, and a nitric oxide donor, molsidomine, prevents development of pulmonary hypertension in chronic hypoxic rats. Two weeks of hypoxia increased right ventricular systolic pressure, and right ventricular and lung weight. Treatment with either sildenafil (10 mg/kg/day) or molsidomine (15 mg/kg/day) in drinking water reduced right ventricular systolic pressure and weight, while lung weight was unchanged. Combining sildenafil and molsidomine did not have additional effects compared to molsidomine alone. The number of muscularized pulmonary arteries with diameters below 50 microm was increased in vehicle and sildenafil-treated, but not in molsidomine-treated hypoxic rats. Acetylcholine relaxation was blunted in arteries from vehicle and molsidomine-treated, but not in sildenafil-treated rats. In conclusion, both sildenafil and molsidomine blunts pulmonary hypertension and right ventricular hypertrophy in chronic hypoxic rats, but no synergistic effects were observed.

Acetylcholine↗

PubMed2005

Glibenclamide reveals role for endothelin in hypoxia-induced vasoconstriction in rat intrapulmonary arteries.

The present study investigated whether activation of vasodilatory mechanisms masks the involvement of endothelin in hypoxic pulmonary vasoconstriction. Rat intrapulmonary arteries were mounted in microvascular myographs. In arteries with endothelium and contracted with phenylephrine, hypoxia, evoked by exchanging 5% CO2 in air for CO2 in N2, caused a transient contraction followed by a sustained contraction. Hypoxia evoked relaxation in preparations without endothelium. An inhibitor of ATP-sensitive K+ channels (KATP), glibenclamide (10 microM), blunted hypoxic relaxation in arteries without endothelium and enhanced the sustained hypoxic vasoconstriction in arteries with endothelium. Hypoxic contraction was more pronounced in endothelin compared with phenylephrine-contracted preparations in the absence, but not in the presence of glibenclamide. Antagonism of the endothelin ETA and ETB receptors with SB217242 or the combination of BQ123 and BQ788 inhibited endothelin and hypoxic contraction, but the latter only in the presence of glibenclamide. An inhibitor of nitric oxide (NO) synthase, N-nitro-L-arginine (100 microM), evoked contractions, which were left unaltered by SB217242 in hypoxic conditions. In conclusion, hypoxic contraction is mediated in part by an unknown endothelium-derived contractile factor and incubation with glibenclamide shows endothelin enhances hypoxic contraction in part through inhibition of KATP channels. Moreover, inhibition of NO formation in pulmonary arteries does not change endothelin receptor activation in severe hypoxia.

Animals↗

PubMed2005

Pathophysiology of erectile dysfunction.

INTRODUCTION: Multiple regulatory systems are involved in normal erectile function. Disruption of psychological, neurological, hormonal, vascular, and cavernosal factors, individually, or in combination, can induced erectile dysfunction (ED). The contribution of neurogenic, vascular, and cavernosal factors was thoroughly reviewed by our committee, while psychological and hormonal factors contributing to ED were evaluated by other committees. AIM: To provide state of the art knowledge on the physiology of ED. METHODS: An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five different continents developed in a process over a 2-year period. Concerning the pathophysiology of ED committee, there were seven experts from five different countries. MAIN OUTCOME MEASURE: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS: The epidemiology and classification of neurogenic ED was reviewed. The evidence for the association between vascular ED and atherosclerosis/hypercholesterolemia, hypertension and diabetes was evaluated. In addition, the pathophysiological mechanisms implicated in vascular ED were defined, including: arterial remodeling, increased vasoconstriction, impaired neurogenic vasodilatation, and impaired endothelium-dependent vasodilatation. The possible mechanisms underlying the association between chronic renal failure and ED were also evaluated as well as the evidence supporting the association of ED with various classes of medications. CONCLUSIONS: A better understanding of how diseases interfere with the physiological mechanisms that regulate penile erection has been achieved over the last few years, which helps establish a strategy for the prevention and treatment of ED.

Cardiovascular Agents↗

PubMed2004

Measurements of nitric oxide concentration and hyporeactivity in rat superior mesenteric artery exposed to endotoxin.

OBJECTIVE: The present study was designed to relate nitric oxide (NO) concentration to changes in vascular reactivity in rat superior mesenteric arteries treated with lipopolysaccharide (LPS, 10 microg ml-1, 1-8 h). METHODS: In rat mesenteric arteries, isometric tension was recorded in wire myographs, protein expression was evaluated by Western blot and/or immunohistochemistry and NO concentration was measured by application of a NO specific electrode. RESULTS: Incubation with LPS (5 h) resulted in inducible NO synthase (iNOS) expression and enhanced superoxide dismutase (Cu/Zn-SOD and Mn-SOD) expression, but it did not modify endothelial NO synthase (eNOS) expression. Noradrenaline (0.5 microM) evoked increases in NO concentration and tension by, respectively, 5.0+/-2.0 nM and 4.4+/-0.1 N m-1 (n=6). While NO concentration was unaltered, incubation with LPS reduced noradrenaline contraction to 3.5+/-0.2 N m-1 (n=39, P<0.05). In contrast to indomethacin, 1400 W (10 microM) restored noradrenaline contraction, while the combination of noradrenaline and oxyhaemoglobin (10 microM) evoked less contraction in LPS compared to control segments. Polyethylene glycol (PEG)-catalase in combination with oxyhaemoglobin reversed noradrenaline hyporeactivity in LPS-treated segments. LPS did not increase, but reduced basal NO concentration, an effect which was reversed by 1400 W and tempol (100 microM). In LPS-treated segments contracted with noradrenaline, the NO synthase substrate, l-arginine (100 microM), relaxed and increased NO concentration with, respectively, 73+/-9% and 19.5+/-6.5 nM (n=5). 1400 W and oxyhaemoglobin reversed l-arginine relaxation and increases in NO concentration. In contrast to tempol and PEG-catalase, N-acetylcysteine (0.1-1 mM), which is able to release NO from intracellular stores, relaxed LPS-treated tissue, an effect that was abolished by long-term, but not by short-term, incubation with 1400 W. CONCLUSIONS: The present study provides direct evidence that exposure to LPS results in induction of iNOS and SOD associated with noradrenaline hyporeactivity, while increased NO is only measured when l-arginine is present. A catalase-sensitive mechanism and release of NO from N-acetylcysteine-sensitive stores could also contribute to the vascular hyporeactivity.

Acetylcysteine↗

PubMed2004

Insulin increases glycolysis without further vasodilation in porcine coronary arteries exposed to hypoxia.

In acute ischaemia, glucose-insulin-potassium administration reduces mortality and beta-adrenoceptor antagonists have favourable effects on the outcome of ischaemic heart disease. The present study was designed to investigate whether insulin (1.4x10(-7) M) and the beta-adrenoceptor antagonist, propranolol (10(-5) M), increase hypoxic vasodilation in correspondence with changes in glycolysis. Porcine coronary arteries, precontracted with 10(-5) M prostaglandin F(2alpha), were mounted in a pressure myograph and a microdialysis catheter was inserted in the tunica media. Hypoxic vasodilation, interstitial lactate/pyruvate ratio and interstitial glucose were measured at low (2 mM) and high (20 mM) glucose concentrations. Hypoxia (60 min) caused vasodilation and doubled the lactate/pyruvate ratio. Treatment with insulin quadrupled the lactate/pyruvate ratio during hypoxia, but did not change hypoxic vasodilation. Propranolol blocked isoprenaline-evoked vasodilation, but hypoxic increases in lactate/pyruvate ratio and vasodilation did not change. The combination of insulin and propranolol did not cause further changes compared with each drug added alone, although the combination increased vasoconstriction during reoxygenation. Interstitial glucose fell during hypoxia at an organ bath glucose concentration of 2 mM, and rose at a glucose concentration of 20 mM. Addition of insulin and propranolol alone or in combination had no effect on interstitial glucose concentration. Accordingly, arteries were found to contain only minute amounts of the glucose transporter isoform GLUT4. Our findings suggest that insulin increases arterial glycolysis, but treatment with insulin, propranolol, or both, is not associated with enhanced coronary vasodilation during hypoxia.

Adrenergic beta-Antagonists↗

PubMed2004

Physiology of erectile function.

INTRODUCTION: There are numerous investigations concerning the balance and interactions between relaxant and contractile factors regulating penile smooth muscle (arterial and trabecular) tone, the determinant of penile flaccidity or erection. Enhanced knowledge of erectile physiology may improve management of men with erectile dysfunction. Aim. To provide state-of-the-art knowledge on the physiology of erectile function. METHODS: An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a two-year period. Concerning the physiology of erectile function and pathophysiology of erectile dysfunction committee, there were seven experts from five countries. MAIN OUTCOME MEASURE: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS: Key roles in the mechanism determining the tone of penile smooth muscle are played by the rise of the intracellular concentration of free calcium and the sensitivity of the contractile machinery to calcium, endothelial health, endothelium-derived nitric oxide, endothelium-derived hyperpolarizing factor (EDHF), neuronal nitric oxide, cyclic guanosine monophosphate-dependent protein kinase and phosphodiesterase type 5. CONCLUSIONS: A number of new mechanisms have been identified for the local regulation of penile smooth muscle contractility and therefore penile erection. Molecules participating in these pathways can be considered targets for the development of new treatments to treat erectile dysfunction.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2003

The superoxide dismutase mimetic, tempol, blunts right ventricular hypertrophy in chronic hypoxic rats.

1. The purpose of this study was to investigate whether a membrane-permeable superoxide dismutase mimetic, tempol, added either alone or in combination with the nitric oxide (NO) donor molsidomine, prevents the development of pulmonary hypertension (PH) in chronic hypoxic rats. 2. Chronic hypobaric hypoxia (10% oxygen) for 2 weeks increased the right ventricular systolic pressure (RVSP), right ventricle and lung wet weight. Relaxations evoked by acetylcholine (ACh) and the molsidomine metabolite SIN-1 were impaired in isolated proximal, but not distal pulmonary arteries, from chronic hypoxic rats. 3. Treatment with tempol (86 mg x kg(-1) day(-1) in drinking water) normalized RVSP and reduced right ventricular hypertrophy, while systemic blood pressure, lung and liver weights, and blunted ACh relaxation of pulmonary arteries were unchanged. 4. Treatment with molsidomine (15 mg x kg(-1) day(-1) in drinking water) had the same effects as tempol, except that liver weight was reduced, and potassium and U46619-evoked vasoconstrictions in pulmonary arteries were increased. Combining tempol and molsidomine did not have additional effects compared to tempol alone. ACh relaxation in pulmonary arteries was not normalized by these treatments. 5. The media to lumen diameter ratio of the pulmonary arteries was greater for the hypoxic rats compared to the normoxic rats, and was not reversed by treatment with tempol, molsidomine, or the combination of tempol and molsidomine. 6. We conclude that tempol, like molsidomine, is able to correct RVSP and reduce right ventricular weight in the rat hypoxic model. Functional and structural properties of pulmonary small arteries were little affected. The results support the possibility that superoxide dismutase mimetics may be a useful means for the treatment of PH.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗