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PubMed2004

[Dysferlinopathy as an extrahepatic cause for the elevation of serum transaminases].

BACKGROUND AND PURPOSE: The aim of the present report is to emphasize that the source of elevated transaminase levels, although usually indicative of hepatocellular damage, can also be of extrahepatic origin. CASE REPORT: A 42-year-old female presented with a moderate persistent elevation of the transaminases glutamic-oxaloacetic transaminase (GOT; synonym: aspartate aminotransferase [AST]) and glutamic-pyruvic transaminase (GPT; synonym: alanine aminotransferase [ALT]) in blood without any apparent clinical symptoms of liver affection. In the course of further diagnostics for clarification of a suspected liver disease, a markedly elevated activity of creatine kinase was found which, in concert with results from myography, magnetic resonance imaging (MRI) and analysis of muscle biopsies, suggested the tentative diagnosis of a distal myopathy type Miyoshi. The diagnosis was confirmed by identification of the underlying mutation in the dysferlin gene. The course of the disease has been slowly but steadily progressive; there is no therapeutic option at present. The relevance of molecular genetic analyses in the diagnostic procedure for distal myopathies, in particular dysferlinopathy, is discussed and the characteristics of this disease are summarized. CONCLUSION: In the case of persistent elevations of the serum transaminases GOT and GPT without liver disorder, a myopathy has to be taken into account as a potential extrahepatic source. In order to avoid needless nondirected expensive investigations and to prevent a delay in diagnostics, activity of serum creatine kinase should be determined which is moderately to strongly elevated in the case of myopathies. If, in particular, a dysferlinopathy is supposed, the underlying mutation should be identified to confirm the diagnosis and as a basis for current and future therapeutic interventions

Adult↗
PubMedDate not supplied

Neomycin inhibits K+-induced force and Ca2+ channel current in rat arterial smooth muscle.

The techniques of small vessel isometric myography and patch clamp were used to investigate the action of neomycin on K+-induced isometric force and voltage-gated Ca2+ channel currents in rat arterial smooth muscle. Neomycin and the dihydropyridine (DHP) Ca2+ channel antagonist (-)202-791 concentration-dependently and reversibly inhibited 40 mM K+-induced isometric force in rings of rat mesenteric and basilar arteries (IC50 values of 70 microM and 1. 2 nM, respectively, n = 10 and 4). Elevation of [Ca2+]o by a factor of 2 significantly reduced the IC50 values for inhibition of K+-induced force for both neomycin and (-)202-791 (192 microM and 3. 7 nM, respectively, n = 6 and 4), but did not affect the Hill coefficient of the concentration/effect relationships. In patch-clamp experiments using freshly isolated basilar arterial myocytes, the voltage-gated inward current carried by Ba2+ was reversibly and concentration-dependently inhibited by neomycin (IC50 32 microM, n = 3). The concentration/effect curve for inhibition of the inward Ba2+ current by neomycin was significantly shifted to the right when [Ba2+]o was raised from 1.8 mM to 10 mM (IC50 144 microM, n = 8). Our findings suggest that neomycin relaxes high-K+-induced force in rat isolated mesenteric and basilar arteries largely by inhibition of voltage-dependent and DHP-sensitive Ca2+ channels.

Animals↗
PubMed1998

A transient dilatation of pressurised rat cerebral arteries during rapid pressure increases is mediated by nitric oxide.

In pressurised resistance arteries in vitro, rapid pressure increases cause a transient "peak" dilatation, followed by a myogenic constriction. The mechanism of transient dilatation was investigated in isolated rat cerebral arteries in vitro using pressure myography. The peak increased with the amplitude of the pressure step. A near-maximal dilatation to 118+/-1.6% (SEM, n=20) of the diameter at 30 mmHg was produced by pressure steps from 30 to 75 mmHg. Nomega-nitro-l-arginine methyl ester (L-NAME, 20 microM) depressed the peak at the onset of a 30 to 75 mmHg pressure step to 49.8+/-14% of the control (n=6; P=0.04). D-NAME (20 microM) had no significant effect (82.1+/-13%; n=4; P=0.13). L-Arginine (400 microM) enhanced the peak (164+/-17% of control; n=8; P=0.01). Oxadiazolol (4,3-a) quinoxalin-1-one (ODQ, 2 microM) depressed the peak to 33.2+/-12% of control (n=5; P=0.012). 6-Anilino-5, 8-quinolinedone (LY 83583, 10 microM) depressed the peak to 18.8+/-2. 9% of control (n=3; P=0.01). Removing the endothelium decreased the peak to 15.3+/-11% of control (n=3; P=0.04). In conclusion, in rat cerebral arteries, the initial dilatation at the onset of a rapid step increase in pressure is an active dilatation involving endothelial NO release.

Aminoquinolines↗
PubMed2005

The involvement of Rho-associated kinases in agonist-dependent contractions of human maternal and placental arteries at term gestation.

OBJECTIVE: The purpose of this study was to assess the involvement of rho kinase (ROK) in agonist-dependent contraction of omental, myometrial, and placental arteries of pregnant women at term. STUDY DESIGN: Wire myography was used to assess if contractions of intact or alpha-toxin-permeabilized arteries obtained from women at elective cesarean section were influenced by the ROK inhibitor Y-27632. RESULTS: Western blotting indicated the presence of ROKalpha in each of the 3 tissue types. In intact human omental, myometrial, or placental arteries, Y-27632 dose-dependently reduced constrictions to the thromboxane-mimetic U46619. In permeabilized vessels, U46619 induced substantial Ca(2+)-sensitization of contraction that was inhibited by Y27632. The phosphatase inhibitor calyculin A induced a Ca(2+)sensitization of contraction similar to that of U46619 in permeabilized omental arteries that was unaffected by Y-27632, suggesting that ROK may signal via myosin phosphatase in these vessels. CONCLUSION: These results are the first report of the involvement of ROK in the receptor-coupled constriction of intact and permeabilized arteries from pregnant women.

Amides↗
PubMed2005

Endothelial function in conduit and resistance arteries in men with coronary disease.

The aims of this study were to determine whether non-invasive measurement of endothelial function in conduit arteries reflects that of subcutaneous resistance arteries measured in vitro and to examine whether there is an endothelial dysfunction also in resistance arteries in patients with a previous myocardial infarction. The brachial artery diameter responses to a hyperemic flow stimulus and an in vitro method, pressure myography, to directly evaluate flow-mediated responses in arteries obtained from biopsies of subcutaneous fat were measured in 25 patients with a previous myocardial infarction and in 8 aged matched healthy subjects. Flow-mediated dilatation of the brachial artery was more pronounced in the healthy group compared with the group with coronary disease, 5.1 +/- 2.5% and 2.6 +/- 2.1%, respectively (p < 0.05). The flow-mediated dilatation in subcutaneous arteries from CHD patients was significantly reduced compared to control subjects (e.g. percent change from initial preconstriction at maximum flow rate of 204 microl/min: 42 +/- 7% CHD (n = 25) versus 84 +/- 24% control (n = 8), ANOVA, p = 0.03). There was a significant correlation between flow-mediated dilatation of the brachial artery and maximum flow-mediated dilatation at microvascular level, (p < 0.01). In conclusion this study demonstrates endothelial dysfunction in both conduit and resistance circulation in patients after myocardial infarction compared to an aged-matched healthy control group. Furthermore, a significant and independent relationship between endothelial function by means of flow-mediated dilatation in large conduit arteries and resistance arteries was observed.

Adult↗
PubMed2005

Evidence that inward rectifier K+ channels mediate relaxation by the PGI2 receptor agonist cicaprost via a cyclic AMP-independent mechanism.

OBJECTIVE: We investigated the role of the inward rectifier potassium (KIR) channel and the cyclic AMP-dependent pathway in mediating vasorelaxation induced by the prostacyclin analogue cicaprost. METHODS: Small vessel myography was used to assess responses to cicaprost in segments of rat tail artery contracted with phenylephrine. Microelectrode recordings were made from helical strips to assess effects on membrane potential. RESULTS: Cicaprost caused relaxation and hyperpolarisation that were significantly inhibited by Ba2+ (30-100 microM), a known blocker of KIR channels. Raising extracellular K+ from 5 to 15 mM elicited membrane hyperpolarisation and an endothelium-independent relaxation that was blocked by Ba2+ (30-100 microM), suggesting the existence of functional KIR channels on the smooth muscle. In contrast, neither glibenclamide (10 microM), a blocker of ATP-sensitive K+ channels, nor fluoxetine hydrochloride (100 microM), a blocker of G-protein-gated inward rectifier K+ channels, nor pertussis toxin (PTX; 1 microg/ml), which irreversibly inhibits Gi/Go, reduced relaxation to cicaprost. Indeed, PTX significantly potentiated responses. Relaxation to cicaprost was not mediated by NO but was partially endothelium-dependent, consistent with a similar inhibition by a combination of charybdotoxin (0.1 microM) and apamin (0.5 microM), blockers of endothelium-derived hyperpolarising factor (EDHF). However, relaxation was unaffected by adenylyl cyclase (SQ22536, dideoxyadenosine) or protein kinase A (Rp-2-O-monobutyryl-cAMP) inhibitors, consistent also with Ba2+ only weakly inhibiting relaxation to the adenylyl cyclase activator forskolin. CONCLUSION: We conclude that cicaprost relaxes rat tail artery by activating KIR channels with some involvement from EDHF. The mechanism appears to be largely independent of cyclic AMP and Gi/Go, although the latter appears to counteract relaxation through an unknown pathway and/or receptor.

Adenine↗
PubMed2005

Diabetes induces Na/H exchange activity and hypertrophy of rat mesenteric but not basilar arteries.

Experimental hyperglycemia produces a marked hypertrophic response in rat mesenteric arteries, accompanied by activation of Na/H exchange (NHE) in medial smooth muscle. This study asked if other vascular beds are similarly affected by examining the hypertrophic and NHE response of the basilar artery. Sections of mesenteric and basilar arteries from adult rats were analysed by standard morphometric techniques at 1 and 3 weeks after streptozotocin injection. NHE activity was assessed as changes in intracellular pH in isolated intact vessels using concurrent myography and fluorescence spectroscopy. Mesenteric arteries showed a significant increase in lumenal (47%), medial (51%) and adventitial (17%) area. In contrast, these parameters were not increased in basilar arteries from the same set of animals. Maximal NHE activity was significantly increased at 1 week (24%) and 3 weeks (20%) in mesenteric arteries, but in basilar arteries there was no change in basal intracellular pH, maximal NHE activity or kinetic properties of the transporter. NHE plays a central role in vascular changes in diabetes. As the mesenteric hypertrophy is amenable to therapeutic intervention these findings add further to the potential of NHE as a therapeutic target for ameliorating vascular disease in diabetes.

Animals↗
PubMed2006

Noradrenaline-induced increases in calcium and tension in skeletal muscle conductance and resistance arteries from rats with post-infarction heart failure.

We tested the hypothesis that arterial reactivity to noradrenaline is augmented in congestive heart failure (CHF), which could contribute to the deleterious changes in peripheral vascular resistance and compliance in this condition. From male Wistar rats with post-infarction CHF and sham-operated rats, skeletal muscle conductance and resistance arteries (mean lumen diameters: 514 and 186 microm) were isolated and mounted on wire myographs, and wall tension was recorded in response to cumulative application of acetylcholine and noradrenaline to the vessel segments. In a subset of experiments, wall tension and cytosolic free calcium ion concentration [Ca(2+)](i) were recorded simultaneously during noradrenaline application, using wire myography and the FURA-2 technique. No significant differences were found in the arterial baseline levels of [Ca(2+)](i) or tension between CHF and sham rats. In the resistance arteries of CHF rats, the noradrenaline-induced increases in [Ca(2+)](i) were significantly enhanced (P=0.003). Despite the augmented [Ca(2+)](i) levels, the tension responses to noradrenaline were unaltered in these arteries. In the conductance arteries, there were no significant differences in noradrenaline-induced [Ca(2+)](i) or tension responses between CHF and control rats. CHF did not alter vascular morphology or change vascular relaxations to acetylcholine in either type of artery. In conclusion, these results do not support the contention that arterial reactivity to noradrenaline is augmented in the skeletal muscle vascular bed in CHF. On the contrary, the unchanged contractile responsiveness in the resistance arteries despite the enhanced levels of [Ca(2+)](i) during noradrenaline application suggests that the contractile function of these vessels is compromised in CHF. Neither vascular remodeling, endothelial dysfunction nor changes in baseline vascular tone could be demonstrated in the skeletal muscle vascular bed of this animal model of heart failure.

Acetylcholine↗
PubMed2005

Effects of oxygen tension and normalization pressure on endothelin-induced constriction of human placental chorionic plate arteries.

OBJECTIVES: Fetoplacental blood vessels constrict in response to endothelin (ET-1) or reduced oxygen tension in the placental cotyledon perfused in vitro. In nonplacental resistance arteries, hypoxia and ET-1 induce constriction by promoting Ca2+ influx into smooth muscle through membrane ion channels, which include voltage-gated Ca2+ channels (VGCCs). We hypothesized that VGCCs are involved in ET-1-induced constriction of fetoplacental resistance vessels and that their contribution to constriction is enhanced at low oxygen tension. METHODS: Chorionic plate small arteries from term placentas were studied using parallel wire myography. Arteries were normalized at 0.9 of L(5.1 kPa) ("low stretch" approximately 25 mm Hg; approximating physiologic vascular pressure) or 0.9 of L(13.3 kPa) ("high stretch" approximately 42 mm Hg) and experiments performed at oxygen tensions of 156, 38, and 15 mm Hg. RESULTS: When chorionic plate arteries were normalized at low stretch, oxygen tension did not affect constriction to ET-1. Nifedipine (10(-4) M), a blocker of L-type VGCCs, inhibited ET-1 (EC80)-induced constriction to a similar extent at each oxygen tension (52% to 64% inhibition). In contrast, when arteries were normalized at high stretch, constriction to ET-1 was greater at 38 than at 156 or 15 mm Hg oxygen and nifedipine inhibition of ET-1-induced constriction was greater at 38 and 15 mm Hg than at 156 mm Hg oxygen. CONCLUSIONS: VGCCs and nifedipine-insensitive processes underlie the contractile response of chorionic plate arteries to ET-1 and their relative contribution to vasoconstriction is modulated by oxygen tension when vessels are normalized at high stretch. However, contrary to our hypothesis, the response of chorionic plate arteries to ET-1 is not modulated by oxygen when vessels are normalized at physiologic pressure.

Arteries↗
PubMed2005

Perivascular adipose tissue modulates vascular function in the human internal thoracic artery.

OBJECTIVE: Recent studies have shown that perivascular adipose tissue from the rat aorta secretes a substance that can dilate the aorta. The purpose of the present study was to examine whether this vasodilator is also present in human internal thoracic arteries. METHODS: Vascular function of human internal thoracic arteries with and without perivascular adipose tissue was assessed with wire myography, and morphology was examined with light microscopy. RESULTS: The presence of perivascular adipose tissue attenuated the maximal contraction to U 46619 and the contraction to phenylephrine (1 micromol/L) by 37% and 24%, respectively. Transfer of the solution incubated with a perivascular adipose tissue-intact vessel (donor) to a vessel without perivascular adipose tissue (recipient) induced a significant relaxation (36%) in the recipient artery precontracted with phenylephrine. Transfer of incubation solution with perivascular adipose tissue alone also induced a relaxation response in the recipient vessel (37%). The relaxation of the recipient artery induced by the transfer of incubation solution from the donor (artery with intact perivascular adipose tissue or perivascular adipose tissue alone) was absent in vessels precontracted by KCl (60 mmol/L) and was prevented by calcium-dependent potassium channel blockers (tetraethylammonium chloride, 1 mmol/L; iberiotoxin, 100 nmol/L), but not by the voltage-dependent potassium channel blocker 4-aminopyridine (1 mmol/L) and the adenosine triphosphate-dependent potassium channel blocker glibenclamide (10 micromol/L). CONCLUSIONS: Perivascular adipose tissue in human internal thoracic arteries releases a transferable relaxation factor that acts through the activation of calcium-dependent potassium channels. Because perivascular adipose tissue is often removed in coronary artery bypass grafting, retaining perivascular adipose tissue might be helpful in reducing the occurrence of vasospasm of the graft vessels.

Adipose Tissue↗
PubMed2006

Reactivity of human placental chorionic plate vessels is modified by level of oxygenation: differences between arteries and veins.

Normal fetal development in utero is dependent upon adequate perfusion of the placental vasculature, yet how fetoplacental blood flow is matched to maternal blood flow is unknown. In the perfused placental cotyledon in vitro, reduced oxygenation promotes vasoconstriction, which may act to direct blood in fetoplacental vessels to effectively perfused regions of the intervillus space. We aimed to demonstrate that oxygen tension could directly modify placental chorionic plate vessel vasoreactivity. Small arteries and veins from the chorionic plate were dissected from biopsies from term placentae of uncomplicated pregnancies and studied using parallel wire myography. Chorionic artery and vein vasoconstriction in 20%, 7% and 2% oxygen was assessed utilizing the thromboxane-mimetic U46619. Reduced oxygenation increased arterial maximal active effective pressure production and sensitivity to U46619. This effect was cyclo-oxygenase independent. In veins, modified oxygenation did not alter vasoconstriction. Vasodilatation in response to the NO donor sodium nitroprusside was increased in lowered oxygenation in veins but not in arteries. We suggest that modified oxygenation may play a role in the control of the blood flow in the fetoplacental circulation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2005

Oxygen tension and normalisation pressure modulate nifedipine-sensitive relaxation of human placental chorionic plate arteries.

Fetoplacental blood vessel constriction in response to reduced oxygenation has been demonstrated in placenta perfused in vitro. In pulmonary vessels, hypoxic vasoconstriction involves Ca2+ influx into smooth muscle through membrane ion channels including voltage-gated Ca2+ channels (VGCCs). We hypothesised that VGCCs are involved in agonist-induced constriction of fetoplacental resistance vessels and that their contribution is modulated by oxygen. Chorionic plate small arteries were studied using wire myography. Arteries were normalised at high (0.9 of L(13.3 kPa)) or low (0.9 of L(5.1 kPa)) stretch and experiments performed at 156, 38 or 15 mmHg oxygen. At low stretch, U46619 (thromboxane-mimetic) or KCl (smooth muscle depolarisation) constriction was greater at 38 than 156 or 15 mmHg oxygen. An L-type VGCC blocker nifedipine, inhibited KCl constriction by >85% but was less effective in U46619 constrictions (43-67%). At high stretch, nifedipine inhibition of KCl- and U46619-induced constriction was less at 15 than 38 or 156 mmHg oxygen. Oxygen did not affect constriction to U46619 or nifedipine-induced relaxation when vessels were normalised at high stretch. In conclusion, oxygen modulates chorionic plate arterial constriction at low stretch but regulation is lost at high stretch. U46619 constriction is underlain by VGCCs and nifedipine-insensitive processes; their relative contribution is influenced by oxygen.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2005

Ca(2+) sensitisation of force production by noradrenaline in femoral conductance and resistance arteries from rats with postinfarction congestive heart failure.

In this study we tested the hypothesis that arterial myofilament Ca(2+) sensitivity and/or the Ca(2+) sensitising effect of noradrenaline (NA) is enhanced in post-infarction congestive heart failure (CHF), which could contribute to the high peripheral vascular resistance in this condition. Femoral skeletal muscle resistance and conductance arteries (mean lumen diameters of 159 and 519 microm) from rats with CHF and sham-operated control rats were used. Isometric tension development and intracellular free calcium concentration ([Ca(2+)](i)) were measured simultaneously in isolated vessel segments using wire myography and the FURA-2 fluorescence technique. In conductance and resistance arteries, the resting levels of [Ca(2+)](i) and tension in physiological saline solution (PSS) and active tension in response to single doses of 125 mM K(+) (KPSS) were unaffected by CHF. During cumulative application of extracellular Ca(2+) to arteries depolarised with 125 mM K(+) or activated with 30 microM NA, [Ca(2+)](i) and vessel wall tension were similar in CHF and control rats. However, the conductance arteries showed significantly higher calcium sensitivity than resistance arteries in these experiments. We conclude that an abnormality in the sensitivity of the contractile apparatus to Ca(2+), or in NA-induced Ca(2+) sensitisation in arterial vascular smooth muscle cells is unlikely to contribute to the ubiquitously elevated vascular resistance associated with CHF. However, our data demonstrate significant differences in vascular Ca(2+) handling, myofilament Ca(2+) sensitivity and tension development between resistance and conductance arteries, regardless of CHF.

Animals↗
PubMed1996

Vertical Duane's retraction syndrome.

PURPOSE: We report three patients with a rare variant of Duane's retraction syndrome. METHODS: Eye movements were recorded by electro-oculography. One patient underwent electro-myography. RESULTS: All patients showed V-incommitance and twitch abduction on vertical saccades. Electromyography showed lateral rectus muscle firing activity during upgaze and downgaze. CONCLUSION: Our patients showed synergistic innervation between the lateral rectus muscle and ipsilateral vertical acting muscles documented by electromyography.

Adolescent↗
PubMed1998

K(+)-induced dilation of a small renal artery: no role for inward rectifier K+ channels.

OBJECTIVE: To investigate the mechanism of K(+)-induced vasodilation in a small artery from the kidney, with a particular emphasis on the role of inward rectifier K+ channels. METHODS: Lumen diameter and isometric tension recordings have been made from rabbit renal arcuate artery using pressurised- and wire-myography respectively. In addition, conventional whole-cell and amphotericin-perforated patch whole-cell recordings have been made from single smooth muscle cells isolated from the vessel. RESULTS: Arcuate arteries dilated when the extracellular K+ concentration was raised to 8-10 mM from either zero or a normal physiological level of about 6 mM. The effect was not endothelium-dependent. Application of 0.01-1 mM Ba2+ to block inward rectifier K+ channels had no significant effect on K(+)-induced vasodilation in the arcuate artery, but under the same experimental conditions K(+)-induced dilation of the rat posterior cerebral artery was abolished by Ba2+. In the presence of 60 mM extracellular K+, inward rectifier K(+)-current was detectable in some single smooth muscle cells isolated from arcuate arteries but on average the current density was low (-1.44 pA pF-1 at -60 mV). K(+)-induced vasodilation of the arcuate artery was abolished by 10 microM ouabain and the half-effective concentration of K+ which induced vasodilation was 0.9-1.5 mM. CONCLUSIONS: The observations suggest that an increase in the extracellular K+ concentration (up to about 10 mM) dilates the rabbit renal arcuate artery and that the primary mechanism underlying the effect may be stimulation of Na(+)-K+ ATPase in the smooth muscle cell membrane. Inward rectifier K+ channels have a low average density in smooth muscle cells isolated from arcuate arteries and play no significant role in K(+)-induced vasodilation.

Animals↗
PubMed2003

Detrimental effects of papaverine on the human internal thoracic artery.

OBJECTIVE: We sought to determine the effects of papaverine on human and canine internal thoracic artery function and structure. METHODS: Vascular function was assessed with wire myography, and apoptosis was examined with confocal microscopy in arteries stained with ApopTag. RESULTS: Acetylcholine-induced endothelium-dependent relaxation in phenylephrine-precontracted arteries was significantly impaired by papaverine treatment in both human and canine internal thoracic arteries (maximal relaxation: 68.35% +/- 7.13% vs 47.5% +/- 9.32% in human arteries and 74.8% +/- 5.5% vs 34.3% +/- 8.5% in canine arteries) but not by incubation with acidified saline solution (pH 3.9, which is equivalent to the pH of 10(-2) mol/L papaverine solution) in canine internal thoracic arteries. Contraction of human internal thoracic arteries to phenylephrine or to U46619 was not significantly affected by papaverine treatment and neither was the contraction of canine internal thoracic arteries to phenylephrine. Total apoptotic endothelial and smooth muscle cells were significantly greater in papaverine-treated human and canine internal thoracic arteries. CONCLUSIONS: Papaverine impairs endothelial function and triggers apoptosis of endothelial and smooth muscle cells of human and canine internal thoracic arteries. The long-term consequence of this impairment on vascular function is not known. Until this question is answered, it will be prudent to use other vasodilators that are less damaging to the internal thoracic artery for cardiac surgery.

Animals↗
PubMed1993

The action of diazepam in the isolated rat detrusor muscle.

Diazepam is one of the benzodiazepines, a group of drugs that depresses the central nervous system. It also inhibits the contractility of smooth muscles in the periphery, but the mechanism of this inhibitory action has not been clarified. Our study was undertaken to investigate the effect of diazepam on the contractility of the detrusor muscle. Detrusor muscle strips isolated from rat urinary bladder were examined by isometric myography. Diazepam, as well as baclofen, a gamma-aminobutyric acid (GABA)B receptor agonist, reduced the electric field stimulation-induced contractions; delta-aminovaleric acid, a GABAB receptor antagonist, completely antagonized the inhibitory effect of baclofen, but not the inhibitory action of diazepam. Diazepam reduced the basal tone of detrusor muscle concentration dependently, and this inhibitory action was not affected by tetrodotoxin. Diazepam suppressed the contractile responses to bethanechol, adenosine triphosphate and potassium chloride. Diazepam diminished the calcium-induced recovery of tension in calcium-free PSS. A23187, a calcium ionophore, partially recovered the basal tone which had been reduced by diazepam in normal physiologic salt solution (PSS). The loss of tension in calcium free PSS containing diazepam could not be recovered by addition of A23187. On the other hand, the loss of tension in calcium-free PSS containing 3,4,5-trimethoxybenzoic acid 8(diethylamino)octyl ester (TMB-8), an inhibitor of intracellular calcium release, was considerably recovered by addition of A23187. Based on these results, it is suggested that diazepam inhibits the contractility of detrusor muscle acting directly on the smooth muscle cell, which is unrelated to the activation of GABA receptors. Its inhibitory action appears to be mediated through interference with the influx of extracellular calcium.

Adenosine Triphosphate↗
PubMed2001

Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease.

OBJECTIVES: We sought to demonstrate non-angiotensin converting enzyme (ACE) dependent angiotensin II (AII) generating pathways in resistance arteries from patients with chronic heart failure (CHF). BACKGROUND: Non-ACE dependent AII generation occurs in resistance arteries from normal volunteers. Inhibition of non-ACE dependent AII generation may have therapeutic potential in CHF. METHODS: Resistance arteries were dissected from gluteal biopsies from patients with coronary heart disease (CHD) and preserved left ventricular function and from patients with CHF. Using wire myography, concentration response curves to angiotensin I (AI) and AII were constructed in the presence of 1) vehicle, 2) chymostatin [an inhibitor of chymase], 3) enalaprilat, and 4) the combination of chymostatin and enalaprilat. RESULTS: In resistance arteries from patients with CHD, the vasoconstrictor response to AI was not inhibited by either inhibitor alone (chymostatin [p > or = 0.05] or enalaprilat [p > or = 0.05]) but was significantly inhibited by the combination (p < 0.001). In arteries from patients with CHF, AI responses were inhibited by enalaprilat (p < 0.05) but not by chymostatin alone (p > 0.05). The combination ofchymostatin and enalaprilat markedly inhibited the response to AI (p < 0.001) to a greater degree than enalaprilat alone (p < or = 0.01). CONCLUSIONS: Non-ACE dependent AII generating pathways exist in resistance arteries from patients with both CHF and CHD. In resistance arteries from patients with CHD, inhibition of either the ACE or chymase pathway alone has no effect on AII generation, and both pathways must be blocked before the vasoconstrictor action of AI is inhibited. In CHF, blockade of ACE results in marked inhibition of responses to AI, but this is enhanced by coinhibition of chymase. These studies suggest that full suppression of the renin-angiotensin system cannot be achieved by ACE inhibition alone and provide a rationale for developing future therapeutic strategies.

Acetylcholine↗