bluuebunny/crossref_metadata_2025 huggingface dataset:
ATP and nitric oxide: inhibitory NANC neurotransmitters in the longitudinal muscle‐myenteric plexus preparation of the rat ileum
Authors: Smits Geert J.M. , Lefebvre Romain A.
Published: July 2012

The nature of neurotransmitter(s) involved in non‐adrenergic non‐cholinergic (NANC) relaxations induced by electrical stimulation (10 s trains, 1–8 Hz) was investigated in the precontracted longitudinal muscle‐myenteric plexus preparation of the rat ileum.

Electrical stimulation of the tissue induced complex responses, consisting of a primary contraction, a primary relaxation, an off‐relaxation and a rebound contraction, which were all tetrodotoxin(TTX)‐sensitive.

Vasoactive intestinal polypeptide (VIP) and carbon monoxide (CO) did not induce relaxations. α‐Chymotrypsin did not reduce the relaxations induced by electrical stimulation, while zinc protoporphyrin IX had non‐specific effects.

Nitric oxide (NO) induced concentration‐dependent relaxations. NG‐nitro‐l‐arginine methylester (L‐NAME) abolished the primary contractions and off‐relaxations, while it partially reduced the primary relaxations.

ATP induced relaxations and ATP‐desensitization of the tissues partially reduced the primary relaxations. Suramin and reactive blue 2 did not consistently influence the primary relaxations.

The ATP‐induced relaxations were not influenced by L‐NAME or TTX. The inhibitory effect of ATP‐desensitization and L‐NAME did not summate.

The cyclic AMP content of the tissue did not increase upon electrical stimulation or after addition of NO or ATP. The cyclic GMP content of the tissue increased upon electrical stimulation and addition of NO, but not after addition of ATP.

It is concluded that the relaxation induced by electrical stimulation consists of two types of responses. The off‐relaxation is completely nitrergic, while the primary relaxation is mediated by NO, ATP and an as yet unknown transmitter which is not VIP or CO.
Effects of selective phosphodiesterase 3 inhibition in the perfused liver of the rat after endotoxin treatment
Authors: Weidenbach H. , Beckh K. , Schricker T. , Georgieff M. , Adler G. , Burger M.
Published: July 2012

This study was designed to investigate the role of rat phosphodiesterase 3 (RPDE3) in regulation of liver metabolism in sepsis. We studied the effects of the phosphodiesterase 3 inhibitor (PDI), enoximone, alone and in combination with regulating factors of hepatic carbohydrate metabolism and bile secretion in the perfused liver of rats treated 4 h earlier with endotoxin. In addition, cyclic AMP and cyclic GMP levels were determined in the effluate and bile by radio immunoassay methods.

After endotoxin treatment, infusion of enoximone at three concentrations (1 μm, 10 βM) resulted in an increased glucose output from −1.4 ± 0.9 to 7.8 ± 2.5 μmol 1g−1 20 min−1. Bile acid‐independent bile flow increased also, in a dose‐dependent manner.

In untreated livers, cyclic AMP release increased in the effluate from 1000 ± 73 fmol g−1 min−1 to 1710 ± 143 fmol g−1 min−1 when enoximone (10 μm) was administered. In bile from untreated livers, the level of cyclic AMP was also significantly increased by enoximone. After endotoxin treatment, the enoximone (10 μm) effect on cyclic AMP levels in effluate and bile was greatly reduced. Levels of cyclic GMP in the effluate and bile appeared unchanged in the presence of enoximone.

During co‐infusion of glucagon (1 nM) and enoximone (10 μm), cyclic nucleotide levels in the effluate and bile of livers after endotoxin treatment were determined. In the effluate, cyclic AMP release increased from 827 ± 144 fmol g−1 min−1 to 17802 ± 2821 fmol g−1 min−1 when glucagon was administered. The presence of enoximone enhanced cyclic AMP further to 41696 ± 920 fmol g−1 min−1. The same changes in cyclic AMP release were found in bile. Levels of cyclic GMP in the effluate and bile were not significantly affected by the administration of glucagon and the PDI.

Glucose release was determined during glucagon, sympathetic nerves stimulation and phenylephrine administration in the presence and absence of enoximone. The addition of enoximone to glucagon increased glucose release by 8.2 ± 2.8 μmol g−1 20 min−1, without alteration of lactate balance. The PDI enhanced the glycogenolytic effects of nerve stimulation and of phenylephrine, accompanied by a reduction in lactate production.

Enoximone significantly enhanced the bile acid independent bile flow after glucagon, nerves stimulation and after administration of phenylephrine. Bile acid secretion was unaffected by the PDI. The vasoconstrictor effect of nerve stimulation was reduced by the PDI.

We conclude that endotoxin treatment reduces the ability of the PDI, enoximone, to increase cyclic AMP release in the perfused liver. The significant increase in cyclic AMP release after stimulation with glucagon and enoximone favours the view that RPDE3 is involved in the degradation of cyclic AMP in the liver after exposure to endotoxin. Additionally, the inhibition of the RPDE3 results in glucose release, vasodilatation and choleresis in endotoxin pretreated livers.
Heterogeneous distribution of benzodiazepine receptors among rat neostriatal neurones
Authors: Munakata Mitsutoshi , Nakanishi Ryoji , Akaike Norio
Published: July 2012

The effects of benzodiazepine receptor (BZR) agonist were investigated in dissociated rat neostriatal neurones by a conventional whole‐cell patch recording configuration at room temperature.

The dissociated neurones, with a longest somatic diameter of larger than 25 μm, were classified as ‘large neurones’, while those having soma measuring less than 15 μm were described as ‘small neurones’. Large neurones were intensely positive for acetylcholinesterase staining, whereas the small ones were not.

CL218,872 enhanced the GABA response in both the large and small neurones with similar EC50s. However, the potentiation efficacy of CL218,872 in large neurones was larger than that of small ones.

Zolpidem also potentiated the GABA response in both neuronal populations with similar EC50s. This compound also enhanced the GABA response more strongly in large neurones than in small ones.

Zopiclone exerted a prominent potentiation in large neurones, although no difference was seen in the EC50s in the large and small neurones.

It was concluded that the BZR in large neurones had a different pharmacological property from that in small ones and that the BZR agonists showed a prominent difference, not in EC50, but in the potentiation efficacy between these neuronal populations.
Inhibition of PAF synthesis by stimulated human polymorphonuclear leucocytes with cloricromene, an inhibitor of phospholipase A2 activation
Authors: Ribaldi E. , Mezzasoma A.M. , Francescangeli E. , Prosdocimi M. , Nenci G.G. , Goracci G. , Gresele P.
Published: July 2012

A phospholipase A2 (PLA2) represents the key enzyme in the remodelling pathway of platelet‐activating factor (PAF) synthesis in human polymorphonuclear (PMN) leucocytes.

PLA2 activation is also the rate‐limiting step for the release of the arachidonic acid utilized for the synthesis of leukotrienes in stimulated leucocytes; however, it is unknown whether the PLA2s involved in the two biosynthetic pathways are identical.

Cloricromene (8‐monochloro‐3‐β‐diethylaminoethyl‐4‐methyl‐7‐ethoxy‐carbonylmethoxy coumarin) is an antithrombotic coumarin derivative which inhibits platelet and leucocyte function and suppresses arachidonic acid liberation by interfering with PLA2 activation.

The aim of the present study was to assess whether chloricromene inhibits PAF synthesis by stimulated human polymorphonuclear leucocytes (PMNs).

Cloricromene (50–500 μm) inhibited in a concentration‐dependent manner the release of PAF, as measured by h.p.l.c. bioassay, from A23187‐stimulated PMNs. Significant inhibition (45%) of PAF‐release was obtained with 50 μm cloricromene and the IC50 was 85 μm. Mepacrine (500 μm), a non‐specific PLA2 inhibitor, strikingly reduced PAF release.

The incorporation of [3H]‐acetate into [3H]‐PAF induced by serum‐treated zymosan in human PMNs was also inhibited concentration‐dependently by cloricromene, with an IC50 of 105 μm. Mepacrine also suppressed [3H]‐acetate incorporation into [3H]‐PAF.

Cloricromene did not affect the activities of the enzymes involved in PAF‐synthesis acetyltransferase or phosphocholine transferase.

Our data demonstrate that cloricromene, an inhibitor of PLA2‐activation in human leucocytes, reduces the synthesis of PAF by stimulated PMNs. This finding has a twofold implication: the PLA2s (or the mechanisms that regulate their activation) involved in PAF synthesis and arachidonate release in human leucocytes are either identical or else indistinguishable by their sensitivity to cloricromene; the inhibition of PAF release by activated leucocytes may contribute to the antithrombotic and anti‐ischaemic activities exerted by cloricromene.
Cardiovascular effects of a novel, potent and selective phosphodiesterase 5 inhibitor, DMPPO: in vitro and in vivo characterization
Authors: Delpy Eric , de Gouville Anne‐Charlotte le Monnier
Published: July 2012

The aim of this study was to investigate the cardiovascular effects of a novel, potent and specific phosphodiesterase 5 (PDE 5) inhibitor, 1,3 dimethyl‐6‐(2‐propoxy‐5‐methane sulphonylamidophenyl)‐pyrazolo[3,4‐d]pyrimidin‐4‐(5H)‐one (DMPPO) in phenylephrine‐precontracted rat aortic rings and different in vivo rat preparations.

DMPPO elicited a concentration‐dependent relaxation of rat aortic rings with functional endothelium. DMPPO‐induced relaxation was abolished by endothelium removal or pretreatment with the soluble guanylate cyclase inhibitor, methylene blue (10 μm).

In aortic rings without endothelium, the potency (pD2 = ‐log10 EC50) of atrial natriuretic peptide (ANP) to induce relaxation increased from 8.13 ± 0.05 in the absence of DMPPO to 8.32 ± 0.05 and 8.52 ± 0.08 in the presence of 30 nM and 100 nM DMPPO, respectively. Similarly, the potency of sodium nitroprusside (SNP) in inducing relaxation increased from 7.38 ± 0.07 in the absence of the PDE 5 inhibitor to 8.07 ± 0.11 and 8.15 ± 0.08 in the presence of 30 nM and 100 nM DMPPO, respectively. In contrast, relaxation to the adenylate cyclase activator, forskolin, was unchanged by DMPPO (100μm).

In rings without endothelium, DMPPO (100 nM) increased by 2.5 fold intracellular levels of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP). Moreover, DMPPO (100 nM) potentiated the increases in cyclic GMP levels induced by ANP (30 nM) by 3 fold and SNP (30 nM) by 2.7 fold. Adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) levels were not modified by DMPPO.

In anaesthetized normotensive or spontaneously hypertensive rats (SHR), DMPPO (2 and 5 mg kg−1, i.v.) lowered blood pressure without affecting heart rate. Similarly, in conscious SHR, orally administered DMPPO (5 mg kg−1) induced a 25 mmHg decrease in blood pressure for at least 7 h without modifying heart rate. Meanwhile, urinary cyclic GMP was increased by 50% whereas cyclic AMP remained unchanged.

In normotensive anaesthetized rats, sodium nitroprusside (SNP) (i.v. bolus) induced a decrease in blood pressure which rapidly returned to baseline. In DMPPO (1 mg kg−1, i.v.)‐treated rats, the hypotensive effects of SNP (10 to 100 μg kg−1) were prolonged over time whereas the peak effect was unchanged.

In pithed rats, phenylephrine (i.v. bolus) induced dose‐dependent increases in blood pressure. Pretreatment with DMPPO (5 mg kg−1, i.v.) partially inhibited the pressor response to phenylephrine (0.3 to 100 μg kg−1).

In conclusion, the potent and selective PDE 5 inhibitor, DMPPO, produces relaxation in isolated vessels in the presence of a cyclic GMP drive and reduces blood pressure of intact animals. Its high oral bioavailability and long duration of action should make it a useful tool to study the role of cyclic GMP in various biological systems.
Biphasic effect of pentobarbitone on chick myotube nicotinic receptor channel kinetics
Authors: Liu Guo Jun , Madsen Barry W.
Published: July 2012

The modulatory action of pentobarbitone on chick myotube nicotinic acetylcholine receptor kinetics was studied by the patch clamp technique, particularly focussing on effects at low concentrations.

Open time sojourn distributions of foetal‐type receptors recorded at room temperature (22–24°C) in cell‐attached mode in the presence of 0.2 μm acetylcholine were well described by two exponentials, with fast and slow time constants of 0.53 ± 0.12 and 16.7 ± 2.2 ms (mean ± s.e.mean) respectively.

The duration of the slow open time constant was increased by low concentrations of pentobarbitone (up to 1 μm), and thereafter decreased with higher concentrations (10–50 μm) in a concentration‐dependent manner.

Complementary evidence for the stimulatory effect of pentobarbitone on open time was obtained (i) by using a backfill technique where drug concentration at the patch gradually increases over time, and (ii) through use of perfused outside‐out preparations where receptors in the same patch were successively exposed to acetylcholine in the absence and presence of pentobarbitone.

The dual action of pentobarbitone on channel kinetics probably indicates that an allosteric interaction mechanism is involved rather than simple steric channel blockade.
Sulprostone‐induced reduction of myocardial infarct size in the rabbit by activation of ATP‐sensitive potassium channels
Authors: Hide Emma J. , Thiemermann Christoph
Published: July 2012

This study examined whether (i) a 1 h pretreatment with or (ii) a continuous infusion of sulprostone reduces myocardial infarct size arising from coronary artery occlusion (60 min) and reperfusion (120 min) in the anaesthetized rabbit. In addition, we investigated whether the observed cardioprotective effect of this selective agonist of prostanoid EP1/EP3 receptors were due to the activation of ATP‐sensitive potassium (KATP) channels.

In anaesthetized rabbits pretreated with vehicle (5% ethanol in 0.9% saline; 0.05 ml min−1, i.v.) infarct size (expressed as a percentage of the area at risk) after 60 min of coronary artery occlusion followed by 120 min of reperfusion was 59 ± 4% (n = 10). Pretreatment of rabbits with sulprostone (1.0 μg kg−1 min−1 for 1 h, discontinued immediately prior to coronary artery occlusion) did not reduce infarct size (60 ± 4%; n = 4). In contrast, a continuous infusion of sulprostone (1.0 μg kg−1 min−1) starting 10 min prior to the onset of LAL occlusion and continued throughout the experiment, significantly reduced infarct size (41 ± 5%, n = 6) when compared to the respective vehicle‐treated controls (57 ± 4%, n = 10; P < 0.05). Sulprostone (pretreatment or continuous infusion) had no effect on any of the haemodynamic parameters measured.

The reduction in infarct size afforded by continuous infusion of sulprostone was abolished by pretreatment of rabbits with the KATP channel blocker 5‐hydroxydecanoate (5‐HD 5 μg kg−1; 63 ± 4%; n = 6). When administered alone, 5‐HD had no effect on infarct size when compared to control (52 ± 6, n = 10).

We propose that a continuous infusion of the selective EP1/EP3 prostanoid receptor agonist, sulprostone, reduces infarct size in the anaesthetized rabbit by a mechanism that involves the opening of KATP channels.
Actions of the digitalis analogue strophanthidin on action potentials and L‐type calcium current in single cells isolated from the rabbit atrioventricular node
Authors: Hancox Jules C. , Levi Allan J.
Published: July 2012

The atrioventricular node (AVN) of the heart is vital to normal cardiac function and is a major site of antiarrhythmic drug action. This study describes the effects of the cardiac glycoside analogue strophanthidin on spontaneous action potentials and L‐type calcium current recorded from single AVN cells isolated from the rabbit heart.

With a standard KCl‐based internal dialysis solution, exposure to 50 μm strophanthidin produced a progressive depolarization of the maximum diastolic potential and a reduction in action potential amplitude and upstroke velocity. Sustained application resulted in the loss of action potentials and occurrence of spontaneous ‘bell‐shaped’ depolarizations.

Cells were whole‐cell voltage clamped at −40 mV and depolarizing voltage clamps applied. With a standard KCl‐based internal dialysis solution, exposure to 50 μm strophanthidin caused a large reduction of ICa,L at all potentials between −30 and +40 mV (n = 4). At +10 mV, the mean ICa,L amplitude was reduced from −232 ± 65 pA to −48 ± 26 pA (P < 0.05; t test; n = 5 cells).

To record ICa,L more selectively, cells were dialysed with a Cs‐based pipette solution. A short strophanthidin exposure reduced ICa,L amplitude from −250 ± 31 pA to −88 ± 19 pA (P < 0.001; n = 8 cells). For both KCl and CsCl‐based solutions it was observed that sustained exposure to strophanthidin for several minutes caused spontaneous inward fluctuations in the membrane current record similar to the ‘ITI’ (arrhythmogenic oscillatory transient inward) current shown for other cardiac cells.

When the calcium chelator BAPTA was added to the pipette solution (10 mM), the reduction in ICa,L by strophanthidin was largely eliminated (P > 0.1), and no spontaneous inward current fluctuations were observed after sustained exposure to strophanthidin (n = 8 cells).

When external Ca in the perfusate was replaced with Ba, strophanthidin did not significantly reduce the Ba current through L‐type calcium channels (n = 5 cells).

We conclude that strophanthidin reduces ICa,L by an indirect action, mediated by the rise in intracellular calcium (Cai) which follows inhibition of the Na/K pump caused by cardiac glycosides. The appearance of spontaneous ITI with strophanthidin would also seem to be mediated by a rise in Cai, and may contribute to the spontaneous oscillations in membrane potential observed after prolonged strophanthidin exposure.
Effects of neuropeptide Y on L‐type calcium current in guinea‐pig ventricular myocytes
Authors: Bryant S.M. , Hart G.
Published: July 2012

Neuropeptide Y (NPY) reduces cell shortening at high concentrations in guinea‐pig ventricular myocytes. We have studied the effects of the peptide on calcium current in cardiac myocytes.

We have recorded L‐type calcium current in guinea‐pig ventricular myocytes under conditions in which the effects of other overlapping currents have been minimised by using Na+‐free, K+‐free external solution and patch‐clamp electrodes containing Cs+.

Peak inward calcium current is reduced by NPY at concentrations in excess of 1 nM, and maximal inhibition (31%) was found at and above concentrations of 100 nM. The IC50 value for NPY inhibition of peak calcium current was 1.72 nM.

NPY had no effect on the voltage‐dependence of calcium current amplitude, on the time course of current inactivation, or on the voltage‐dependence of the steady‐state gating variables.

NPY did not reduce the calcium current in the presence of 8‐Br‐cyclic AMP, and it was also without effect when GTP‐γ‐S or GDP‐β‐S were included in the patch pipette.

We conclude that in guinea‐pig ventricular myocytes NPY acts at low concentration to reduce L‐type calcium current, via a G‐protein‐mediated pathway and reduction in intracellular cyclic AMP.
Tissue distribution of adenosine receptor mRNAs in the rat
Authors: Dixon Alistair K. , Gubitz Amelie K. , Sirinathsinghji Dalip J.S. , Richardson Peter J. , Freeman Tom C.
Published: July 2012

A degree of ambiguity and uncertainty exists concerning the distribution of mRNAs encoding the four cloned adenosine receptors. In order to consolidate and extend current understanding in this area, the expression of the adenosine receptors has been examined in the rat by use of in situ hybridisation and the reverse transcription‐polymerase chain reaction (RT‐PCR).

In accordance with earlier studies, in situ hybridisation revealed that the adenosine A1 receptor was widely expressed in the brain, whereas A2A receptor mRNA was restricted to the striatum, nucleus accumbens and olfactory tubercle. In addition, A1 receptor mRNA was detected in large striatal cholinergic interneurones, 26% of these neurones were also found to express the A2A receptor gene. Central levels of mRNAs encoding adenosine A2B and A3 receptors were, however, below the detection limits of in situ hybridisation.

The more sensitive technique of RT‐PCR was then employed to investigate the distribution of adenosine receptor mRNAs in the central nervous system (CNS) and a wide range of peripheral tissues. As a result, many novel sites of adenosine receptor gene expression were identified. A1 receptor expression has now been found in the heart, aorta, liver, kidney, eye and bladder. These observations are largely consistent with previous functional data. A2A receptor mRNA was detected in all brain regions tested, demonstrating that expression of this receptor is not restricted to the basal ganglia. In the periphery A2A receptor mRNA was also found to be more widely distributed than generally recognised. The ubiquitous distribution of the A2B receptor is shown for the first time, A2B mRNA was detected at various levels in all rat tissues studied. Expression of the gene encoding the adenosine A3 receptor was also found to be widespread in the rat, message detected throughout the CNS and in many peripheral tissues. This pattern of expression is similar to that observed in man and sheep, which had previously been perceived to possess distinct patterns of A3 receptor gene expression in comparison to the rat.

In summary, this work has comprehensively studied the expression of all the cloned adenosine receptors in the rat, and in so doing, resolves some of the uncertainty over where these receptors might act to control physiological processes mediated by adenosine.
KW‐4679‐induced inhibition of tachykininergic contraction in the guinea‐pig bronchi by prejunctional inhibition of peripheral sensory nerves
Authors: Ikemura Toshihide , Okamura Kyoko , Sasaki Yasuo , Ishii Hidee , Ohmori Kenji
Published: July 2012

Sensory mechanisms play an important role in the vagal regulation of tracheobronchial smooth muscle tone. We examined the effect of KW‐4679, an anti‐allergic drug, on guinea‐pig tachykinin‐mediated contractile responses induced by electrical field stimulation (EFS) in guinea‐pig bronchial muscles.

EFS (8 Hz, 0.5 ms, 15 V, for 15 s) evoked biphasic contractile responses in the guinea‐pig isolated main bronchus in the presence of 5 μm indomethacin. The contractions consisted of a fast phase of an atropine‐sensitive transient contraction and a slow phase of a sustained contraction which was inhibited by a combination of the tachykinin NK1 receptor antagonist, (±)‐CP‐96,345 (1 μm) and the NK2 receptor antagonist, SR 48968 (0.1 μm).

KW‐4679 preferentially inhibited the slow phase in a concentration‐dependent manner by 43.2 ± 7.7% at 10 μm, whereas the drug had no effect on the fast phase at concentrations up to 10 μm. KW‐4679, at a concentration of 100 μm, inhibited not only the slow phase by 49.2 ± 11.4%, but also the fast phase by 36.8 ± 9.3%.

KW‐4679 (10 μm and 100 μm) did not affect the substance P‐induced or neurokinin A‐induced contraction. Against the acetylcholine‐induced contractile responses, 100 μm KW‐4679 had a marked effect producing a 10.2 fold shift to the right in the curve.

The inhibitory effect of KW‐4679 (10 μm) on the slow phase contraction was not influenced by treatment with naloxone (100 nM), propranolol (1 μm), thioperamide (1 μm), saclofen (50 μm), yohimbine (1 μm), methiothepin (1 μm) or methysergide (1 μm).

The inhibitory effect of KW‐4679 (10 μm) on the slow phase contraction was not influenced by treatment with intermediate or large conductance Ca2+‐activated K+ channel blockers (charybdotoxin (10 nM) or iberiotoxin (10 nM)), but suppressed by treatment with small conductance Ca2+‐activated K+ channel blockers, apamin (500 nM) or scyllatoxin (300 nM). Apamin or scyllatoxin per se did not influence the slow phase contractions.

The results suggest that KW‐4679 preferentially inhibits the release of tachykinins from the bronchial sensory nerves through activation of small conductance Ca2+‐activated K+ channels.
Suramin ‐ a powerful inhibitor of neural ecto‐diadenosine polyphosphate hydrolase
Authors: Mateo Jesus , Rotllán Pedro , Miras‐Portugal M. Teresa
Published: July 2012

The neural ecto‐diadenosine polyphosphate hydrolase (ecto‐ApnAase) from plasma membranes of Torpedo synaptic terminals is inhibited by suramin. This study was carried out by discontinuous h.p.l.c. and continuous fluorometric methods. The concentration‐dependence studies showed a non‐competitive mechanism for suramin in the Dixon plot, with a Ki value of 1.79 ± 0.03 μm with respect to ɛ‐(Ap3A) as the substrate and 1.69 ± 0.05 μm and 1.86 ± 0.06 μm for ɛ‐(Ap4A) and ɛ‐(Ap5A) respectively. These results indicate that suramin could be a base compound inhibiting ecto‐ApnAase and providing an alternative way of studying the pharmacology of diadenosine polyphosphate receptors.
Impaired arterial reactivity following cytomegalovirus infection in the immunosuppressed rat
Authors: Eerdmans Pedro H.A. , Persoons Maike C.J. , Debets Sjaak J.M. , Boudier Harry A.J. Struijker , Smits Jos F.M. , Bruggeman Catrien A. , De Mey Jo G.R.
Published: July 2012

Cytomegalovirus (CMV) is a major pathogen in immunocompromised individuals and may participate in the pathogenesis of atherosclerosis in the general population. We evaluated whether CMV‐infection alters the function of arterial smooth muscle.

Blood pressure (BP) and arterial reactivity were recorded in immunosuppressed rats that had been infected with CMV (105 plaque forming units i.p.). Furthermore, the reactivity of isolated arteries was compared between CMV‐infected rats and rats injected with bacterial endotoxin (LPS).

Initially resting BP and heart rate (HR) were not modified in CMV‐infected rats, but baroreflex control of HR was impaired. By the eighth day post‐CMV, BP dropped precipitously and could no longer be raised by phenylephrine (PHE).

In mesenteric resistance arteries, isolated at this stage from CMV‐infected rats, contractile responses to nerve stimulation, noradrenaline, PHE and 5‐hydroxytryptamine (5‐HT) were virtually absent while those to high potassium and vasopressin (AVP) were not modified. In aortae of CMV‐infected rats, responses to 5‐HT and AVP were impaired while those to PHE or potassium were hardly affected. Reduced contractile responses could not be restored by NG‐nitro‐L‐arginine methyl ester (L‐NAME).

Continuous treatment of CMV‐infected rats with prazosin (0.1 mg kg−1 day−1) prevented blood pressure lowering and resistance artery changes.

Observations in arteries of LPS‐treated rats (5–10 mg kg−1, i.p.) differed markedly from those in vessels of CMV‐infected animals. The contractile reactivity of their mesenteric resistance arteries was not altered while in their aortae, responses to PHE, 5‐HT and AVP were reduced. With the exception of the AVP responses, this was more pronounced in the presence of L‐arginine and reversed by L‐NAME.

These findings indicate that CMV‐infection results in a reduction of resistance artery reactivity and hypotonia. This seems not to involve cytokine‐mediated induction of NO synthase in the vascular wall but may be due to alterations of excitation‐contraction coupling in arterial smooth muscle in response to increased sympathetic nervous input.
Cyclic GMP‐independent effects of nitric oxide on guinea‐pig uterine contractility
Authors: Kuenzli Karri A. , Bradley Michael E. , Buxton Iain L.O.
Published: July 2012

The role of nitric oxide (NO) in the regulation of uterine contractility has yet to be clearly defined. We evaluated the effect of NO (in the form of S‐nitroso‐L‐cysteine, CysNO) upon uterine contractility and guanosine 3′,5′‐cyclic monophosphate (cyclic GMP) accumulation in pregnant and nonpregnant guinea‐pig myometrium.

While CysNO had no effect upon spontaneous contractile activity in either pregnant or nonpregnant uterine tissues, addition of CysNO resulted in an immediate and reversible relaxation of oxytocin‐ or acetylcholine (ACh)‐evoked contractions.

Relaxation of agonist‐evoked contractions in response to CysNO was associated with significant elevations in intracellular cyclic GMP concentrations ([cyclic GMP]i).

Elevations in [cyclic GMP]i were not required for relaxation, as inhibition of guanylyl cyclase by methylene blue prevented [cyclic GMP]i accumulation while having no effect upon the ability of CysNO to relax agonist‐evoked contractions.

Addition of the cyclic GMP‐analogues, 8‐Br‐cyclic GMP and PET‐cyclic GMP, only at high concentrations, produced partial relaxation of agonist‐contracted tissues, suggesting the possibility that cyclic GMP may be sufficient but not necessary for myometrial relaxation.

Our studies not only provide evidence for a functional role for NO‐modulation of agonist‐evoked contractions in the pregnant and nonpregnant guinea‐pig uterus, but also that these occur by a mechanism which is not dependent upon guanylyl cyclase activity.
Effect of amlodipine on renin secretion and renin gene expression in rats
Authors: Schricker Karin , Hamann Marlies , Macher Andreas , Krämer Bernhard K. , Kaissling Brigitte , Kurtz Armin
Published: July 2012

This study was done to characterize the influence of calcium channel blockade on renin secretion and renin gene expression in normal rats and rats with renovascular hypertension. To this end we studied the effects of the 1,4‐dihydropyridine derivative, amlodipine, on plasma renin activity and renal renin m‐RNA levels in normal rats and rats with unilateral renal hypoperfusion induced by applying 0.2 mm left renal artery clips over four days.

In normotensive rats, amlodipine significantly decreased basal blood pressure by about 20 mmHg when applied in a concentration of 5, 15 and 45 mg kg−1. Plasma renin activity and also renin mRNA levels were not changed after application of 5 mg kg−1 of amlodipine. However, at a concentration of 15 or 45 mg kg−1, amlodipine, significantly increased not only plasma renin activity by about 250% and 300%, but also renin mRNA levels by about 100% and 500%. The action of amlodipine on all these parameters was maximal after 24 h. Treatment with amlodipine in a concentration of 15 mg kg−1 also increased renin immunoreactive areas in the kidney cortex by retrograde recruitment of renin expressing cells in the afferent arterioles.

In 2kidney‐1 clip rats, systolic blood pressure rose continuously whilst plasma renin activity and renin m‐RNA in the clipped kidney increased transiently and renin m‐RNA in the contralateral kidney was constantly suppressed. Amlodipine at a concentration of 15 mg kg−1 markedly attenuated the increase of blood pressure in 2kidney‐1 clip rats, produced an almost additive effect on plasma renin activity and showed a tendency to increase renin m‐RNA levels in the clipped kidneys. Renin m‐RNA levels in the contralateral kidney were also significantly suppressed in the animals receiving additional treatment with amlodipine.

These findings suggest that inhibition of calcium channels by amlodipine stimulates renin secretion and renin gene expression in vivo. These stimulatory effects are almost additive to the changes of renin secretion occurring after an unilateral fall of renal perfusion pressure.
Role of nitric oxide in the circulatory failure and organ injury in a rodent model of Gram‐positive shock
Authors: Kengatharan Ken. M. , De Kimpe Sjef J. , Thiemermann Christoph
Published: July 2012

The pathological features of Gram‐positive shock can be mimicked by the co‐administration of two cell wall components of Staphylococcus aureus, namely lipoteichoic acid (LTA) and peptidoglycan (PepG). This is associated with the expression of the inducible isoform of nitric oxide synthase (iNOS) in various organs. We have investigated the effects of dexamethasone (which prevents the expression of iNOS protein) or aminoguanidine (an inhibitor of iNOS activity) on haemodynamics, multiple organ dysfunction syndrome (MODS) as well as iNOS activity elicited by LTA + PepG in anaesthetized rats.

Co‐administration of LTA (3 mg kg−1, i.v.) and PepG (10 mg kg−1, i.v.) resulted in a significant increase in the plasma levels of tumour necrosis factor‐α (TNFα, maximum at 90 min) as well as a biphasic fall in mean arterial blood pressure (MAP) from 120 ± 3 mmHg (time 0) to 77 ± 5 mmHg (at 6 h, w = 8; P < 0.05). This hypotension was associated with a significant tachycardia (4–6 h, P < 0.05) and a reduction of the pressor response elicited by noradrenaline (NA, 1 μg kg−1, i.v., at 1–6 h; n = 8, P < 0.05). Furthermore, LTA + PepG caused time‐dependent increases in the serum levels of markers of hepatocellular injury, glutamate‐pyruvate‐transaminase (GPT) and glutamate‐oxalacetate‐transaminase (GOT). In addition, urea and creatinine (indicators of renal dysfunction) were increased. There was also a fall in arterial oxygen tension (PaO2), indicating respiratory dysfunction, and metabolic acidosis as shown by the significant drop in pH, PaCO2 and HCO3−. These effects caused by LTA + PepG were associated with the induction of iNOS activity in aorta, liver, kidney and lungs as well as increases in serum levels of nitrite + nitrate (total nitrite).

Pretreatment of rats with dexamethasone (3 mg kg−1, i.p.) at 120 min before LTA + PepG administration significantly attenuated these adverse effects as well as the increases in the plasma levels of TNFα caused by LTA + PepG. The protective effects of dexamethasone were associated with a prevention of the increase in iNOS activity (in aorta, liver, lung, kidney), the expression of iNOS protein (in lungs), as well as in the increase in the plasma levels of total nitrite.

Treatment of rats with aminoguanidine (5 mg kg−1 + 10 mg kg−1 h−1) starting at 120 min after LTA + PepG attenuated most of the adverse effects and gave a significant inhibition of iNOS activity (in various organs) as well as an inhibition of the increase in total plasma nitrite. However, aminoguanidine did not improve renal function although this agent caused a substantial inhibition of NOS activity in the kidney.

Thus, an enhanced formation of NO by iNOS importantly contributes to the circulatory failure, hepatocellular injury, respiratory dysfunction and the metabolic acidosis, but not the renal failure, caused by LTA + PepG in the anaesthetized rat.
Selecting for Tolerance against Pathogens and Herbivores to Enhance Success of Reintroduction and Translocation
Authors: VENESKY MATTHEW D. , MENDELSON III JOSEPH R. , SEARS BRITTANY F. , STILING PETER , ROHR JASON R.
Published: July 2012

Abstract:  Some species have insufficient defenses against climate change, emerging infectious diseases, and non‐native species because they have not been exposed to these factors over their evolutionary history, and this can decrease their likelihood of persistence. Captive breeding programs are sometimes used to reintroduce individuals back into the wild; however, successful captive breeding and reintroduction can be difficult because species or populations often cannot coexist with non‐native pathogens and herbivores without artificial selection. In captive breeding programs, breeders can select for host defenses that prevent or reduce pathogen or herbivore burden (i.e., resistance) or traits that limit the effects of parasitism or herbivory on host fitness (i.e., tolerance). We propose that selection for host tolerance may enhance the success of reintroduction or translocation because tolerant hosts generally have neutral effects on introduced pathogens and herbivores. The release of resistant hosts would have detrimental effects on their natural enemies, promoting rapid evolution to circumvent the host resistance that may reduce the long‐term probability of persistence of the reintroduced or translocated species. We examined 2 case studies, one on the pathogenic amphibian chytrid fungus ( Batrachochytrium dendrobatidis [Bd]) and the other on the herbivorous cactus moth ( Cactoblastis cactorum) in the United States, where it is not native. In each case study, we provide recommendations for how captive breeders and managers could go about selecting for host tolerance. Selecting for tolerance may offer a promising tool to rescue hosts species from invasive natural enemies as well as new natural enemies associated with climate change‐induced range shifts.
Analytical Solutions to Trade‐Offs between Size of Protected Areas and Land‐Use Intensity
Authors: BUTSIC VAN , RADELOFF VOLKER C. , KUEMMERLE TOBIAS , PIDGEON ANNA M.
Published: July 2012

Abstract:  Land‐use change is affecting Earth's capacity to support both wild species and a growing human population. The question is how best to manage landscapes for both species conservation and economic output. If large areas are protected to conserve species richness, then the unprotected areas must be used more intensively. Likewise, low‐intensity use leaves less area protected but may allow wild species to persist in areas that are used for market purposes. This dilemma is present in policy debates on agriculture, housing, and forestry. Our goal was to develop a theoretical model to evaluate which land‐use strategy maximizes economic output while maintaining species richness. Our theoretical model extends previous analytical models by allowing land‐use intensity on unprotected land to influence species richness in protected areas. We devised general models in which species richness (with modified species‐area curves) and economic output (a Cobb–Douglas production function) are a function of land‐use intensity and the proportion of land protected. Economic output increased as land‐use intensity and extent increased, and species richness responded to increased intensity either negatively or following the intermediate disturbance hypothesis. We solved the model analytically to identify the combination of land‐use intensity and protected area that provided the maximum amount of economic output, given a target level of species richness. The land‐use strategy that maximized economic output while maintaining species richness depended jointly on the response of species richness to land‐use intensity and protection and the effect of land use outside protected areas on species richness within protected areas. Regardless of the land‐use strategy, species richness tended to respond to changing land‐use intensity and extent in a highly nonlinear fashion.
Consensus on Criteria for Potential Areas for Wolf Reintroduction in Mexico
Authors: ARAIZA MARCELA , CARRILLO LUIS , LIST RURIK , GONZÁLEZ CARLOS A. LÓPEZ , MEYER ENRIQUE MARTÍNEZ , MARTÍNEZ‐GUTIÉRREZ PATRICIA G. , MOCTEZUMA OSCAR , SÁNCHEZ‐MORALES NAHUM E. , SERVÍN JORGE
Published: July 2012

Abstract: Given the conflict with human interests that in many cases results in the extirpation of large carnivores, acceptance of their reintroduction is a considerable challenge. By the 1980s Mexican wolves (Canis lupus) were extinct in the wild. In 1998 a population was reintroduced in the Blue Range Mountains of New Mexico (U.S.A.). Efforts to reintroduce the species in Mexico have been ongoing since the late 1980s. Four teams working independently identified 6 areas in northern Mexico in the historic range of Mexican wolves, where reintroductions could potentially be successful. Each team used different methods and criteria to identify the areas, which makes it difficult to prioritize among these areas. Therefore, members of the different teams worked together to devise criteria for use in identifying priority areas. They identified areas with high, intermediate, and low potential levels of conflict between wolves and humans. Areas with low potential conflict had larger buffers (i.e., distance from human settlement to areas suitable for wolves) around human settlements than high‐ and intermediate‐conflict areas and thus were thought most appropriate for the first reintroduction. High‐conflict areas contained habitat associated with wolf presence, but were closer to human activity. The first reintroduction of Mexican wolves to Mexico occurred in October 2011 in one of the identified low‐conflict areas. The identification of suitable areas for reintroduction represents a crucial step in the process toward the restoration of large carnivores. Choice of the first reintroduction area can determine whether the reintroduction is successful or fails. A failure may preclude future reintroduction efforts in a region or country.
Measurement of Health‐Related Quality of Life in the Care of Patients with ESRD: Isn’t This the Metric That Matters?
Authors: Naik Nimish , Hess Rachel , Unruh Mark
Published: July 2012

An outcome can take many forms in the health care of an individual. Common measures in clinical research may include mortality, time to ESRD, or change in glomerular filtration rate. While a patient surely may share an interest with a clinician regarding these endpoints, individual life priorities expectedly vary. Outcomes of great value to a clinician (or their performance quality measures) may not be shared by their patient. While continued education and efforts in effective communication may help each party understand the reasons behind these differences, the time required to foster such dialogues remains a major hurdle for most clinicians. Through the use of contemporary computers such as smartphones, tablets, and laptops, healthcare providers can gain meaningful insight from patient‐reported data such as pain, sleep, and sexual function. This review will detail how carefully constructed questionnaires with equivalent reliability as long annual surveys, such as KDQOL, can be more quickly completed by using novel technology, which can be transmitted from the patient to the clinician and back to the bedside in minutes rather than in weeks.
Embodied Resource Flows in a Global Economy
Authors: Duchin Faye , Levine Stephen H.
Published: July 2012

This article presents a methodology for identifying critical links in global resource supply chains by tracking resources from their extraction in one region of the world economy through their embodiment in intermediate products in the same and other regions to eventual embodiment in final goods. We build on previous work that applied an absorbing Markov chain (AMC) to results obtained using an input‐output (IO) model of a single region to define a resource‐specific network within that economy. In the absence of model calculations, the AMC can also be applied to standard IO data for a past year. This article first generalizes the analytic framework from a single region to the important case of the global resource‐specific network. This network typically includes cycling of embodied resources between sectors not only within each economy, but also among regions, as subsequent rounds of intermediate products are traded. Next, we refine that analysis to exhibit a crucial subnetwork, the resource end‐use network, which only tracks the portion of the resource that ends up embodied in a specific final product in a given region. Finally, we develop techniques to distinguish key branches of these networks and provide detailed insights about the structure of global resource dependence. A numerical example is applied to results of scenario analysis using an IO model of the world economy. Two alternative scenarios are compared. In each scenario, embodied resources are carried over specific branches of a global network in three regions using three resources to produce four goods.
Disruptions in Task Groups
Authors: Sell Jane , Knottnerus J. David , Adcock‐Azbill Christina
Published: July 2012

Objective

This research addresses the effect of interruptions on task groups; interactions and individual group members’ feelings about the task and the group itself. The interruptions that we consider are not generated from within the group, but have their source outside the group. Emphasizing the theories of structural ritualization, relational cohesion, and productive exchange, we predict that interruptions that have positive, negative, or neutral effects on the group all cause problems with the resolution of routine.

Methods

We design and conduct a four‐condition experiment to test our predictions.

Results

There was more stability in group procedures when there was no interruption than when there was any kind of interruption. There were no differences in efficiency or activities between positive and negative interruptions. However, there were more agreements in positive interruption groups than in negative interruption groups. Additionally, group members’ perceptions varied by the type of interruption: those in positively interrupted groups reported higher levels of competence and feelings of success.

Conclusions

We find that interruption, in and of itself, creates problems with resumption of group processes. Whether the interruption is positive or negative, however, does create interaction differences and differences in group members’ perceptions and affect related to the group and each other.
The Foreclosure Crisis and Crime: Is Housing‐Mortgage Stress Associated with Violent and Property Crime in U.S. Metropolitan Areas?
Authors: Jones Roderick W. , Pridemore William Alex
Published: July 2012

Objective

The objective of this study was to determine if the housing‐mortgage stress caused by the foreclosure crisis is associated with violent and property crime in U.S. metropolitan areas.

Method

Using a sample of 142 metropolitan statistical areas and controlling for other structural factors thought to be associated with urban violence rates, we employ weighted least squares regression to estimate the association between the Housing‐Mortgage Stress Index (HMSI) and six serious crimes: homicide, robbery, aggravated assault, burglary, larceny, and motor vehicle theft.

Results

Our results showed no evidence of an association between the HMSI and any of the crime rates.

Conclusions

Despite anecdotal evidence of and growing fear that the foreclosure crisis was accompanied by increasing crime rates in cities hardest hit by the foreclosure crisis, we found no evidence that metropolitan areas with higher levels of housing‐mortgage stress had higher rates of violent or property crime.
Commentary: Biopolitical injustice and contemporary capitalism
Authors: Benson Peter
Published: July 2012

How is big industry linked to rising obesity in the United States? This issue is tangentially explored in the article that I consider. My commentary expands on this point to apprehend the role of corporations and industries in producing and profiting from population health problems. Taking the cases of obesity and cigarette smoking together, I examine how corporations claim social‐responsibility values as a strategic means of forestalling criticism and protecting their markets while shifting accountability for the risks and harms that are related to consumption onto consumers themselves. These dynamics reveal the centrality of biopolitical injustice to the workings of contemporary capitalism.
Accidents of equity and the aesthetics of Chinese offshore incorporation
Authors: Maurer Bill , Martin Sylvia J.
Published: July 2012

The British Virgin Islands is second only to Hong Kong as a source for foreign investment into China. Over the past two decades or so, Chinese entrepreneurs have demonstrated a preference for incorporating in the offshore finance centers of the Caribbean. Chinese offshore structures are different from earlier uses of the offshore in their unique and seemingly transparent aesthetic form. We show how equity—a legal argument and tradition that moderates the letter of the law—and these structures mutually engage one another through spatiotemporal reference and framing. We argue that this engagement is accidental, a coincidence of aesthetic form rather than an emergent phenomenon of any larger process or the product of a plan. It is also not a contingent articulation of compatible elements from the corporate and legal domains. In exploring the aesthetics of Chinese offshore incorporation and court cases that invoke equity, we argue that the accidental discovery of equity can reorient certain analytical conceits about capital and how we can know it.