bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuropeptide Y (NPY) metabolism by endopeptidase‐2 hinders characterization of NPY receptors in rat kidney
Authors: Price J.S. , Kenny A.J. , Huskisson N.S. , Brown M.J. 
Published: July 2012

Despite the observation of pharmacological responses to neuropeptide Y (NPY) in mammalian kidneys, there are species differences in the ease with which specific NPY binding sites can be demonstrated; we have investigated whether this can be explained by differential metabolism of NPY by a membrane‐bound peptidase.
NPY receptors were identified on cell membranes isolated from the rabbit kidney (KD = 97 ± 16 pm, Bmax = 290 ± 30 fmol mg−1protein), and this preparation did not degrade [125I]‐NPY. However, a similar preparation of cell membranes from the rat kidney exhibited a much lower apparent receptor affinity (IC50 approximately 30 nm); these membranes rapidly degraded [125I]‐NPY to fragments which did not bind NPY receptors in either tissue.
[125I]‐NPY binding sites were revealed in the rat kidney when degradation was inhibited by insulin B chain. Chelating agents also inhibited degradation, but interfered with receptor binding. Binding sites could not be demonstrated in sections of rat kidney, even in the presence of insulin B chain.
The difference in degradative activity between rat and rabbit renal cell membranes, inhibition of degradation by chelating agents and insulin B chain, and insensitivity to phosphoramidon suggest that the enzyme responsible was endopeptidase‐2, and this was confirmed by comparing the hydrolysis of [125I]‐NPY by purified enzyme with rat renal tissue. Activity of this enzyme explains the difficulties encountered demonstrating receptors in the rat kidney.
Renal cell membranes from the mouse digested [125I]‐NPY in a similar manner and this may be due to the closely related enzyme, meprin. NPY degradation has not previously been reported. The results suggest that NPY should be added to the list of peptides sensitive to these enzymes.
The relationship of KCl‐ and prostaglandin F2α‐mediated increases in tension of the porcine coronary artery with changes in intracellular Ca2+measured with fura‐2
Authors: Balwierczak Joseph L. 
Published: July 2012

Changes in intracellular free Ca2+concentration ([Ca2+]i) were measured simultaneously with changes in muscle tension by use of the fluorescent Ca2+indicator, fura‐2, in coronary arterial rings of the Pig.
Changes in [Ca2+]i were measured by monitoring the ratio of fluorescence due to excitation at 340 nm (F340) to that at 380 nm (F380).
Increases in tension of the porcine coronary artery induced by prostaglandin F2α (PGF2α) (2–30 μm) and KCl (25–70 mm) were accompanied by increases in the F340/F380 fluorescence ratio of fura‐2.
KCl‐induced increases in muscle tension, equivalent to those produced by PGF2α, were observed to occur in the presence of a higher [Ca2+]i.
Nearly complete relaxation of KCl‐induced contractions by sodium nitroprusside (SNP) was accompanied by only a partial reversal of the increase in [Ca2+]i that occurred during contraction.
Complete relaxation of the PGF2α‐contracted coronary artery by cromakalim (BRL 34915) was accompanied by a nearly complete reversal of the increase in [Ca2+]i caused by the contractile agent.
The contractile state of smooth muscle is not an indicator of [Ca2+]i. The [Ca2+]itension relationship is dependent upon the type of pharmacological agent that is used to change muscle tension.
Inhibition of the tocolytic activity of atrial natriuretic factor by progesterone and potentiation by progesterone receptor antagonist RU486 in rats
Authors: Potvin W. , Mulay S. , Varma D.R. 
Published: July 2012

The influence of progesterone on the activity of atrial natriuretic factor (ANF) on rat myometrial motor activity was determined in vitro.
ANF inhibited the tension development by myometrium from cycling or oestrogen‐treated rats in a dose‐dependent manner; maximal inhibition was 100%.
Injections of progesterone into rats inhibited the tocolytic activity of ANF in a dose‐ and time‐dependent manner. The tocolytic effects of ANF were completely abolished by 3 daily injections of 1 mg kg−1progesterone.
Pregnancy‐related increase in plasma progesterone was accompanied by a corresponding decrease in the tocolytic effects of ANF; myometria from gestational day 10 to 21 were completely refractory and those from earlier gestational age and immediate postpartum were responsive to ANF to varying degrees.
Treatment of pregnant rats with the progesterone antagonist, RU486, caused abortions and vaginal bleeding, decreased plasma progesterone concentrations and restored the tocolytic activity of ANF. Tocolytic activity of ANF on virgin rat myometria was potentiated by RU486.
Progesterone also inhibited the effects of ANF on myometria from ovariectomzed rats.
Tocolytic activity of isoprenaline was not modified by progesterone, pregnancy, RU486 or ovariectomy.
It is concluded that progesterone antagonizes myometrial effects of ANF by an oestrogen‐independent mechanism and the pregnancy‐induced refractoriness to the tocolytic effects of ANF is caused by progesterone.
Adenosine receptors and nucleoside transport sites in cardiac cells
Authors: Parkinson F.E. , Clanachan A.S. 
Published: July 2012

Potential mechanisms responsible for the prominent depression of atrioventricular conduction by adenosine have been investigated in guinea‐pig heart.
Adenosine A1 receptors and nucleoside transport (NT) sites were identified and enumerated in cardiac myocytes, atrioventricular conduction cells and coronary endothelial cells in 10 μm sections by autoradiographical analysis of the binding of the A1 selective antagonist 8‐cyclopentyl‐1,3‐[3H]‐dipropylxanthine ([3H]‐DPCPX) and the NT ligand [3H]‐nitrobenzylthioinosine ([3H]‐NBMPR), respectively.
Atrioventricular conduction cells were identified by acetylcholinesterase histochemistry and endothelial cells by von Willebrand factor immunohistochemistry.
Site‐specific binding of [3H]‐DPCPX, when expressed as grains per cell nucleus was significantly higher (30 fold) in conduction cells than in surrounding myocytes. [3H]‐DPCPX site density on endothelial cells in adjacent coronary vessels was not significantly different from myocytes.
In contrast, autoradiography of [3H]‐NBMPR sites in these areas indicated that, relative to myocytes, conduction cells and endothelial cells were significantly enriched (2 fold and 4.5 fold, respectively) in NT sites.
The pronounced dromotropic effect of adenosine in guinea‐pig heart is correlated with a higher density of adenosine A1 receptors in atrioventricular conduction cells than in myocytes. The NT capacity of these cells, as estimated by [3H]‐NBMPR binding site density, is not increased in proportion to A1 receptors.
Comparison of the electrophysiological effects of Org 7797, disopyramide, mexiletine and propafenone in anaesthetized dogs with myocardial infarcts
Authors: Campbell J.K. , Marshall R.J. , Winslow E. 
Published: July 2012

The electrophysiological effects of intravenously administered Org 7797 were compared with those of disopyramide (class Ia), mexiletine (Ib) and propafenone (Ic) in anaesthetized dogs with 5–6 day‐old left ventricular myocardial infarcts.
Org 7797 (0.5 mg kg−1) slowed conduction at all levels of the myocardium as shown by increases in St‐A, AH, HV and QRS intervals, very modestly prolonged atrial and ventricular refractory periods and slightly shortened ventricular repolarization. Sinus node recovery time was increased whilst the RR interval was unchanged. A higher dose (2 mg kg−1) prolonged RR and rendered 5 out of 8 dogs unable to follow an atrial pacing stimulus of mean cycle length 322 ms.
Electrophysiological changes induced by propafenone (2 mg kg−1) were qualitatively similar to those of Org 7797 (0.5 mg kg−1).
Electrophysiological changes induced by mexiletine (2 mg kg−1) were small or insignificant. The most noticeable effect was a modest increase in the St‐A interval and a slight shortening of ventricular repolarization. A higher dose (8 mg kg−1) additionally slowed conduction in the His‐Purkinje system and in the ventricular myocardium.
Disopyramide (2 and 5 mg kg−1) prolonged all cardiac intervals including JTc, QTc and QT during pacing and prolonged cardiac refractory periods.
It was concluded that the electrophysiological profile of Org 7797 is more like that of the Ic agent propafenone than that of the class Ia and Ib drugs, disopyramide and mexiletine.
The presence of five cyclic nucleotide phosphodiesterase isoenzyme activities in bovine tracheal smooth muscle and the functional effects of selective inhibitors
Authors: Shahid Mohammed , van Amsterdam Ronald G.M. , de Boer Jacob , ten Berge Ronald E. , Nicholson C David , Zaagsma Johan 
Published: July 2012

The profile of cyclic nucleotide phosphodiesterase (PDE) isoenzymes and the relaxant effects of isoenzyme selective inhibitors were examined in bovine tracheal smooth muscle. The compounds examined were the non‐selective inhibitor 3‐isobutyl‐1‐methylxanthine (IBMX), zaprinast (PDE V selective), milrinone and Org 9935 (4,5‐dihydro‐6‐(5,6‐dimethoxy‐benzo[b]thien‐2‐yl)‐5‐methyl‐1(2H)‐pyridazinone; both PDE III selective), rolipram (PDE IV selective) and Org 30029 (N‐hydroxy‐5,6‐dimethoxy‐benzo[b]‐thiophene‐2‐carboximidamide HCl a dual PDE III/IV inhibitor).Ion exchange chromatography showed three main peaks of PDE activity. The first peak was stimulated by Ca2+/calmodulin (PDE I), the adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) hydrolytic activity of the second peak was stimulated by guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) (PDE II) whilst that of the third peak was not significantly modified by any regulator (PDE IV). Calmodulin affinity chromatography revealed the additional presence of cyclic GMP‐specific PDE (PDE V) in the first peak. A clearly distinct peak of cyclic GMP‐inhibited PDE (PDE III) was not observed. However, Org 9935 inhibited the third activity peak more effectively in the presence, than in the absence, of rolipram (3 μmol l−1), indicating the presence of PDE III activity.Rolipram was the most potent inhibitor of PDE IV. The mean −log50IC50values for rolipram, IBMX, milrinone, Org 30029, Org 9935 and zaprinast were 5.9 ± 0.1, 4.9 ± 0.1, 4.7 ± 0.1, 4.6 ± 0.1 and 4.6 ± 0.1, respectively.Rolipram was a potent relaxant of both histamine (1 μmol1−1) and methacholine (0.03 μmol1−1) precontracted preparations; (pD2values; histamine 7.1 ± 0.1, methacholine 6.8 ± 0.2 and 4.5 ± 0.1, biphasic relaxation). IBMX also relaxed all preparations (pD2values; histamine 5.6 ± 0.1, methacholine 5.6 ± 0.1) whilst zaprinast (pD2values; histamine 5.2 ± 0.1, methacholine 4.4 ± 0.3), milrinone (pD2values; histamine 5.2 ± 0.1, methacholine 4.3 ± 0.3) and Org 9935 (pD2values; histamine 4.1 ± 0.1, methacholine 4.1 ± 0.2) did not completely relax preparations at concentrations up to 100 μmol1−1. Org 30029 (pD2values; histamine 6.2 ± 0.1, methacholine 5.4 ± 0.1) was a more effective relaxant than can be explained on the basis of PDE IV inhibition alone.We conclude that bovine tracheal smooth muscle contains five distinct PDE isoenzymes. PDE IV appears to be more important in the modulation of tissue function than PDE III and PDE V.
Thermogenic and lipolytic effect of yohimbine in the dog
Authors: Galitzky Jean , Vermorel Michel , Lafontan Max , Montastruc Paul , Berlan Michel 
Published: July 2012

Lipid mobilization during a hypocaloric diet may be enhanced by a pharmacological approach using α2‐adrenoceptor antagonists since these drugs are known to increase sympathetic tone and stimulate lipolysis. Studies were undertaken in the dog in order to evaluate the effects of oral yohimbine administration (α2‐adrenoceptor antagonist) on heat production, metabolic, endocrinological and cardiovascular parameters.
Acute oral yohimbine (0.25 or 0.40 mg kg−1) provoked an increase in plasma non‐esterfied fatty acids. The drug increased sympathetic nervous system activity as indicated by the increased level of plasma noradrenaline. These effects persisted during the entire experimental period (4 h). The increase in plasma noradrenaline level was two fold higher with the higher dose of yohimbine (0.4 mg kg−1). The plasma adrenaline level was increased only with the higher dose.
Yohimbine transiently increased plasma insulin and the effect was dose‐dependent.
Yohimbine (0.25 mg kg−1) enhanced heart rate and arterial blood pressure.
The effect of yohimbine on oxygen consumption, carbon dioxide and heat production was determined by indirect calorimetry. The drug (0.25 mg kg−1) increased O2 consumption and CO2 and heat production 30 min after its administration and the effect persisted over the experimental period. The respiratory quotient, rather low in the fasting animals, remained unchanged.
The present work indicates that thermogenesis and lipid mobilization are enhanced during fasting in the dog by α2‐adrenoceptor blockade. Yohimbine also induced a transient increase in plasma insulin level and increased heart rate and blood pressure. The lipid mobilization plus the action on thermogenesis observed after yohimbine draw attention to the putative interest of α2‐antagonists in the pharmacological treatment of obesity during restricted calorie intake.
Alkaline phosphatase prevents platelet stimulation by thromboxane‐mimetics
Authors: Hatmi Mohamed , Haye Bernard , Gavaret J. Michel , Vargaftig B. Boris , Jacquemin Claude 
Published: July 2012

The effects of alkaline phosphatase on platelet aggregation, secretion and thromboxane B2 (TxB2) generation induced by the full dose‐range of common platelet agonists were studied in human platelet‐rich plasma and washed platelets.
Platelet aggregation and adenosine 5′‐triphosphate (ATP) secretion induced by threshold and supramaximal concentrations of arachidonate and stable TxA2 and prostaglandin endoperoxide‐mimetics (compounds U46619 and EP171) were abolished in the presence of alkaline phosphatase (0.5–1 u ml−1), even though the synthesis of TxB2 persisted. In contrast, platelet aggregation by PAF‐acether and by supramaximal concentrations of thrombin as well as the primary wave of aggregation by adenosine diphosphate (ADP) and adrenaline were unaffected by alkaline phosphatase under conditions where the secondary wave of aggregation by ADP was blocked.
Alkaline phosphatase, unlike prostacyclin, failed to raise the adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) content of the platelets. Also, the pretreatment of platelets by inorganic phosphate or by ATP plus creatine phosphate/creatine phosphokinase reversed the inhibitory effect of alkaline phosphatase.
Experiments performed in the guinea‐pig in vivo showed that alkaline phosphatase was effective on thrombocytopenia induced by arachidonate.
Our results provide the first direct evidence for a specific inhibitory effect of alkaline phosphatase at a site sensitive to TxA2 and prostaglandin endoperoxides and suggest that its phosphorylation/dephosphorylation state may play an important role in modulating platelet activation. These results also suggest the presence of ecto‐protein kinases on membrane platelets.
Adenine nucleotide‐induced inhibition of binding of sulphonylureas to their receptor in pancreatic islets
Authors: Schwanstecher M. , Löser S. , Brandt Ch. , Scheffer K. , Rosenberger F. , Panten U. 
Published: July 2012

The effects of the Mg complex of adenosine 5′‐triphosphate (MgATP) on binding of sulphonylureas to microsomes obtained from mouse pancreatic islets were examined.
MgATP inhibited the binding of both glibenclamide and tolbutamide to microsomes.
Binding of [3H]‐glibenclamide inhibited by MgATP was not further diminished by Mg2+‐bound adenosine 5′‐(β,γ‐imidotriphosphate) (AMP‐PNP) or free adenosine 5′‐diphosphate (ADP). Higher concentrations of MgAMP‐PNP induced a partial reversal of the inhibitory effect of MgATP on [3H]‐glibenclamide binding.
The apparent dissociation constant (K'D) for binding of [3H]‐glibenclamide remained constant when the MgATP concentration was increased from 100 to 500 μm.
Extracellular ADP did not markedly stimulate insulin release from mouse pancreatic islets.
It is concluded that sulphonylureas and cytosolic nucleotides exert their inhibitory effects on the K‐ATP‐channels of β‐cells by binding to different sites. The binding properties of the sulphonylurea receptor seem to be modulated by protein phosphorylation.
Sympathoinhibitory effects of rilmenidine may be mediated by sites located below the brainstem
Authors: Sannajust Frédéric , Barrès Christian , Koenig‐Bérard Elisabeth , Sassard Jean 
Published: July 2012

To determine the site of action of rilmenidine, we examined its effects on arterial blood pressure (BP), heart rate (HR) and postganglionic renal sympathetic nerve activity (RSNA) after intracerebroventricular (i.c.v.) administration (300 μg kg−1), in groups (all n = 6) of conscious and freely moving, pentobarbitone‐anaesthetized and pentobarbitone‐anaesthetized and spinally transected, fifteen week‐old male spontaneously hypertensive rats (SHRs).
In conscious SHRs, which exhibited a low sympathetic nerve activity (RSNA: 3.4 ± 0.9 μV), rilmenidine was inactive on systolic BP (SBP), diastolic BP (DBP), HR and RSNA.
In intact pentobarbitone‐anaesthetized SHRs, which exhibited an elevated sympathetic nerve activity (RSNA: 10.6 ± 0.9 μV), rilmenidine exerted potent antihypertensive (ΔSBP: −37 ± 4%; ΔDBP: −43 ± 6%), bradycardic (ΔHR: −32 ± 3%) and sympathoinhibitory (ΔRSNA: −68 ± 9%) activities.
In pentobarbitone‐anaesthetized SHRs with cervical spinal cord transection, BP was markedly decreased and sympathetic nerve activity (RSNA: 10.3 ± 3.1 μV) returned to the level observed in conscious SHRs (RSNA: 3.6 ± 0.5 μV). In these conditions, rilmenidine remained sympathoinhibitory (ARSNA: −74 ± 5%).
In conclusion, we have shown that pentobarbitone‐anaesthesia enhances the peripheral sympathetic tone by a central action, as the spinal cord transection allows RSNA to return to normal levels and that, spinal or ganglionic structures could be a major site of the sympathoinhibitory action of rilmenidine.
Influence of anaesthesia on the cardiovascular effects of rilmenidine and clonidine in spontaneously hypertensive rats
Authors: Sannajust Frédéric , Cerutti Catherine , Koenig‐Bérard Elisabeth , Sassard Jean 
Published: July 2012

The acute cardiovascular effects of two α2‐adrenoceptor agonists, rilmenidine and clonidine, were studied in 15‐week‐old male spontaneously hypertensive rats (SHRs). The effects of these drugs were compared with intravenous (i.v.) and intracerebroventricular (i.c.v.) administration in conscious and pentobarbitone‐anaesthetized SHRs, in which aortic blood pressure (BP) was continuously recorded.
In conscious SHRs, i.v. doses of either rilmenidine (30, 100, 300 μg kg−1) or clonidine (3, 10, 30 μg kg−1) induced dose‐dependent short‐lasting increases in BP followed by moderate decreases associated with bradycardia, while the same three doses of both drugs given i.c.v. were devoid of BP and heart rate (HR) effects.
Pentobarbitone‐anaesthesia increased the sympathetic control of BP and suppressed the cardiac baroreflex sensitivity.
In anaesthetized SHRs, i.v. injections of the same 3 doses of rilmenidine and clonidine induced a slight increase in BP, rapidly followed by profound and long‐lasting BP and HR decreases. Surprisingly, when given i.c.v., these 3 doses lowered BP and HR to the same extent but in a more progressive manner.
The lack of efficacy of both drugs in conscious SHRs after the i.c.v. administration of i.v. active doses and the lack of more marked and rapid effects in anaesthetized SHRs, after i.c.v. than after i.v. injections, question the involvement of a major central site of action for these antihypertensive α2‐adrenoceptor agonists. Moreover, these results show that the cardiovascular effects of these drugs are profoundly influenced by baseline sympathetic nervous system activity which is enhanced by pentobarbitone‐anaesthesia.
CI988, a selective antagonist of cholecystokininB receptors, prevents morphine tolerance in the rat
Authors: Xu X.‐J. , Wiesenfeld‐Hallin Z. , Hughes J. , Horwell D.C. , Hökfelt T. 
Published: July 2012

The effect of chronic treatment with CI988, a recently developed selective antagonist of cholecystokinin type‐B receptors (CCKB receptors) on the tolerance to morphine analgesia was studied in rats with the hot plate test.
Morphine tolerance was induced with the use of two paradigms. Morphine was injected i.p. either in a schedule of increasing doses (1–32 mg kg−1) twice daily for 6 days or at a fixed dose (3 mg kg−1) daily for 29 days.
In both series of experiments, tolerance to the analgesic effect of morphine was prevented by simultaneous treatment with i.p. CI988. Chronic treatment with only CI988 daily for up to 29 days did not reduce the analgesic effect of a weekly injection of morphine.
CI988 did not diminish the physical dependence to morphine, as examined with naloxone precipitated withdrawal.
The present results provide evidence that chronic treatment with a selective CCKB receptor antagonist could prevent tolerance to the analgesic effect of morphine without affecting morphine‐induced physical dependence. Application of CCK antagonists may be clinically important in treating chronic pain patients by preventing morphine tolerance and by eliminating the need to increase morphine doses to unacceptable levels.
Pharmacological and histological examinations of regional differences of guinea‐pig lung: a role of pleural surface smooth muscle in lung strip contraction
Authors: Wong Wai‐shiu Fred , Bloomquist Shari L. , Bendele Alison M. , Fleisch Jerome H. 
Published: July 2012

Parenchymal lung strip preparations have been widely used as an in vitro model of peripheral airway smooth muscle. The present study examined functional responses of 4 consecutive guinea‐pig lung parenchymal strips isolated from the central region (segment 1) to the distal edge (segment 4) of the lower lung lobe. The middle two segments were designated as segments 2 and 3.
Lung segments 1 and 4 exhibited significantly greater contraction than the other 2 segments to KCl when responses were expressed as mg force per mg tissue weight. Contractile responses to bronchospastic agents including histamine, carbachol, endothelin‐1, leukotrienes (LT) B4 and D4, and the thromboxane A2‐mimetic U46619 demonstrated no significant difference in EC50 values among the 4 lung segments.
Contractile responses of segments 1 and 4 to antigen‐challenge (ovalbumin), ionophore A23187 and substance P were significantly greater than the other 2 segments with respect to either sensitivity or maximum responsiveness.
U46619‐induced contractions of the 4 lung segments were relaxed in similar manner by papaverine and theophylline up to 100%, salbutamol up to 80%, and sodium nitroprusside by only 20%. In contrast, sodium nitroprusside markedly reversed U46619‐induced contraction of pulmonary arterial rings and bronchial rings.
Histological studies identified 2–4 layers of smooth muscle cells underlying the lung pleural surface. Mast cells were prominent in this area. Moreover, morphometric studies showed that segment 4 possessed the least amount of smooth muscle structures from bronchial/bronchiolar wall and vasculatures as compared to the other 3 segments, and a significant difference in this respect was evident between segment 1 and segment 4.
Since lung segments 1 and 4 are covered with larger surface area of lung pleura, the present results suggest that the significantly greater intrinsic contractile responses of segments 1 and 4 are associated with the presence of increased lung pleural surface possibly together with more mast cells. Thus, a primary contribution to the net contraction of the lung parenchymal strips may be smooth muscle from the lung pleura, alveolar ducts and interstitial contractile cells rather than from bronchi/bronchioles and micro‐vasculatures.