bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel kainate derivatives: potent depolarizing actions on spinal motoneurones and dorsal root fibres in newborn rats
Authors: Ishida M. , Shinozaki H. 
Published: July 2012

Neuropharmacological actions of several kainate derivatives (kainoids) were examined for electrophysiological effects in the isolated spinal cord and the dorsal root fibre of the newborn rat.
Some kainoids caused depolarization of the motoneurone much more effectively than kainic acid or domoic acid and others were weaker. The rank order of the depolarizing activities of the kainoids tested here is as follows: 4‐(2‐methoxyphenyl)‐2‐carboxy‐3‐pyrrolidineacetic acid (MFPA) > acromelic acid A > domoic acid ≧ 4‐(2‐hydroxyphenyl)‐2‐carboxy‐3‐pyrrolidineacetic acid (HFPA) ≧ acromelic acid B > kainic acid.
In the isolated dorsal root fibre, domoic acid caused the most significant depolarization. There were distinct differences with regard to the rank order of the depolarizing activity between the motoneurone and the dorsal root fibre. The rank order in the dorsal root fibre is domoic acid > acromelic acid B > 5‐bromowillardiine ≧ MFPA > acromelic acid A > HFPA > kainic acid.
Significant desensitization of kainate receptors was observed in the isolated dorsal root fibre during prolonged application of l‐glutamate, kainate and its derivatives. Cross desensitization was also observed among these excitatory amino acids. Receptors desensitized by kainate did not respond to MFPA, HFPA and acromelic acids, suggesting that these kainate derivatives activated common kainate receptors in the dorsal root fibre.
In both motoneurones and dorsal root fibres, 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) effectively depressed the depolarization induced by kainoids, and neither 3‐[(±)‐2‐carboxypiperazin‐4‐yl]propyl‐1‐phosphonic acid (CPP) nor picrotoxin blocked or affected the depolarization, but there were some differences in pharmacological potencies of glutamate antagonists between both preparations.
MFPA, HFPA and acromelic acids should provide valuable pharmacological tools for analysis of physiological functions of excitatory amino acids, in particular, as specific agonists for some subtypes of kainate receptors.
Chronic treatment with the angiotensin I converting enzyme inhibitor, perindopril, protects in vitro carbachol‐induced vasorelaxation in a rat model of vascular calcium overload
Authors: Henrion Daniel , Chillon Jean‐Marc , Capdeville‐Atkinson Christine , Vinceneux‐Feugier Marion , Atkinson Jeffrey 
Published: July 2012

Treatment of young rats with vitamin D3 plus nicotine produced 31 and 4 fold increases in the calcium content of the aorta and the mesenteric arterial bed, respectively.
Aortic rings and perfused mesenteric arterial beds from vitamin D3/nicotine‐treated animals showed a diminished contractile response to noradrenaline in vitro.
In vascular preparations from vitamin D3/nicotine‐treated animals, precontracted with noradrenaline, relaxation by the endothelium‐dependent vasodilator, carbachol, was attenuated but responses to sodium nitroprusside were not modified.
Prolonged treatment with the angiotensin I converting enzyme inhibitor, perindopril, at a dose (1 mg kg−1) which did not significantly modify blood pressure, failed to prevent vascular calcium overload.
Perindopril treatment diminished noradrenaline‐evoked vasoconstrictor responses of aortic rings in both groups, but restored responses in mesenteric arterial beds of vitamin D3/nicotine‐treated rats.
Perindopril treatment also restored the maximal responses to carbachol of both aortic rings and mesenteric arterial beds of vitamin D3/nicotine‐treated rats.
In conclusion, in the vitamin D3 plus nicotine model of calcium overload, reduced endothelial‐mediated relaxation can be prevented by perindopril treatment.
Characterization of the effects of the new inotropic agent BDF 9148 in isolated papillary muscles and myocytes of the guinea‐pig heart
Authors: Ravens Ursula , Wettwer Erich , Pfeifer Thomas , Himmel Herbert , Armah Benjamin 
Published: July 2012

The cardiotonic agent BDF 9148 (4‐[3′‐(1″‐benzhydryl‐azetidine‐3″‐oxy)‐2′‐hydroxypropoxy]‐1H‐indole‐2‐carbonitrile) is structurally related to DPI 201‐106 (4‐[3′‐(4″‐benzhydryl‐1″‐piperazinyl)‐2′‐hydroxypropoxy]‐1H‐indole‐2‐carbonitrile) which is known to modify cardiac sodium channels. In guinea‐pig papillary muscles, both compounds increase force of contraction with similar concentration‐response curves. Like DPI 201‐106, BDF 9148 prolongs the action potential duration in a tetrodotoxin‐sensitive manner. With high concentrations (> 3 μm), however, the action potential duration shortens again. In order to elucidate the underlying changes in membrane currents, we have investigated the effects of BDF 9148 in isolated ventricular myocytes of the guinea‐pig heart.
In isolated cells, a concentration of 1 μm BDF 9148 prolonged the action potential duration and markedly enhanced unloaded cell shortening, indicating that the procedure of cell isolation does not abolish the effect of the drug.
Membrane currents were studied with the single electrode voltage clamp technique. With clamp steps from −80 mV to −40 mV, BDF 9148 (1 μm) induced a slowly decaying inward current which was suppressed by tetrodotoxin. Therefore, like DPI 201‐106, BDF 9148 slows the inactivation of the sodium channels.
In order to quantify the effects of BDF 9148 and DPI 201‐106 on sodium current inactivation, we have measured the inward current amplitude still present at 100 ms after a depolarizing clamp step from −80 mV to −30 mV. Both drugs increased this current component in a concentration‐dependent manner; however, BDF 9148 had a larger effect in the low concentration range.
The calcium current was inhibited by BDF 9148 and DPI 201‐106 in a concentration‐dependent manner; the pD2 values were 5.70 and 5.95, respectively.
The two compounds are thought to produce similar positive inotropic effects by imposing a sodium load on the muscle cells via modification of the sodium channels. The differences in action potential duration could be due to different contributions of ionic currents other than sodium or calcium currents and of pump and exchange currents. At present, there is not sufficient data to identify clearly distinct current components responsible for the differences in action potential prolongation.;
Amelioration of cisplatin‐induced acute renal failure with 8‐cyclopentyl‐1,3‐dipropylxanthine
Authors: Knight R.J. , Collis M.G. , Yates M.S. , Bowmer C.J. 
Published: July 2012

The effect of the selective adenosine A1‐receptor antagonist, 8‐cyclopentyl‐1,3‐dipropylxanthine (CPX), on the development of cisplatin‐induced acute renal failure was investigated in the rat.
CPX at doses of 0.03, 0.1 and 0.3 mg kg−1, i.v. caused increasing degrees of antagonism of adenosine‐induced bradycardia in anaesthetized rats. The magnitude of antagonism was not directly proportional to the increment in dose, but for each dose, it was similar in rats injected with either saline or cisplatin. CPX at a dose of 0.03 mg kg−1 significantly antagonized adenosine‐induced bradycardia for up to 2.5 h, while doses of 0.1 and 0.3 mg kg−1 produced significant blockade for periods longer than 5 h.
Administration of cisplatin (6 mg kg−1, i.v.) caused acute renal failure characterized by decreased inulin and p‐aminohippurate clearances, increased urine volume but decreased excretion of Na+, K+ and Cl− ions and by increased plasma levels of urea and creatinine. Kidney weight was increased in cisplatin‐treated rats and renal tubule necrosis occurred.
Administration of CPX (0.03 mg kg−1, i.v.; twice daily for two days) to rats given cisplatin did not reduce the severity of the resultant renal failure. However, treatment with 0.1 mg kg−1 CPX attenuated the increases in plasma creatinine/urea levels observed in rats on days 3 and 7 after induction of renal failure. In addition, this dose significantly reduced renal tubule damage and increased inulin and p‐aminohippurate clearances. A similar pattern of protection was noted with CPX at a dose of 0.3 mg kg−1 although the increase in inulin clearance was not statistically significant. However, this higher dose of CPX significantly increased Na+ and K+ excretion compared to vehicle‐treated rats.
CPX at doses of 0.03, 0.1 and 0.3 mg kg−1 produced blockade of an A1‐receptor mediated response i.e. adenosine‐induced bradycardia, but only treatment with the higher doses of CPX (0.1 and 0.3 mg kg−1) ameliorated nephrotoxicity produced by cisplatin. The lack of any protective effect afforded by the lowest dose of CPX could be a result of its shorter duration of action.
This study indicates that adenosine plays a significant role in the pathophysiology of cisplatin‐induced acute renal failure.;
Evidence that epithelium‐dependent relaxation of vascular smooth muscle detected by co‐axial bioassays is not attributable to hypoxia
Authors: Spina D. , Fernandes L.B. , Preuss J.M.H. , Hay D.W.P. , Muccitelli R.M. , Page C.P. , Goldie R.G. 
Published: July 2012

The present study was undertaken to examine further the contribution of hypoxia to airway epithelium‐dependent relaxation of rat aorta in the co‐axial bioassay.
Endothelium‐denuded rat aorta contracted with phenylephrine (0.05 μm) relaxed in a time‐dependent manner (t½ = 8.3 ± 0.4 min, n = 38) when the bathing solution was bubbled with 95% N2 and 5% CO2. In co‐axial bioassays, the t½ for histamine (100 μm; guinea‐pig trachea)‐ and methacholine (100 μm; rabbit bronchus)‐ induced relaxation was 1.9 ± 0.2 min (n = 14) and 1.2 ± 0.1 min (n = 26), respectively.
Hypoxia‐induced relaxation was not associated with a rise in intracellular guanosine 3′:5′‐cyclic monophosphate (cyclic GMP). This contrasts with previous findings of an elevation in cyclic GMP associated with epithelium‐dependent relaxation of rat aorta in co‐axial bioassays.
Hypoxia‐induced vascular relaxation was antagonized by the ATP‐sensitive K+ channel blocker, glibenclamide (100 μm). In contrast, glibenclamide (100 μm) failed to inhibit histamine (100 μm; guinea‐pig trachea)‐ and methacholine (0.1–100 μm; rabbit bronchus)‐induced release of epithelium‐derived inhibitory factor (EpDIF), in co‐axial bioassays. Glibenclamide (100 μm) antagonized BRL 38227 (lemakalin), but not isoprenaline‐induced relaxation of phenylephrine‐contracted rat aorta.
These data strongly suggest that the airway epithelium‐dependent relaxant responses observed in co‐axial bioassays cannot be attributed to hypoxia.
Tachykininergic transmission to the circular muscle of the guinea‐pig ileum: evidence for the involvement of NK2 receptors
Authors: Bartho Lorand , Santicioli Paolo , Patacchini Riccardo , Maggi Carlo Alberto 
Published: July 2012

The effect of newly developed, receptor‐selective tachykinin antagonists (GR 71,251 for NK1 receptors, MEN 10,376 and L 659,877 for NK2 receptors) on noncholinergic transmission to the circular muscle of the guinea‐pig ileum has been investigated.
In circular muscle strips of the ileum, electrical field stimulation in the presence of atropine (2 μm) and apamin (0.1 μm) evoked a complex motor response. The tonic primary contraction in this response was reduced by GR 71,251 (10 μm) and MEN 10,376 (3–10 μm) but not by L 659,877 (up to 10 μm). The presence of apamin was necessary in this experimental arrangement to unmask an atropine‐resistant primary contraction, sensitive to tachykinin antagonists. The motor response was abolished by tetrodotoxin.
In circular strips of the ileum GR 71,251 (10 μm) inhibited the tonic contraction produced by [Sar9] substance P sulphone, a selective NK1 receptor agonist but not that produced by [β Ala8] neurokinin A (4–10), a selective NK2 receptor agonist. By contrast, MEN 10,376 antagonized the effect of the NK2 agonist while leaving the response to the NK1 agonist unaffected.
In whole segments of the ileum, distension of the gut wall by an intraluminal balloon placed at about 1 cm from the point of recording of mechanical activity of the circular muscle produced atropine‐sensitive phasic contractions (ascending enteric reflex). In the presence of atropine (2 μm), a noncholinergic response was elicited, which required larger volumes of distension that the cholinergic one. The atropine‐resistant ascending enteric reflex was enhanced by apamin (0.1 μm) and abolished by tetrodotoxin, either in the presence or absence of apamin.
MEN 10,376 (3–10 μm) inhibited the atropine‐resistant ascending enteric reflex in the presence of apamin while GR 71,251 or L 659,877 (10 μm each) were ineffective. MEN 10,376 inhibited the atropine‐resistant ascending enteric reflex to a larger extent in the absence than in the presence of apamin and also slightly inhibited the ascending enteric reflex in the absence of atropine.
These findings provide evidence for an involvement of NK2 tachykinin receptors in excitatory transmission to the circular muscle of the guinea‐pig ileum. NK2 receptors are also involved in the physiological‐like circular muscle activation produced by stimulation of intramural neuronal pathways which subserve the atropine‐resistant ascending enteric reflex.
Effect of α‐human atrial natriuretic peptide on the synthesis of dopamine in the rat kidney
Authors: Soares‐da‐Silva P. , Fernandes M. Helena 
Published: July 2012

The present study has examined the influence of α‐human atrial natriuretic peptide (α‐hANP) on the synthesis of dopamine and its deamination into 3,4‐dihydroxyphenylacetic acid (DOPAC) in rat kidney slices loaded with exogenous l‐dihydroxyphenylalanine (l‐DOPA).
α‐hANP (3.3 and 330 nm) was found to produce a marked reduction (63– 78% reduction) in the time‐dependent accumulation of newly‐formed dopamine and of its deaminated metabolite DOPAC in kidney slices loaded with 10 μm l‐DOPA. α‐hANP (330 nm) was also found to decrease the accumulation of newly‐formed dopamine (45– 66% reduction) and DOPAC (38– 61% reduction) in experiments in which increasing concentrations (1– 100 μm) of l‐DOPA were used. This inhibitory effect was found to be potentiated by zaprinast (M&B 22,948; 10 μm), a guanosine cyclic 3′,5′‐monophosphate (cyclic GMP) phosphodiesterase inhibitor. Alone, zaprinast also decreased the accumulation of both dopamine (54–71% reduction) and DOPAC (73– 92% reduction).
In kidney homogenates, α‐hANP (330 nm) was found to affect neither the formation of dopamine nor its deamination to DOPAC.
Both α‐hANP (330 nm) and zaprinast (10 μm) were found not to affect the formation of dopamine and DOPAC in kidney slices obtained from rats on a high salt diet during the previous 6 weeks. A similar situation was also found to occur when kidney slices obtained from 24‐months old rats were used.
The results obtained suggest that the inhibitory effect of α‐hANP on the renal synthesis of dopamine is dependent on the activation of a membrane‐operated mechanism, coupled to the enzyme guanylate cyclase, controlling the entry of l‐DOPA into the cells.
Direct and indirect stimulations of cyclic AMP formation in human brain
Authors: Kendall D.A. , Millns P.J. , Firth J.L. 
Published: July 2012

Adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) formation, by use of an [3H]‐adenine prelabelling assay, was measured in fragments of human cerebral cortex, taken in the course of various neurosurgical procedures.
Large accumulations of [3H]‐cyclic AMP due to isoprenaline, noradrenaline and adenosine and small effects due to forskolin were observed. Histamine, 5‐hydroxytryptamine (5‐HT) and the excitatory amino acids glutamate and quisqualate were ineffective.
The response to noradrenaline consisted of two components; a direct β‐adrenoceptor response and an enhancement mediated by an α.‐adrenoceptor which appears to be similar to that in rat cerebral cortex.
The response to isoprenaline was also potentiated by histamine H1 receptor stimulation but the direct effect of 2‐chloroadenosine was not altered by histamine, 5‐HT or quisqualate.
It is concluded that some, but not all, of the indirect modulations of cyclic AMP formation previously observed in experimental animal brain exist in human cerebral cortex.
Differences in neurokinin receptor pharmacology between rat and guinea‐pig superior cervical ganglia
Authors: Seabrook G.R. , Main M. , Bowery B. , Wood N. , Hill R.G. 
Published: July 2012

The depolarizations elicited by seven neurokinin receptor agonists were examined in both rat and guinea‐pig superior cervical ganglia by use of grease‐gap methodology in the presence of tetrodotoxin (0.1 μm). Responses were normalised with respect to 1 μm eledoisin.
The rank order of agonist potency in the rat ganglia was senktide > substance P > substance P methyl ester = eledoisin = Sar‐Met‐substance P > neurokinin B > neurokinin A, whereas in guinea‐pig superior cervical ganglion (SCG) the rank order was senktide > Sar‐Met‐substance P > neurokinin B = eledoisin = substance P methyl ester. The concentration‐effect curves for substance P and neurokinin A in guinea‐pig ganglia were biphasic which precluded the determination of meaningful potency values.
The maximal depolarization achieved by subtype selective ligands was different between these two species. On rat and guinea‐pig SCG, the NK3‐selective ligand, senktide, produced a maximal depolarization of 27% and 274% respectively, whereas the NK1‐selective ligand, substance P methyl ester, produced depolarizations of 77% and 64% respectively.
The depolarizations induced by substance P methyl ester and senktide in either species were unaffected by atropine (1 μm), suggesting a lack of involvement of presynaptic neurokinin receptors in the generation of the response.
The potency of substance P methyl ester, senktide, and neurokinin A were unaffected by pretreating ganglia with the peptidase inhibitors bacitracin (40 μg ml−1), leupeptin (4 μg ml−1), and chymostatin (2 μg ml−1). Similarly, these peptidase inhibitors had no effect on the maximal depolarizations achieved by any of these agonists.
It is evident that rat and guinea‐pig superior cervical ganglia possess both NK1 and NK3 receptors, but that their net contribution to depolarizations are different between the two species. The depolarizations in guinea‐pig SCG are mediated predominantly by an NK3 subtype and in rat SCG by an NK1 receptor subtype.
Studies on the cardiac actions of flosequinan in vitro
Authors: Gristwood R.W. , Beleta J. , Bou J. , Cardelús I. , Fernández A.G. , Llenas J. , Berga P. 
Published: July 2012

We have investigated the in vitro cardiac actions of flosequinan and of its major metabolite in man, BTS 53554.
Positive inotropic activity was seen with flosequinan in guinea‐pig isolated ventricles, the threshold concentration for effect being less than 1 × 10−5 m. BTS 53554 was approximately half as potent as the parent compound.
In guinea‐pig working whole hearts flosequinan increased left ventricular dp/dtmax, indicating a positive inotropic action. This effect was accompanied by increases in heart rate, cardiac output and stroke volume.
The virtual complete inhibition of inotropic responses to flosequinan and BTS 53554 by carbachol suggests that these responses are adenosine 3′:5′‐cyclic monophosphate (cyclic AMP)‐mediated.
Flosequinan was shown to increase calcium inward current in guinea‐pig ventricle, an action consistent with a cyclic AMP involvement in the response.
The inotropic activity of flosequinan was not potentiated by the selective phosphodiesterase (PDE) III inhibitor SK&F 94120, a result which indicates that flosequinan does not increase cyclic AMP concentrations via stimulation of adenylate cyclase.
Flosequinan inotropic responses were potentiated by rolipram, a selective PDE IV inhibitor, a result consistent with flosequinan being itself a PDE III inhibitor.
Biochemical studies with purified enzymes confirmed that flosequinan and BTS 53554 are relatively selective inhibitors of PDE III.
A comparison of pharmacological and biochemical data for both flosequinan and BTS 53554 indicates that their PDE III inhibitory potency is sufficient to account for their inotropic activity.
Ramipril prevents left ventricular hypertrophy with myocardial fibrosis without blood pressure reduction: a one year study in rats
Authors: Linz Wolfgang , Schaper Jutta , Wiemer Gabriele , Albus Udo , Schölkens Bernward A. 
Published: July 2012

Angiotensin converting enzyme (ACE)‐inhibitors have been demonstrated to be effective in the treatment of cardiac hypertrophy when used in antihypertensive doses. The aim of our one year study with an ACE‐inhibitor in rats was to separate local cardiac effects produced by a non‐antihypertensive dose from those on systemic blood pressure when an antihypertensive dose was used.
Rats made hypertensive by aortic banding were subjected to chronic oral treatment for one year with an antihypertensive dose of the ACE inhibitor, ramipril 1 mg kg−1 daily, (RA 1 mg) or received a low dose of 10 μg kg−1 daily (RA 10 μg) which did not affect high blood pressure.
Chronic treatment with the ACE‐inhibitor prevented left ventricular hypertrophy in the antihypertensive rats as did the low dose which had no effects on blood pressure. Similar effects were observed on myocardial fibrosis. Plasma ACE activity was inhibited in the RA 1 mg but not in the RA 10 μg group although conversion of angiotensin (Ang) I to Ang II in isolated aortic strips was suppressed in both treated groups. Plasma catecholamines were increased in the untreated control group, but treatment with either dose of ramipril normalized the values. The myocardial phosphocreatine to ATP ratio (an indicator of the energy state in the heart) was reduced in the vehicle control group whereas the hearts from treated animals showed a normal ratio comparable to hearts from sham‐operated animals.
After one year, five animals were separated from each group, treatment withdrawn, and housed for additional six months. In the RA 1 mg group, blood pressure did not reach the value of the control vehicle group and surprisingly, left ventricular hypertrophy and myocardial fibrosis did not recur in animals during withdrawal of treatment.
These data show that long term ACE inhibitor treatment with ramipril in antihypertensive and non‐antihypertensive doses prevented cardiac hypertrophy and myocardial fibrosis. This protective effect was still present after 6 months treatment withdrawal.
Phosphoramidon blocks big‐endothelin‐1 but not endothelin‐1 enhancement of vascular permeability in the rat
Authors: Lehoux Stéphanie , Plante Gérard E. , Sirois Martin G. , Sirois Pierre , D'Orléans‐Juste Pedro 
Published: July 2012

Changes in vascular permeability following intravenous injections of human big‐endothelin‐1 (big‐ET‐1) and endothelin‐1 (ET‐1) were measured by extravasation of Evans blue dye (EB, 20 mg kg−1) in selected tissues.
A low dose of big‐ET‐1 (40 pmol kg−1) failed to alter vascular permeability but a dose of 400 pmol kg−1 increased EB extravasation in the trachea, upper and lower bronchi, and lung parenchyma by 55 to 69% (P < 0.05). Vascular permeability was also enhanced in the liver, spleen, kidney, heart, and diaphragm by 20, 14, 41, 25, and 67%, respectively (P < 0.05).
Upon injection of ET‐1 (400 pmol kg−1), EB extravasation increased in the upper and lower bronchi, lung parenchyma, liver, pancreas, kidney, heart, and diaphragm.
Administration of ET‐1 and big‐ET‐1 was not associated with significant systemic responses.
Pretreatment with phosphoramidon (PA) blocked the response to big‐ET‐1 in all tissues examined but this inhibitor failed to alter the response to ET‐1.
We conclude from these results that the dose‐dependent increase in vascular permeability induced by big‐ET‐1 in various tissues follows its conversion to ET‐1 by the endothelin converting enzyme, a PA‐sensitive process.