bluuebunny/crossref_metadata_2025_split huggingface dataset:
Possible mechanism of the potent vasoconstrictor actions of ryanodine on femoral arteries from spontaneously hypertensive rats
Authors: Asano Masahisa , Kuwako Miho , Nomura Yukiko , Ito Kaoru M. , Ito Katuaki , Uyama Yoshiaki , Imaizumi Yuji , Watanabe Minoru 
Published: July 2012

The Ca2+ buffering function of sarcoplasmic reticulum (SR) in the resting state of arteries from spontaneously hypertensive rats (SHR) was examined. Differences in the effects of ryanodine that removes the function of SR, on tension and cellular Ca2+ level were assessed in endothelium‐denuded strips of femoral arteries from 13‐week‐old SHR and normotensive Wistar‐Kyoto rats (WKY).
The addition of ryanodine to the resting strips caused a concentration‐dependent contraction in SHR. This contraction was extremely small in WKY. In the presence of 10−5 m ryanodine, caffeine (20 mM) failed to cause a further contraction in SHR, but it caused a small contraction in WKY. After washout of the strips with a Krebs solution, the resting tone was greatly elevated in SHR when compared with WKY.
The elevated resting tone in SHR strips was abolished by 10−7 m nifedipine. The ryanodine‐induced contraction was also abolished by 10−7 m nifedipine. Nifedipine itself caused a relaxation from the resting tone of SHR strips, suggesting the maintenance of myogenic tone.
In strips preloaded with fura‐PE3, the addition of 10−5 m ryanodine caused a large and moderate elevation of cytosolic Ca2+ level ([Ca2+]i) in SHR and WKY, respectively. After washout, the resting [Ca2+]i was greatly elevated in SHR. The ryanodine‐induced elevation of [Ca2+]i was decreased by 5 × 10−6 m verapamil in SHR. Verapamil itself caused a decrease in resting [Ca2+]i which was significantly greater in SHR than in WKY, and caused a relaxation only in SHR.
The resting Ca2+ influx in arteries measured by a 5 min incubation with 45Ca was significantly increased in SHR when compared with WKY. The resting Ca2+ influx was not increased by 10−5 m ryanodine in both SHR and WKY. The net cellular Ca2+ uptake in arteries measured by a 30 min incubation with 45Ca was decreased by 10−5 m ryanodine in both strains.
The resting Ca2+ influx was decreased by 10−7 m nifedipine in the SHR artery, but it was unchanged in the WKY artery.
These results suggest that (1) the Ca2+ influx via L‐type voltage‐dependent Ca2+ channels was increased in the resting state of the SHR femoral artery, (2) the greater part of the increased Ca2+ influx was buffered by Ca2+ uptake into the SR and some Ca2+ reached the myofilaments resulting in the maintenance of the myogenic tone, and (3) therefore the functional removal of SR by ryanodine caused a potent contraction in this artery.
Prevention by the 5‐HT3 receptor antagonist, ondansetron, of morphine‐dependence and tolerance in the rat
Authors: Hui Siu‐Chun G. , Sevilla Elenita L. , Ogle Clive W. 
Published: July 2012

The effect of ondansetron, a selective 5‐hydroxytryptamine3 (5‐HT3) receptor antagonist, was studied in morphine‐addicted rats. Morphine‐dependence and tolerance, induced by drinking increasing concentrations of morphine sulphate in 5% sucrose solution for 3 weeks, were demonstrated by the naloxone‐precipitated withdrawal syndrome and tail flick response to a thermal noxious stimulus (water at 50°C), respectively.
Morphine‐dependence, assessed by naloxone precipitated withdrawal, was undetectable by the 6th day, when the animals drank only tap water for 7 days after the 3‐week induction period.
When detoxified rats were offered sucrose and morphine solutions for 10 days, the recurrence of opiate solution preference with relapse to dependence and tolerance was observed.
Giving ondansetron (0.1 or 1 μg kg−1; i.p.; twice daily) on the 14th day of, or 7 days prior to, the 3‐week induction period reduced dependence and tolerance seen during the 3‐week morphine induction and the 10‐day drinking preference periods.
5‐Hydroxytryptamine2 (5‐HT2) receptor antagonism by cyproheptadine (100 or 250 μg kg−1; i.p.; twice daily) did not influence morphine‐dependence and tolerance.
These findings suggest that ondansetron may be useful for treating opiate addiction and lowering the recidivism rate.
Effect of lignocaine in myocardial contusion: an experiment on rabbit isolated heart
Authors: Pu Qian , Mazoit Jean Xavier , Cao Lin Sen , Mao Wieke , Samii Kamran 
Published: July 2012

The reported incidence of myocardial contusion after blunt chest trauma varies from 16 to 76%. Of these patients, about 6% present a severe, life threatening contusion. We used an isolated heart preparation to examine the effect of lignocaine on myocardial performance after contusion.
Thirty hearts obtained from male New Zealand rabbits were perfused at constant flow according to the Langendorff technique and were divided into four groups. The following parameters were measured at frequent intervals for 60 min: mean coronary perfusion pressure (CPP), left ventricular diastolic pressure (LVDP), developed pressure (DP), dP/dtmax, dP/dtmin.
Group 1 (n = 6) served as control, group 2 (n = 7) received lignocaine for 20 min (15 μm for the first 10 min and 30 μm for the following 10 min), group 3 (n = 9) had a contusion leading to a 30–50% decrease in dP/dtmax and group 4 (n = 8) had the contusion and the lignocaine infusion was started 10 min after the contusion and stopped after 30 min. Lignocaine concentration was measured in the effluent.
Lignocaine alone moderately decreased contractility in group 2. In group 3, after contusion, DP, dP/dtmax, and dP/dtmin were markedly decreased during the 60 min recording period. In group 4, lignocaine infusion rapidly restored contractility. DP, dP/dtmax and dP/dtmin returned towards their basal values. This improvement of contractility remained stable, even after lignocaine infusion was discontinued.
In our rabbit isolated heart preparation, lignocaine at a low therapeutic concentration was able to restore contractility after contusion. These results need to be confirmed by other studies but this may lead to promising therapeutic intervention.
Inositol hexakisphosphate binding sites in rat heart and brain
Authors: Rowley Kevin G. , Gundlach Andrew L. , Cincotta Marion , Louis William J. 
Published: July 2012

. Inositol 1,4,5‐trisphosphate (Ins(1,4,5)P3) and inositol hexakisphosphate (InsP6) are produced in response to stimulation of cardiac α1‐adrenoceptors. While the role of Ins(1,4,5)P3 and Ins(1,4,5)P3 receptors is well‐defined in many tissues including brain, the functional role of the putative InsP6‐InsP6 receptor system in cardiac function is less clear. Using quantitative autoradiography, this study examined the characteristics and regional localization of [3H]‐InsP6 binding sites in rat heart and compared the affinity of a range of inositol polyphosphates for [3H]‐InsP6 and [3H]‐Ins(1,4,5)P3 binding sites in heart and brain.
. [3H]‐InsP6 bound to a single, high affinity site in sections of rat heart (KD ranging from 22 ± 1.9 nM in right atria to 35 ± 2.6 nM in the interventricular septum, n = 7). The maximal number of binding sites (Bmax) ranged from 5.1 ± 0.48 to 12 ± 1.8 pmol mg−1 protein in left atrium and left ventricle, respectively. Inositol phosphates inhibited binding of [3H]‐InsP6 with the order of potency: InsP6 > Ins(1,4,5)PS3 > inositol 1,3,4,5‐tetrakisphosphate ≥ inositol pentakisphosphate > Ins(1,4,5)P3 > > inositol mono‐ and bisphosphates, consistent with the labelling of an InsP6 binding site.
. The Ins(1,4,5)P3 analogue, Ins(1,4,5)PS3, originally investigated as a putative selective radioligand for the Ins(1,4,5)P3 receptor, was a potent inhibitor of [3H]‐InsP6 binding in all heart regions (KI = 170–260 nM). The KI of Ins(1,4,5)PS3 for the inhibition of [3H]‐Ins(1,4,5)P3 binding in rat brain (60–220 nM) was similar to that observed for the inhibition of [3H]‐InsP6 binding in heart, suggesting that Ins(1,4,5)PS3 is not a specific ligand for either Ins(1,4,5)P3 or InsP6 receptor binding sites.
. Previous studies have detected [3H]‐InsP6 binding in mitochondrial and sarcoplasmic reticulum fractions of heart and links between InsP6 and cardiac mitochondrial Ca2+ regulation have been proposed, suggesting further studies are warranted to determine the functional role(s) of InsP6 and InsP6 receptor binding sites in cardiac tissue.
Inhibition by tetranactin of interleukin 1β‐ and cyclic AMP‐induced nitric oxide synthase expression in rat renal mesangial cells
Authors: Kunz Dieter , Walker Gaby , Wiesenberg Irmgard , Pfeilschifter Josef 
Published: July 2012

. We have investigated whether tetranactin, a cyclic antibiotic produced by Streptomyces aureus with a molecular structure related to cyclosporin A, influences inducible nitric oxide synthase (iNOS; EC 1.14.13.39) induction in rat glomerular mesangial cells.
. Previously we have shown that iNOS is expressed in renal mesangial cells in response to two principal classes of activating signals comprising inflammatory cytokines such as interleukin 1 (IL‐1) or tumour necrosis factor α and agents that elevate cellular levels of cyclic AMP. Treatment of mesangial cells with IL‐1β or the membrane‐permeable cyclic AMP analogue, N6, 0–2′‐dibutyryladenosine 3′,5′‐phosphate (Bt2 cyclic AMP) for 24 h induces iNOS activity measured as nitrite levels in cell culture supernatants by 44 fold or 33 fold, respectively. Incubation of mesangial cells with tetranactin inhibits IL‐1β‐ and cyclic AMP‐dependent production of nitrite in a dose‐dependent fashion with IC50 values of 50 nM and 10 nM, respectively.
. Western‐blot analyses of mesangial cell extracts reveal that the inhibition of nitrite synthesis by tetranactin is due to a suppression of iNOS protein levels. This effect is preceded by a reduction of iNOS mRNA steady state levels as demonstrated by Northern blot analyses of total cellular RNA isolated from stimulated mesangial cells.
. Thus, tetranactin is a potent inhibitor of iNOS expression in cytokine‐ and cyclic AMP‐stimulated mesangial cells and represents a new class of iNOS inhibitors with IC50s in the low nanomolar range. This compound may be useful in the therapy of diseases associated with pathological NO overproduction due to iNOS expression.
Effect of verapamil on intimal thickening and vascular reactivity in the collared carotid artery of the rabbit
Authors: Üstünes Levent , Yasa Mukadder , Kerry Zeliha , Özdemir Necmettin , Berkan Tayfun , Erhan Yildiz , Özer Asli 
Published: July 2012

. Intimal thickening is a common site for atherosclerosis. Therefore, we investigated whether the calcium entry blocker verapamil (10 mg kg−1 body weight day−1, s.c.) can retard intimal thickening and changes in vascular reactivity induced by a non‐occlusive, silicone collar positioned around the left carotid artery of rabbits. The contralateral carotid artery was sham‐operated and served as a control.
. Verapamil and placebo (saline 0.1 ml kg−1 day−1, s.c.) treatments were initiated 7 days before placing the collar and lasted 3 weeks. Thereafter, segments were cut from collared and sham‐treated arteries for histology and isometric tension recording.
. The intima/media (I/M) ratio increased after 14 days of collar treatment, but intimal thickening was not inhibited by verapamil (I/M ratio placebo 0.31 ± 0.07, verapamil 0.32 ± 0.09).
. The collar decreased the capacity to develop force, as indicated by the response to a supramaximal concentration of KC1, decreased the sensitivity (pD2) to acetylcholine (ACh) and phenylephrine (Phe), but increased the sensitivity to 5‐hydroxytryptamine (5‐HT).
. Although verapamil did not affect intimal thickening, it normalized the hypersensitivity to 5‐HT in collared arteries.
. The contraction to the supramaximal concentration of KC1 was not affected by verapamil. Verapamil decreased the Emax of ACh, but this was only seen in collar‐treated arteries. Verapamil also decreased the sensitivity to ACh and Phe, in both sham‐ and collar‐treated arteries.
. We conclude that verapamil, without preventing thickening of the intima, can modify collar‐induced changes in vascular reactivity.
Role of protein kinase C in desensitization of spinal δ‐opioid‐mediated antinociception in the mouse
Authors: Narita Minoru , Mizoguchi Hirokazu , Kampine John P. , Tseng Leon F. 
Published: July 2012

. Receptor phosphorylation and down‐regulation by protein kinases may be a key event initiating desensitization. The present studies were designed to investigate the effect of a potent protein kinase C (PKC) activator, phorbol 12,13‐dibutyrate (PDBu), on antinociception induced by intrathecal (i.t.) administration of a selective δ‐opioid receptor agonist [D‐Ala2]deltorphin II in the male ICR mouse and on the specific binding of [3H]‐[D‐Ser2, Leu5]enkephalin‐Thr6 (DSLET), a δ‐opioid receptor ligand, in the crude synaptic membrane of the spinal cord.
. Intrathecal (i.t.) pretreatment with PDBu at low doses, which injected alone did not affect the basal tail‐flick latency, dose‐dependently attenuated the antinociception induced by i.t. administration of [D‐Ala2]deltorphin II. The attenuation of i.t.‐administered [D‐Ala2] deltorphin II‐induced antinociception by PDBu was reversed in a dose‐dependent manner by i.t. concomitant pretreatment with a specific PKC inhibitor, calphostin C.
. In the binding experiment, incubation of the crude synaptic membrane of the spinal cord for 2 h at 25°C with PDBu (0.03 to 10 μm) caused a dose‐dependent inhibition of the [3H]‐DSLET binding. Scatchard analysis of [3H]‐DSLET binding revealed that PDBu at 10 μm displayed a 30.7% reduction in the number of [3H]‐DSLET binding sites with no significant change in affinity, compared with the non‐treatment control, indicating that the activation of membrane‐bound PKC by PDBu causes a decrease in the number of specific δ‐opioid agonist binding sites.
. An i.t. injection of [D‐Ala2]deltorphin II produced an acute antinociceptive tolerance to the antinociceptive effect of a subsequent i.t. challenge of [D‐Ala2]deltorphin II. Concomitant pretreatment with calphostin C markedly prevented the development of acute tolerance to the i.t.‐administered [D‐Ala2]deltorphin II‐induced antinociception. On the other hand, a highly selective protein kinase A (PKA) inhibitor, KT5720, did not have any effect on the development of acute tolerance to [D‐Ala2]deltorphin II antinociception.
. These findings suggest that a loss of specific δ‐agonist binding by the activation of PKC by PDBu is involved in the PDBu‐induced antinociceptive unresponsiveness to δ‐opioid receptor agonist in the mouse spinal cord. Based on the acute tolerance studies, we propose that PKC, but not PKA, plays an important role in the process of homologous desensitization of the spinal δ‐opioid receptor‐mediated antinociception.
Relevance of p‐glycoprotein for the enteral absorption of cyclosporin A: in vitro‐in vivo correlation
Authors: Fricker G. , Drewe J. , Huwyler J. , Gutmann H. , Beglinger C. 
Published: July 2012

. The interaction of cyclosporin A (CyA) with p‐glycoprotein during intestinal uptake was investigated by a combination of in vitro experiments with human Caco‐2 cells and an intubation study in healthy volunteers.
. CyA uptake into the cells was not saturable and exhibited only a low temperature sensitivity, suggesting passive diffusion. When the permeation of CyA across Caco‐2 monolayers from the apical to the basolateral side was determined, overall transport had an apparently saturable component up to a concentration of 1 μm. At higher concentrations permeation increased over‐proportionally. Calculation of the kinetic parameters of apical to basolateral permeation suggested a diffusional process with a KD of 0.5 μl min−1 per filter, which was overlayed by an active system in basolateral to apical direction with a KM of 3.8 μm and a Jmax of 6.5 picomol min−1 per filter.
. CyA permeation was significantly higher when the drug was given from the basolateral side as compared to the permeation from the apical side. Apical to basolateral transport of CyA was increased in the presence of vinblastine, daunomcyin and a non‐immunosuppressive CyA‐derivative. All compounds inhibit p‐glycoprotein‐mediated transport processes. Basolateral to apical permeation of CyA showed a dose‐dependent decrease in the presence of vinblastine. Permeation of daunomycin across Caco‐2 cell monolayers was also higher from the basolateral to the apical side than vice versa. Basolateral to apical permeation was decreased in the presence of SDZ PSC 833 and cyclosporin A.
. Western blot analysis of Caco‐2 cells with the monoclonal antibody C219 confirmed the presence of p‐glycoprotein in the used cell system.
. When the absorption of CyA in the gastrointestinal (G***I)‐tract of healthy volunteers was determined, a remarkable decrease of the plasma AUC could be observed dependent on the location of absorption in the rank order stomach > jejunum/ileum > colon. The decrease in absorption exhibited a marked correlation (r = 0.994) to the expression of mRNA for p‐glycoprotein over the G**I‐tract (stomach < jejunum < colon).
. All data provide evidence that CyA is a substrate of p‐glycoprotein in the G***I‐tract, which might explain the local differences and the high variability in cyclosporin absorption found in vivo.
The cardiovascular and renal functional responses to the 5‐HT1A receptor agonist flesinoxan in two rat models of hypertension
Authors: Chamienia Andrzej L. , Johns Edward J. 
Published: July 2012

This study investigated the importance of renal sympathetic nerves in regulating sodium and water excretion from the kidneys of stroke prone spontaneously hypertensive and 2K1C Goldblatt hypertensive rats anaesthetized with chloralose/urethane (17.5/300 mg initially and supplemented at regular intervals), and prepared for measurement of renal function.
In stroke prone spontaneously hypertensive rats, flesinoxan, 30–1000 μg kg−1, i.v., caused graded reductions in blood pressure and heart rate of 74±5 mmHg and 63±9 beats min−1, respectively at the highest dose (P<0.001). Renal blood flow did not change at any dose of drug while glomerular filtration rate fell by some 20% (P<0.001) at the highest dose of drug, absolute and fractional sodium excretions, approximately doubled at 100 μg kg−1, and thereafter fell to below the baseline level at 1000 μg kg−1.
This pattern of excretory response was abolished following acute renal denervation when flesinoxan caused dose‐related reductions in urine flow and sodium excretion, similar to that obtained by a mechanical reduction of renal perfusion pressure.
Flesinoxan administration (30–1000 μg kg−1, i.v.) into 2K1C Goldblatt hypertensive rats caused a maximum decrease in blood pressure and heart rate (both P<0.001) of 34±3 mmHg and 20±6 beats min−1 and while renal blood flow and glomerular filtration rate were autoregulated, from 160 to 125 mmHg, there were dose‐related decreases in urine volume and sodium excretion from the clipped and non‐clipped kidneys of approximately 50–60% at the highest dose.
These findings suggest that in the stroke prone spontaneously hypertensive rat the renal nerves importantly control sodium and water reabsorption at the level of the tubules, whereas in 2K1C Goldblatt hypertensive rats, they play a minor role.
The role of endogenous bradykinin in blood pressure homeostasis in spontaneously hypertensive rats
Authors: Holte Hege Ruge , Bjørnstad‐Østensen Anniken , Berg Torill 
Published: July 2012

The role of endogenous bradykinin in mean arterial blood pressure (BP) homeostasis was studied in spontaneously hypertensive (SHR) and normotensive (WKY) rats by the use of a bradykinin B2‐receptor antagonist (BKant; Hoe 140, 11.6 μg kg−1) and converting enzyme (kininase II) inhibitor (captopril, 10 mg). To obtain a response to captopril that was induced through inhibition of kinin‐degradation only and not through inhibition of angiotensin II‐formation, the studies were performed on binephrectomized male rats to eliminate the renin‐angiotensin system.
The role of the nitric oxide (NO) and the adrenergic systems were evaluated by the use of NO‐synthase inhibitor (L‐NAME, 0.3 g kg−1) and phentolamine (2 mg kg−1), respectively.
The rats were anaesthetized and pretreated with two injections of vehicle (PBS) or drugs spaced 5 min apart: PBS + PBS; BKant + PBS; PBS + L‐NAME; BKant + L‐NAME; or phentolamine + L‐NAME. All rats were given captopril 15 min later. Time‐control groups were treated with L‐NAME but not captopril.
In WKY rats, captopril did not significantly alter BP in any of the groups. In the SHR‐PBS + PBS group, on the other hand, captopril induced an immediate fall in BP (ΔBP = −23 ± 4 mmHg, P < 0.0017) which was completely blocked by BKant (ΔBP = 2 ± 2 mmHg) (P < 0.0011). L‐NAME did not significantly alter the immediate hypotensive response to captopril but disclosed a later hypertensive reaction. In L‐NAME + BKant‐treated rats, both the hypotensive response and the late hypertension was abolished. In rats treated with phentolamine + L‐NAME, the immediate fall in BP was not different from the controls whereas the late hypertension was absent.
BKant itself had no effect on basal BP in either WKY or SHR even when a 10 times higher dose was tested in a separate set of experiments. This was true also for conscious, nonnephrectomized SHR rats.
It was concluded that endogenous production of bradykinin was demonstrable through kininase II‐inhibition in hypertensive but not in normotensive rats. However, this endogenous bradykinin did not play a role in basal BP homeostasis. The captopril‐induced hypotension depended on kinin but, under the present conditions, not on NO as a mediator. The fall in BP induced a compensatory adrenergic hypertensive response which was revealed when the continuous NO‐synthesis was blocked by L‐NAME.
Photolysis of the novel inotropes EMD 57033 and EMD 57439: evidence that Ca2+sensitization and phosphodiesterase inhibition depend upon the same enantiomeric site
Authors: Lee John A. , Palmer Sue , Kentish Jonathan C. 
Published: July 2012

We studied the effects of flash photolysis on the novel enantiomeric cardiac inotropes EMD 57033 (a calcium sensitizer) and EMD 57439 (a phosphodiesterase III inhibitor) in rat isolated ventricular trabeculae.In skinned trabeculae, EMD 57439 had no effect on force production, consistent with lack of an active cyclic AMP system in this preparation. In contrast, EMD 57033 potentiated force at partial and maximal activation. A single flash of near u.v. light given at partial activation (30–70%) reduced force potentiation by 52.4 ± 5.2%. No effect was produced by flashes in the presence of EMD 57439 or in the absence of either drug.The time course of relaxation induced by EMD 57033 photolysis was indistinguishable from that obtained on deactivating the muscle by rapidly lowering Ca2+using photolysis of the caged chelator of calcium, diazo‐2.In intact, twitching trabeculae, EMD 57033 increased diastolic and peak force and slowed relaxation. These effects were simultaneously reduced by a light flash. In these muscles EMD 57439 reduced force, without affecting the twitch time course. These effects were also reduced by a light flash.The u.v. absorbance spectra of EMD 57033 and EMD 57439 were identical. After photolysis optical density decreased substantially and the peak shifted from 320 nm to 280 nm.The proton n.m.r. spectra of these compounds were identical. The main change post‐photolysis was a decrease in the proton signal associated with the enantiomeric carbon atom.This novel manipulation of the molecular structure of EMD 57033 and EMD 57439 within an experiment thus provides direct evidence linking calcium sensitization to a particular molecular structure. The three main effects of the sensitizer on the twitch were simultaneously abolished and may be mechanistically linked. Flash photolysis may be a useful tool for further investigations of the actions of these compounds. In particular, flash photolysis of the sensitizer represents a novel method of rapidly deactivating cardiac muscle.