bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential effect of ω‐conotoxin on release of the adrenergic transmitter and the vasoconstrictor response to noradrenaline in the rat isolated kidney
Authors: El‐Din Mahmoud m. Mohy , Malik Kafait U. 
Published: July 2012

The effects of the Ca2+ channel blockers ω‐conotoxin (ω‐CgTx), nifedipine and diltiazem, on the increase in tritium overflow and perfusion pressure elicited by renal nerve stimulation (RNS), veratridine (Vt) and potassium chloride (KCl), and on the vasoconstrictor response produced by noradrenaline (NA) were investigated in the isolated kidney of the rat perfused with Tyrode solution and prelabelled with [3H]‐noradrenaline ([3H]‐NA).
RNS (1–4Hz), Vt (15–90 nmol) and KCl (150–500 μmol) produced renal vasoconstriction and enhanced the tritium overflow in a frequency‐ and concentration‐dependent manner, respectively.
Administration of ω‐CgTx (50 nm) inhibited RNS‐, Vt‐ and KCl‐induced overflow of tritium; the associated renal vasoconstriction produced by RNS or Vt but not by KCl was inhibited. In contrast, ω‐CgTx failed to alter the vasoconstrictor response elicited by exogenous NA.
Infusion of nifedipine (10 μm) enhanced the tritium overflow elicited by RNS and KCl but not by Vt; a low dose of nifedipine (1.4 μm) enhanced the tritium overflow elicited by all these stimuli. Low doses of diltiazem (6 μm) failed to alter the tritium overflow produced by these stimuli. However, higher doses of diltiazem (60 μm) reduced the tritium overflow elicted by RNS or Vt but enhanced that caused by KCl. The renal vasoconstriction produced by RNS, Vt and KCl as well as by exogenous NA was inhibited by low and high doses of nifedipine and diltiazem.
These data suggest that (a) RNS, Vt and KCl enhance the release of adrenergic transmitter by promoting the influx of Ca2+ into the nerve terminal through specific Ca2+ channels, probably N‐type Ca2+ channels that are distinct from those located in the vascular smooth muscle and (b) ω‐CgTx could be a useful tool to differentiate between Ca2+ channels at the adrenergic nerve terminal and vascular smooth muscle.
Regional differences in the mechanical properties of rabbit airway smooth muscle
Authors: Fujiwara Takashi , Itoh Takeo , Kuriyama Hirosi 
Published: July 2012

In studies of rabbit airway smooth muscle, differences in mechanical responses to acetylcholine, histamine and high K+ in intact muscles, and in Ca2+ sensitivity in skinned muscles, have been examined in tissue taken from 5 different regions of the airway. Interactions between prostaglandin F2aL and epithio‐thromboxane A2 and the above spasmogenic agencies were also studied.
Mechanical responses to histamine (10 μm) and to 128 mM K+ were smallest in trachea and were largest in 3rd and 4th order bronchi. In all regions, spasm evoked by 10 μm acetylcholine was greater than that evoked by 10 μm histamine or 128 mM K+.
In the third and fourth branches of the rabbit right middle bronchus, contractions evoked by 10 μm acetylcholine, 10 μm histamine and 128 mM K+ showed similar amplitudes of phasic response. In Ca2+‐free solution containing 2 mM EGTA, the phasic components of the acetylcholine‐ or histamine‐induced contraction remained unchanged in comparison with that observed in Krebs solution, but the phasic and tonic components of the K+‐induced contraction and the tonic changes induced by acetylcholine and histamine were abolished.
Two subtypes of the histamine receptor, excitatory H1‐ and inhibitory H2‐ receptors were detected on the bronchial smooth muscle. The H1‐induced contraction was mediated by release of stored Ca2+ together with activation of Ca2+ influx relatively insensitive to Ca2+ antagonists.
The ‐log(EC50) values for acetylcholine and histamine (in the presence of cimetidine and atropine) were 6.11 ± 0.11 and 5.33 ± 0.08, respectively, in the third branch of right middle bronchus. These values were similar to those observed for trachea.
Prostaglandin F2α (10 μm) and 9,11‐epithio‐11,12‐methano‐thromboxane A2 (0.1 μm) neither provoked nor enhanced the contractions evoked by any stimulants.
No difference was observed between the Ca2+ sensitivity of chemically skinned muscle from the trachea and that of muscle from the third branch of the right middle bronchus.
Regional differences in the response to histamine and acetylcholine observed in airway smooth muscles are discussed and it is concluded that these may be due to differences in receptor numbers.
Pharmacological properties of GR38032F, a novel antagonist at 5‐HT3 receptors
Authors: Butler A. , Hill J.M. , Ireland S.J. , Jordan C.C. , Tyers M.B. 
Published: July 2012

This paper describes the pharmacology of the novel 5‐hydroxytryptamine3 (5‐HT3) receptor antagonist GR38032F.
On the isolated vagus nerve and superior cervical ganglion of the rat, R,S‐GR38032F behaved as a reversible competitive antagonist of 5‐HT‐induced depolarization with pKB values of 8.61 ± 0.08 (n = 19) and 8.13 ± 0.07 (n = 16), respectively. The resolved R‐ and S‐isomers of GR38032F were approximately equipotent as 5‐HT antagonists on the rat vagus nerve: the pKB values were 8.95 ± 0.05 (n = 16) and 8.63 ± 0.08 (n = 17), respectively. R,S‐GR38032F was also an effective antagonist of 5‐HT on the rabbit isolated vagus nerve: in this case the pKB value was 9.40 ±0.14 (n = 4).
On the rabbit isolated heart, low concentrations of R,S‐GR38032F (3 × −1011 −1 × 10‐9 m) antagonized the positive chronotropic effect of 5‐HT and 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT). However, the effects of the compound did not appear consistent with simple reversible competition.
On the longitudinal smooth muscle of the guinea‐pig ileum, R,S‐GR38032F caused concentration‐dependent parallel rightward displacement of the 2‐methyl‐5‐HT concentration‐contraction response curve; in contrast, a portion of the response to 5‐HT appeared resistant to R,S‐GR38032F. pKB values estimated from the effects of the compound against 2‐methyl‐5‐HT or the inhibitable portion of the response to 5‐HT were 7.31 ± 0.06 (n = 8) and 7.33 ± 0.13 (n = 8), respectively. Against 2‐methyl‐5‐HT, R‐GR38032F seemed more potent (pKB 7.20 ± 0.10; n = 6) than S‐GR38032F (pKB 6.30 ± 0.05; n = 6).
R,S‐GR38032F is highly selective for 5‐HT3 receptors, and at concentrations of 3 × 10−6‐3 × 10−5m, had negligible agonist or antagonist activity on other 5‐HT or non‐5‐HT receptor‐containing tissues on which it was tested.
The potency and duration of action of R,S‐GR38032F in blocking 5‐HT3 receptors in vivo were assessed by measuring its ability to antagonize the bradycardic response to 5‐HT or 2‐methyl‐5‐HT administered intravenously (i.v.) to anaesthetized animals. For i.v. administration to the rat, the ED50 for R,S‐GR38032F against 2‐methyl‐5‐HT (100 μg kg−1) was 0.4 (95% confidence limits 0.18–0.87) μg kg−1 (n = 10); the corresponding value for oral administration to this species was 7.0 (3.0–22.0) μg kg−1 (n = 8–10 per dose level). R,S‐GR38032F was similarly effective in the anaesthetized cat.
The present results are discussed with reference to the postulated existence of subtypes of the 5‐HT3 receptor.
Heterogeneous vasomotor responses of anatomically distinct feline cerebral arteries
Authors: Hamel Edith , Edvinsson Lars , MacKenzie Eric T. 
Published: July 2012

The vasomotor reactivity to a number of neurotransmitters and blood‐borne substances was evaluated in several anatomically distinct arteries of the cat cerebral circulation. Few regional differences were observed in their vasoconstrictor responses to noradrenaline, dopamine, 5‐hydroxytryptamine and prostaglandin F2α. Only the anterior cerebral artery reacted strongly to all vasoconstrictor agents.
Adenosine, acetylcholine and histamine induced pronounced relaxation in the vast majority of the major cerebral arteries. The relaxation elicited by adenosine showed a slight degree of heterogeneity between the arteries and the overall response accounted for 81 ± 6% of the pharmacologically‐induced tone. On the other hand, the dilatation induced by acetylcholine and histamine varied as a function of the anatomical localization of the cerebral arteries. The acetylcholine‐induced vasodilatation was significantly more pronounced in the middle cerebral, anterior communicating and anterior cerebellar arteries, with respective responses of 72, 66 and 83% of the induced tone as compared to 43% in the other vessels. However, all arteries were equally sensitive to acetylcholine with an overall mean pD2 value of 7.47 ± 0.06. The most heterogeneous results were obtained with histamine and applied both to the magnitude of the maximal response and the sensitivity of the various arteries to this amine. The intensity of the relaxation varied from 20% (anterior communicating artery) to 118% (posterior cerebellar artery).
Among the neuropeptides studied, substance P and bradykinin were considerably less potent than vasoactive intestinal peptide on all the cerebral arteries. The least responsive vessel to bradykinin was the anterior cerebral artery with a maximal response of 22 ± 5% of the induced‐tone and a pD2 value of 7.56 ± 0.24. All vessels responded weakly to substance P and those from the vertebrobasilar circulation were significantly less sensitive to this neuropeptide with pD2 values around 8.07 as compared to 9.82 in the more rostral arteries. Although all vessels were equally sensitive to vasoactive intestinal peptide, the dilator responses were significantly less pronounced in the middle cerebral and basilar arteries (maximal response of 86 ± 5% and 69 ± 6% of the induced‐tone, respectively, as compared to 110 ± 9% in the other vessels).
The vertebrobasilar arteries were as reactive, if not more reactive, to vasoconstrictors than the vessels originating from the carotid circulation. In contrast, the dilator responses were less marked in most caudal arteries. Such dichotomies may be important in the regulation of local cerebral blood flow.
The results emphasize the considerable heterogeneity in the vasomotor responses to a given substance among the various cerebral arteries. Further, they suggest the presence of multiple receptor populations which mediate opposite effects and which are distributed in different proportions among the cephalic arteries.
Impairment of endothelium‐dependent relaxation in aortae from spontaneously diabetic rats
Authors: Durante William , Sen Amar K. , Sunahara Fred A. 
Published: July 2012

Diabetes mellitus is known to produce alterations in vascular reactivity. The present study examined the effects of endothelium‐dependent and endothelium‐independent relaxing substances on thoracic aorta from control and spontaneously diabetic rats.
Endothelium‐dependent relaxation produced by acetylcholine or the calcium ionophore, A23817, in aortic rings precontracted with phenylephrine was significantly attenuated in diabetic vessels.
Relaxations produced by sodium nitroprusside or adenosine in diabetic preparations were comparable to those in control vessels.
The results show that diabetes leads to a specific impairment of endothelial‐dependent relaxation.
Evidence for excitatory 5‐HT2‐receptors on rat brainstem neurones
Authors: Davies Michael , Wilkinson Lawrence S. , Roberts Malcolm H.T. 
Published: July 2012

The technique of microiontophoresis was used to investigate the identity of the receptor mediating the excitatory effects of 5‐hydroxytryptamine (5‐HT) upon neurones in the midline of the medullary brainstem of the rat in vivo.
The 5‐HT1‐like receptor agonists 5‐carboxamidotryptamine (5‐CT) and 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT) failed to excite the majority of neurones excited by 5‐HT. The mobilities of 5‐CT and 8‐OH‐DPAT when tested in vitro were found not to differ significantly from that of 5‐HT, suggesting that the lack of effect of these agonists was not due to a lower rate of release from the microelectrodes.
The excitatory responses to 5‐HT were attenuated by the 5‐HT2‐receptor antagonists ketanserin and methysergide when applied microiontophoretically or administered intravenously (0.3 and 1 mg kg−1 respectively). Excitatory responses to glutamate and noradrenaline were not reduced.
The 5‐HT3‐receptor antagonist MDL 72222 failed to attenuate selectively the excitatory response to 5‐HT when applied either by microiontophoresis or administered intravenously (1 mg kg−1).
Microiontophoretic application of the α1‐adrenoceptor antagonist prazosin did not attenuate excitatory responses to either 5‐HT or noradrenaline. Intravenously administered prazosin (0.8 mg kg−1) also failed to attenuate excitatory responses to 5‐HT, but did block excitatory responses to noradrenaline.
These results suggest that 5‐HT2‐receptors, but not 5‐HT1‐like receptors, 5‐HT3‐receptors or α1‐adrenoceptors, are involved in the excitatory response of midline medullary neurones to 5‐HT.
Adrenoceptor‐mediated changes of action potential and force of contraction in human isolated ventricular heart muscle
Authors: Jakob Helga , Nawrath Hermann , Rupp Johanna 
Published: July 2012

The effects of α‐adrenoceptor stimulation on the action potential and force of contraction were investigated in human isolated ventricular heart muscle and compared with those of β‐adrenoceptor Stimulation.
The maximal stimulation by isoprenaline of β‐adrenoceptors produced large changes in the force of contraction, which were accompanied by moderate increases in the height of the action potential. The maximal inotropic effect produced by stimulation of α‐adrenoceptors with phenylephrine, in the presence of propranolol (1 μmol l−1) was much smaller (about 10% of that seen in response to β‐adrenoceptor stimulation), and no significant changes of the action potential configuration were observed.
The effects of noradrenaline and adrenaline on the force of contraction were not affected by prazosin.
It is concluded that the adrenoceptor‐mediated changes of the force of contraction (in the presence of either noradrenaline or adrenaline) in the human ventricle are due virtually exclusively to the stimulation of β‐adrenoceptors.
Modulation of divalent cation‐activated chloride ion currents
Authors: Scott R.H. , McGuirk S.M. , Dolphin A.C. 
Published: July 2012

Voltage‐sensitive calcium channel currents carried by Ca2+ (ICa) or Ba2+ (IBa) were followed by tail currents carried by Cl− ions in approximately 45% of cultured dorsal root ganglion neurones.
Extracellular application of (−)‐baclofen (100 μm) inhibited IBa and ICl(Ba) BaY K 8644 (5 μm) potentiated both currents.
Intracellular GTP‐γ‐S increased the proportion of neurones in which ICl(Ba) was recorded. In addition, the activation by GTP‐γ‐S of a pertussis toxin‐sensitive GTP binding (G)‐protein resulted in a steady increase in the Cl− tail current with time, despite a concurrent reduction in IBa.
Extracellular application of 10 mM caffeine selectively reduced ICl(Ba) without significant change in IBa. When Ca2+ was the charge carrier, caffeine had little effect on ICl(Ca), and increased the inactivation of ICa.
We conclude that, in addition to being regulated by divalent cation entry through Ca2+ channels, the Cl− current is also regulated by G‐protein activation. The mechanism of activation of ICl(Ba) may involve Ca2+ release from intracellular stores.
Selective regulation of β1‐and β2‐adrenoceptors in the human heart by chronic β‐adrenoceptor antagonist treatment
Authors: Michel M.C. , Pingsmann A. , Beckeringh J.J. , Zerkowski H.‐R. , Doetsch N. , Brodde O.‐E. 
Published: July 2012

In 44 patients undergoing coronary artery bypass grafting, the effect of chronic administration of the β‐adrenoceptor antagonists sotalol, propranolol, pindolol, metoprolol and atenolol on β‐adrenoceptor density in right atria (containing 70% β1‐ and 30% β2‐adrenoceptors) and in lymphocytes (having only β2‐adrenoceptors) was studied.
β‐Adrenoceptor density in right atrial membranes and in intact lymphocytes was assessed by (−)−[125I]‐iodocyanopindolol (ICYP) binding; the relative amount of right atrial β‐ and β2‐adrenoceptors was determined by inhibition of ICYP binding by the selective β2‐adrenoceptor antagonist ICI 118,551 and analysis of the resulting competition curves by the iterative curve fitting programme LIGAND.
With the exception of pindolol, all β‐adrenoceptor antagonists increased right atrial β‐adrenoceptor density compared to that observed in atria from patients not treated with β‐adrenoceptor antagonists.
All β‐adrenoceptor antagonists increased right atrial β1‐adrenoceptor density; on the other hand, only sotalol and propranolol also increased right atrial β2‐adrenoceptor density, whereas metoprolol and atenolol did not affect it and pindolol decreased it.
Similarly, in corresponding lymphocytes, only sotalol or propranolol increased β2‐adrenoceptor density, while metoprolol and atenolol did not affect it and pindolol decreased it.
It is concluded that β‐adrenoceptor antagonists subtype‐selectively regulate cardiac and lymphocyte β‐adrenoceptor subtypes. The selective increase in cardiac β1‐adrenoceptor density evoked by metoprolol and atenolol may be one of the reasons for the beneficial effects observed in patients with end‐stage congestive cardiomyopathy following intermittent treatment with low doses of selective β1‐adrenoceptor antagonists.
Peripheral sympatho‐inhibitory cardiovascular effects of opioid peptides in anaesthetized rabbits
Authors: Szabo Bela , Hedler Liselotte , Schurr Claudia , Starke Klaus 
Published: July 2012

Opioid agonists influence isolated cardiovascular tissues from rabbits, as well as the cardiovascular system of pithed rabbits, through presynaptic receptors on postganglionic sympathetic nerve fibres. The present experiments were carried out in order to study effects which result from activation of these receptors in anaesthetized rabbits.
In pithed rabbits with electrically stimulated sympathetic outflow, infusion of [D‐Ala2‐D‐Leu5]‐enkephalin (DADLE) 10 μg kg−1 min−1 and dynorphin‐(1–13) (dynorphin) 1 μg kg−1 min−1 decreased the plasma noradrenaline concentration, mean arterial pressure (MAP) and heart rate. The effects of dynorphin and, less completely, those of DADLE were antagonized by the peripherally selective opioid antagonists N‐methyl naloxone bromide (NMN) 1.3 mg kg−1 and N‐methyl levallorphan methanesulphonate (NML) 1–3 mg kg−1.
In pentobarbitone‐anaesthetized rabbits, DADLE 3–30 μg kg−1 min−1 and dynorphin 0.3–3 μg kg−1 min−1 decreased the plasma noradrenaline concentration and MAP. The highest dose of dynorphin also decreased heart rate, whereas DADLE 10 μg kg−1 min−1 caused slight cardioacceleration. The effects of DADLE but not those of dynorphin decreased upon repeated administration.
The effects of dynorphin 10 μg kg−1 min−1 were abolished or greatly attenuated by NMN 1.3 mg kg−1 and NML 3 mg kg−1. In contrast, the antagonists reduced only slightly the blood pressure‐lowering effect of DADLE 10 μg kg−1 min−1 and did not reduce significantly the effects of DADLE on the plasma noradrenaline level and heart rate.
It was concluded that systemically administered dynorphin produces sympatho‐inhibition and an ensuing fall in blood pressure by an action at peripheral receptors, in all probability presynaptic κ‐receptors on postganglionic sympathetic nerve fibres. The effects of DADLE are more complex and may involve both central and peripheral components.
Temperature‐dependence of the kinetics of the binding of [3H]‐(+)‐N‐methyl‐4‐methyldiphenhydramine to the histamine H1‐receptor: comparison with the kinetics of [3H]‐mepyramine
Authors: Treherne J.M. , Young J.M. 
Published: July 2012

The dissociation of [3H]‐(+)‐N‐methyl‐4‐methyldiphenhydramine ([3H]‐QMDP) from the histamine H1‐receptor was markedly temperature‐dependent. The t1/2 was 4 min at 37°C and 16 h at 6°C. The association rate constant, k1, was also temperature‐dependent, but not to the same extent as k‐1.
Plots of the observed rate constant for [3H]‐QMDP‐receptor complex formation, kon, versus [3H‐QMDP] were linear at both 30°C and 10°C, consistent with the interaction of [3H]‐QMDP with the H1‐receptor being a simple, one‐step equilibrium.
The ratio of the kinetic constants, k1/k‐1, indicated that the affinity constant of [3H]‐QMDP for the H1‐receptor should increase with decreasing temperature. Measurement of (+)‐QMDP antagonism of the contraction of longitudinal muscle strips from guinea‐pig small intestine induced by histamine at 37°C, 30°C and 25°C provided some evidence that the affinity of (+)‐QMDP is greater at 25°C than 37°C. However, the flattening of the concentration‐response curves for histamine at low concentrations of (+)‐QMDP at 30°C and 25°C is consistent with a slow dissociation of the (+)‐QMDP‐receptor complex and hence an incomplete equilibration with the agonist.
Arrhenius plots for k1 and k‐1 for [3H]‐QMDP were linear between 37°C and 6°C. The activation energies, Ea, for complex formation and dissociation were 77 ± 4 and 129 ± 3 kJ mol−1, respectively.
An Arrhenius plot for k‐1 for the dissociation of [3H]‐mepyramine from the H1‐receptor was also linear between 37°C and 6°C. The activation energy was 140 ± 2 kJ mol−1.
Activation energies for complex formation with the H1‐receptor, Eaf, and complex dissociation, Ead, were similar for [3H]‐QMDP and [3H]‐mepyramine. The energy difference, Eaf — Ead, equivalent to the enthalpy change, did not differ significantly for the two ligands (‐52 and −48 kJ mol−1, respectively). The larger values of k1 and k‐1 for [3H]‐mepyramine compared to [3H]‐QMDP imply the presence of an entropic component in the interaction.
The simplest explanation for these observations is that transfer from the aqueous phase into a hydrophobic region is a significant factor in antagonist‐H1‐receptor interaction. This would be entropically more favourable for [3H]‐mepyramine, a tertiary amine, than for [3H]‐QMDP, a quaternary amine.
Endothelium‐dependent effects of acetylcholine in rat aorta: a comparison with sodium nitroprusside and cromakalim
Authors: Taylor S.G. , Southerton J.S. , Weston A.H. , Baker J.R.J. 
Published: July 2012

The mechanisms involved in the mechano‐inhibitory effects of acetylcholine (ACh) have been compared with those of sodium nitroprusside (SNP) and cromakalim on the rat isolated thoracic aorta.
Relaxations produced by ACh were endothelium‐dependent, whereas those produced by SNP or cromakalim were endothelium‐independent.
ACh, cromakalim and SNP relaxed established contractions produced by noradrenaline (NA) and KCl (20 mm) and these relaxations were well‐maintained.
SNP was a relatively effective inhibitor of contractions produced by KCl (80 mm). ACh was relatively ineffective and cromakalim was without effect against such contractions.
Membrane potential and cyclic GMP concentrations were higher in tissues with an intact endothelium whereas rubbed tissues had a higher 86Rb efflux rate coefficient.
ACh and cromakalim produced a transient and long‐lasting hyperpolarization, respectively. These changes were accompanied by increases in the 86Rb efflux rate coefficient with a time course comparable to that of the electrical changes.
Tissue cyclic GMP concentrations were significantly increased in the presence of ACh or SNP, whereas cromakalim had no effect.
Transmission electron microscopy showed the presence of endothelial cells on intact tissues. On rubbed preparations, such cells were absent and some damage to the underlying smooth muscle cells was detected.
It is concluded that at least two inhibitory substances are released from the endothelial cells by ACh. One of these increases tissue cyclic GMP concentrations and produces an electrically‐silent relaxation. The other produces a transient hyperpolarization associated with the opening of 86Rb‐permeable K‐channels. This event may serve to initiate relaxation processes and to close any open voltage‐dependent Ca‐channels.