bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure‐activity studies on endothelin (16–21), the C‐terminal hexapeptide of the endothelins, in the guinea‐pig bronchus
Authors: Rovero Paolo , Patacchini Riccardo , Maggi Carlo Alberto 
Published: July 2012

We describe the results of a structure‐activity study in which the C‐terminal hexapeptide of the endothelins, endothelin (16–21), is compared with shorter fragments; hexapeptides bearing amino‐acid substitutions and the corresponding C‐terminal fragments of sarafotoxins. The guinea‐pig bronchus was used in this study since it is the most sensitive preparation for endothelin (16–21) thus far developed.
The biological results obtained with endothelin (16–21) and analogues demonstrate that the contractile activity of the C‐terminal hexapeptide of endothelin on the guinea‐pig bronchus depends on quite close structural requirements, strongly suggestive of a receptor interaction. The following features appear to be essential for the biological activity: (a) the C‐terminal free carboxylic function; (b) the L‐configuration of Trp‐21; (c) the β‐carboxylic function of Asp‐18; (d) the presence of Leu‐17 and (e) the imidazole moiety of His‐16.
The hexapeptide corresponding to the C‐terminal portion of sarafotoxin, sarafotoxin (16–21), was devoid of biological activity. This behaviour might be related to the proposed existence of more than one receptor for the endothelin/sarafotoxin family in the guinea‐pig bronchus.
Electrical effects of okadaic acid extracted from black sponge on rabbit sinus node
Authors: Kondo Noriaki , Kodama Itsuo , Kotake Hiroshi , Shibata Shoji 
Published: July 2012

Effects of okadaic acid on electrical responses and spontaneous activity in the dominant pacemaker cells of rabbit sinus node were investigated by use of microelectrode techniques.
Okadaic acid (10−5 m to 4 × 10−5 m) caused a shortening of cycle length of spontaneous firing (SPCL) accompanied by increases in both maximum upstroke velocity at phase 0 and amplitude of action potential.
All of the effects of okadaic acid were relatively well preserved in a low‐Ca2+ medium (0.12 mm). Okadaic acid restored the spontaneous activity of sinus node pacemaker cells even in a Ca2+‐deficient medium.
The effects of okadaic acid were markedly inhibited or abolished in a low Na+ medium (24 mm or 70 mm) and in the presence of a slow channel blocking agent, verapamil (10−6 m).
In voltage‐clamp experiments using a two‐microelectrode technique, okadaic acid (10−5 m) caused an increase in the slow inward current without affecting the outward current. At a higher concentration (4 × 10−5 m), the drug increased the outward current.
These results indicate that okadaic acid causes an increase in spontaneous activity of sinus node pacemaker cells mediated by an enhancement of slow inward current (Isi) through verapamil‐sensitive Ca2+ channels.
Thermal trauma alters myocardial cyclic nucleotides and protein content in mice
Authors: Tomera John F. , Martyn J.A. Jeevendra 
Published: July 2012

This study tested the hypothesis that the systemic effects of burn include altered metabolic activity in the heart. Metabolic activity was studied by measuring alterations in cyclic nucleotide levels and protein concentrations in atrial and ventricular muscle in mice at 14 and 22 days after a 20% body surface area (BSA) burn. Thermal injury was produced on the dorsal surface of anesthetized male CD mice by immersion in water at 95°C for 8 s. This resulted in a full‐thickness, 3° scald burn. In atrial and ventricular tissues, levels of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) and guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) were analyzed by 125I‐radioimmunoassay.
The protein content (mg prot g−1 dry wt) increased in the atria. The cyclic AMP content (nmol g−1 dry wt) was significantly increased fourfold and ninefold at 14 and 22 days, respectively, in atria from burned animals compared to controls. The cyclic AMP/cyclic GMP ratios were similarly increased.
In the ventricle, the protein content and cyclic AMP levels were not altered, but the cyclic AMP/cyclic GMP ratios (nmol g−1 dry wt) were increased at both 14 and 22 days. These changes both in atria and ventricles were less prominent when cyclic nucleotide concentrations or ratios were expressed as pmol mg−1 protein.
The data confirm the hypothesis that a 20% BSA thermal injury evokes effects in sites remote from burn injury such as in the atria and ventricles. These effects include total body weight loss, elevated cyclic AMP, cyclic AMP/cyclic GMP ratios, and protein levels in the atria, and elevated cyclic AMP/cyclic GMP ratios in both atrial and ventricular tissues at 2 and 3 weeks after thermal injury. To prevent underestimation of cyclic nucleotide levels such changes should preferably be expressed on a prot g−1 dry weight basis.
Adrenalectomy abolishes antagonism of α‐adrenoceptor‐mediated hypotension by a β‐blocker in conscious rats
Authors: Tabrizchi R. , Pang C.C.Y. 
Published: July 2012

The effects of a single bolus injection of propranolol, atenolol or ICI 118,551, non‐selective β‐, selective β1‐ and selective β2‐adrenoceptor antagonists, respectively, on mean arterial pressure (MAP) and plasma catecholamine concentrations were examined in seven groups of conscious and unrestrained adrenalectomized rats receiving a continuous infusion of the α‐adrenoceptor antagonist phentolamine. In all rats adrenaline was undetectable in the plasma four days after adrenalectomy.
In the first three groups, phentolamine significantly decreased MAP and increased the plasma concentrations of noradrenaline. The injection of propranolol, atenolol or ICI 118,551 in Groups I, II and III, respectively, caused a small increase in MAP and a small, but not significant, decrease in plasma noradrenaline concentrations.
Groups IV, V and VI were given a continuous infusion of adrenaline for 1 h prior to the infusion of phentolamine, followed by a bolus injection of propranolol, atenolol or ICI 118,551, respectively. Group VII was treated similarly to IV, but was also given daily cortisone replacement after adrenalectomy. Adrenaline slightly, but not significantly, decreased MAP while phentolamine significantly decreased MAP and increased plasma noradrenaline concentrations in all groups. A subsequent injection of a β‐blocker caused a significant increase in MAP in each group and a slight decrease in the plasma level of noradrenaline which reached statistical significance in group VII. The pressor effect of propranolol was significantly greater in the cortisone‐treated rats (Group VII) than in Group IV.
The results suggest that adrenaline and adrenocortical steroids are both involved in the antagonism of α‐adrenoceptor‐induced hypotension by a β‐blocker.
Chronic β1‐adrenoceptor antagonist treatment sensitizes β2‐adrenoceptors, but desensitizes M2‐muscarinic receptors in the human right atrium
Authors: Motomura S. , Deighton N.M. , Zerkowski H.‐R. , Doetsch N. , Michel M.C. , Brodde O.‐E. 
Published: July 2012

In 64 patients undergoing coronary artery bypass grafting the effects of chronic β1‐adrenoceptor antagonist (metoprolol, atenolol, bisoprolol) treatment on right atrial β‐adrenoceptor and muscarinic M2‐receptor number and functional responsiveness were investigated.
The β1‐adrenoceptor antagonists increased right atrial β1‐adrenoceptor number, did not affect β2‐adrenoceptor number, and decreased muscarinic M2‐receptor number.
Concomitantly, activation of right atrial adenylate cyclase by 10 μm GTP, 10 μm isoprenaline and 1 μm forskolin was enhanced and inhibition by 100 μm carbachol was diminished.
On isolated, electrically driven right atria the β1‐adrenoceptor‐mediated positive inotropic effect of noradrenaline was — even with β1‐adrenoceptor number increased — not altered, while the β2‐adrenoceptor‐mediated effect of procaterol was markedly enhanced. However, the carbachol‐induced negative inotropic effect was decreased.
It is concluded that chronic β1‐adrenoceptor antagonist treatment increases β1‐adrenoceptor number and concomitantly sensitizes β1‐adrenoceptor function, but desensitizes muscarinic M2‐receptor function in the human heart.
Methoxyphenamine inhibits basal and histamine‐induced nasal congestion in anaesthetized rats
Authors: Lau W.A.K. , King R.G. , Boura A.L.A. 
Published: July 2012

Nasal resistance in anaesthetized rats was assessed by measuring air overflow during ventilation of the nasal passages at constant pressure. Nasal basal resistance was reduced in a dose‐dependent manner by methoxyphenamine hydrochloride (0.01–30 mg kg−1, i.v.), pseudoephedrine hydrochloride (0.03–3 mg kg−1, i.v.) and adrenaline bitartrate (0.01–3 μg kg−1, i.v.). Both methoxyphenamine and pseudoephedrine were less potent and less efficacious than adrenaline but caused longer‐lasting responses.
Nasal congestion induced by histamine (0.2% nebulised solution passed into the nasal passages for 15 s) was inhibited by i.v. administration of methoxyphenamine, pseudoephedrine, adrenaline, methoxamine or tyramine: the ID50s against 0.2% histamine‐induced nasal congestion were 1.16 (95% confidence limits; 0.5, 1.8) mg kg−1, 0.25 (0.19, 0.33)mg kg−1, 0.037 (0.018, 0.06) μg kg−1, 8.12 (6.74, 9.65) μg kg−1 and 30.6(26.1, 35.8) μg kg−1 respectively.
The inhibitory effects of both methoxyphenamine and tyramine on histamine‐induced nasal congestion were reduced after administration of desmethylimipramine (0.1 and 1 mg kg−1, i.v.) or prazosin (0.1 and 0.3 mg kg−1, i.v.). Similarly, the inhibitory effects of methoxamine were reduced after prazosin (0.1 and 0.3 mg kg−1).
These results indicate that methoxyphenamine (1 mg kg−1, i.v.) inhibits histamine‐induced nasal congestion in the rat. This action, at least in part, is probably indirect being mediated by release of neuronal noradrenaline which then acts on α1‐adrenoceptors.
Influence of N‐ethylmaleimide on action potential and force of contraction of guinea‐pig papillary muscles
Authors: von Poehl Corona , Iven H. , Brasch H. 
Published: July 2012

Standard microelectrode techniques were used to investigate the influence of N‐ethylmaleimide on the action potential, slow response action potential and force of contraction of guinea‐pig papillary muscles.
N‐ethylmaleimide, 3 × 10−5 to 10−4 moll−1, concentration‐dependently increased the force of contraction. The positive inotropic effect developed quickly and, with the largest drug concentration, was followed by a progressive decline of the contractile force. The action potential duration was progressively shortened by N‐ethylmaleimide.
The effects of N‐ethylmaleimide were not prevented in the presence of tetrodotoxin 3 × 10−8 moll−1 and propranolol 4 × 10−6 moll−1 or by a reduction of the Na+‐concentration to 70 mmoll−1.
Verapamil, 10−6 moll−1, reduced the positive inotropic, but not the action potential shortening effect of N‐ethylmaleimide.
In K+‐depolarized muscles in the presence of propranolol and tetrodotoxin, N‐ethylmaleimide 10−4 moll−1 increased the maximum depolarization velocity and the duration of the slow response action potential. The latter effect was transient and was followed by a progressive reduction of the action potential duration.
The most likely explanation for the action potential shortening effect of N‐ethylmaleimide seems to be an increase of an outward potassium current while the transient inotropic effect of the drug may be caused, at least in part, by an increase of the slow inward calcium current.
The effect of capsaicin on voltage‐gated calcium currents and calcium signals in cultured dorsal root ganglion cells
Authors: Bleakman D. , Brorson J.R. , Miller R.J. 
Published: July 2012

The effects of capsaicin on voltage‐gated Ca2+ currents (ICa), and intracellular Ca2+ concentrations ([Ca2+]i) in cultured dorsal root ganglion (DRG) neurones of the rat were examined in vitro by use of combined patch clamp‐microfluorometric recordings.
Under voltage‐clamp conditions, capsaicin (0.1–10 μm) caused a concentration‐dependent decrease in the magnitude of the ICa, an elevation in the holding current (Ih) and a concomitant rise in the [Ca2+]i in most cells examined. Repeated application of capsaicin produced marked desensitization.
Some decrease in the ICa produced by capsaicin was also observed when the rise in [Ca2+]i was buffered with EGTA or BAPTA and when Ba2+ was used as the charge carrier; under these conditions the desensitization previously observed was smaller.
The decrement in voltage‐gated current was smaller in Ba2+ containing solutions than in Ca2+ containing solutions suggesting that the capsaicin‐induced influx of Ca2+ partially mediated the observed decrease in the voltage‐gated current. In cells which showed a marked response to capsaicin an outward (positive) current was sometimes observed upon depolarization from −80 to 0mV. This effect was consistent with an outward movement of cations through the capsaicin conductance pathway which may also account, in part, for the apparent reduction in ICa by capsaicin.
The effects of capsaicin under voltage‐clamp conditions were prevented by ruthenium red (1 μm).
Under current clamp conditions, capsaicin depolarized and caused a rise in [Ca2+]i in the majority of DRG cells examined. Both of these effects could be prevented by ruthenium red (500 nm).
It is concluded that capsaicin reduces the ICa of rat DRG neurones primarily by indirect mechanisms.
Protein kinase C‐mediated contractile responses of arteries from diabetic rats
Authors: Abebe W. , MacLeod K.M. 
Published: July 2012

The role of protein kinase C (PKC) in mediating enhanced contractile responses of aortae and mesenteric arteries from male rats with 12–14 week streptozotocin‐induced diabetes to noradrenaline (NA) was investigated using the PKC activator, phorbol 12,13‐dibutyrate (PDB), and the PKC inhibitor, staurosporine.
Maximum contractile responses of aortae and mesenteric arteries from diabetic rats to NA were significantly enhanced compared with responses of arteries from age‐matched control animals. The maximum NA responses were increased by 59.6 ± 7.9% in aortae and by 54.9 ± 7.4% in mesenteric arteries from diabetic animals, compared to their respective controls.
Pretreatment of aortae and mesenteric arteries from both control and diabetic animals with staurosporine (5 × 10−8 m) caused marked inhibition of contractile responses to a maximum concentration of NA (10−5 m in aortae; 3 × 10−5 m in mesenteric arteries). In the presence of staurosporine, no difference was observed in the magnitude of contractile responses of arteries from control and diabetic rats to NA.
Maximum contractile responses of mesenteric arteries from diabetic rats to PDB were significantly increased (by 45.0 ± 4.9%) compared to responses of arteries from control animals. In contrast, no significant difference was found in the magnitude of contractile responses of aortae from control and diabetic rats to PDB.
Staurosporine (5 × 10−8 m) caused marked attenuation of contractile responses of arteries from control and diabetic rats to a maximum concentration of PDB (3 × 10−6 m). In the presence of staurosporine, the difference in magnitude of contractile responses of mesenteric arteries from control and diabetic rats to PDB was abolished.
Contractile responses of aortae and mesenteric arteries from control and diabetic rats to PDB were reduced in the absence of extracellular Ca2+, and in the presence of the Ca2+ channel blockers, nifedipine (3 × 10−6 m) or verapamil (3 × 10−6 m). Under these conditions, no difference was found in the magnitude of contractile responses of mesenteric arteries from control and diabetic rats to PDB.
These data suggest that enhanced contractile responses of aortae and mesenteric arteries from streptozotocin‐induced diabetic rats to NA may result, at least in part, from increased activation of PKC. In addition, increased activation of PKC‐mediated processes, which are dependent on the presence of extracellular Ca2+, may further contribute to the enhanced contractile responses of diabetic mesenteric arteries to NA.
Stereoselective inhibition of muscarinic receptor subtypes by the enantiomers of hexahydro‐difenidol and acetylenic analogues
Authors: Feifel R. , Wagner‐Röder M. , Strohmann C. , Tacke R. , Waelbroeck M. , Christophe J. , Mutschler E. , Lambrecht G. 
Published: July 2012

The affinities of the (R)‐ and (S)‐enantiomers of hexahydro‐difenidol (1) and its acetylenic analogues hexbutinol (2), hexbutinol methiodide (3) and p‐fluoro‐hexbutinol (4) (stereochemical purity > 99.8%) for muscarinic receptors in rabbit vas deferens (M1), guinea‐pig atria (M2) and guinea‐pig ileum (M3) were measured by dose‐ratio experiments.
The (R)‐enantiomers consistently showed higher affinities than the (S)‐isomers. The stereoselectivity ratios [(R)/(S)] were greatest with the enantiomers of 1 (vas deferens: 550; ileum: 191; atria: 17) and least with those of the p‐Fluoro‐analogue 4 (vas deferens: 34; ileum: 8.5; atria: 1.7).
The enantiomeric potency ratios for compounds 1–4 were highest in rabbit vas deferens, intermediate in guinea‐pig ileum and much less in guinea‐pig atria. Thus, these ratios may serve as a predictor of muscarinic receptor subtype identity.
(S)‐p‐Fluoro‐hexbutinol [(S)‐4] showed a novel receptor selectivity profile with preference for M3 receptors: M3 > M2 ≥ M1.
These results do not conform to Pfeiffer's rule that activity differences between enantiomers are greater with more potent compounds.
Mediation of bradykinin‐induced contraction in canine veins via thromboxane/prostaglandin endoperoxide receptor activation
Authors: Aksoy Mark O. , Harakal Concetta , Smith J. Bryan , Stewart Gwendolyn J. , Zerweck Charles R. 
Published: July 2012

Canine jugular and femoral veins were studied to determine the possible importance of thromboxane (TXA2) and prostaglandin endoperoxides (prostaglandin H2, PGH2) in mediating bradykinin(BK)‐induced contraction.
Isolated vein rings incubated in modified Krebs solution contracted to TXA2/PGH2 analogs SQ26655 and U44069 with potency of contraction exceeding that for BK. The potency ranking for both veins was SQ26655 > U44069 > BK > PGF2α > TXB2 > PGD2.
The cyclo‐oxygenase inhibitors indomethacin (3 × 10−7 m) and flufenamic acid (10−5 m) reduced BK contractions without affecting those induced by noradrenaline (NA).
TXA2/PGH2 receptor antagonists SQ29548 (10−8 m) and BM13177 (10−6 m) strongly inhibited BK‐induced tension. The action of antagonists was reversible with negligible influence on NA‐elicited contraction. Selective removal of endothelium had no effect on BK‐induced contraction or the action of the antagonists.
The thromboxane synthase inhibitors dazoxiben (10−4 m) and CGS 12970 (10−5 m) had no significant inhibitory effect on BK‐induced tension.
These results suggest that in canine jugular and femoral vein, the action of BK is largely dependent upon stimulation of the cyclo‐oxygenase pathway to produce PGH2 and possibly TXA2, which can activate a smooth muscle TXA2/PGH2 receptor to elicit vasoconstriction.
Suppression by neuropeptide Y of capsaicin‐sensitive sensory nerve‐mediated contraction in guinea‐pig airways
Authors: Grundemar Lars , Grundström Nils , Johansson Irene G.M. , Andersson Rolf G.G. , Håkanson Rolf 
Published: July 2012

In the present study we have examined whether neuropeptide Y (NPY) interferes with non‐adrenergic, non‐cholinergic nerve‐mediated contractions and relaxations in the guinea‐pig airways. In these experiments we have used ring preparations of bronchi and trachea, incubated in the presence of atropine, propranolol and indomethacin (each 1 μm).
The contractile response to electrical stimulation of non‐adrenergic, non‐cholinergic nerve fibres was suppressed by NPY and NPY 13–36 in a concentration‐dependent manner, these agents having similar inhibitory potencies. NPY caused a more complete inhibition than the C‐terminal fragment.
NPY affected neither the basal tension nor the substance P‐evoked contraction in the bronchi and trachea and did not interfere with nerve‐mediated, non‐adrenergic relaxation in the trachea.
On the basis of these results, it is suggested that NPY may act on the terminals of sensory neurones in the airways to prevent antidromic, excitatory neurotransmission by inhibiting transmitter release.
A bradykinin (BK)1 receptor antagonist blocks capsaicin‐induced ear inflammation in mice
Authors: Mantione Charles R. , Rodriguez Richard 
Published: July 2012

The effect of various peptide antagonists on capsaicin‐induced (250 μg per ear) ear inflammation has been examined.
Co‐administration of the substance P (SP) antagonist [d‐Pro2,d‐Trp7,9]SP at 100 and 300 μg per ear with capsaicin markedly attenuated oedema, whereas a vasopressin antagonist was ineffective.
Using the same scheme, the mixed BK2 and BK1 bradykinin (BK) antagonist NPC 567 (d‐Arg[Hyp3, d‐Phe7]BK) did not inhibit oedema at 100 μg per ear, but did inhibit at a higher dose (300 μg). The BK1 antagonist [Leu8,desArg9]BK produced significant inhibition at both doses.
When BK was used to induce ear inflammation (30 μg per ear), the SP antagonist inhibited ear oedema. Both BK receptor subtype antagonists inhibited inflammation with the BK1 being more potent than the BK2 antagonist.
These results suggest that BK1 along with BK2 receptors are located on capsaicin‐sensitive fibres, where they may modulate the degree of neurogenic inflammation.
Vascular effects of helodermin, helospectin I and helospectin II: a comparison with vasoactive intestinal peptide (VIP)
Authors: Grundemar Lars , Högestätt Edward D. 
Published: July 2012

Helodermin, helospectin I and helospectin II, peptides recently isolated from the salivary gland venom of Heloderma suspectum, were compared to vasoactive intestinal peptide (VIP) with respect to effects on systemic blood pressure and on isolated femoral arteries in the rat.
They all reduced blood pressure in a dose‐dependent manner; helodermin was less effective than VIP. However, at doses higher than 1 nmol kg−1 all four peptides reduced blood pressure to about the same extent.
The half‐life of the hypotensive effect of VIP was longer than that of helodermin and the helospectins.
VIP and helodermin were equally potent in relaxing femoral arteries precontracted with phenylephrine or prostaglandin F2α.
Helospectin I and II relaxed phenylephrine‐contracted vessels to the same extent as VIP but with a lower potency.
Addition of VIP 1 μm to preparations exposed to helodermin 1 μm or to either of the helospectins did not produce a further relaxation.
The findings indicate that VIP, helodermin and helospectin I and II have a similar profile of action and therefore may act on a common receptor.
Effect of quinine on the release of catecholamines from bovine cultured chromaffin cells
Authors: Tang R. , Novas M.L. , Glavinović M.I. , Trifaró J.‐M. 
Published: July 2012

The effects of quinine on catecholamine release from cultured bovine chromaffin cells were studied.
Quinine (25–400 μm) produced a dose‐related inhibition of catecholamine release in response to depolarizing concentrations (12.5–50 mm) of K+.
The inhibition of the secretory response to high K+ produced by quinine decreased with the increase in the extracellular concentration of Ca2+.
Stimulation of cultured chromaffin cells with 50 mm K+ produced a significant increase in Ca2+ influx. In the presence of 100 μm quinine a 54% inhibition of the K+‐induced Ca2+ influx was observed.
Quinine treatment of chromaffin cell cultures produced a small but significant decrease in membrane resting potential and a less pronounced depolarization in response to 50 mm K+.
The results suggest that the inhibition of the K+‐evoked release of catecholamines produced by quinine is at least partly due to a decrease in Ca2+ influx. Ca2+ influx is lower because quinine reduces the sensitivity of the membrane potential to changes in extracellular K+ but direct effects of quinine on Ca2+ channels cannot be excluded.