bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reversal of haemorrhagic shock in rats by cholinomimetic drugs
Authors: Guarini Salvatore , Tagliavini Simonetta , Ferrari William , Bertolini Alfio 
Published: July 2012

In an experimental model of haemorrhagic shock resulting in the death of all rats within 20–30 min, the intravenous (i.v.) injection of the tertiary amine cholinesterase inhibitor physostigmine (17–70 μgkg−1) induced a prompt, sustained and dose‐dependent improvement of cardiovascular and respiratory function, with marked increase in the volume of circulating blood and survival of all treated animals, at least for the 2 h of observation.
Similar results were obtained with the i.v. injection of the cholinoceptor agonist oxotremorine (5–25 μg kg−1), while neostigmine (54 or 70 μgkg−1), a quaternary cholinesterase inhibitor which cannot cross the blood‐brain barrier, had negligible effects.
The anti‐shock activities of oxotremorine and physostigmine were blocked by the intracerebroventricular injection of either of the combined nicotinic and M2‐muscarinic receptor antagonists gallamine and pancuronium, or of the nicotinic antagonist mecamylamine. They were also blocked by intraperitoneal injection of the adrenergic neurone blocking agent guanethidine, but they were not antagonized by either the combined M1‐ and M2‐muscarinic receptor antagonist atropine, the M1‐muscarinic receptor antagonist pirenzepine, or the M2‐muscarinic receptor antagonist 4‐diphenylacetoxy‐N‐methylpiperidine methobromide.
It is concluded that cholinomimetic drugs can reverse hypovolaemic shock through central activation (seemingly mediated by nicotinic receptors) of sympathetic tone, with mobilization and redistribution of the residual blood.
Kallikrein‐kinin system in the plasma of the snake Bothrops jararaca
Authors: Abdalla F.M.F. , Hiraichi E. , Picarelli Z.P. , Prezoto B.C. 
Published: July 2012

Bothrops jararaca venom (BJV) caused a fall in the carotid artery blood pressure of the anaesthetized snake. This effect was tachyphylactic and was potentiated by captopril, a kininase II inhibitor; it was partially antagonized by promethazine plus cimetidine and was not affected by atropine.
Similar hypotensive effects were obtained by administration of trypsin or a partially purified BJV kininogenase to the snake.
Incubation of Bothrops jararaca plasma (BJP) with trypsin released a substance (or substance(s) that produced hypotension in the snake but not in the rat; this hypotensive effect was also potentiated by captopril.
The trypsinised plasma contracted Bothrops jararaca isolated uterus, a pharmacological preparation weakly sensitive to bradykinin. Trypsinised plasma was inactive on pigeon oviduct and rat uterus and displayed a weak action on the guinea‐pig ileum. Similar effects were observed with incubates of a fraction of BJP, containing globulins, with a partially purified BJV kininogenase.
Like mammalian kinins, the substance(s) was(were) dialysable, thermostable in acid but not in alkaline pH, and inactivated by chymotrypsin but not by trypsin. Its(their) inactivation by BJP or BJP kininase II was inhibited by captopril.
These findings strongly suggest that, besides releasing histamine, BJV or trypsin release a kininlike substance (or substances) from the snake plasma.
Since BJV and other kininogenases active on mammalian plasmas were shown to be unable to release kinins from BJP, in experiments conducted on pharmacological preparations suitable for the assay of mammalian kinins, these data also suggest that the snake Bothrops jararaca, like birds, may have developed its own kallikrein‐kinin system.
Chronotropic and inotropic actions of amrinone, carbazeran and isobutylmethyl xanthine: role of phosphodiesterase inhibition
Authors: Shahid M. , Rodger I.W. 
Published: July 2012

The chronotropic and inotropic effects of amrinone, carbazeran and 3‐isobutyl‐1‐methyl xanthine (IBMX) were examined in isolated preparations of papillary muscle and right atria from rabbit heart. The effects of the drugs on cardiac phosphodiesterase and cyclic nucleotide content were also examined.
Amrinone (2.4 × 10−4 M‐2 × 10−3 M), carbazeran (9.1 × 10−6 M‐1.2 × 10−3 M), and IBMX (1.8 × 10−5 M‐4.5 × 10−4 M) produced concentration‐dependent positive inotropic responses of papillary muscle preparations, the rank order of potency being carbazeran = IBMX > amrinone. Sub‐threshold positive inotropic concentrations of all three compounds potentiated the positive inotropic effects of isoprenaline; leftward shifts in the concentration‐effect curves were 5 fold (IBMX), 11 fold (amrinone) and 46 fold (carbazeran).
Amrinone and IBMX produced concentration‐dependent positive chronotropic responses in isolated right atria and showed a similar rate selectivity to isoprenaline, but carbazeran elicited a decrease in beating frequency. None of these drugs potentiated the positive chronotropic effects of isoprenaline.
Concentrations of amrinone, carbazeran and IBMX that produced similar positive inotropic responses were associated with different increases in papillary muscle cyclic AMP and cyclic GMP concentrations.
All three compounds inhibited right atrial and ventricular phosphodiesterase, with amrinone being the least potent. There was, however, a marked difference between the IC50 and EC50 values for phosphodiesterase inhibition and positive inotropy. In contrast the positive chronotropic effects of amrinone and IBMX were observed in the same concentration ranges that produced phosphodiestrease inhibition.
The results indicate that amrinone possesses a similar rate/force selectivity to isoprenaline and IBMX. In contrast, carbazeran exerts both positive inotropic and negative chronotropic effects. Phosphodiesterase inhibition and elevation of intracellular cyclic AMP concentration may be involved, at least in part, in the cardiac effects of these drugs.
Comparison of the effects of isobutylmethylxanthine and milrinone on ischaemia‐induced arrhythmias and platelet aggregation in anaesthetized rabbits
Authors: Holbrook Mark , Coker Susan J. 
Published: July 2012

The aim of this study was to compare the effects of the non‐selective phosphodiesterase (PDE) inhibitor, isobutylmethylxanthine (IBMX) and the selective PDE III inhibitor, milrinone, in a rabbit model of acute myocardial ischaemia.
Coronary artery occlusion caused changes in the ST‐segment of the ECG and ectopic activity in all control rabbits. Ventricular fibrillation occurred in 10 out of 14 (71%) of these animals. Pretreatment with IBMX 100 μg kg−1 plus 10 μg kg−1 min−1, starting 10 min before coronary artery occlusion, reduced ischaemia‐induced ST‐segment changes and ventricular fibrillation occurred in only 10% of this group (n = 10). A similar dose of milrinone had no antiarrhythmic activity, whereas with a lower dose of milrinone, 30 μ g kg−1 plus 3 μgkg−1 min−1 (n = 10), only 30% of rabbits fibrillated and ST‐segment changes were attenuated.
Acute administration of both IBMX and milrinone reduced arterial blood pressure. With the higher dose of milrinone a significant effect was still present after 10 min of drug infusion. A greater hypotensive response to the higher dose of milrinone was observed in the rabbits which subsequently fibrillated during ischaemia. A marked tachycardia was also observed after administration of the higher dose of milrinone.
At the end of the experiment platelet aggregation was studied ex vivo. ADP‐induced aggregation was reduced by pretreatment of the rabbits with milrinone but not IBMX. Both PDE inhibitors enhanced the ability of isoprenaline to inhibit ADP‐induced platelet aggregation but milrinone was more effective, particularly at the higher dose.
The results demonstrate that IBMX was antiarrhythmic but that this activity was not directly related to inhibition of platelet aggregation. Adverse haemodynamic effects may explain the failure of milrinone to have similar activity during myocardial ischaemia.
Calcium antagonizes the magnesium‐induced high affinity state of the hepatic vasopressin receptor for the agonist interaction
Authors: Wang Hao , Gopalakrishnan Venkat , McNeill J. Robert , Sulakhe Prakash V. , Triggle Chris R. 
Published: July 2012

The present study describes the role of Ca2+ in the regulation of the hepatic vasopressin V1 receptor. With low concentrations of Ca2+, there was a small increase in [3H]‐arginine vasopressin ([3H]‐AVP) binding, but above 10 mm, Ca2+ decreased the binding of this agonist. In contrast, low concentrations of Mg2+ were associated with a dramatic concentration‐dependent increase in [3H]‐AVP binding, reaching a maximal effect of 650% above control at concentrations ranging between 1–5 mm. At higher concentrations of Mg2+, the stimulatory effect of this cation was less pronounced, falling to 210% of control at 100 mm Mg2+. Strikingly, Ca2+‐inhibited the stimulatory effect of Mg2+ in a concentration‐dependent fashion.
Saturation binding data revealed that Ca2+ (2 to 10 mm) per se promotes the high affinity conformation of the V1 receptor for the agonist binding with the KD decreased from a control value of 2.3 nm to 0.5 nm in the presence of 10 mm Ca2+. This effect was attenuated with an increase in Ca2+ above 10 mm. With an increase in Ca2+ to 20 mm, however, the Bmax for [3H]‐AVP binding was decreased. Ca2+ also decreased the high affinity/high capacity state (KD 100 pm) of the receptor induced by 1 mm Mg2+ for agonist interaction.
[3H]‐V1 antagonist binding was inhibited by both Ca2+ and Mg2+. The IC50 values (mean ± s.e.mean) for Ca2+ and Mg2+ were 32 ± 8 and 53 ± 9 mm respectively. Maximal inhibition achieved at 100 mm was 29% for Ca2+ and 42% for Mg2+. Both cations decreased the affinity and increased the capacity of the V1 receptor for the antagonist.
The results suggest that the divalent metal ion binding site(s) modulated by Mg2+ is also accessible to Ca2+. Although Ca2+ opposes the powerful stimulatory effects of Mg2+ on agonist binding, the effects of Ca2+ and Mg2+ on the Bmax of [3H]‐AVP binding were different, suggesting that the divalent cations may bind to two different sites, thereby regulating the affinity and the capacity characteristics of the V1 receptor.
Demonstration of extrapulmonary activity of angiotensin converting enzyme in intact tissue preparations
Authors: Lembeck F. , Griesbacher T. , Eckhardt M. 
Published: July 2012

The activity of angiotensin converting enzyme (ACE) has been studied on functional parameters of intact isolated preparations of extrapulmonary tissues. The conversion of angiotensin I (A I) to angiotensin II (A II) and the cleavage of bradykinin (BK) were used as indicators of ACE activity. Captopril was employed as a specific inhibitor of ACE.
Captopril augmented the BK‐induced contractions of the rat isolated uterus, the BK‐ and substance P‐induced contractions of the guinea‐pig ileum, and the BK‐induced venoconstriction in the isolated perfused ear of the rabbit. Degradation of BK by ACE was calculated to be 52% in the rat uterus and 75% in the rabbit perfused ear.
Captopril inhibited the A I‐induced contractions of the rat isolated colon, the A I‐induced vasoconstriction in the isolated perfused ear of the rabbit and the rise in blood pressure induced by i.a. injections of A I in pithed rats. Conversion of A I to A II was calculated to be 13% in the rat colon and 26% in the rabbit perfused ear.
From estimations of the A II activity (bioassay on the rat colon) in the effluent of the perfused ear of the rabbit after injections of A I into the arterial inflow cannula it was calculated that approximately one tenth of A I was converted to A II during a single passage through the ear (less than 15 s).
The present experiments suggest that the high activity of ACE in endothelium of blood vessels of extrapulmonary tissues may provide an additional (endothelium‐dependent) local vasoconstrictor mechanism by the rapid formation of A II and inactivation of BK. The ACE activity in non‐vascular smooth muscles, other than those of blood vessels, may also affect the physiological functions of these tissues.
Interactions between adenosine and phorbol esters or lithium at the frog neuromuscular junction
Authors: Sebastião A.M. , Ribeiro J.A. 
Published: July 2012

Interactions between the effects of adenosine or 2‐chloro‐adenosine (CADO) and the effects of substances that interfere with the phosphoinositides/protein kinase C transducing system or with the adenylate cyclase transducing system, on endplate potentials (e.p.ps), were investigated. The preparation used was the innervated sartorius muscle of the frog in which twitches had been prevented with high magnesium concentrations.
The activator of protein kinase C, 4β‐phorbol‐12,13‐diacetate (PDAc), reversibly increased the amplitude and the quantal content of e.p.ps and attenuated the inhibitory effects of adenosine and CADO on e.p.p. amplitude. The affinity of the adenosine receptor antagonist, 8‐phenyltheophylline, was not modified by PDAc.
The phorbol ester 4α‐phorbol‐12,13‐didecanoate, which does not activate protein kinase C, did not modify either e.p.p. amplitude or the inhibitory effect of adenosine on e.p.ps.
The inhibitor of protein kinase C, polymyxin B, reversibly decreased the amplitude and the quantal content of e.p.ps, prevented the enhancement caused by PDAc on e.p.p. amplitude, but did not modify the inhibitory effect of adenosine on e.p.ps. H‐7, another inhibitor of protein kinases, also decreased e.p.p. amplitude but did not modify the effect of PDAc on the amplitude of e.p.ps.
Lithium chloride, which alters phosphoinositide signal transduction by inhibiting the breakdown of inositol phosphates, reversibly increased the amplitude and the quantal content of the e.p.ps. In the presence of adenosine or CADO the effect of lithium on e.p.p. amplitude was markedly attenuated.
The activator of adenylate cyclase, forskolin, reversibly increased the amplitude and the quantal content of the e.p.ps. MDL 12,330A, an inhibitor of adenylate cyclase, irreversibly decreased e.p.p. amplitude, an effect which was prevented by forskolin. Neither forskolin nor MDL 12,330A modified the inhibitory effect of adenosine on e.p.ps.
The results suggest that the phosphoinositides/protein kinase C transducing system, but not the adenylate cyclase transducing system, might be involved in the inhibitory effect of adenosine on neuromuscular transmission.
Pharmacological properties of FPL 63547, a novel inhibitor of angiotensin‐converting enzyme
Authors: Carr R.D. , Higgs L. , Killingback P.G. , Nicol A.K. , O'Connor S.E. , Robson A. , Wells E. , Simpson W.T. 
Published: July 2012

FPL 63547, in its active diacid form, was a potent inhibitor of rabbit lung angiotensin converting enzyme (ACE) in vitro (IC50 0.51 nm).
In conscious normotensive dogs, FPL 63547 (10–300 μg kg−1 i.v.) produced prolonged, dose‐related inhibition of plasma ACE activity and angiotensin I pressor responses, without affecting basal blood pressure, heart rate or pressor responses to angiotensin II.
In anaesthetized dogs, FPL 63547 diacid (3–300 μg kg−1 i.v. cumulatively) produced dose‐related increases in cardiac output accompanied by falls in total peripheral resistance indicative of vasodilatation. Mild stimulation of cardiac rate and contractility was also observed. Enalapril diacid had a similar profile.
FPL 63547 was a highly effective antihypertensive agent after oral administration to spontaneously hypertensive rats (SHR) pretreated with a diuretic. It lowered systolic blood pressure (SBP) on acute administration over the range 3 × 10−7–10−5 mol kg−1 p.o. (⋍ 0.13–4.5 mg kg−1 p.o.). FPL 63547 was more potent than other ACE inhibitors tested, threshold active doses for lisinopril, enalapril and captopril being 10−6, 10−6 and 3 × 10−5 mol kg−1 p.o., respectively. The antihypertensive effects of FPL 63547, unlike those of enalapril and captopril, were of long duration.
The antihypertensive efficacy of FPL 63547 was also observed following chronic oral administration. A dose of 0.5 mg kg−1 day−1 once daily for 23 days produced a sustained reduction of SBP. By the end of the treatment period, SBP was significantly lowered both pre‐ and post‐dose, i.e. effective 24 h control had been achieved.
The profile of FPL 63547 is consistent with it being a potent, selective and long‐acting ACE inhibitor. As an antihypertensive agent in SHR it compared favourably with other members of this class with respect to potency and duration of action.
Ryanodine facilitates calcium‐dependent release of transmitter at mouse neuromuscular junctions
Authors: Nishimura Masakazu , Tsubaki Kikuko , Yagasaki Osamu , Ito Katsuaki 
Published: July 2012

Quantal release of transmitter was measured intracellularly at mouse neuromuscular junctions in the presence and absence of ryanodine (Rnd).
Rnd at concentrations up to 1 μm did not significantly alter the frequency of miniature endplate potentials (m.e.p.ps) in the presence or absence of Ca2+, suggesting that Rnd is unlikely to alter the internal concentration of Ca2+ ([Ca2+]i) at rest.
In a high‐K+ (10 mm) bathing solution, Rnd further potentiated the facilitatory effect of Ca2+ on the frequency (F, s−1) of m.e.p.ps. Rnd shifted the relationship between ln(F) and ln[Ca2+]o to lower concentrations.
In a high‐Mg2+ bathing solution, Rnd did not affect the frequency of m.e.p.ps at any value of [Ca2+]o. However, Rnd slightly but significantly increased the quantal content (m) of e.p.ps. It shifted the relationship between ln(m) and ln[Ca2+]o to lower concentrations. These results suggest that Rnd potentiates the quantal release of transmitter after depolarization of the membrane or nerve impulse, in keeping with the cooperativity of Ca2+ at the active site.
A series of two closely spaced nerve impulses produced a facilitation of transmitter release, as judged by the quantal content (m2) of the second response in relation to that of the first one (m1), m2/m1. Rnd did not change the ratio m2/m1. Thus Rnd is unlikely to affect the rapid phase of the sequestration of Ca2+ inside the nerve terminal.
High levels of K+ (5 mm) and caffeine (2 mm) potentiated both modes of transmitter release, in a manner dependent on [Ca2+]o. Caffeine did not potentiate facilitation of transmitter release.
These results indicate that Rnd facilitates the quantal release of transmitter presumably via an increase in [Ca2+]i by a manner different from that of high‐K+ or caffeine. The results suggest that Rnd probably affects calcium turnover in neuronal cells.
Hexocyclium derivatives with a high selectivity for smooth muscle muscarinic receptors
Authors: Micheletti R. , Schiavone A. , Cereda E. , Donetti A. 
Published: July 2012

The affinity of a number of derivatives of the muscarinic antagonist, hexocyclium, containing an amidine cationic head, for guinea‐pig cardiac and ileal receptors was investigated.
All the compounds studied displayed a greater affinity for muscular than for cardiac muscarinic receptors.
The 5 fold ileal selectivity of hexocyclium was increased by a number of chemical substitutions. The largest discrimination between receptors (about 200 fold) was found for the formamidine derivative.
The selectivity displayed by the hexocyclium derivatives stemmed from a greater decrease in affinity towards cardiac as compared to ileal receptors.
ω‐Conotoxin GVIA is a potent inhibitor of sympathetic neurogenic responses in rat small mesenteric arteries
Authors: Pruneau D. , Angus J.A. 
Published: July 2012

We have investigated the effects of the N‐type calcium channel blocker, ω‐conotoxin GVIA, on contractile responses to nerve stimulation, noradrenaline and KCl in rat small mesenteric arteries. In separate experiments, single and summated excitatory junctional potentials (e.j.ps) evoked by nerve stimulation were recorded with an intracellular electrode in the absence and presence of ω‐conotoxin.
Electrical field stimulation of intramural sympathetic nerves (30 V; 0.25 ms pulse width; 3 s train length; 4–24 Hz) caused frequency‐dependent contractions. Cumulative concentration‐response curves for the contractions induced by noradrenaline and KCl were constructed in the same preparations. Stimulation at 0.2 Hz and 10 Hz induced respectively single e.j.ps without contractions and summated e.j.ps associated with a contractile response.
ω‐Conotoxin (0.1 to 3 nm) inhibited markedly and in a concentration‐dependent manner both the contractions and e.j.ps to electrical field stimulation. The concentration‐response curves to exogenous noradrenaline and KCl remained unaffected.
The time‐course for the effects of ω‐conotoxin (0.3 to 3 nm) indicated a slow onset of action with at least one hour to achieve an equilibrium.
The experiments indicate that ω‐conotoxin acts prejunctionally to inhibit sympathetic neurotransmission in rat small arteries presumably by inhibition of noradrenaline release. We suggest that ω‐conotoxin could be a useful tool to study the control of vascular tone through the autonomic nervous system.
Bay K 8644, modifier of calcium transport and energy metabolism in rat heart mitochondria: a new intracellular site of action
Authors: Baydoun Anwar R. , Markham Anthony , Morgan Rae M. , Sweetman Alan J. 
Published: July 2012

The dihydropyridine Ca2+ channel agonist Bay K 8644 (10–200 μm) produced a concentration‐dependent increase in State 4 respiration in the rat heart mitochondria with the highest concentration (200 μm) increasing the rate from 33.1 ± 0.7 to 187.0 ± 13.3 ng atoms O2 consumed min−1 mg−1 protein.
Bay K 8644 (200 μm) reduced State 3 respiration from 247.2 ± 11.7 to 174.4 ± 0.06 ng atoms O2 min−1 mg−1 protein, reduced the respiratory control index (RCI) from 5.3 ± 0.45 to 1.1 ± 0.03 and reduced the ADP:O ratio from 2.75 ± 0.03 to 1.3 ± 0.15.
A similar, but smaller, stimulation of State 4 respiration was seen with nitrendipine (25–200 μm), the rate increasing from 22.6 ± 1.0 to 33.1 ± 1.8 ng atoms O2 consumed min−1 mg−1 protein in the presence of 200 μm nitrendipine.
Bay K 8644 (10–60 μm) increased the total Ca2+ uptake into rat heart mitochondria, the total increasing from 248.8 ± 8.4 to 406.9 ± 17.6 ng Ca2+ mg−1 protein at 60 μm Bay K 8644 (EC50 = 18.9 ± 1.4 μm).
Bay K 8644 (10–60 μm) produced a concentration‐dependent reduction in the Ca2+ influx rate (IC50 = 52.5 ± 2.8 μm). Similar effects were seen with (+)‐Bay K 8644 and (−)‐Bay K 8644.
Nitrendipine (40–120 μm) stimulated Ca2+ efflux from mitochondria preloaded with the ion; the efflux rate increasing from 2.9 ± 0.05 to 114.2 ± 6.2 nmol Ca2+ min−1 mg−1 protein (EC50 = 57.3 ± 1.3 μm).
These data indicate dihydropyridine‐induced changes in the activity of the mitochondrial Na+/Ca2+. antiporter pathway; nitrendipine causing stimulation and Bay K 8644 causing inhibition.
The effects of (−)‐daurisoline on Ca2+ influx in presynaptic nerve terminals
Authors: Lu Y. Ming , Liu G. Qing 
Published: July 2012

The effects of (−)‐daurisoline on 45Ca2+ uptake and [3H]‐γ‐aminobutyric acid ([3H]‐GABA) release from synaptosomes of rat cerebral cortex and on contractile activity of rat aorta were examined.
Application of (−)‐daurisoline (1–100 μm) produced concentration‐related inhibition of high K+‐stimulated 45Ca2+ uptake and [3H]‐GABA release (IC50 = 7.7 ± 0.9 μm and 10.0 ± 1.5 μm, respectively) in synaptosomes but verapamil was only weakly active.
Neither (−)‐daurisoline (100 μm) nor verapamil (100 μm) modified 45Ca2+ uptake in control medium (5 mM K+, resting uptake) and [3H]‐GABA release in Ca‐free medium (45 mM K+ basal release).
High K+ and noradrenaline‐evoked contractions of rat aorta were inhibited by both (−)‐daurisoline and verapamil.
In conclusion, (−)‐daurisoline, which differed from verapamil in its mode of blocking Ca2+ influx may be a potent Ca2+ antagonist of Ca2+ channels in neurones.