bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of milrinone and piroximone on intracellular calcium handling in working myocardium from the ferret
Authors: Gwathmey Judith K. , Morgan James P. 
Published: July 2012

The effects of milrinone and piroximone were compared to those of isoprenaline, dibutyryl adenosine 3′:5′‐cyclic monophosphate (dibutyryl cyclic AMP), forskolin, isobutylmethylxanthine, increased extracellular calcium ([Ca2+]o) and caffeine in ferret right ventricular papillary muscles that were loaded intracellularly with aequorin, a bioluminescent calcium indicator that emits light when it combines with calcium.
The positive inotropic action of each drug, except caffeine, was associated with an increase in the peak amplitude of the aequorin light signal (i.e. intracellular Ca2+ transient) reflecting an increased amount of calcium available for excitation‐contraction coupling; the positive inotropic effect of caffeine appears to occur by other mechanisms.
The time courses of the aequorin light signal and corresponding tension response were shortened by isoprenaline, forskolin, isobutylmethylxanthine, dibutyryl cyclic AMP, milrinone and piroximone; unchanged by increased [Ca2+]o and prolonged by caffeine, suggesting that the rates of Ca2+ release and uptake by the sarcoplasmic reticulum were respectively increased, unchanged or decreased by these groups of drugs.
Relative to changes in [Ca2+]o, the ratio of the peak of the aequorin light signal to the peak of the tension response was increased by isoprenaline, milrinone and piroximone, and decreased by caffeine, indicating that the Ca2+‐sensitivity of the myofilaments was respectively decreased, and increased by these drugs.
The effects of milrinone and piroximone on the amplitude and time course of the aequorin light signal, as they relate to changes in uptake and release of calcium from the sarcoplasmic reticulum and to changes in the sensitivity of the myofilaments to Ca2+, are consistent with the findings that positive inotropic doses of these agents act by increasing intracellular concentrations of cyclic AMP.
Higher doses of milrinone and piroximone produced negative inotropic effects that were characterized by diminution of developed tension but no change or an increase in the amplitude of the aequorin light signal, suggesting a decrease in the sensitivity of the contractile elements to Ca2+.
Toxic doses of milrinone, piroximone and isoprenaline were associated with development of a Ca2+‐overload state characterized by the presence of after‐glimmers, after‐contractions and dysrhythmias, and by decreased amplitude of both the aequorin light signal and tension response.
The negative inotropic and toxic effects of milrinone and piroximone can be explained only in part by increased intracellular concentrations of cyclic AMP; we suggest that these drugs may have other cardiac actions.
Clonidine and presynaptic adrenoceptor theory
Authors: Kalsner Stanley 
Published: July 2012

The effects of clonidine, a presumed selective presynaptic α2‐adrenoceptor agonist or partial agonist, were examined in guinea‐pig atria.
Split left atrial preparations were stimulated transmurally at 2 Hz with 100 pulses of 0.5 ms duration and the efflux of 3H‐transmitter determined.
Clonidine inhibited efflux at 3 × 10−8 M to 3 × 10−7 M by about 30%. Yohimbine, at a concentration (10−6 M) which caused a 3 fold increase in the release of 3H‐transmitter during field stimulation, did not alter the ability of clonidine to inhibit transmitter efflux.
At 10−6 M clonidine alone had no significant effect on the stimulation‐induced efflux of 3H‐transmitter, but in the presence of yohimbine (10−6 M), inhibited efflux by over 50%.
The inhibitory effect of noradrenaline (10−6M) on 3H‐transmitter efflux was antagonized by clonidine at 10−6M but not at 10−8M, although neither concentration of clonidine alone inhibited transmitter efflux.
The present findings indicate that the effects of clonidine on the efflux of noradrenaline from sympathetic nerves cannot be accommodated within the currently held view that the compound is an agonist or partial agonist on presynaptic α2‐adrenoceptors. It appears that clonidine has multiple sites of action few of which are antagonized by a concentration of the prototypical presynaptic antagonist yohimbine, which enhances efflux 3 fold.
Age‐related changes in the sensitivity to verapamil and sodium nitroprusside of vascular smooth muscle of rabbit aorta
Authors: Karaki H. , Nakagawa H. , Urakawa N. 
Published: July 2012

Age‐related changes in the sensitivity to verapamil and sodium nitroprusside were examined in isolated aortic strips of the rabbit.
In the aortae of newborn rabbits within 10 days of birth, the resting tone of the muscle was strongly reduced by sodium nitroprusside but not by either Ca‐deficient solution or by verapamil. High It‐induced contraction and noradrenaline‐induced contraction were both inhibited by verapamil or sodium nitroprusside.
In the aortae of 24 day‐old rabbits, resting tension was slightly reduced by sodium nitroprusside but not by verapamil. High K‐induced contraction was less sensitive to sodium nitroprusside than to verapamil whereas noradrenaline‐induced contraction was less sensitive to verapamil than to sodium nitroprusside.
In the aortae isolated from 60 day‐old or older rabbits, resting tension was not affected by either sodium nitroprusside or verapamil. High K‐induced contraction was inhibited by verapamil whereas sodium nitroprusside showed only a weak inhibitory effect. Noradrenaline‐induced contraction was inhibited by sodium nitroprusside although verapamil had only a slight inhibitory effect.
In the aortae of 1 day‐old and also in adult rabbits, noradrenaline induced an additional increase in muscle tension when applied during the sustained contraction induced by high K.
It is suggested that, in the newborn rabbit aorta, the voltage‐dependent Ca channel is sensitive to both verapamil and sodium nitroprusside and the sensitivity to sodium nitroprusside gradually decreases during maturation whereas the receptor‐linked Ca channel is also sensitive to both of the inhibitors at birth but the sensitivity to verapamil gradually decreases with age.
A comparison of several calcium antagonists on uterine, vascular and cardiac muscles from the rat
Authors: Granger Susan E. , Hollingsworth M. , Weston A.H. 
Published: July 2012

An assessment was made of the potencies of nifedipine, gallopamil, diltiazem, cinnarizine and salbutamol as inhibitors of tension development by the uterus and cardiovascular tissues from the term pregnant rat.
The rank order of potency was nifedipine > gallopamil > diltiazem for those preparations on which these compounds were potent, viz. spontaneous and oxytocin‐induced tension development of the uterus, spontaneous tension development of hepatic portal vein, potassium chloride (KCl)‐induced pressure rises of perfused mesenteric bed and electrically‐stimulated (0.5 Hz) ventricular muscle.
The rank order of potency of nifedipine, gallopamil and diltiazem was different for those preparations on which they exhibited low potency, viz. noradrenaline‐induced pressure rises of perfused mesenteric bed and tension development of aorta.
Gallopamil and diltiazem, but not nifedipine, were more potent against tension development by ventricular muscle stimulated at 2.5 Hz than at 0.5 Hz, suggesting that nifedipine interacts at a different site from the other compounds.
Cinnarizine was less potent than the other calcium antagonists on the uterus and portal vein, was the second most potent compound against KCl‐induced pressure rises of the mesenteric bed and was equipotent against responses to noradrenaline and KCl of the mesenteric bed (unlike the other compounds). This suggests that the site of action of cinnarizine differs from that of the other calcium antagonists.
Nifedipine, gallopamil and diltiazem, like salbutamol, exhibited selectivity for inhibition of tension development by the uterus relative to the cardiovascular tissues.
The effect of diltiazem on noradrenaline release
Authors: Wolchinsky Camille , Zsotér Thomas T. 
Published: July 2012

The effects of diltiazem in rat tail arteries and guinea‐pig vasa deferentia have been investigated.
Superfusion of the rat tail artery with diltiazem (10−6–10−4 M) resulted in a dose‐related increase in 3H‐overflow (P < 0.001) both in Wistar Kyoto (WKY) and in spontaneously hypertensive (SHR) rats. Release of 3H by transmural stimulation (1 Hz, 2 ms, 10 V) was also much greater in vessels perfused with diltiazem; this effect was dose‐dependent.
Diltiazem did not significantly alter the proportion of noradrenaline and its metabolites in 3H‐overflow, as analysed by column chromatography.
In the vasa deferentia of guinea‐pigs, diltiazem (10−9–10−5 M) increased spontaneous 3H‐release.
The results indicate that diltiazem acts on sympathetic nerves and causes the release of noradrenaline.
Potentiation by TRH of the effect of imipramine on the forced‐swimming test
Authors: Reny‐Palasse Véronique , Rips Richard 
Published: July 2012

Discovery of the potentiation of thyrotropin releasing hormone (TRH)‐induced hyperthermia in mice by antidepressants which activate α‐adrenergic systems instigated investigation of other relations between TRH and antidepressants.
For this study the forced‐swimming test using mice was chosen since this test is more sensitive for selection of antidepressants which modify catecholaminergic systems than for those affecting 5‐hydroxytryptaminergic systems.
The effects of imipramine were potentiated by TRH. The involvement of α‐adrenergic systems was then investigated in this effect since it is already known that these systems are directly implicated in the potentiation of TRH‐induced hyperthermia by some antidepressants. Then the involvement of opiate systems was investigated since endogenous opiates are implicated in the action of some antidepressants, and some interactions between TRH and opiate systems are known to exist.
TRH made effective a completely inactive dose of imipramine as small as 2 mg kg−1 (i.p.) or 1 μg per mouse (i.c.v.). Pretreatment by both α1‐ and α2‐adrenoceptor antagonists (phenoxybenzamine, 8 mg kg−1 i.p; phentolamine, 4 mg kg−1 i.p.) or by a α1‐adrenoceptor antagonist (prazosin, 2 mg kg−1 i.p.) did not prevent this potentiation. In contrast the α2‐adrenoceptor antagonist (Yohimbine, 2 mg kg−1 i.p.) blocked the TRH effect. The imipramine potentiation by TRH was blocked by pretreatment with an opiate antagonist (naloxone, 1 mg kg−1 i.p.) and the potentiation was decreased in morphine‐tolerant mice.
These data indicate that potentiation of the effects of imipramine on the forced‐swimming test does not seem to be associated with an increase of effective levels of noradrenaline in the synaptic clefts and suggest an interaction between TRH and the opiate systems.
Mode of stimulatory actions of cadmium ion on the mouse diaphragm
Authors: Fu W.M. , Lin‐Shiau S.Y. 
Published: July 2012

Effects of Cd2+ on the phrenic nerve‐diaphragm preparation of the mouse varied markedly in media containing various Ca2+ concentrations. In normal 2.5 mM Ca2+ medium, Cd2+ inhibited acetylcholine release from nerve endings without appreciable effect on the muscle membrane. However, Cd2+ elicited stimulatory effects on the muscle membrane in low Ca2+ medium (10−3–1 mM). These stimulatory effects included the induction of spontaneous contractions, augmentation of twitch responses to direct electrical stimulation and potentiation of the muscle contracture induced by acetylcholine, carbachol and high K+. By contrast, caffeine contracture was not affected by Cd2+.
Tetrodotoxin, procaine, cysteine and glycerol pretreatment abolished these stimulatory effects of Cd2+. Moreover, changing the ionic composition of the bathing medium to one containing low Na+, high K+, high Mg2+ or high Ca2+ also antagonized these effects of Cd2+. In contrast, low Mg2+ markedly potentiated the frequency of spontaneous contractions induced by Cd2+.
(+)‐Tubocurarine and β‐bungarotoxin had no effect on Cd2+‐induced spontaneous contractions indicating that they may be myogenic rather than neurogenic in origin.
By use of conventional microelectrodes, it was found that Cd2+ not only depolarized the muscle membrane but also induced spontaneous action potentials at a high frequency (173 ± 17 Hz).
It is concluded that increased Na+ permeability of the muscle membrane is the essential step bringing about spontaneous contractions. The binding of Cd2+ to ‐SH groups of the membrane is closely related to the induction of these effects.
Histamine‐induced inositol phospholipid breakdown in the longitudinal smooth muscle of guinea‐pig ileum
Authors: Donaldson J. , Hill S.J. 
Published: July 2012

The characteristics of histamine‐stimulated inositol phospholipid breakdown in slices of guinea‐pig ileal smooth muscle and cerebellum have been investigated.
In cerebellar slices the inhibition of the inositol phospholipid response to histamine by mepyramine was consistent with competitive antagonism of histamine H1‐receptors.
In slices of the longitudinal smooth muscle of guinea‐pig ileum, mepyramine produced only a weak inhibition of the response to histamine, at concentrations up to 1 μM. This was in striking contrast to the potent competitive antagonism of the H1‐mediated contractile responses obtained with mepyramine in this tissue.
The H1‐receptor antagonists (+)‐chlorpheniramine and promethazine similarly had no effect on the EC50 value for histamine in guinea‐pig ileum, while promethazine competitively antagonized the muscarinic receptor‐mediated inositol phospholipid response in this tissue (Ka 3.6 × 107 M−1).
Cimetidine, on its own, did not significantly inhibit the inositol phosphate accumulation elicited by histamine in ileum. In the presence of 0.2 μM mepyramine, cimetidine (0.1 mM) produced a small parallel shift of the histamine concentration‐response curve (Ka 3 × 104 M−1). This inhibition, however, was not consistent with antagonism of an H2‐receptor‐mediated response.
The effect of a range of histamine analogues on inositol phospholipid breakdown was determined. Dose‐response curves were constructed and characterized in terms of the EC50, slope and maximal response attainable relative to histamine.
The H1‐agonists, Nα, Nα‐dimethylhistamine, Nα‐methylhistamine, 2‐pyridylethylamine and 2‐thiazolylethylamine produced the largest accumulations of [3H]‐inositol‐1‐phosphate. A very weak response was produced by the H2‐selective agonist impromidine, while dimaprit (also H2‐selective) was without significant effect.
Mepyramine appeared to antagonize competitively the response to the H1‐selective agonist 2‐pyridylethylamine. This was in contrast to the data obtained with other H1‐agonists, where mepyramine produced only a small dextral shift of the agonist curves at low agonist concentrations and an increase in the Hill coefficient. This was particularly striking in the case of 2‐methylhistamine.
The results suggest that an H1‐receptor component in guinea‐pig ileum, may coexist with a larger inositol phospholipid response to histamine which is independent of the activation of H1‐ or H2‐receptors.
Pharmacokinetic and pharmacodynamic studies with two α‐adrenoceptor antagonists, doxazosin and prazosin in the rabbit
Authors: Hamilton Carlene A. , Reid John L. , Vincent John 
Published: July 2012

The cardiovascular effects of doxazosin, a quinazoline derivative related to prasozin were investigated and compared to prazosin in the rabbit.
Radioligand binding studies using rabbit cerebral membranes showed that both doxazosin and prazosin were roughly equipotent at displacing [3H]‐prazosin from specific binding sites. However, the lower pA2 value for doxazosin at α1‐adrenoceptors in isolated thoracic aorta preparations suggests a lower potency compared to prazosin.
The dose‐related pressor effects of intravenous phenylephrine were used to assess vascular α1‐adrenoceptor antagonism in vivo. There was a close agreement between α1‐adrenoceptor antagonist potency and maximum hypotensive effects with both doxazosin and prazosin. The α1‐adrenoceptor antagonist effects of doxazosin were more prolonged than those of prazosin.
Studies using either radioligand binding or pressor responses to B‐HT 920 showed that doxazosin did not show any significant affinity for the α2‐adrenoceptor. Similarly, no direct vasodilator effects were observed either in animals administered angiotensin II or in isolated thoracic aorta spiral strip preparations contracted with potassium.
Doxazosin has a longer terminal elimination half‐life than prazosin. The pharmacokinetics of doxazosin were linear over the dose range examined.
Following pharmacological ‘autonomic blockade’ and treatment with prazosin, doxazosin did not cause any further fall in blood pressure.
These observations suggest that doxazosin, like prazosin, appears to exert its hypotensive action through α1‐adrenoceptor antagonism. The prolonged fall in blood pressure and well sustained α1‐adrenoceptor antagonism after doxazosin raise the possibility of an active metabolite which also has α1‐adrenoceptor blocking properties.
Effects of pinaverium bromide and verapamil on the motility of the rat isolated colon
Authors: Baumgartner A. , Drack E. , Halter F. , Scheurer U. 
Published: July 2012

Pinaverium bromide was 30 times less potent than verapamil in inhibiting intraluminal pressure responses of in vitro rat colonic segments to barium chloride, acetylcholine, FK 33–824 or field stimulation.
The inhibitory effects of both verapamil and pinaverium bromide on the pressure responses to field stimulation were antagonized similarly by exogenous calcium administration.
These results support the concept that pinaverium bromide acts on calcium channels in the smooth muscle cell membrane.
Effects of noradrenaline, vasopressin and angiotensin on the Na‐K pump in rat isolated liver cells
Authors: Berthon Brigitte , Capiod Thierry , Claret Michel 
Published: July 2012

The effects of noradenaline (via α1‐adrenoceptors) and of the peptidic hormones vasopressin and angiotensin on the Na‐K pump have been studied in rat isolated liver cells.
The three hormones increased the cytosolic Ca concentration, stimulated the Na‐K pump and decreased the internal Na concentration of the cells. The effects were dose‐dependent and were blocked by the corresponding antagonists.
The simultaneous addition of maximal doses of noradrenaline and angiotensin or vasopressin were not additive suggesting that the hormones use a common mechanism to stimulate the carrier.
Incubating the cells in Ca‐free medium for long periods (Ca‐depletion) increased the Na‐K pump activity and reduced the stimulatory action of vasopressin, angiotensin and noradrenaline.
The effect of the Ca indicator quin2, used as an intracellular Ca chelator, was also studied. The cells were loaded with a maximal concentration of [3H]‐quin2 acetoxymethyl ester in the presence of external Ca for 6 min. The final cell content was 3.1 nmol quin2 mg−1 cell dry wt. In these cells the cytosolic Ca, as monitored from the fluorescence emission of the indicator, was about 200 nM and Na‐K pump activity was normal and the cells remained responsive to the three hormones.
Loading the cells with quin2 in the absence of external Ca reduced the [Ca]i from 200 nM to about 40 nM and increased the Na‐K pump activity but not as a result of a rise in internal Na concentration. In addition, the rat hepatocytes were no longer sensitive to the hormones.
It is proposed that Ca inhibits the Na‐K pump by binding the internal sites and that vasopressin, angiotensin and noradrenaline stimulate the carrier by interfering with the inhibitory Ca sites.
Changes in the mechanical properties of the longitudinal and circular muscle tissues of the rat myometrium during gestation
Authors: Izumi Hidetaka 
Published: July 2012

Changes in the mechanical properties of the longitudinal and circular muscle tissues of the rat myometrium during gestation were investigated.
In isolated longitudinal and circular muscles of the rat myometrium, spontaneous contractions and contractions per unit cross‐sectional area induced by 128 mM K+ and 1 × 10−5 M acetylcholine (ACh) increased with the progress of gestation. These increases appeared in longitudinal muscles to a greater extent than in circular muscles.
ACh induced the largest contraction for both intact muscle tissues, at all stages of gestation. In both muscle layers, the ACh‐induced contraction reached the same amplitude as the 1 × 10−5 M Ca‐induced contraction of skinned muscles, except for the longitudinal muscle at the 22nd day of gestation.
In Ca‐free solution containing 2 mM EGTA, ACh produced contraction in both intact muscle tissues at all stages and the amplitude was increased during the progress of gestation, whereas the It‐induced and spontaneous contractions ceased.
In saponin‐treated skinned muscles of both layers, the free Ca concentration required to produce contraction was lowered, the maximum amplitudes of the contraction were increased and the pCa‐tension relationships shifted to the left during the progress of gestation.
The results indicate that during the progress of gestation, Ca sensitivity of the contractile proteins and mechanical responses to agonists increased and that the properties of the intracellular Ca store site were also altered in both muscle layers.
Determination of the receptor selectivity of opioid agonists in the guinea‐pig ileum and mouse vas deferens by use of β‐funaltrexamine
Authors: Hayes A.G. , Sheehan M.J. , Tyers M.B. 
Published: July 2012

The irreversible inhibitor of μ‐opioid receptor‐mediated effects, β‐funaltrexamine (β‐FNA), was used to investigate the selectivity of various opioid agonists at μ‐opioid receptors in the electrically stimulated guinea‐pig ileum and mouse vas deferens preparations in vitro.
In the guinea‐pig ileum, pretreatment with β‐FNA (3 × 10−8 − 3 × 10−6 M) produced a concentration‐dependent antagonism of the inhibitory effect produced by the μ‐opioid receptor agonist [D‐Ala2, MePhe4, Gly(ol)5]enkephalin (DAGO). High concentrations of β‐FNA (3 × 10−6 − 1 × 10−5 M) also antagonized the inhibitory effects of the K‐opioid agonist U50488.
Pretreatment of guinea‐pig ileum with β‐FNA at 1 × 10−6 M resulted in blockade of the effect of some opioid agonists. The compounds which showed the largest rightward shifts in their concentration‐response curves, and hence the greatest μ/k opioid receptor selectivity, were nalbuphine, [D‐Ser2, Leu5]enkephalinyl‐Thr6(DSLET), morphine, DAGO and normophine. Responses to tifluadom, Mr 2034, ethylketocyclazocine, butorphanol, nalorphine, proxorphan and U50488 were not inhibited by β‐FNA.
In the mouse vas deferens, pre‐treatment with β‐FNA (1 × 10−6 M) produced a similar shift in the dose‐response curves for normophine as in the guinea‐pig ileum. The concentration‐response curves for the δ‐receptor agonists [D‐Ala2, D‐Leu5] enkephalin (DADLE) and DSLET were, however, also shifted, indicating that β‐FNA will also block δ‐opioid receptors.
Since β‐FNA does not block k‐opioid receptor‐mediated effects, it can be used in the guinea‐pig ileum preparation as a selective μ‐receptor inhibitor. However, its lack of selectivity between μ‐ and δ‐opioid receptors should be taken into account in many other isolated tissues and experiments in vivo.