bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of carbachol and (−)‐N6‐phenylisopropyladenosine on myocardial inositol phosphate content and force of contraction
Authors: Kohl Claudia , Linck Bettina , Schmitz Wilhelm , Scholz Hasso , Scholz Jens , Tóth Mathias 
Published: July 2012

The effects of carbachol and the A1‐adenosine receptor agonist (−)‐N6‐phenylisopropyladenosine (PIA) on force of contraction and inositol lipid metabolism were studied in electrically driven left auricles and papillary muscles isolated from guinea‐pig hearts. Both carbachol and PIA (0.01–10 μm) had concentration‐dependent negative inotropic effects in auricles. In papillary muscles PIA had no inotropic effect. Carbachol also had no inotropic effect at low concentrations (0.01–1 μm) but at 10–100 μm it exerted a slight positive inotropic effect.
In auricles and papillary muscles both carbachol and PIA concentration‐dependently increased inositol trisphosphate (IP3; significant at 1 μm). Accordingly phosphatidylinositol bisphosphate (PIP2), the precursor of IP3, was reduced. All effects of carbachol and PIA were antagonized by atropine (10 μm) and 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX; 20 μm) respectively, indicating receptor‐mediated effects.
In auricles the negative inotropic effects of carbachol and PIA preceded the increase in IP3.
In papillary muscles the increase in IP3 preceded the slight positive inotropic effect of carbachol, indicating that the M‐cholinoceptor‐mediated increase in IP3 and force of contraction may be related. However, PIA showed a comparable increase in IP3 but no inotropic effect, indicating a dissociation between those parameters.
In conclusion, in previous studies a close relation between increases in IP3 and force of contraction has been shown after α1‐adrenoceptor stimulation. The present study with carbachol supports this view. However, the present data for PIA could not show such a close relationship, questioning the role of IP3 as an endogenous regulator of force of contraction.
Different profiles of desensitization dynamics in guinea‐pig jejunal longitudinal smooth muscle after stimulation with histamine and methacholine
Authors: Leurs R. , Smit M.J. , Bast A. , Timmerman H. 
Published: July 2012

In the present study we investigated desensitization phenomena of guinea‐pig jejunal longitudinal smooth muscle responses after stimulation with 100 μm histamine or methacholine, using a superfusion method.
Histamine H1‐receptor‐mediated contractions appear to be rapidly reduced after application of 100 μm histamine. Muscarinic responses were not affected following desensitization with 100 μm histamine, indicating a homologous desensitization.
Initial contractions to 0.3 μm histamine were reduced by 90%, recovered quickly, but did not reach control levels within 1 h. Desensitization of histamine responses could be separated into two phases; a rapid, but transient, desensitization and a more sustained desensitization. As a consequence of this sustained effect the pD2 for histamine shifted from 6.7 ±0.1 (control) to 6.1 ±0.1 (desensitized).
Desensitization with 100 μm methacholine caused a heterologous desensitization, reflected by the development of a refractory period, in which neither histamine nor methacholine was able to elicit a contraction. After a few minutes responses to both agents recovered to control levels.
During the refractory period after methacholine desensitization, muscle strips were still responsive to 40 mm KCl but did not contract in response to 10 mm caffeine, suggesting that the heterologous desensitization is caused by a modification of an intracellular Ca2+‐store, which is used by both histamine and methacholine.
The recovery of the responses after methacholine desensitization was not dependent on extracellular Ca2+, suggesting that the recovery is not dependent on refilling of the intracellular Ca2+ store with extracellular Ca2+.
The protein kinase C activator, phorbol‐12,13‐dibutyrate, concentration‐dependently inhibited histamine‐ and methacholine‐induced contractions. Protein kinase C seems therefore not to be implicated in the observed homologous H1‐receptor desensitization.
These data suggest that different forms of desensitization can be distinguished in this model, each with a different time course and dependent on the applied stimulus.
The use of oxyhaemoglobin to explore the events underlying inhibition of platelet aggregation induced by NO or NO‐donors
Authors: Salvemini Daniela , Radziszewski Waldemar , Korbut Richard , Vane John 
Published: July 2012

Full inhibition of thrombin‐induced platelet aggregation was elicited by the least maximal platelet inhibitory concentrations of nitric oxide (NO; 7 ± 1 μm) or NO‐donors which included sodium nitroprusside (NaNp; 80 ± 13 μm), 3‐morpholinosydnonimine (SIN‐1; 3 ± 0.1 μm) or endothelial cells (EC; 2.36 ± 0.12 × 105) added 1 min before thrombin. Oxyhaemoglobin (oxyHb; 10 μm) administered 30s to 10 min after stimulation with thrombin caused a time‐dependent reversal of the inhibition induced by these agents. OxyHb was ineffective when these agents were co‐incubated with the non‐selective phosphodiesterase inhibitor 3‐isobutyl‐1‐methylxanthine (IBMX, 0.05 mm).
OxyHb did not reverse the platelet inhibition with IBMX (0.2 mm) or that caused by a selective guanosine 3′: 5′‐cyclic monophosphate (cyclic GMP) phosphodiesterase inhibitor 2‐O‐propoxyphenyl‐8‐azapurin‐6‐one, (M & B 22948; 20 μm). In addition, oxyHb did not reverse the inhibition with iloprost (1 nm) which inhibits platelet aggregation through stimulation of adenylate cyclase.
The inhibition of platelet aggregation by NO (7 ± 1 μm) or NaNp (80 ± 13 μm) was accompanied by a 13 fold increase in cyclic GMP levels occurring within 15 s of addition of these agents. In the continued presence of NO or NaNp, the reversing effect of oxyHb given 1 min after thrombin was associated with a pronounced decrease in cyclic GMP levels.
We conclude that the inhibition of platelet aggregation by activators of guanylate cyclase depends in the first few minutes on continuous stimulation of the enzyme in order to maintain intracellular concentrations of cyclic GMP, except when its breakdown is inhibited.
The addition of agents such as oxyHb after the inhibition of platelet aggregation offers another way of investigating the biochemical changes involved in maintaining platelets in an inactive state.
Pharmacological characterization of tachykinin‐stimulated inositol phospholipid hydrolysis in peripheral tissues
Authors: Suman‐Chauhan N. , Guard S. , Williams B.J. , Watling K.J. 
Published: July 2012

Tachykinin‐stimulated inositol phospholipid hydrolysis was examined in slices of rat parotid gland, hamster urinary bladder and guinea‐pig ileum longitudinal muscle.
In the presence of lithium, substance P and other naturally‐occurring and synthetic tachykinins induced large, dose‐dependent increases in [3H]‐inositol monophosphate accumulation.
In slices of rat parotid gland, [pGlu6,l‐Pro9]SP(6–11) was considerably more potent in stimulating inositol phospholipid hydrolysis than [pGlu6,d‐Pro9]SP(6–11).
In contrast, in slices of hamster urinary bladder, [pGlu6,d‐Pro9]SP(6–11) exhibited greater potency in evoking inositol phospholipid breakdown than [pGlu6,l‐Pro9]SP(6–11).
The differential selectivity of these C‐terminal fragments of substance P suggests that they may be useful tools for distinguishing between NK1 and NK2 receptors.
L‐659,837 and L‐659,874 antagonized eledoisin‐stimulated inositol phospholipid hydrolysis in slices of hamster urinary bladder. Neither compound significantly reduced substance‐P evoked inositol phospholipid breakdown in slices of rat parotid gland, or senktide‐induced inositol phospholipid hydrolysis in slices of guinea‐pig ileum.
L‐659,837 and L‐659,874 had no effect on the atropine‐sensitive, carbachol‐stimulated inositol phospholipid hydrolysis in slices of rat parotid gland.
These data further support the notion that L‐659,837 and L‐659,874 are potent and selective NK2 receptor antagonists.
Differences in hepatic drug accumulation and enzyme induction after chronic amiodarone feeding of two rat strains: role of the hydroxylator phenotype?
Authors: Pirovino M. , Honegger U. , Müller O. , Zysset Th. , Küpfer A. , Tinel M. , Pessayre D. 
Published: July 2012

It has previously been shown that the extent of hepatic phospholipidosis induced by chronic amiodarone treatment correlates with the degree of drug accumulation in liver tissue.
To investigate a possible influence of pharmacogenetic factors, biochemical and morphological investigations were carried out in two rat strains differing in debrisoquine hydroxylation.
Plasma and liver tissue concentrations of amiodarone and its main metabolite, desethyl‐amiodarone, were significantly higher in rats with deficient hydroxylation. Microsomal enzyme induction, drug cytochrome P‐450 complex formation and typical ultrastructural features of phospholipidosis were only seen in rats with deficient hydroxylation and in a more sensitive species, the guinea‐pig.
It remains to be seen whether deficient debrisoquine hydroxylation in man is associated with an increased susceptibility to amioadarone side effects.
Cardiac β‐adrenoceptor binding characteristics with age following adrenal demedullation
Authors: Turner Nihal , Houck Wayne T. , Boehm Cheryl , Roberts Jay 
Published: July 2012

The role of adrenal medullary catecholamines in the regulation of cardiac function becomes more important when adrenergic neural influences in the heart are decreased. Since adrenergic nervous input to the heart decreases with age, it would be expected that catecholamine influence on cardiac neuroeffector junction would increase.
Fischer‐344 rats of 6‐, 12‐ and 24‐months were adrenal demedullated or sham‐operated and the animals were killed at the end of two weeks. β‐Adrenoceptors were studied in the membrane preparations from the ventricles of rat hearts. [125I]‐iodopindolol was used as the radioligand. The density of β‐receptors (Bmax), dissociation constant (KD) and the ratio of cardiac β‐adrenoceptor subtypes were studied. The relative percentages of β‐receptor subtypes were determined by use of ICI 89,406 (β1‐selective antagonist) and ICI 118,551 (β2‐selective antagonist).
In 24‐month‐old animals which were adrenal demedullated, hydrocortisone replacement was employed for one week; the animals were killed one week later.
The data indicate that there was a diminution of the Bmax following adrenal demedullation at all ages but that the ratios of β1:β2‐adrenoceptors remain the same as in the controls (67:33). The effect of adrenal medullary catecholamines on cardiac β‐receptor binding characteristics did not seem to be influenced by age.
Regional haemodynamic effects of endothelin‐1 and endothelin‐3 in conscious Long Evans and Brattleboro rats
Authors: Gardiner S.M. , Compton A.M. , Bennett T. 
Published: July 2012

The regional haemodynamic effects of bolus doses (4 and 40 pmol) and infusions (12 and 120 pmol h−1) of endothelin‐1 and endothelin‐3 were assessed in conscious, Long Evans and Brattleboro (i.e. vasopressin‐deficient) rats, chronically‐instrumented with pulsed Doppler flow probes.
In both strains of rat the lower bolus dose of endothelin‐1 caused only a slight pressor effect, but there were marked renal and mesenteric vasoconstrictions and hindquarters vasodilatation.
The lower bolus dose of endothelin‐3 did not affect blood pressure significantly, although the changes in regional haemodynamics were qualitatively similar to those seen following endothelin‐1 in Long Evans and Brattleboro rats.
The higher dose of endothelin‐1 caused an initial hypotension accompanied by substantial hindquarters vasodilatations in Long Evans and Brattleboro rats. Subsequently, in both strains, there was a rise in blood pressure accompanied by renal, mesenteric and hindquarters vasoconstrictions.
The higher bolus dose of endothelin‐3 caused initial hypotension and hindquarters vasodilatation similar to those seen with endothelin‐1. However, the subsequent pressor effect was less with endothelin‐3, as was the renal vasoconstriction, and it did not cause any increase in hindquarters vascular resistance.
Infusion of endothelin‐1 at the lower rate (12 pmol h−1) caused renal and mesenteric vasoconstrictions in both strains of rat, whereas endothelin‐3 at this rate caused only mesenteric vasoconstriction.
Infusion of endothelin‐1 at the higher rate (120 pmol h−1) caused progressive hypertension and vasoconstrictions in all three vascular beds studied; these were similar in both strains of rat. Endothelin‐3 had a smaller pressor effect and a lesser constrictor action on the renal and mesenteric vascular beds; it did not constrict the hindquarters vascular bed.
These results show, that in conscious Long Evans and Brattleboro rats, the initial depressor effects of the higher bolus doses of endothelin‐1 and −3 were similar, and, hence, not influenced by the absence of endogenous vasopressin. Endothelin‐1 and −3 appear equipotent in their initial hyperaemic vasodilator effects in the hindquarters vasculature in both strains, making it unlikely that this effect is dependent on the release of atrial natriuretic peptide (ANP), since ANP does not cause significant increases in hindquarters blood flow in Brattleboro rats. The greater delayed pressor effect of endothelin‐1 is associated with its more marked vasoconstrictor effects on renal and mesenteric vascular beds and is accentuated, relative to endothelin‐3, by the lack of a constrictor effect of endothelin‐3 in the hindquarters vasculature.
In vitro cardiac models of dog Purkinje fibre triggered and spontaneous electrical activity: effects of nicorandil
Authors: Lathrop David A. , Nànàsi Pèter P. , Varrò Andràs 
Published: July 2012

The effects of nicorandil (30 μm and 100 μm) on two models of triggered activity [early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs)] and on spontaneous automaticity occurring from both normal and depolarized levels of membrane potential were examined in isolated cardiac Purkinje fibres of the dog. Standard intracellular microelectrode techniques were used.
Nicorandil (30 μm) abolished EADs provoked by superfusion with Tyrode solution containing 2.7 mm K+ and 3 mm Cs.
DADs were induced by 0.2 μm acetylstrophanthidin in Tyrode solution containing 5.4 mm K+. Nicorandil (30 μm) significantly reduced the amplitude of these DADs from 12.5 ± 2.5 mV to 5.5 ± 0.2 mV (P > 0.02, n = 6), while DADs were fully abolished by 100 μm nicorandil.
In unstimulated Purkinje strands, superfused with 2.7 mm K+ containing Tyrode solution having a pH of either 7.4 or 6.8, spontaneous depolarizations developed with a mean maximum diastolic potential (MDP) of −84.6 ± 1.6 mV (n = 9) or −54.0 ± 1.2 mV (n = 9), respectively. Nicorandil significantly reduced the frequency of this automatic activity and caused its cessation, at either level of MDP. Nicorandil, however, produced significant hyperpolarization only when automaticity occurred from the depolarized level of potential.
These results suggest that nicorandil may exert significant antiarrhythmic actions in vivo by abolishing both spontaneous and triggered electrical activity.
β1‐Adrenoceptors mediate smooth muscle relaxation in mouse isolated trachea
Authors: Henry Peter J. , Goldie Roy G. 
Published: July 2012

The relaxant effects to the β‐adrenoceptor agonists isoprenaline, adrenaline, noradrenaline, RO363, procaterol and fenoterol were investigated in carbachol‐contracted mouse isolated tracheal preparations.
The order of potencies for those β‐adrenoceptor agonists that induced full relaxation of carbachol‐contracted mouse tracheal preparations was isoprenaline > RO363 > noradrenaline = adrenaline > fenoterol. The EC50 value of isoprenaline for relaxation was 46 nm. The β1‐adrenoceptor‐selective agonist, RO363, was ten times more potent than the β2‐adrenoceptor‐selective agonist, fenoterol. The highly β2‐adrenoceptor‐selective agonist procaterol was a partial relaxant and induced only 28 ± 4% relaxation.
Relaxations induced by noradrenaline and isoprenaline were not significantly affected by the neuronal uptake inhibitor, cocaine (10 μm) or by the extraneuronal uptake inhibitor, deoxycorticosterone acetate (25 μm) respectively. The α‐adrenoceptor agonist methoxamine induced no observable elevation of mouse tracheal smooth muscle tone.
Schild plots for the β‐adrenoceptor antagonists, atenolol and betaxolol (β1‐adrenoceptor‐selective) and ICI 118,551 (β2‐adrenoceptor‐selective) were linear, with slope values approaching unity. Mean pA2 values derived for atenolol, betaxolol and ICI 118,551 for antagonism of β‐adrenoceptor‐mediated relaxation were 7.1, 8.4 and 7.2, respectively. These data were independent of the use of isoprenaline or noradrenaline as the agonist.
These findings indicate that β‐adrenoceptor‐mediated relaxations of mouse isolated trachea occur predominantly through activation of β1‐adrenoceptors.
Distribution of β1‐ and β2‐adrenoceptors in mouse trachea and lung: a quantitative autoradiographic study
Authors: Henry Peter J. , Rigby Paul J. , Goldie Roy G. 
Published: July 2012

Binding and quantitative autoradiography were used to detect [125I]‐iodocyanopindolol (I‐CYP) associated with β1‐ and β2‐adrenoceptors in mouse tracheal epithelium and airway smooth muscle as well as in lung parenchymal tissue.
Specific I‐CYP binding to slide‐mounted tissue sections of both trachea and parenchyma was of high affinity (KD = 49.0 pm, n = 3, trachea; KD = 118.9 pm, n = 3, parenchyma) and saturable, involving single populations of non‐interacting binding sites (Hill coefficient nH = 1.00 ± 0.02, trachea; nH = 0.99 ± 0.03, parenchyma).
Direct measurement of tissue radioactivity also showed that specific I‐CYP binding was competitively inhibited in the presence of the β‐adrenoceptor antagonists (−)‐propranolol (non‐selective), CGP 20712A (β1‐selective) and ICI 118,551 (β2‐selective). Analysis of the competition binding curves for the two selective antagonists revealed mixed populations of β1‐ and β2‐adrenoceptors in the approximate proportions 33% and 67% respectively in mouse trachea and 28% and 72% respectively in mouse lung parenchyma.
Densities of autoradiographic grains derived from specific I‐CYP binding to alveolar wall tissue and to tracheal epithelium and airway smooth muscle were quantified by a computer‐assisted image analysis system, which allowed the construction of competition binding curves in the presence of the selective β‐adrenoceptor antagonists CGP 20712A and ICI 118,551. Analysis of these data demonstrated that in alveolar wall, β1‐ and β2‐adrenoceptors co‐existed in the proportions 18% and 82%, respectively.
Quantitative autoradiographic analyses also showed that β1‐ and β2‐adrenoceptors were differentially distributed in tracheal epithelium and airway smooth muscle. The β2‐adrenoceptor subtype accounted for 71% of all β‐adrenoceptors in epithelium. Conversely, β1‐adrenoceptors which mediate relaxant responses of mouse trachea to β‐adrenoceptor agonists (Henry & Goldie, 1990), accounted for 69% of all β‐adrenoceptors in the airway smooth muscle.
Differential inhibition by two hetrazepine PAF antagonists of acute inflammation in the mouse
Authors: Henriques Maria G.M.O. , Weg Vivian B. , Martins Marco A. , Silva Patricia M.R. , Fernandes Patricia D. , Cordeiro Renato S.B. , Vargaftig B.B. 
Published: July 2012

The injection of 100 or 300 μg of carrageenin into the mouse paw or pleural cavity produced a delayed inflammatory reaction at 48 h while platelet activating factor (PAF)‐induced paw oedema and pleurisy were maximal 30 min after its injection.
The PAF antagonist, WEB 2086, failed to inhibit mouse paw oedema and pleurisy induced by PAF, but reduced the first phase of oedema (1–4 h) induced by carrageenin without interfering with the second one (48–72 h). In contrast, another structurally‐related PAF antagonist, WEB 2170, inhibited dose‐dependently both oedema and pleurisy induced by PAF and by carrageenin (48 h).
Repeated injections of PAF into the mouse paw or pleural cavity led to significant auto‐desensitization. The animals desensitized to PAF and injected with carrageenin also displayed a significantly reduced oedema.
Our results suggest that PAF may be involved in the inflammatory response to carrageenin in mice. Furthermore, because the different receptor antagonists displayed distinct effects against PAF itself, different sites for in vivo interaction of PAF are available and are species‐ and drug‐dependent.
Motor response of the human isolated small intestine and urinary bladder to porcine neuromedin U‐8
Authors: Maggi Carlo Alberto , Patacchini Riccardo , Giuliani Sandro , Turini Damiano , Barbanti Gabriele , Rovero Paolo , Meli Alberto 
Published: July 2012

Porcine neuromedin U‐8 produced a concentration (0.3 nm−1 μm)‐dependent contraction of the longitudinal muscle of the human isolated ileum, which was unaffected by either atropine (1 μm) or tetrodotoxin (1 μm).
By contrast, neuromedin U‐8 had only a weak effect on the circular muscle of the human isolated ileum.
Neuromedin U‐8 also produced a concentration‐dependent contraction of mucosa‐free muscle strips from the dome of the human isolated urinary bladder, its action being unaffected by either atropine or tetrodotoxin.
These findings indicate that neuromedin U‐8 exerts a direct contractile effect on smooth muscle of the human intestinal and urinary tract.
Developmental changes in β‐adrenoceptors, muscarinic cholinoceptors and Ca2+ channels in rat ventricular muscles
Authors: Kojima Michio , Ishima Tsuyoshi , Taniguchi Norihisa , Kimura Kiyoshi , Sada Hideaki , Sperelakis Nicholas 
Published: July 2012

In an attempt to explain the previous electrophysiological data on the ontogeny of β‐adrenergic and muscarinic cholinergic interactions on cardiac Ca2+ current, biochemical studies were performed on the ontogeny of β‐adrenoceptors, muscarinic cholinoceptors and Ca2+ channels in cardiac muscle of developing rats: 16–20 days old foetuses, 0–20 days old neonates, and 2–3 months old adults.
Developmental changes in cardiac β‐adrenoceptors, muscarinic cholinoceptors, and Ca2+ channels were determined with the use of specific radioligands, [3H]‐dihydroalprenolol (DHA), [3H]‐quinuclidinyl benzilate (QNB), and [3H]‐nitrendipine (NTD), respectively.
The Bmax value (fmol mg−1 tissue) for [3H]‐DHA binding started to increase on post‐gestation day 20, reached almost its maximum level on neonatal day 6, kept almost the same level until neonatal day 20, and then decreased slightly to its adult level.
The Bmax value (fmol mg−1 tissue) for [3H]‐QNB binding started to increase on post‐gestation day 16, reached almost its maximum level on neonatal day 0, remained almost constant until neonatal day 15, and then decreased to its adult level.
The Bmax value (fmol mg−1 tissue) for [3H]‐NTD binding increased with age between post‐gestation day 18 and neonatal day 15, stayed almost constant until neonatal day 20, and then decreased to its adult level.
The Kd values for [3H]‐DHA, [3H]‐QNB, and [3H]‐NTD bindings remained almost constant during the developmental period examined.
Isoprenaline (Iso) increased the of slow action potentials (APs) from post‐gestation day 18, and the adult level was reached at about 2 weeks after birth; this developmental time course is similar to that of Ca2+ channels. The number of β‐adrenoceptors also started to increase a few days before birth, but attained its peak about one week earlier than did the of slow APs or the number of Ca2+ channels.
Acetylcholine (ACh) almost completely abolished the Iso‐induced increase in observed from post‐gestation day 18 to neonatal day 20; this developmental time course for the ACh effect is consistent with the finding that the number of muscarinic cholinoceptors started to increase on post‐gestation day 16 and reached a peak on the day of birth.
Previous electrophysiological and the present biochemical findings strongly suggest that the functional coupling between muscarinic cholinoceptors and Ca2+ current is already established when the coupling between β‐adrenoceptors and Ca2+ current starts to operate in developing rat hearts.