bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of oxodipine on 45Ca movements and contractile responses in vascular smooth muscle
Authors: Tamargo J. , Tejerina T.
Published: July 2012

The inhibitory effects of oxodipine, a new dihydropyridine, were compared with those of nifedipine on contractile responses in rat isolated aortic strips and on spontaneous mechanical activity in portal vein segments.

In rat isolated aorta oxodipine (IC50 = 7.8 ± 1.8 × 10−9 m) and nifedipine (IC50 = 8.5 ± 2.5 × 10−9 m) dose‐dependently inhibited the contractile responses induced by high K (80 mm), whereas responses to noradrenaline (NA, 10−6 m) were only slightly affected (IC50 > 10−7 m). These inhibitory actions were observed with both drugs added either before or after the induced contractions.

Contractile responses induced by addition of Ca to 0 Ca high‐K solution were also dose‐dependently inhibited by oxodipine (IC50 = 4.5 ± 2.5 × 10−9 m). However, oxodipine up to 10−6 m did not modify the contractile responses obtained in strips incubated in 0 Ca when Ca was added in the presence of NA.

Oxodipine and nifedipine also inhibited the development of spontaneous mechanical activity in portal vein segments.

Oxodipine inhibited 45Ca uptake stimulated by high K (I50 = 8.7 ± 2.5 × 10−9 m) or by NA (I50 > 10−7 m). However, it did not modify 45Ca uptake and 45Ca efflux in resting strips or 45Ca efflux stimulated by NA.

These results indicate that the effects of oxodipine on vascular smooth muscle may be due to the blockade of Ca entry through potential‐ and receptor‐operated channels; it was at least 10 times more selective for potential‐operated channels. Oxodipine did not modify Ca entry through passive leak channels and NA‐induced intracellular Ca release.
Arachidonic acid‐induced mobilization of calcium in human neutrophils: evidence for a multicomponent mechanism of action
Authors: Naccache Paul H. , McColl Shaun R. , Caon Adriana C. , Borgeat Pierre
Published: July 2012

The mechanism(s) involved in the mobilization of calcium induced by arachidonic acid in human neutrophils was investigated.

The addition of arachidonic acid to a suspension of human neutrophils led to a time‐ and concentration‐dependent mobilization of calcium which was the result of two separate and experimentally differentiable processes. The latter consisted of a rapid and transient phase followed by a slower and more sustained response.

The initial phase of calcium mobilization elicited by arachidonic acid was decreased in the presence of EGTA, inhibited by pertussis toxin as well as by nordihydroguaiaretic acid (NDGA), and diminished following a pre‐incubation with leukotriene B4, but not platelet‐activating factor.

The characteristics of the first phase of the mobilization of calcium were consistent with an interaction of the fatty acid with the leukotriene B4 receptors, either directly or indirectly following the synthesis of leukotriene B4, as well as with a release of internal calcium.

The second, slower and more sustained phase of calcium mobilization was more apparent at high concentrations (≥8–16 μm) of arachidonic acid, and was relatively insensitive to pertussis toxin, EGTA or NDGA.

The characteristics of the ‘slow’ phase of calcium mobilization by arachidonic acid are consistent with its being associated primarily with a release of calcium from internal storage pools.

The data presented indicate that the mechanism of mobilization of calcium by arachidonic acid in human neutrophils is complex and involves specific activation pathways employed, in part at least, by other neutrophil agonists. These findings may have relevance to various inflammatory situations in which the elevated levels of extracellular arachidonic acid known to be present could modulate the functional responsiveness of the neutrophils to other stimuli.
Identification of M1 muscarinic receptors in pulmonary sympathetic nerves in the guinea‐pig by use of pirenzepine
Authors: Maclagan Jennifer , Fryer Allison D. , Faulkner David
Published: July 2012

The effect of pirenzepine, a muscarinic antagonist considered to be selective for M1 receptors, was studied on bronchoconstriction and bradycardia elicited by preganglionic stimulation of the parasympathetic vagal nerves and by i.v. injections of acetylcholine (ACh) in anaesthetized guinea‐pigs.

Pirenzepine was equipotent in the heart and lung as an antagonist of the effects of i.v. ACh at postjunctional muscarinic receptors. Doses of pirenzepine in excess of 1 μmol kg−1 abolished all muscarinic responses consistent with non‐selective blockade of M3 receptors on airway smooth muscle and M2 receptors on atrial cells.

In the lung, low doses of pirenzepine (1–100 nmol kg−1) increased vagally‐induced bronchoconstriction despite concurrent partial blockade of the postjunctional receptors. This suggests blockade of neuronal muscarinic receptors.

Propranolol (1 mg kg−1) increased control bronchoconstrictor responses elicited by ACh and vagal stimulation but did not alter the potency of pirenzepine for postjunctional receptors in heart or lung. However, pirenzepine‐induced enhancement of vagally‐induced bronchoconstriction was abolished by propranolol, suggesting that pirenzepine may be an antagonist for muscarinic receptors located in the sympathetic nerves innervating airway smooth muscle.

These results confirm that bronchoconstrictor stimuli indirectly initiate activation of an opposing sympathetic reflex in the guinea‐pig lung. This response is facilitated by muscarinic receptors located in the sympathetic nervous pathway.

The high potency of pirenzepine for the neuronal receptors in the sympathetic nerves suggests that these are M1 receptors. In contrast, the parasympathetic nerves innervating airway smooth muscle in this species contain M2 receptors which inhibit neurotransmission.
Beneficial effect of amosulalol and phentolamine on post‐hypoxic recovery of contractile force and energy metabolism in rabbit hearts
Authors: Tanonaka Kouichi , Matsumoto Masayo , Minematsu Reiko , Miyake Keiko , Murai Reiko , Takeo Satoshi
Published: July 2012

The effects of phentolamine, an α‐adrenoceptor blocking agent and amosulalol, an α1 and β‐adrenoceptor antagonist on hypoxia‐induced impairment in cardiac function and metabolism were examined using the isolated heart Langendorff preparation of the rabbit.

Hypoxia induced cessation of cardiac contractile force, a rise in resting tension, a decrease in myocardial high‐energy phosphates, an increase in tissue calcium content and the release of ATP metabolites from the heart. Subsequent reoxygenation resulted in little recovery of cardiac contractile force, and there were further increases in tissue calcium content and in the release of creatine kinase from the heart.

Treatment of hypoxic hearts with either 83 μm phentolamine or 45 μm amosulalol resulted in a suppression of the rise in resting tension, the tissue calcium accumulation and the release of creatine kinase and ATP metabolites during hypoxia. This treatment also elicited significant recovery of cardiac contractile force, restoration of myocardial high‐energy phosphates, suppression of the release of creatine kinase and the accumulation of tissue calcium during reoxygenation. Both 83 μm phentolamine and 45 μm amosulalol exerted a significant prolongation of the effective refractory period of rabbit isolated atria.

Lower concentrations of phentolamine (16 μm) and amosulalol (9 μm), which are sufficient to exert an α‐adrenoceptor blocking action, did not elicit an appreciable effect on the post‐hypoxic recovery of cardiac contractile force.

These results suggest that phentolamine and amosulalol are capable of protecting the myocardium from hypoxia‐induced derangements in cardiac function and metabolism. This effect is probably attributable to their membrane stabilizing effect, rather than to their α‐adrenoceptor blocking action.
Effects of amiloride in guinea‐pig and rat left atrial contraction as affected by frequency of stimulation and [Ca2+]0‐[Na+]0 ratio: role of Na+/Ca2+exchange
Authors: Cargnelli Gabriella , Bova Sergio , Luciani Sisto
Published: July 2012

The effect of amiloride (0.5 mm) on guinea‐pig and rat left atria driven at various rates of stimulation and different [Ca2+]0‐[Na+]0 ratios has been studied.

Amiloride elicited a positive inotropic response in guinea‐pig left atria driven at 0.1 Hz, 0.5 Hz and 1 Hz when [Ca2+]0 was 3.6 mm, 1.8 mm and 0.9 mm respectively but not when [Ca2+]0 was 2.7 mm at 0.1 Hz, 0.9 mm at 0.5 Hz and 0.45 mm at 1 Hz.

A positive inotropic response was obtained in guinea‐pig left atria driven at 0.1 Hz and 1 Hz when [Ca2+]0‐[Na+]20 was increased respectively from 8 × 10−5 to 16 × 10−5 and from 2 × 10−5 to 8 × 10−5. The positive inotropic effect was evident only when the ratio was increased by increasing [Ca2+]0 and not by decreasing [Na+]0.

In the presence of amiloride, the force of contraction of guinea‐pig left atria decreased instead of increasing, when the rate of stimulation was lowered from 1 Hz to 0.01 Hz. Amiloride inhibited the post‐rest potentiation.

In rat left atria amiloride was devoid of any effect in all the above‐mentioned experimental conditions.

It is suggested that the pattern of cardiac actions of amiloride can be explained by the inhibition of the Na+/Ca2+ exchange system.
The role of GABAA receptor function in peristaltic activity of the guinea‐pig ileum: a comparative study with bicuculline, SR 95531 and picrotoxinin
Authors: Tonini Marcello , de Petris Giovanni , Onori Luciano , Manzo Luigi , Rizzi Carlo A. , Crema Antonio
Published: July 2012

The peristaltic activity of the guinea‐pig ileum was studied in the absence and in the presence of the blockade of GABAA receptors.

Bicuculline (1–30 μm), improved at the highest concentrations the efficiency of peristalsis by enhancing the frequency of propulsive contractions and the amount of fluid ejected per unit of time.

Neither SR 95531 (0.3–10 μm), a novel GABAA receptor antagonist, which competitively antagonized 3‐aminopropane sulphonic acid induced contractions in myenteric plexus‐longitudinal muscle preparations (pA2 value: 6.47), nor picrotoxinin (1–30 μm) modified peristaltic parameters or influenced the potentiating effect of bicuculline on peristaltic activity.

In myenteric plexus‐longitudinal muscle preparations, bicuculline (1–30 μm) enhanced the amplitude of electrically‐induced cholinergic contractions without modifying submaximal contractions to applied acetylcholine. SR 95531 and picrotoxinin had no effect on twitch amplitude. In the presence of each of these compounds, bicuculline retained its potentiating effect.

The results obtained with SR 95531 and picrotoxinin question the view that GABAA receptors may exert a critical role in intestinal propulsion by modulating the activity of nerve pathways subserving peristalsis. Bicuculline potentiates the peristaltic activity of the ileum probably via a facilitatory effect on enteric cholinergic transmission that is independent of GABAA receptor blockade.
Evidence for prazosin‐resistant, rauwolscine‐sensitive α‐adrenoceptors mediating contractions in the isolated vascular bed of the rat tail
Authors: Templeton A.G.B. , Macmillan J. , McGrath J.C. , Storey N.D. , Wilson V.G.
Published: July 2012

The postjunctional α‐adrenoceptors mediating contractions in the isolated vascular bed of the perfused rat tail have been investigated, in the presence and absence of an increase in perfusion pressure by arginine vasopressin (AVP).

In the absence of AVP, bolus doses of noradrenaline (NA) and phenylephrine produced pressor responses of similar time course, while UK‐14,304 was practically inactive. Responses to noradrenaline were inhibited more by 0.05 μm prazosin than by 1 μm rauwolscine, suggesting the presence of α1‐adrenoceptors.

Following a sustained elevation in perfusion pressure by AVP, both UK‐14,304 and NA (the latter in the presence of 0.05 μm prazosin to inhibit α1‐adrenoceptors) elicited dose‐dependent pressor responses. The maximum response to UK‐14,304 under these conditions was approximately 30% of the maximum response to NA in the absence of prazosin and AVP. Responses to phenylephrine were not affected by the AVP‐induced increase in vascular tone.

In the presence of AVP, pressor responses to UK‐14,304 were resistant to 0.05 μm prazosin and susceptible to antagonism by 1 μm rauwolscine (‐log Kb 7.65 ± 0.15). Similarly, responses to NA in the presence of 0.05 μm prazosin and AVP were inhibited by 1 μm rauwolscine. This represents the first demonstration of prazosin‐resistant, rauwolscine‐sensitive α2‐adrenoceptor‐mediated responses in the vasculature of the rat tail.

These results suggest that in isolated vascular preparations, functional populations of postjunctional α2‐adrenoceptors may be ‘uncovered’ by the presence of AVP.
Local opioid‐sensitive afferent sensory neurones in the modulation of gastric damage induced by Paf
Authors: Esplugues J.V. , Whittle B.J.R. , Moncada S.
Published: July 2012

The role of local sensory neurones in modulating the extent of gastric mucosal damage induced by close‐arterial infusion of platelet‐activating factor (Paf 50 ng kg−1 min−1 for 10 min) has been investigated in the anaesthetized rat.

Local intra‐arterial infusion of the neurotoxin, tetrodotoxin (TTX), substantially augmented the mucosal damage induced by Paf, as assessed by both macroscopic and histological techniques.

In rats pretreated with capsaicin 2 weeks prior to study, to induce a functional ablation of primary afferent neurones, gastric damage induced by Paf was significantly augmented.

Administration of morphine (0.75–3 mg kg−1 i.v.) or its peripherally acting quaternary analogue, N‐methyl morphine (15 mg kg−1 i.v.), also significantly enhanced the gastric damage induced by Paf.

The potentiation by morphine of Paf‐induced gastric damage was inhibited by administration of the opioid antagonists, naloxone (1 mg kg−1 i.v.) or the peripherally acting N‐methyl nalorphine (3 mg kg−1 i.v.).

Administration of TTX or morphine alone, or pretreatment with capsaicin did not induce any detectable mucosal damage, suggesting that interference with local sensory neuronal activity itself does not directly induce mucosal disruption.

These results indicate that peripheral opiate‐sensitive afferent sensory neurones play a physiological defensive role in the mucosa, attenuating the extent of gastric damage induced by Paf.
Impairment of endothelium‐dependent relaxation and changes in levels of cyclic GMP in aorta from streptozotocin‐induced diabetic rats
Authors: Kamata Katsuo , Miyata Noriyuki , Kasuya Yutaka
Published: July 2012

Acetylcholine (ACh)‐induced relaxation of aortic strips with endothelium and production of cyclic GMP between streptozotocin‐induced diabetic and age‐matched control rats were compared.

The concentration‐response curve for ACh‐induced relaxation was shifted to the right in diabetic rats. IC50 values for ACh were 4.57 ± 0.67 × 10−8 m and 1.00 ± 0.87 × 10−7 m in aortic strips from age‐matched control and diabetic rats, respectively (n = 6, P < 0.05).

Relaxations produced by atrial natriuretic peptide (ANP) in diabetic aortae were similar to those in age‐matched vessels.

Relaxations produced by sodium nitroprusside (SNP) in diabetic aortae were similar to those in age‐matched vessels.

Basal levels of cyclic GMP and ACh‐induced production of cyclic GMP were significantly decreased in diabetic rats.

These results suggest that functional changes in endothelium but not in guanylate cyclase activity in the aorta may occur in diabetes, and, thus, spontaneous and ACh‐induced formation of cyclic GMP may be decreased. This decrease in production of cyclic GMP may be responsible for the decreased response of the aorta to the relaxant effect of ACh.
Absence of P2‐purinoceptors in hippocampal pathways
Authors: Stone T.W. , Cusack N.J.
Published: July 2012

Many apparent actions of adenosine 5″‐triphosphate (ATP) are mediated by adenosine produced by enzymatic hydrolysis of the nucleotide. Previously described actions of ATP in the CNS have been partly due to this phenomenon. In the present study analogues of ATP, which are not hydrolysed to adenosine, were used to seek responses to activating nucleotide (P2) receptors in the hippocampus. The analogues used were l‐adenosine‐5″‐(β,γ‐methylene)‐triphosphonate and 2‐methylthio‐adenosine‐5″‐(β,γ‐difluoromethylene)‐triphosphonate.

Neither of the stable nucleotides had any effect on orthodromically evoked synaptic potentials in the CAl region of rat hippocampal slices. Adenosine and ATP had inhibitory actions that could be prevented by the P1‐receptor blocker 8‐phenyltheophylline.

The stable nucleotides had no consistent effects on the firing rate of single neurones in stratum pyramidale of the CA1 region, although adenosine and ATP produced a xanthine‐sensitive inhibition.

Adenosine selectively reduced the sensitivity of CA1 neurones to microiontophoretically applied carbachol whereas stable nucleotides did not.

It is concluded that there are neither P2X‐ nor P2Y‐receptors for adenine nucleotides on rat hippocampal CA1 pyramidal cells at the Schaffer collateral and commissural terminals in stratum radiatum.
Platelet‐activating factor (Paf) antagonist, WEB 2086, protects against Paf‐induced hypotension in Macaca fascicularis
Authors: Stanton A.W.B. , Izumi T. , Antoniw J.W. , Piper Priscilla J.
Published: July 2012

The actions of intravenously administered platelet‐activating factor (Paf) (0.1–3.33 nmol kg−1) and the effect of a recently described Paf antagonist, WEB 2086, were investigated in the anaesthetized open‐chest monkey, Macaca fascicularis.

Paf dose‐dependently reduced blood pressure, left ventricular pressure (LVP) and its first differential LV dP/dt.

Mean pulmonary artery pressure, recorded in three animals, was essentially unchanged by any dose of Paf.

WEB 2086 (0.22 μmol kg−1, i.v.) attenuated the Paf‐induced changes in BP, LVP and LV dP/dt. The dose‐response curve for fall in BP was shifted to the right by one order of magnitude.

Histamine‐induced cardiovascular changes (systemic hypotension and tachycardia) were not affected by prior administration of WEB 2086.

WEB 2086 should be of value in assessing the role of Paf in pathophysiological conditions.
The effect of Paf antagonists on bronchial hyperresponsiveness induced by Paf, propranolol or indomethacin
Authors: Dixon E.J.A. , Wilsoncroft P. , Robertson D.N. , Page C.P.
Published: July 2012

Intravenous administration of platelet activating factor, Paf (600 ng kg−1 h−1) to ventilated anaesthetised guinea‐pigs induced bronchial hyperresponsiveness to i.v. acetylcholine.

Pretreatment of ventilated, anaesthetised guinea‐pigs with the β‐adrenoceptor antagonist, propranolol, or the non‐steroidal anti‐inflammatory drug, indomethacin, induced bronchial hyperresponsiveness to i.v. histamine.

Paf‐induced bronchial hyperresponsiveness was significantly attenuated by pretreatment with three different Paf antagonists, CV‐3988, BN 52021 and WEB 2086.

Pretreatment of guinea‐pigs with CV‐3988, BN 52021 or WEB 2086 at doses inhibiting Paf‐induced bronchial hyperresponsiveness, had no significant effect on propranolol or indomethacin‐induced bronchial hyperresponsiveness.

It is suggested that bronchial hyperresponsiveness induced by propranolol or indomethacin is not secondary to Paf release in the guinea‐pig.
The effect of arginine and nitric oxide on resistance blood vessels of the perfused rat kidney
Authors: Bhardwaj R. , Moore P.K.
Published: July 2012

The vasodilator effects of arginine, nitric oxide (NO), acetylcholine (ACh) and sodium nitroprusside (NP) in the noradrenaline‐preconstricted (‘high tone’) perfused rat kidney have been examined.

L‐Arginine (0.6–23 μmol) caused a biphasic change in renal perfusion pressure. D‐Arginine (0.6–23 μmol) was without effect. The second vasodilator component was abolished and the first vasoconstrictor effect augmented following CHAPS‐induced removal of the vascular endothelium suggesting that vasodilatation was endothelium‐dependent.

L‐Arginine salts produced transient and dose‐related vasodilatation. L‐Arginine methylester was the most potent with an ED50 of 2.2 ± 0.4 μmol (n = 6). The rank order of potency of the salts tested was: methylester > hydroxamate > chloride. L‐Homoarginine chloride was also vasodilator (ED50, 12.0 ± 1.3 μmol, n = 5). D‐Arginine chloride was without effect at doses up to 170 μmol. Responses to L‐arginine chloride were endothelium‐derived relaxing factor (EDRF)‐dependent being abolished by CHAPS (4.7 mg ml−1, 30s) and significantly inhibited (>70%) by gossypol (3 μm) and nordihydroguaiaretic acid (NDGA, 10 μm).

Vasodilatation due to NO was unaffected by CHAPS and gossypol treatment but inhibited by NDGA. NO was approximately 3 times less potent than ACh but 3000 times more potent than L‐arginine methylester.

Kidneys perfused for 1 h with Krebs solution containing L‐arginine chloride (100 μm) or L‐canavanine (50 μm) showed no change in sensitivity towards ACh or NP. Higher concentrations of L‐arginine chloride (500 μm) or L‐canavanine (150 μm) significantly reduced the response to both vasodilators.

L‐Arginine salts dilate resistance blood vessels of the perfused rat kidney by a mechanism which may involve the release of EDRF from vascular endothelial cells of the perfused rat kidney.
Interaction of potassium channel openers and blockers in canine atrial muscle
Authors: Yanagisawa Teruyuki , Hashimoto Hiroo , Taira Norio
Published: July 2012

The possibility that the interaction between potassium channel openers, e.g. cromakalim, pinacidil and nicorandil, and some potassium channel blockers involves a common site was investigated in canine atrial muscle.

Cromakalim, pinacidil and nicorandil produced a negative inotropic effect, their pD2 (‐log EC50) values being 6.11 ± 0.07, 5.37 ± 0.09 and 4.55 ± 0.07, respectively.

The potassium channel blockers, tetraethylammonium (TEA), tetrabutylammonium (TBA), 3,4‐diaminopyridine (DAP), CsCl and BaCl2 all produced a positive inotropic effect.

The concentration‐effect curves for the negative inotropic actions of pinacidil were shifted in a parallel way to the right by low concentrations of TEA, TBA or BaCl2. Maximum responses to pinacidil were depressed by higher concentrations of the blockers. An analysis of the noncompetitive antagonism by TEA yielded pKA (‐log KA) values of 4.00–4.05 for pinacidil.

The concentration‐effect curves for cromakalim and nicorandil were shifted by TEA similarly to those for pinacidil, and a similar analysis yielded pKA values of 4.47–4.68 for cromakalim and 3.47–3.74 for nicorandil.

The KA values of cromakalim, pinacidil and nicorandil were about 10–30 times greater than their EC50 values, indicating that there are non‐linear stimulus‐effect relationships between the binding of the three potassium channel openers to their binding sites at potassium channels and their negative inotropic effects.

The dissociation constants for TEA could also be estimated from pA2 and pKB values for antagonizing competitively and non‐competitively the negative inotropic effects of the three potassium channel openers; they were 3.47–3.89, and did not differ between the potassium channel openers.

The concentration‐effect curves for the three potassium channel openers were not affected by DAP or CsCl.

These results suggest the following: (i) quaternary ammonium compounds like TEA and TBA antagonize the negative inotropic effect of cromakalim, pinacidil and nicorandil by binding to potassium channels, thus preventing binding of the channel openers to the same sites or closely related sites in canine right atrial muscles. (ii) The potassium channels responsible for the negative inotropic effects of the three potassium channel openers seem to be akin to apamin‐insensitive and calciuminsensitive potassium channels in smooth muscle and are opened at the resting membrane potential.
Comparison of the survival of endothelium‐derived relaxing factor and nitric oxide within the isolated perfused mesenteric arterial bed of the rat
Authors: Warner T.D. , de Nucci G. , Vane J.R.
Published: July 2012

The survival of the endothelium‐derived relaxing factor (EDRF) released by acetylcholine (ACh) in the rat isolated perfused mesenteric vascular bed was compared to that of exogenously applied nitric oxide (NO) by direct bioassay of the effluent from the mesenteric bed on rabbit aortic strips (RbAs).

NO (0.1–10 nmol) produced dose‐related vasodilatations in the mesenteric vascular bed and also survived in the effluent in concentrations sufficient to provoke relaxations of the RbAs. ACh (1.7 pmol‐300 nmol) caused dose‐related vasodilatations in the mesenteric bed but no EDRF was detected in the effluent. This was true even when ACh provoked much larger vasodilatations in the mesenteric bed than those to doses of NO that survived passage through the bed.

Removal of the endothelial cells in the mesenteric vascular bed abolished vasodilatations in response to ACh but did not significantly affect those to NO. Survival of NO through the mesenteric bed was not increased.

Superoxide dismutase (SOD, 10 u ml−1) did not significantly affect the vasodilator effects of either ACh or NO. It did increase the survival of NO through the mesenteric vascular bed but native EDRF was still not detected in the effluent.

The absence of bioassayable EDRF in the effluent following ACh‐induced vasodilatations might be explained by the volume into which EDRF is released abluminally being much smaller than that into which it is released luminally.
The effects of drugs interacting with opioid receptors on the early ventricular arrhythmias arising from myocardial ischaemia
Authors: Sitsapesan Rebecca , Parratt J.R.
Published: July 2012

The effects of a range of opioid receptor agonists and antagonists with differing opioid receptor selectivities on ischaemia‐induced arrhythmias in anaesthetised rats was investigated.

Naloxone was antiarrhythmic only at doses expected to antagonise κ‐ and δ‐receptors in addition to μ‐receptors.

The opioid receptor antagonist Mr 2266, which is twice as potent at κ‐receptors as at μ‐receptors dose‐dependently reduced the incidence and severity of the arrhythmias resulting from coronary artery occlusion.

The opioid receptor antagonist m 8008 (1 mg kg−1), which is twice as potent at δ‐receptors as at μ‐receptors but has very little affinity for the κ‐receptor, did not exhibit any beneficial antiarrhythmic properties.

MrZ 2593, a quarternary complex of naloxone which does not readily cross the blood brain barrier, was antiarrhythmic which implies that the antiarrhythmic actions of opioid receptor antagonists may be mediated via peripheral opioid receptors.

The agonists, diamorphine, [Leu] enkephalin and U‐50,488H exhibited no significant arrhythmogenic effects under the present experimental conditions.

It is tentatively suggested that blockade of peripheral κ‐receptors during acute myocardial ischaemia may result in an antiarrhythmic effect.
The antiarrhythmic and cardiac electrophysiological effects of buprenorphine
Authors: Boachie‐Ansah G. , Sitsapesan R. , Kane K.A. , Parratt J.R.
Published: July 2012

The effects of buprenorphine, given intravenously, on the incidence and severity of early acute coronary artery occlusion‐induced arrhythmias were examined in anaesthetised rats. The electrophysiological effects of buprenorphine were also examined in sheep Purkinje fibres and rat papillary muscles, superfused in vitro with either a normal or a hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS).

In anaesthetised rats subjected to acute coronary artery occlusion, pretreatment with buprenorphine (1 mg kg−1 i.v.) markedly reduced the incidence of ventricular extra‐systoles during the initial 30 min post‐occlusion period. The incidence of ventricular fibrillation (VF) was also significantly reduced from 56% to 10%.

At the antiarrhythmic dose (1 mg kg−1), buprenorphine also attenuated the sudden fall in systemic arterial blood pressure induced by acute coronary artery ligation.

In normal sheep Purkinje fibres and rat papillary muscles, buprenorphine (10−6‐10−5 m) significantly reduced the action potential height and maximum rate of depolarisation of phase zero (MRD) and prolonged the duration of the action potential.

Superfusion of sheep Purkinje fibres and rat papillary muscles with a hypoxic, hyperkalaemic and acidotic PSS resulted in marked reductions in resting membrane potential, upstroke and duration of the action potential.

In the presence of the modified compared with normal PSS, buprenorphine reduced the action potential height and MRD of both sheep Purkinje fibres and rat papillary muscles to a greater extent, although its ability to prolong the action potential duration was attenuated.

The antiarrhythmic effects of buprenorphine observed in vivo may be explained by its direct cardiac electrophysiological effects. Buprenorphine might be useful in relieving pain and in reducing the severity of arrhythmias in the early stages of acute myocardial infarction.
Effects of endogenous and synthetic prostanoids, the thromboxane A2 receptor agonist U‐46619 and arachidonic acid on [3H]‐noradrenaline release and vascular tone in rat isolated kidney
Authors: Rump L.C. , Schollmeyer P.
Published: July 2012

Rat kidneys were perfused with Krebs‐Henseleit solution and the perfusion pressure was monitored. After incubation with [3H]‐noradrenaline the renal nerves were stimulated. The stimulation‐induced (S‐I) outflow of radioactivity was taken as an index of noradrenaline release. The effect of prostaglandins on perfusion pressure, pressor responses to renal nerve stimulation (RNS) and S‐I outflow of radioactivity was assessed.

Prostaglandin E2 (PGE2, 0.06 and 0.6 μm), PGF2α (0.6 μm), PGI2 (0.6 and 3 μm) and iloprost (0.6 μm) increased perfusion pressure and enhanced pressor responses to RNS. These facilitatory effects of the prostaglandins were not a result of an enhanced transmitter release. In contrast, PGE2 dose‐dependently inhibited, whereas the other prostaglandins failed to modulate S‐I outflow of radioactivity. PGE2 (0.6 μm) also enhanced pressor responses to exogenous noradrenaline.

Arachidonic acid (1 μm) increased perfusion pressure and enhanced pressor responses to RNS. These effects were abolished in the presence of indomethacin (10 μm) suggesting that local production of prostaglandins from exogenous arachidonic acid was responsible for this facilitation. However, arachidonic acid (1 μm) did not modulate S‐I outflow of radioactivity. Arachidonic acid (10 μm), despite causing a marked increase in perfusion pressure, failed to alter pressor responses to RNS and only slightly inhibited S‐I outflow of radioactivity.

The thromboxane A2 (TxA2) receptor agonist U‐46619 (0.1 μm) increased vascular tone and enhanced pressor responses to RNS. These effects were blocked by the newly developed selective TxA2 receptor antagonist, daltroban (BM 13505; 3 μm), suggesting that these facilitatory effects of U‐46619 were due to activation of TxA2 receptors. However, U‐46619 failed to alter the S‐I outflow of radioactivity from rat isolated kidney.

The α1‐adrenoceptor agonist methoxamine (1 μm) also increased perfusion pressure and enhanced pressor responses to RNS without affecting the S‐I outflow of radioactivity in the presence of the prostaglandin synthesis inhibitor indomethacin (10 μm).

The results suggest that PGE2 modulates noradrenaline release through an inhibitory prejunctional receptor mechanism. There is no evidence for prejunctional PGF2α, PGI2 or TxA2 receptors in the rat isolated kidney. All prostaglandins increased vascular tone in the rat isolated kidney and this alone may provide a condition for enhanced pressor responses to RNS since methoxamine also enhanced pressor responses to RNS without affecting S‐I outflow of radioactivity. It is probable that postjunctionally active PGF2α and PGI2 is formed locally from exogenous arachidonic acid, but not enough prejunctionally active PGE2 is synthesized to modulate renal transmitter release.
Mode of antinociceptive action of flupirtine in the rat
Authors: Szelenyi I. , Nickel B. , Borbe H.O. , Brune K.
Published: July 2012

Flupirtine is a novel, centrally acting, non‐opioid analgesic agent. The present investigation was undertaken to ascertain which neuronal systems might be responsible for its antinociceptive effect in rodents. The antinociceptive responses to the test compounds were examined in the tail‐flick test.

The selective destruction of noradrenergic pathways by 6‐hydroxydopamine considerably reduced the flupirtine‐induced inhibition of nociceptive responses but not the clonidine‐induced antinociception which was significantly enhanced. Depletion of spinal 5‐hydroxytryptaminergic pathways by pretreatment with 5,7‐dihydroxytryptamine failed to affect the action of flupirtine and clonidine.

The depletion of neurotransmitters by reserpine totally abolished the antinociceptive action of flupirtine. By contrast, clonidine‐induced inhibition of nociceptive responses remained unchanged.

Inhibition of the synthesis of noradrenaline by α‐methyl‐L‐p‐tyrosine attenuated the antinociception induced by flupirtine. In contrast, inhibition of the synthesis of 5‐hydroxytryptamine by (±)−6‐fluorotryptophan did not influence the antinociceptive activity of flupirtine.

Inhibition of noradrenaline uptake by imipramine led to a significant augmentation of flupirtine‐induced antinociception.

Selective antagonists at α‐adrenoceptors significantly decreased the antinociceptive action of flupirtine. Antinociception induced by clonidine was significantly diminished by idazoxan but not by prazosin.

The 5‐hydroxytryptamine (5‐HT) antagonist, ketanserin diminished the antinociceptive activity of flupirtine, probably due to its additional α1‐adrenoceptor antagonist activity. The antinociceptive effect of clonidine was not influenced by ketanserin.

Cholinoceptor antagonists such as mecamylamine and pirenzepine did not alter the antinociceptive action of flupirtine. Flupirtine‐induced antinociception also remained unchanged after pretreatment with haloperidol.

Flupirtine has no pharmacologically relevant affinity for α1‐, α2‐adrenoceptors, 5‐HT1‐ and 5‐HT2‐receptors as shown in direct binding studies.

The present results indicate that the antinociceptive action induced by flupirtine depends on the descending noradrenergic pain‐modulating system.
Actions of constrictor (NPY and endothelin) and dilator (substance P, CGRP and VIP) peptides on pig splenic and human skeletal muscle arteries: involvement of the endothelium
Authors: Pernow John
Published: July 2012

The effects of various vasoactive peptides and the involvement of the endothelium in these effects were studied on small human skeletal muscle arteries (SMA) and pig splenic arteries (SA) in vitro.

Under control conditions, neuropeptide Y (NPY) caused potent and strong contractions of both arteries. The maximal effect of NPY 500 nM was similar to that of phenylephrine and noradrenaline (10 μm). Endothelin was approximately 10 fold more potent than NPY in contracting SA, and the maximal response to endothelin 50 nM was 130% of that evoked by phenylephrine.

After removal of the endothelium (by rubbing the inner surface of the arteries) neither the maximal effect nor the EC50 value of NPY on SMA and SA or those of endothelin on SA were changed from control conditions.

The substance P (SP)‐induced relaxation of precontracted SMA and SA during control conditions (80–90%) was abolished or greatly reduced after endothelium removal.

Under control conditions, calcitonin gene‐related peptide (CGRP) was about 10 times more potent than vasoactive intestinal polypeptide (VIP) in relaxing SMA. After endothelium removal the relaxation induced by CGRP on SMA and SA and that of VIP on SMA were not changed from control conditions.

It is concluded that, in the SMA and SA, the potent vasoconstrictor effects of NPY and endothelin are mediated by direct actions on the vascular smooth muscle and not via a release of an endothelium‐derived contracting factor. Relaxation induced by SP but not that of CGRP and VIP seems to be mediated via the endothelium.
Alterations in atrial reactivity in a strain of spontaneously diabetic rats
Authors: Durante William , Sunahara Fred A. , Sen Amar K.
Published: July 2012

The present study examined the reactivity of atria from control and spontaneously diabetic rats to various adrenoceptor agonists and to adenosine.

Isoprenaline (1.5 nM‐1500 nm) produced concentration‐dependent increases in inotropy which were unchanged in diabetic atria. However, the sensitivity to isoprenaline‐induced changes in chronotropy was reduced in diabetic preparations.

In the presence of propranolol (2 μm), phenylephrine (0.2 μm‐100 μm) produced concentration‐dependent increases in both inotropy and chronotropy; however, atria from diabetic rats exhibited a much greater maximal response. The diabetic state did not alter the sensitivity to phenylephrine.

Adenosine (0.15 μm‐300 μm) produced concentration‐dependent decreases in both inotropy and chronotropy which were unchanged in diabetic atria.

Radioligand binding studies revealed that both α1‐and β‐adrenoceptor populations were substantially reduced in atria from diabetic rats. However, there was no change in receptor affinity for either adrenoceptor.

These results show that diabetes leads to an alteration in atrial reactivity to adrenoceptor stimulation. Future studies examining steps following hormone‐receptor coupling are required in order to characterize this defect.
Sodium salicylate facilitates calcium‐dependent release of transmitter at mouse neuromuscular junctions
Authors: Nishimura Masakazu , Awano Hideto , Yagasaki Osamu
Published: July 2012

The effects of sodium salicylate on the frequency of miniature endplate potentials (m.e.p.ps) and on the quantal content of endplate potentials (e.p.ps) in mouse diaphragm muscles at 36°C and 24°C were studied by conventional microelectrode techniques.

At 36°C, salicylate (10 mm) elevated the frequency of m.e.p.ps in a manner which was insensitive to [Mg2+]o and independent of the presence of [Ca2+]o. Lowering the temperature to 24°C abolished the stimulating effect. 2,4‐Dinitrophenol (10 μm) had similar effects at 36°C and these disappeared at 24°C. All subsequent experiments were performed at 24°C.

Salicylate (10 mm) further increased the frequency (F) of m.e.p.ps stimulated by [Ca2+]o in a depolarizing solution. When [Ca2+]o was varied in the absence of salicylate, a linear relationship between ln(F) and ln([Ca2+]o) was obtained. Salicylate shifted this relationship to the left, with respect to the control, without altering the slope.

Salicylate (5 mm) also increased the quantal content (m) of e.p.ps in a solution that contained 5 mM Mg2+, in a concentration‐dependent fashion. As [Ca2+]o was varied in the absence of salicylate, a linear relationship between ln(m) and ln([Ca2+]o) was observed. Salicylate shifted this linear relationship to the left, with respect to the control, without altering the slope. Doubling the concentration of [Mg2+]o antagonized this effect of salicylate on the quantal content of e.p.ps.

These results indicate that salicylate enhances the effect of changing [Ca2+]o. Salicylate probably facilitates the entry of Ca2+ into the nerve terminal or sensitizes the process that is regulated by Ca2+, thereby stimulating the release of transmitter. Surface negative charges may have an important role in the effect of [Ca2+]o.
Action of atrial natriuretic peptide (ANP) on dog cerebral arteries: evidence that neurogenic relaxation is not mediated by release of ANP
Authors: Okamura Tomio , Inoue Seiji , Toda Noboru
Published: July 2012

Atrial natriuretic peptide (ANP) (10−9 to 10−8m) produced a concentration‐related relaxation in helical strips of dog cerebral arteries partially contracted with prostaglandin F2α. The relaxation was not affected by treatment with ouabain, quinidine, oxyhaemoglobin, methylene blue, or removal of endothelium.

Relaxations induced by nicotine or transmural electrical stimulation were not reduced in arteries in which tachyphylaxis to ANP had developed.

In arteries exposed to Ca2+‐free media under severe hypoxia, contractions due to prostaglandin F2α and Ca2+ were attenuated by treatment with ANP, whereas the reoxygenation‐induced contraction was unaffected.

The results suggest that ANP does not mediate neurogenic relaxation of dog cerebral arteries. The ANP‐induced relaxation is not associated with activation of the sodium pump but is due to an inhibitory action on the release and influx of Ca2+, probably as a result of stimulation of guanylate cyclase.
Apparent affinity of 1,3‐dipropyl‐8‐cyclopentylxanthine for adenosine A1 and A2 receptors in isolated tissues from guinea‐pigs
Authors: Collis M.G. , Stoggall S.M. , Martin F.M.
Published: July 2012

The classification of adenosine receptor subtypes (A1 and A2) in intact tissues has been based on the order of agonist potency. In this study the apparent affinity of 1,3‐dipropyl‐8‐cyclopentylxanthine (CPX), an antagonist which has been reported to be A1 selective, and the nonselective antagonist 1,3‐dimethyl‐8‐phenylxanthine (8PT) has been evaluated on isolated tissues from the guinea‐pig.

The isolated tissues used were atria (bradycardic response, proposed A1 sub‐type), aorta and trachea (relaxant response, proposed A2 sub‐type).

Both the xanthines antagonized responses to adenosine in the three tissues but had little or no effect on responses to carbachol (atria), sodium nitrite (aorta) or isoprenaline (trachea).

pA2 values for 8PT were similar on the three tissues (6.3–6.7), however, the pA2 value for CPX on the atria (7.9‐8.4) was greater than that on the aorta (6.6) or trachea (6.6).

These results support the suggestion that the adenosine receptors which mediate bradycardia in the atrium are of the A1 sub‐type and that those which mediate relaxation in the aorta and trachea are of the A2 type.
Effects of N‐ethylmaleimide on 5‐hydroxytryptamine transport and sodium content in rabbit platelets
Authors: Wölfel R. , Halbrügge T. , Graefe K.‐H.
Published: July 2012

The present study analysed the mechanism underlying the inhibitory action of N‐ethylmaleimide (NEm) on the 5‐hydroxytryptamine (5‐HT) uptake by blood platelets.

Rabbit platelets suspended in protein‐free buffer were first preincubated for 45 min in the absence and presence of NEM (20 to 160 μm) or ouabain (0.5‐2.0 μm) and then either analysed for their Na+ and K+ content or incubated (15 s) with various concentrations of [3H]‐5‐HT (0.13‐4.03 μm) to determine Km and Vmax for 5‐HT uptake.

Both NEM and ouabain produced concentration‐dependent decreases in Vmax with IC50 values of 52 and 0.58 μm, respectively. Neither drug changed Km significantly.

Both NEM and ouabain increased the Na+ and decreased the K+ content of platelets in a concentration‐dependent manner.

There was a linear correlation between Vmax (expressed in % of control) and the reciprocal cellular Na+ content, with the results for both drugs falling onto one and the same regression line (r = 0.992; n = 8). This regression showed that an increase in Na+ content by 69% sufficed to reduce Vmax by 50%.

At concentrations that reduced 5‐HT uptake by about 60%, neither NEM nor ouabain altered the potency of imipramine for inhibition of 5‐HT uptake.

Hence, NEM inhibits 5‐HT transport by inhibiting the Na+/K+‐ATPase and not by a direct interaction with the 5‐HT carrier. The consequential increase in the intracellular Na+ concentration reduces the transmembrane Na+ gradient and, therefore, hinders 5‐HT inward transport. This action of the drug does not affect the ability of the carrier to bind 5‐HT or imipramine.
Angiotensin converting enzyme activity is present in the endothelium‐denuded aorta
Authors: Pipili Eva , Manolopoulos Vangelis G. , Catravas John D. , Maragoudakis Michael E.
Published: July 2012

Angiotensin converting enzyme activity was measured in intact aortic rings utilizing the synthetic tripeptide [3H]‐benzoyl‐Phe‐Ala‐Pro as the substrate. Intact aortic rings possessed angiotensin converting enzyme activity which was blocked by captopril. Enzyme activity was reduced by approximately 30% after removal of the endothelium by chemical or mechanical methods. The remaining activity was also captopril‐sensitive. These results suggest that in addition to endothelium, angiotensin converting enzyme activity is present in other vascular cells and may contribute to the metabolism of angiotensin I generated within the vessel wall.
A comparison of basal and agonist‐stimulated release of endothelium‐derived relaxing factor from different arteries
Authors: Christie M.I. , Griffith T.M. , Lewis M.J.
Published: July 2012

The release of endothelium‐derived relaxing factor (EDRF) from rabbit aorta and pig coronary artery vessels in response to acetylcholine (ACh), substance P (SP) and the calcium ionophore A23187 has been studied by means of a bioassay cascade system.

A technique is described which allows the quantification of EDRF release rates from vessels of different sizes, perfused at different flow rates and with different donor‐recipient transient times.

Rabbit aorta and pig coronary arteries, perfused at flow rates which equalise endothelial shear stress, released EDRF at a similar basal rate.

In response to ACh, rabbit aortic endothelium released EDRF at a significantly greater maximum rate than pig coronary artery endothelium.

In response to SP, both endothelium types released EDRF; SP was a significantly more potent agonist in pig coronary artery than in rabbit aorta, but maximum SP‐induced EDRF release from rabbit aorta was twice that of pig coronary artery.

These data indicate that different endothelium types can release EDRF at widely different rates, according to the agonist used, and that the previously obtained lack of relaxant response to ACh in pig coronary artery was due to a lack of EDRF release rather than concomitant smooth muscle constriction.
Prejunctional modulatory action of neuropeptide Y on peripheral terminals of capsaicin‐sensitive sensory nerves
Authors: Giuliani Sandro , Maggi Carlo Alberto , Meli Alberto
Published: July 2012

We have determined the effect of neuropeptide Y (NPY) on motor responses produced by activation of capsaicin‐sensitive primary afferents in the guinea‐pig isolated left atria (reserpine‐pretreatment, atropine in the bath) and bronchi (atropine and indomethacin in the bath) using capsaicin itself and electrical field stimulation as stimuli.

In both preparations, NPY inhibited or suppressed the response produced by electrical field stimulation while leaving the response to a submaximal concentration of capsaicin unaffected.

NPY had no effect on motor responses produced by a submaximal concentration of calcitonin gene‐related peptide (atria) or neurokinin A (bronchi), the putative endogenous mediators of the responses produced by activation of the ‘efferent’ function of sensory fibres in these preparations.

We conclude that NPY exerts a prejunctional inhibitory action on transmitter release from peripheral endings of capsaicin‐sensitive nerves. Failure of NPY to modulate responses activated by capsaicin provides further evidence for the existence of two independent modes of activation of the ‘efferent’ function of capsaicin‐sensitive sensory nerves.