bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.