bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of the effects of IVth ventricular administration of the 5‐HT2 agonist, 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI), on autonomic outflow in the anaesthetized cat
Authors: Shepheard Sara L. , Jordan David , Ramage Andrew G. 
Published: July 2012

The effects of IVth ventricular injections of 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI) on renal, splanchnic and cardiac sympathetic nerve activities, phrenic nerve activity, arterial blood pressure, heart rate, femoral arterial conductance, tracheal and intragastric pressures were investigated in α‐chloralose anaesthetized, neuromuscular blocked and artificially ventilated cats.
Cumulative doses of DOI (80, 160 and 320 nmol kg−1) injected into the IVth ventricle caused an increase in mean arterial blood pressure, a fall in femoral arterial conductance, an increase in tracheal pressure and a decrease in the rate of phrenic nerve bursts but did not affect any of the other variables recorded.
Even after i.v. administration of the peripheral 5‐HT2 antagonist BW501C67 (2 mg kg−1) following the highest dose of DOI there was still a significant pressor response, a fall in femoral arterial conductance and small increase in tracheal pressure.
In control experiments, intravenous infusion of noradrenaline to raise blood pressure to the levels obtained during the cumulative doses of DOI caused large falls in renal, splanchnic and cardiac nerve activities which were all significantly lower than those recorded during the cumulative doses of DOI.
The results of this study provide evidence for a brainstem site of action of DOI in producing hypertension and further support the hypothesis that central 5‐HT2 receptors are involved in the control of skeletal muscle and skin vascular beds.
Adenosine modulation of potassium currents in postganglionic neurones of cultured avian ciliary ganglia
Authors: Bennett Max R. , Kerr Rod , Nichol Kerry 
Published: July 2012

Potassium currents in cultured postganglionic neurones of avian ciliary ganglia were analysed under whole‐cell voltage clamp and their modulation by adenosine determined.
In the presence of tetrodotoxin (200 nm), and with moderate holding potentials (Vh = −40 mV), the steady‐state current‐voltage (I/V) curve was N‐shaped over the range from −70 mV to +155 mV. CsCl (1 m) blocked the current, indicating that it was carried by K+. If Ca2+influx was blocked by CdCl2 (500 μm) then the outward current was reduced and the N‐shaped I–V curve lost, indicating the presence of a calcium‐activated potassium current (IK(Ca)); the remaining current, due to the delayed rectifier (IK), increased with depolarization up to about a conductance of 10 nS near +50 mV. This IK was 50% activated at about +20 mV and 50% inactivated at about −50 mV. Adenosine (10 μm) had similar affects on the N‐shaped I/V curve as did CdCl2, indicating that it blocked IK(Ca). However, adenosine had little affect on the steady‐state current in the presence of CdCl2, indicating that it did not much affect IK.
In the presence of tetrodotoxin (200 nm), a large inward current occurred for large hyperpolarizations from a Vh = −50 mV. This inward rectifying current (IIR) had a reversal potential near EK and showed 50% activation at about −130 mV. Adenosine (10 μm) reduced IIR, by as much as 50% at large hyperpolarizations beyond −80 mV.
Relaxations of the outward current on hyperpolarization from Vh = −30 mV were blocked by carbachol (10 μm), had a reversal potential near EK, and an I/V curve typical of IM currents. These currents were little affected by adenosine (10 μm).
A fast transient outward current, due to depolarizing pulses from a large Vh = −110 mV was observed in the presence of tetrodotoxin (200 nm). This had the characteristics of an IA current as it could be blocked with 4‐aminopyridine (5 mm) and was 50% activated at about −20 mV and 50% inactivated at about −94 mV. The IA current was reduced by 42% at a depolarization of −20 mV by adenosine (10 μm).
Many neurones possessed a fast transient outward current that was blocked by tetrodotoxin (200 nm). This current could be blocked with 4‐aminopyridine (5 mm); it therefore has the characteristics of a sodium‐activated potassium current (IK(Na)). This IK(Na) was unaffected by adenosine (10 μm).
These results are discussed in relation to the role of adenosine in blocking Ca2+channels and thereby modifying calcium‐dependent components of K+currents.
Microinjections of 5‐HT1A agonists into the dorsal motor vagal nucleus produce a bradycardia in the atenolol‐pretreated anaesthetized rat
Authors: Sporton Simon C.E. , Shepheard Sara L. , Jordan David , Ramage Andrew G. 
Published: July 2012

The effects of microinjections (100 nl) into the dorsal motor vagal nucleus of the 5‐HT1A receptor agonists 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) and flesinoxan, the 5‐HT2 receptor agonist (±)‐1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane hydrochloride (DOI), the 5‐HT3 receptor agonist phenylbiguanide (PBG), the α2‐adrenoceptor agonist clonidine and the excitatory amino acid glutamate on heart rate, blood pressure, tracheal pressure and phrenic nerve activity were investigated in atenolol‐pretreated rats anaesthetized with sodium pentobarbitone.
Microinjections of glutamate (2.5 nmol) caused decreases in blood pressure, heart rate and phrenic nerve activity. In contrast, microinjections of 5‐HT (1.2 nmol), 8‐OH‐DPAT (1.2 nmol) and flesinoxan (1.3 nmol) all caused a bradycardia but had no effect on blood pressure. In addition, 8‐OH‐DPAT and flesinoxan caused an increase in phrenic nerve activity.
Microinjections of DOI, PBG and clonidine had no significant effect on any of the variables recorded. None of the drugs used had any significant effect on tracheal pressure.
These results support the hypothesis that activation of 5‐HT1A receptors causes excitation of cardiac vagal motoneurones and suggest that these receptors are also important in the control of central respiratory drive.
The guinea‐pig ileum preparation as a model for 5‐HT1A receptors: anomalous effects with RS‐30199–193
Authors: Small Catherine , Brown Christine M. , Redfern William S. , Spedding Michael 
Published: July 2012

Agents that have high and selective affinity for the 5‐HT1A site such as 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) and N,N‐dipropyl‐5‐carboxamidotryptamine (DP5CT) inhibited the responses to field stimulation in guinea‐pig ileum preparations; the inhibitory effects were antagonized by methiothepin and spiperone, consistent with effects at the 5‐HT1A site.
The inhibitory effects of DP5CT were pronounced in Tyrode solution containing low Ca2+(0.9 mm), but were much less apparent in Tyrode solution containing 1.8 or 5.4 mm Ca2+.
Responses to DP5CT were abolished by pretreatment with phorbol dibutyrate (3 μm), whereas the responses to UK14304 were only slightly inhibited.
Buspirone and ipsapirone (1 μm) inhibited the responses to field stimulation, and the effects were resistant to idazoxan, but inhibited by 8‐OH‐DPAT or spiperone.
RS‐30199–193 (5‐chloro‐2‐methyl‐1,2,3,4,8,9,10,10a‐octahydronaphth‐[1,8‐cd]‐azepine hydrochloride) an azepine with high affinity for the 5‐HT1A site in rat cerebral cortex in binding experiments, augmented contractions, but did not antagonize the responses to DP5CT or to 8‐OH‐DPAT.
The hybrid compound of RS‐30199–193 with buspirone, RS‐64459–193 (5‐chloro‐2‐[4‐(8‐azaspiro[4,5] decane‐7,9‐dione)‐but‐1‐yl]‐1,2,3,4,8,9,10,10a‐octahydronaphth[1,8‐cd]‐3‐azepine hydrochloride) maintained high affinity for the 5‐HT1A binding site in rat brain and both inhibited the response to field stimulation and antagonized the responses to 8‐OH‐DPAT and DP5CT. Thus the buspirone side chain when added to RS‐30199–193 appears either to induce affinity for a distinct subset of receptors in the guinea‐pig ileum or is required for functional effectiveness at the 5‐HT1A receptor.
Effects of histamine and activators of the cyclic AMP system on protein synthesis in and release of high molecular weight glycoproteins from isolated gastric non‐parietal cells
Authors: Heim H.‐K. , Oestmann A. , Sewing K.‐Fr. 
Published: July 2012

Glycoprotein and protein synthesis in and release from pig isolated, enriched gastric mucous cells were measured by the incorporation of N‐acetyl‐[14C]‐d‐glucosamine and [3H]‐l‐leucine, respectively, into cellular and released acid precipitable material.
Histamine and activators of the adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) system maximally stimulated total protein and glycoprotein synthesis in and release from the cells at concentrations of histamine (10 μm), forskolin (10–100 μm), 3‐isobutyl‐1‐methylxanthine (100 μm), and dibutyryl cyclic AMP (1–3 mm), respectively. In the presence of 3‐isobutyl‐1‐methylxanthine (30 μm) histamine stimulation was enhanced.
As shown by gel chromatography, stimulation by histamine (100 μm), forskolin (10 μm), 3‐isobutyl‐1‐methylxanthine (100 μm) and dibutyryl cyclic AMP (1 mm) resulted in a release of high molecular weight (≅2 × 106daltons) glycoproteins from the cells. The histamine H2‐receptor antagonist, ranitidine (100 μm), blocked the effect of histamine.
We conclude that cyclic AMP‐dependent processes are involved in the regulation of protein and glycoprotein synthesis in and the release of high molecular weight (mucous) glycoproteins from pig gastric non‐parietal cells and that histamine may be a physiological activator of this system.
Endogenous nitric oxide modulates adrenergic neural vasoconstriction in guinea‐pig pulmonary artery
Authors: Liu S.F. , Crawley D.E. , Evans T.W. , Barnes P.J. 
Published: July 2012

Electrical field stimulation (EFS) of guinea‐pig isolated pulmonary artery induced a frequency‐dependent contraction. This was abolished by tetrodotoxin (1 μm) and prevented by phentolamine and prazosin (both 1 μm), indicating a role for α1‐adrenoceptors activated by noradrenaline (NA) released from perivascular adrenergic nerves.
l‐NG‐monomethyl arginine (l‐NMMA, 0.3–100 μm) caused a concentration‐dependent enhancement of the EFS‐induced contraction with a 3.4 ± 0.5 fold increase at 100 μm (n = 6). The augmenting effect of 30 μm l‐NMMA on the contraction to EFS was completely reversed by 100–300 μm l‐arginine, but not by an identical concentration of d‐arginine.
The contractile response to exogenous NA was similarly enhanced by 30 μm l‐NMMA (2.9 ± 0.6 fold increase, n = 5).
The contractile responses to exogenous phenylephrine and prostaglandin F2α which matched the contraction to EFS (4 Hz) were equally augmented by 30 μm l‐NMMA.
In vessel rings submaximally contracted with the thromboxane analogue U44069 (2 μm), the selective α2‐adrenoceptor agonist UK14304 induced concentration‐dependent relaxation, which was abolished by removal of endothelium. NA had little relaxant effect on these precontracted vessel rings unless in the presence of prazosin (1 μm).
Indomethacin had no significant effect on the contractile response to EFS or NA, indicating that vasodilator cyclo‐oxygenase products such as prostacyclin are not involved in modulating these responses.
Our results suggest that endogenous nitric oxide inhibits the contractile response to adrenergic nerve stimulation in the guinea‐pig pulmonary artery by a postjunctional mechanism, but release of prostacyclin does not modulate these responses. Basal release of nitric oxide from endothelial cells may account for this inhibition.
Induction and potential biological relevance of a Ca2+‐independent nitric oxide synthase in the myocardium
Authors: Schulz R. , Nava E. , Moncada S. 
Published: July 2012

We have investigated whether the myocardium and isolated cardiac myocytes can express a Ca2+‐independent NO synthase after treatment with endotoxin or cytokines. Nitric oxide synthesis was measured in cytosols from the left ventricular wall from rats treated with endotoxin, or from freshly isolated myocytes from adult rats treated in vitro with cytokines.
Cytosols from the ventricle of saline‐treated control animals showed only Ca2+‐dependent NO synthesis. After treatment with endotoxin, the expression of an inducible, Ca2+‐independent NO synthase was observed. The activity of this enzyme was maximal at 6 h and returned towards control levels by 18 h; no alterations occurred in the Ca2+‐dependent NO synthase activity. Parallel to this enzyme induction there was an increase in myocardial guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) and plasma nitrite and nitrate (NO−x). All these changes were prevented by pretreatment of the rats with dexamethasone.
Myocytes possessed Ca2+‐dependent NO synthase activity and expressed, after treatment with tumour necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β), a Ca2+‐independent NO synthase, the induction of which was prevented by dexamethasone and cycloheximide.
Since increases in cyclic GMP levels in the heart are associated with reduced myocardial contractility, it is possible that the enhanced production of NO by a Ca2+‐independent enzyme accounts, at least in part, for the depression of myocardial contractility seen in septic shock, cardiomyopathies, allograft rejection, burn trauma, as well as during anti‐tumour therapy with cytokines.
Pharmacological characterization of angiotensin‐induced depolarizations of rat superior cervical ganglion in vitro
Authors: Hawcock A.B. , Barnes J.C. , Michel A.D. 
Published: July 2012

The depolarizing responses to angiotensin II and angiotensin III of the rat superior cervical ganglion have been characterized in vitro, by the use of peptidase inhibitors, peptide and non‐peptide antagonists and dithiothreitol (DTT).
Angiotensin II and III depolarized the ganglion in a concentration‐related manner. Angiotensin II was approximately 30 fold more potent than angiotensin III.
The endopeptidase inhibitor, bacitracin, increased the potency of angiotensin II and III by approximately 4 and 20 fold respectively. The aminopeptidase inhibitor, amastatin, further increased the potency of angiotensin III (but not angiotensin II) by approximately 4 fold. In the presence of bacitracin and amastatin, angiotensin II and III were equipotent.
The peptide antagonist [Il7]angiotensin III (0.01–0.3 μm) produced a non‐parallel rightward displacement of the angiotensin II concentration‐response curve, with a suppression of the maximum response. The potency of [Ile7]angiotensin III was increased by bacitracin and amastatin.
The AT1‐selective non‐peptide antagonist losartan (DuP 753; 0.03 and 0.1 μm) produced a parallel rightward displacement of the angiotensin II concentration‐response curve, with an apparent pKB of 8.3 ± 0.1. A higher concentration of losartan (0.3 μm) depressed the maximum agonist response by 32 ± 6.5%, possibly reflecting non‐competitive behaviour of the antagonist. The potency of losartan was not influenced by bacitracin.
The AT2‐selective non‐peptide antagonist, PD123177 (3 μm) failed to antagonize the angiotensin II‐induced depolarizations.
DTT (1 mm) produced a 22% reduction of the maximum response to angiotensin II.
We conclude that the angiotensin II‐induced depolarizations of the rat superior cervical ganglion are mediated by angiotensin II receptors of the AT1 subclass. The ability of peptidase inhibitors to modify the potency of peptide agonists and antagonists highlights the difficulties associated with the use of peptide agents to characterize angiotensin II receptors in this preparation.
Separation of putative α1A‐ and α1B‐ adrenoceptor mediated components in the tension response of the rat vas deferens to electrical field stimulation
Authors: Mallard N.J. , Marshall R.W. , Sithers A.J. , Spriggs T.L.B. 
Published: July 2012

The effects of the putative α1B‐adrenoceptor antagonist, chloroethylclonidine (CEC), on tension responses of the rat isolated whole vas deferens to single and multiple pulses of electrical field stimulation have been evaluated by use of a microcomputer system which enables the averaging of like‐responses throughout their time course.
CEC (10−7 to 3 × 10−6 m) selectively and in a concentration‐dependent manner blocked the noradrenergic component of the response to a single field stimulus in the absence or presence of nifedipine (10−5 m, which blocked the purinergic but not the noradrenergic component of the response). The concentration‐response curve of the vas to exogenously‐applied noradrenaline (NA) was unaffected by CEC (10−6 m) but was flattened by nifedipine (10−5 m).
The tension response to 10 Hz trains of pulses was biphasic, with an early (< 2 s) and a plateau (> 4 s) phase. We deduce from our pharmacological analysis that the early phase contains a putative α1B‐adrenoceptor component (susceptible to CEC or prazosin but not to nifedipine) and a P2‐purinoceptor component (susceptible to suramin or nifedipine) whereas the plateau phase contains an α1A‐adrenoceptor component (susceptible to prazosin or nifedipine but not to CEC) and a P2‐purinoceptor component (susceptible to suramin or nifedipine).
We suggest that the putative α1B‐adrenoceptors may be functionally confined to the synaptic region whereas the putative α1A‐adrenoceptors are excluded from this region. Trains of pulses would allow NA to accumulate and spill out beyond the synaptic region to reach and activate the putative α1A‐adrenoceptors.
Calmodulin antagonists inhibit endothelium‐dependent hyperpolarization in the canine coronary artery
Authors: Nagao Tetsuhiko , Illiano Stephane , Vanhoutte Paul M. 
Published: July 2012

The effects of the calmodulin antagonists, calmidazolium and fendiline were investigated on endothelium‐dependent hyperpolarization in the canine coronary artery. The membrane potential of vascular smooth muscle cells was measured with the microelectrode technique.
Smooth muscle cells of the canine coronary artery had a resting membrane potential of −50 mV. Bradykinin and the Ca2+‐ionophore, A23187, induced concentration‐ and endothelium‐dependent hyperpolarization. The hyperpolarization induced by a supramaximal concentration of bradykinin (10−6 m) reached approximately 20 mV.
Calmidazolium (10−5 m) and fendiline (10−4 m) inhibited hyperpolarization induced by bradykinin and A23187. By contrast, calmidazolium did not affect the hyperpolarization induced by lemakalim, an opener of ATP‐sensitive K+‐channels.
These observations suggest that calmodulin is involved in the generation of endothelium‐dependent membrane hyperpolarization of vascular smooth muscle.
Endothelium‐dependent relaxation and noradrenaline sensitivity in mesenteric resistance arteries of streptozotocin‐induced diabetic rats
Authors: Taylor Paul D. , McCarthy Andrew L. , Thomas Chris R. , Poston Lucilla 
Published: July 2012

Noradrenaline sensitivity and acetylcholine‐induced relaxation were investigated in mesenteric resistance arteries of control and streptozotocin‐induced diabetic rats.
The diabetic rats demonstrated enhanced vascular sensitivity to noradrenaline compared with age‐matched controls (pEC50 5.99 ± 0.06 for diabetic rats, n = 25, versus 5.82 ± 0.03 for controls, n = 45, P < 0.05).
Significant impairment of acetylcholine‐induced relaxation was observed in arteries from the diabetic animals compared with controls (pEC50 6.81 ± 0.17 for diabetic rats, n = 21, versus 7.54 ± 0.17 for controls, n = 45, P < 0.001).
The difference between acetylcholine‐induced relaxation in diabetic and control arteries remained in the presence of 10 μm indomethacin (pEC50 6.41 ± 0.11 for diabetic rats, n = 16, versus 7.59 ± 0.08 for controls, n = 20, P < 0.001).
The nitric oxide synthase inhibitor, NG‐monomethyl‐m‐arginine (l‐NMMA, 1 mm) produced profound inhibition of acetylcholine‐induced relaxation in diabetic arteries but partial inhibition in controls. The incomplete inhibition of acetylcholine‐induced relaxation by m‐NMMA in the control arteries was the result of ineffective inhibition of nitric oxide synthase since an alternative inhibitor, NG‐nitro‐l‐arginine methyl ester (l‐NAME, 0.1 mm), led to similar inhibition to that seen in the diabetic arteries with l‐NMMA. The endothelium‐derived relaxing factor (EDRF)‐mediated component of acetylcholine‐induced relaxation determined by use of the nitric oxide synthase inhibitors was, therefore, apparently reduced in diabetic rats compared with control animals.6 In further experiments l‐NAME was found to enhance the response to noradrenaline in control rats but not in diabetic animals, suggesting that the abnormal response to noradrenaline in the diabetic animals was also due to reduced EDRF release.7 Nitroprusside‐induced relaxation (endothelium‐independent) was similar in arteries from control and diabetic rats (pEC50 7.61 ± 0.13 for diabetic arteries, n = 18, versus 7.68 ± 0.15 in the controls, n = 20, P not significant).8 These results suggest that endothelial function is abnormal in mesenteric resistance arteries of streptozotocin‐induced diabetic rats and that this is predominantly due to reduced EDRF release.
Control of cyclic AMP levels in primary cultures of human tracheal smooth muscle cells
Authors: Hall I.P. , Widdop S. , Townsend P. , Daykin K. 
Published: July 2012

[3H]‐adenosine 3′:5′‐cyclic monophosphate ([3H]‐cyclic AMP) responses were studied in primary cultures of human tracheal smooth muscle cells derived from explants of human trachealis muscle and in short term cultures of acutely dissociated trachealis cells.
Isoprenaline induced concentration‐dependent [3H]‐cyclic AMP formation wtih an EC50 of 0.2 μm. The response to 10 μm isoprenaline reached a maximum after 5–10 min stimulation and remained stable for periods of up to 1 h. After 10 min stimulation, 1 μm isoprenaline produced a 9.5 fold increase over basal [3H]‐cyclic AMP levels. The response to isoprenaline was inhibited by ICI 118551 (10 nm), (apparent KA 1.9 × 109 m−1) indicating the probable involvement of a β2‐adrenoceptor in this response in human cultured tracheal smooth muscle cells. However, with 50 nm ICI 118551 there was a reduction in the maximum response to isoprenaline. Prostaglandin E2 also produced concentration‐dependent [3H]‐cyclic AMP formation (EC50 0.7 μm, response to 1 μm PGE2 6.4 fold over basal).
Forskolin (1 nm‐100 μm) induced concentration‐dependent [3H]‐cyclic AMP formation in these cells. A 1.6 fold (over basal) response was also observed following stimulation with NaF (10 mm).
The nonselective phosphodiesterase inhibitor 3‐isobutyl‐1‐methylxanthine (IBMX) (0.1 mm) and the type IV, cyclic AMP selective, phosphodiesterase inhibitor rolipram (0.1 mm) both elevated basal [3H]‐cyclic AMP levels by 1.8 and 1.5 fold respectively. IBMX (1–100 μm) and low concentrations of rolipram (< 10 μm), also potentiated the response to 1 μm isoprenaline. Inhibitors of the type III phosphodiesterase isoenzyme (SK&F 94120 and SK&F 94836) were without effect upon basal or isoprenaline‐stimulated cyclic AMP responses in these cells.
Carbachol (1 nm‐100 μm) produced concentration‐dependent inhibition of the [3H]‐cyclic AMP response to 1 μm isoprenaline in human cultured tracheal smooth muscle cells (IC50 0.24 μm). Carbachol (1 μm) inhibited the [3H]‐cyclic AMP response to 1 μm isoprenaline by 60%. This effect of carbachol was itself inhibited by atropine (50 nm) (KA 2.3 × 109 m−1) indicating the involvement of a muscarinic receptor.6 These results show that primary cultures of human tracheal smooth muscle cells demonstrate cyclic AMP responses to direct receptor stimulation, adenylyl cyclase activation and inhibition with nonselective and type IV‐selective cyclic AMP phosphodiesterase isoenzyme inhibitors, and that the cyclic AMP response to isoprenaline can be inhibited by muscarinic receptor stimulation.