bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exogenous NPY modulation of cardiac autonomic reflexes and its pressor effect in the conscious rabbit
Authors: Serone Adrian P. , Angus James A. , Wright Christine E. 
Published: January 2005

Neuropeptide Y (NPY) may inhibit sympathetic and vagal transmission via presynaptic Y2 receptors and cause vasoconstriction via postsynaptic Y1 receptors. We examined the effects of NPY and related peptides on cardiovascular parameters and autonomic reflexes in the conscious rabbit. Further, the postjunctional effects of NPY and related peptides were assessed on acetylcholine (ACh) and isoprenaline agonist dose‐chronotropic response curves.In conscious rabbits the cardiac baroreceptor‐heart rate reflex (baroreflex), Bezold‐Jarisch like and nasopharyngeal reflexes were assessed in control, propranolol‐treated or methscopolamine‐treated (baroreflex only) groups, before and 30 min after i.v. administration of NPY (10 μg kg−1+ 5 μg kg−1min−1) or vehicle (saline, 10 ml h−1). The effects of equivalent pressor doses of [Leu31, Pro34]NPY or methoxamine on the baroreflex were also examined. In separate animals, dose‐heart rate (HR) response curves to isoprenaline or ACh were constructed before and 15 min after administration of NPY, [Leu31,Pro34]NPY (ACh only) or [Leu31,Pro34]NPY + sodium nitroprusside (ACh only).Administration of NPY‐receptor agonists caused sustained bradycardia (in the absence of methscopolamine) and rightward shifts of the barocurves in all 3 groups. The range of sympathetically‐mediated tachycardia was significantly decreased by NPY or [Leu31,Pro34]NPY in the methscopolamine‐treated group. However, these changes in the baroreflex were no different from those elicted by equipressor doses of methoxamine. There was no vagal inhibition by any NPY‐receptor agonist in all three autonomic reflexes examined. ACh or isoprenaline dose‐HR response curves were not affected by NPY peptide administration.We conclude that in the conscious rabbit, at a single dose that elicits a significant pressor response, exogenous NPY has no direct effect on modulation of cardiac and autonomic reflexes. Non‐specific effects of exogenous NPY on the baroreflex may be fully explained by its pressor action. There was no effect of NPY on postjunctional ACh or isoprenaline agonist dose‐response curves. Therefore, it is unlikely that endogenous NPY has a functional role in directly modulating cardiac autonomic neurotransmission in the rabbit.British Journal of Pharmacology(1998)123, 1375–1384; doi:10.1038/sj.bjp.0701752
Ca2+ mobilization in the aortic endothelium in streptozotocin‐induced diabetic and cholesterol‐fed mice
Authors: Kamata Katsuo , Nakajima Masato 
Published: January 2005

Experiments were performed to compare Ca2+ mobilization in the aortic endothelium in streptozotocin (STZ)‐induced diabetic and cholesterol‐fed mice with that in age‐matched controls.
The intracellular free Ca2+ ([Ca2+]i) in the fura PE‐3 loaded endothelium of aortic rings was dose‐dependently increased by cumulative administration of acetylcholine (ACh). ACh caused a transient rise in [Ca2+]i in Ca2+‐free medium. The ACh‐induced increase in [Ca2+]i in normal or Ca2+‐free medium was significantly weaker in both STZ‐induced diabetic and cholesterol‐fed mice.
The weaker [Ca2+]i response in Ca2+‐containing medium in STZ‐induced diabetic and cholesterol‐fed mice was normalized by chronic administration of cholestyramine.
The increased low density lipoprotein (LDL) levels seen in both STZ‐induced diabetic and cholesterol‐fed mice were normalized by the same chronic administration of cholestyramine (300 mg kg−1, p.o. daily for 10 weeks). Chronic administration of cholestyramine had no effect on the plasma glucose level.
Lysophosphatidylcholine (LPC) decreased the [Ca2+]i responses to ACh in the aortic endothelium from normal mice.
These results suggest that ACh increases both Ca2+ influx and Ca2+ release from storage in the aortic endothelium. The weaker [Ca2+]i influx seen in the endothelium of aortae from both STZ‐induced diabetic and cholesterol‐fed mice was improved by the chronic administration of cholestyramine, and we suggest that this improvement is due, at least in part, to a lowering of the plasma LDL level. It is further suggested that LPC may have an important influence over Ca2+ mobilization in the endothelium.

British Journal of Pharmacology (1998) 123, 1509–1516; doi:10.1038/sj.bjp.0701754
Characterization of calcitonin gene‐related peptide(CGRP) receptors in intramural coronary arteries from male and female Sprague Dawley rats
Authors: Sheykhzade Majid , Berg Nyborg Niels C. 
Published: January 2005

In this study we characterized the CGRP‐receptor subtype by Schild‐plot analysis using the C‐terminal fragment, human‐αCGRP(8–37), a putative competitive CGRP1‐receptor selective antagonist. In addition, the effect of rat‐αCGRP was compared with that of homologous peptides rat‐βCGRP, rat‐amylin, rat‐adrenomedullin and [Cys(Acm)2,7]‐human‐αCGRP, a putative selective CGRP2‐receptor agonist, in the left coronary arteries of 3 months old male and female Sprague Dawley rats.
Isolated rings from the distal, intramural part of the left anterior descending (LAD) coronary artery in both groups of rats were mounted on a double wire‐myograph. The arteries were then stretched to their optimal lumen diameter for active tension development and precontracted with 10−5 m prostaglandin F2α (PGF2α), after which agonists were added to the organ bath in a cumulative manner.
Rat‐αCGRP induced endothelium‐independent relaxations in male and female Sprague‐Dawley rats. Rat‐βCGRP concentration‐response relations (10−11–10−7 m) were similar to those of rat‐αCGRP in either sex. The maximal relaxations induced by rat‐amylin and rat‐adrenomedullin, both at 10−6 m, were significantly (P<0.05) lower than those induced by rat‐α‐ and rat‐βCGRP. In contrast, the selective CGRP2‐receptor agonist [Cys(Acm)2,7]‐human‐αCGRP failed to induce significant relaxations at the highest concentration used (10−7 m) in the coronary arteries of male and female rats.
The C‐terminal fragment, human‐αCGRP(8–37) blocked concentration‐dependently (10−7–10−6 m) the rat‐αCGRP‐induced relaxation in 10−5 m PGF2α‐precontracted coronary arteries. The slopes of the regression lines of the Schild‐plots for both male and female rats were not significantly (P>0.05) different from unity and the pA2 values for human‐αCGRP(8–37) were 6.93 and 6.98 in arteries from male and female rats, respectively. There was no significant (P>0.05) difference in estimated pKB values for human‐αCGRP(8–37) between male (6.99±0.10, n=13) and female (6.95±0.08, n=13) rats.
The concentration‐response relationships for rat‐α‐ and rat‐βCGRP were similar in male and female Sprague Dawley rats. The predominant CGRP receptor subtype in small intramural coronary arteries appeared to belong to the CGRP1‐receptor subtype in both sexes.

British Journal of Pharmacology (1998) 123, 1464–1470; doi:10.1038/sj.bjp.0701760
Preservation of vascular function in rat mesenteric resistance arteries following cold storage, studied by small vessel myography
Authors: McIntyre C. A. , Williams B. C. , Lindsay R. M. , McKnight J. A. , Hadoke P. W. F. 
Published: January 2005

The use of isolated blood vessels to investigate the physiological and pharmacological control of the vasculature is limited by the requirement to use freshly isolated vessels. Hence, the aim of this study was to determine whether vascular smooth muscle and endothelial cell function could be preserved in resistance arteries by storing them in physiological salt solution (PSS) at 4°C.
Third order mesenteric resistance arteries (mean internal diameter 237±6 μm) were dissected from the mesenteric bed of male Cob‐Wistar rats. The vessel segments were mounted in a small vessel myograph for measurement of isometric tension, and equilibrated at their optimum resting force. Contractile responses to noradrenaline (NA; 1×10−9–3×10−5 M), phenylephrine (PE, 1×10−9–3×10−5 M), potassium chloride (KCl; 2.5–140 mM) and endothelin (ET‐1, 1×10−11–3×10−7 M) and relaxant responses to acetylcholine (ACh; 1×10−9–3×10−5 M) and 3‐morpholinosydnonimine (SIN‐1; 1×10−9–1×10−4 M) were obtained in arteries, immediately after dissection (day 0) and following one to four days storage (day 1–day 4).
All arteries produced concentration‐dependent contractions in response to each of the vasoconstrictors. There were no significant differences in the magnitude or sensitivity (pD2) of the vasoconstrictor responses between fresh and stored vessels.
Arteries precontracted with NA to approximately 80% of the maximum response, relaxed in a concentration‐dependent manner in response to ACh and SIN‐1. Vessel storage for up to three days resulted in no change in response to ACh or SIN‐1.
Vessels analysed after four days of storage demonstrated a significant increase in sensitivity to ACh and SIN‐1 (−logIC50 (M) values; ACh; day 0, 7.46±0.13 vs day 4, 7.97±0.11, P<0.01 and SIN‐1; day 0, 4.87±0.10 vs day 4, 5.52±0.08, P<0.01). There was also a significant increase in the maximum relaxant response to ACh after four days of storage (% relaxation; day 0, 92.65±2.84 vs day 4, 100.36±0.36, P<0.05).
These results demonstrate that small resistance arteries remain viable if stored in PSS at 4°C for up to four days, with no loss in endothelial cell function. The altered sensitivity to the vasodilators on day 4 suggests that vessels should only be stored for up to three days following dissection for analysis of functional responses.

British Journal of Pharmacology (1998) 123, 1555–1560; doi:10.1038/sj.bjp.0701768
Characterization of 5‐HT receptors mediating constriction of porcine carotid arteriovenous anastomoses; involvement of 5‐HT1B/1D and novel receptors
Authors: De Vries Peter , Villalón Carlos M. , Heiligers Jan P. C. , Saxena Pramod R. 
Published: January 2005

It was previously shown that porcine cranial arteriovenous anastomoses (AVAs) constrict to 5‐hydroxytryptamine (5‐HT), ergotamine, dihydroergotamine, as well as sumatriptan and that sumatriptan acts exclusively via 5‐HT1B/1D receptors. The present study was devoted to establish the contribution of 5‐HT1B/1D receptors in the constriction of AVAs elicited by 5‐HT (in presence of 0.5 mg kg−1 ketanserin), ergotamine and dihydroergotamine in anaesthetized pigs.
Intracarotid infusion of 5‐HT (2 μg kg−1 min−1) and intravenous doses of ergotamine (2.5–20 μg kg−1) and dihydroergotamine (3–100 μg kg−1) reduced AVA and increased nutrient blood flows and vascular conductances. The vasodilator response to 5‐HT, observed mainly in the skin and ear, was much more prominent than that of the ergot alkaloids.
Treatment with the 5‐HT1B/1D receptor antagonist GR127935 (0.5 mg kg−1, i.v.) significantly attenuated both ergot‐induced AVA constriction and arteriolar dilatation, whereas GR127935 only slightly affected the carotid vascular effects of 5‐HT.
The results suggest that 5‐HT constricts carotid AVAs primarily via receptors, which seem to differ from those (5‐HT1B/1D) stimulated by sumatriptan. The ergot alkaloids produce AVA constriction for a substantial part via 5‐HT1B/1D receptors, but also stimulate unidentified receptors. Both these non‐5‐HT1B/1D receptors may be targets for the development of novel antimigraine drugs.
The moderate vasodilator response to the ergot derivatives seems to be mediated, at least in part, by 5‐HT1B/1D receptors, whereas the arteriolar dilatation caused by 5‐HT may be mediated by other, possibly 5‐HT7 receptors.

British Journal of Pharmacology (1998) 123, 1561–1570; doi:10.1038/sj.bjp.0701770
Dependence of P2‐nucleotide receptor agonist‐mediated endothelium‐independent relaxation on ectonucleotidase activity and A2A‐receptors in rat portal vein
Authors: Guibert Christelle , Loirand Gervaise , Vigne Paul , Savineau Jean‐Pierre , Pacaud Pierre 
Published: January 2005

The mechanism of action of P2 nucleotide receptor agonists that produce endothelium‐independent relaxation and the influence of ecto‐ATPase activity on this relaxing effect have been investigated in rat portal vein smooth muscle.
At 25°C, ATP, 2‐methylthioATP (2‐MeSATP) and 2‐chloroATP (2‐ClATP), dose‐dependently inhibited spontaneous contractile activity of endothelium‐denuded muscular strips from rat portal vein. The rank order of agonist potency defined from the half‐inhibitory concentrations was 2‐ClATP (2.7±0.5 μM, n=7)>ATP (12.9±1.1 μM, n=9)2‐MeSATP (21.9±4.8 μM, n=4). In the presence of αβ‐methylene ATP (αβ‐MeATP, 200 μM) which itself produced a transient contractile effect, the relaxing action of ATP and 2‐MeSATP was completely abolished and that of 2‐ClATP strongly inhibited.
The non‐selective P2‐receptor antagonist pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS, 100 μM) did not affect the relaxation induced by ATP, 2‐MeSATP, and 2‐ClATP.
The A2A‐adenosine receptor antagonist ZM 241385 inhibited the ATP‐induced relaxation in a concentration‐dependent manner (1–100 nM). In the presence of 100 nM ZM 241385, the relaxing effects of 2‐MeSATP and 2‐ClATP were also inhibited.
ADP, AMP and adenosine also produced concentration‐dependent inhibition of spontaneous contractions. The relaxing effects of AMP and adenosine were insensitive to αβ‐MeATP (200 μM) but were inhibited by ZM 241385 (100 nM).
Simultaneous measurements of contraction and ecto‐ATPase activity estimated by the degradation of [γ‐32P]‐ATP showed that muscular strips rapidly (10–60 s) hydrolyzed ATP. This ecto‐ATPase activity was abolished in the presence of EDTA and was inhibited by 57±11% (n=3) by 200 μM αβ‐MeATP.
These results suggest that ATP and other P2‐receptor agonists are relaxant in rat portal vein smooth muscle, because ectonucleotidase activity leads to the formation of adenosine which activates A2A‐receptors.

British Journal of Pharmacology (1998) 123, 1732–1740; doi:10.1038/sj.bjp.0701773
Involvement of protein kinases in the induction of NO synthase II in human DLD‐1 cells
Authors: Kleinert Hartmut , Euchenhofer Christian , Fritz Gerhard , Ihrig‐Biedert Irmgard , Förstermann Ulrich 
Published: January 2005

Protein phosphorylation is involved in the induction of nitric oxide synthase II (NOS II, iNOS) in several types of animal cells. Here we have investigated the possible involvement of major protein kinases in the induction of NOS II expression in human DLD‐1 cells.
In DLD‐1 cells, interferon‐γ alone induced a submaximal NOS II expression; a cytokine mixture consisting of interferon‐γ, tumour necrosis factor‐α and interleukin‐1β produced maximal NOS II induction.
Activators of protein kinase A (forskolin, 8‐dibutyryl‐cyclic AMP), of protein kinase C (tetradecanoylphorbol‐13‐acetate), and of protein kinase G (8‐bromo cyclic GMP) did not induce NOS II mRNA by themselves, nor did they alter NOS II mRNA induction in response to cytokines.
Inhibitors of protein kinase A (compound H89), of protein kinase C (bisindolylmaleimide, chelerythrine or staurosporine), of phosphatidylinositol 3‐kinase (wortmannin), of p38 mitogen‐activated protein kinase (compound SB 203580) and of extracellular signal‐regulated kinase (compound PD 98059) also had no influence on basal or cytokine‐induced NOS II mRNA expression.
Immunoprecipitation kinase assays showed no activation of extracellular signal‐regulated kinase or p38 mitogen‐activated protein kinase in cytokine‐incubated DLD‐1 cells. The c‐Jun NH2‐terminal kinase was activated by cytokines, but the most efficacious cytokine was tumour necrosis factor‐α which did not induce NOS II by itself.
In contrast, the protein tyrosine kinase inhibitor tyrphostin B42 (a specific inhibitor of interferon‐γ‐activated janus kinase 2) and the protein tyrosine kinase inhibitor tyrphostin A25 both reduced CM‐induced NOS II mRNA expression in a concentration‐dependent manner.
These results suggest that activation of NOS II expression in DLD‐1 cells is independent of the activities of protein kinases A, C and G, phosphatidylinositol 3‐kinase, extracellular signal regulated kinase and p38 mitogen‐activated protein kinase, but seems to require protein tyrosine kinase activity, especially the interferon‐γ‐activated janus kinase 2.

British Journal of Pharmacology (1998) 123, 1716–1722; doi:10.1038/sj.bjp.0701782
Further insights into the anti‐aggregating activity of NMDA in human platelets
Authors: Franconi Flavia , Miceli Mauro , Alberti Luisa , Seghieri Giuseppe , De Montis M Graziella , Tagliamonte Alessandro 
Published: January 2005

In the present study the effect of N‐methyl‐D‐aspartate (NMDA) on thromboxane B2 synthesis and on [Ca2+]i was studied in human platelets.
NMDA (10−7M) completely inhibited the synthesis of thromboxane B2 from exogenous arachidonic acid (AA), while it did not interfere with the aggregating effect of the thromboxane A2 receptor agonist U‐46619.
NMDA (0.1 μM–10 μM) dose‐dependently increased intracellular calcium in washed platelets pre‐loaded with fura 2 AM, and this effect was not additive with that of AA.
NMDA shifted the dose‐response curve of AA to the right. At the highest AA concentrations platelet aggregation was not inhibited.
The antiaggregating effect of NMDA was not antagonized by NG‐monomethyl‐L‐arginine (L‐NMMA), a nitric oxide synthase (NOS) inhibitor.
Finally, NMDA (0.01 nM–100 nM) associated with either aspirin or indomethacin significantly potentiated the antiaggregating activity of both cyclo‐oxygenase inhibitors.
It was concluded that NMDA is a potent inhibitor of platelet aggregation and thromboxane B2 synthesis in human platelet rich plasma (PRP).
Pharmacological characterization of muscarinic receptors in the uterus of oestrogen‐primed and pregnant rats
Authors: Munns Melinda , Pennefather Jocelyn N. 
Published: January 2005

Radioligand binding and contractility studies were undertaken to determine the subtype/s of muscarinic receptors present in uteri of oestrogen‐treated and late pregnant rats.
Competition binding studies with uterine membrane preparations and [3H]‐QNB (quinuclidinyl benzilate) provided negative log dissociation constants (pKi) for each antagonist as follows; oestrogen‐treated – atropine (7.98)himbacine (7.83)>methoctramine (7.52)hexahydrosiladiphenidol (HHSiD; 7.32)5,11‐dihydro‐11‐[[[2‐[2 ‐ [(dipropylamino)methyl] ‐ 1piperidinyl]ethyl]amino] ‐ carbonyl] ‐ 6H‐pyrido‐ [2,3 ‐ b][1,4] ‐ benzodiazepin ‐ 6‐one (AF ‐ DX 384; 7.10)>11 ‐ [[2 ‐ [(diethylamino)methyl]‐1‐piperidinyl]‐ acetyl]5,11‐dihydro‐6H‐pyridol]2,3,‐b][1,4]benzodiazepin‐6‐one (AF‐DX 116, 6.77)>pirenzepine (6.17); late pregnant – atropine (8.05)methoctramine (7.95)himbacine (7.71)HHSiD (7.52)AF‐DX 384 (7.34)>AF‐DX 116 (6.72)>pirenzepine (6.18).
The potency of carbachol in causing uterine contraction was similar in preparations from pregnant and non‐pregnant animals (pD2=5.57 and 5.46, respectively). Each muscarinic antagonist caused parallel, rightward shifts of carbachol concentration‐response curves. The pA2 estimates were: oestrogen‐treated – atropine (9.42)>himbacine (8.73)HHSiD (8.68)methoctramine (8.49)AF‐DX 384 (7.91)AF‐DX 116 (7.36)pirenzepine (7.26); late pregnant – atropine (9.48)>himbacine (8.37)HHSiD (8.22)methoctramine (8.01)AF‐DX 116 (7.73)AF‐DX 384 (7.44)pirenzepine (6.92).
The relative pKi estimates for antagonists obtained in membrane preparations from oestrogen‐treated rats suggest the presence of muscarinic M2 subtypes. In functional studies pA2 values indicated the additional presence of muscarinic M3 receptor or, possibly an atypical receptor subtype. The similarity between pKi and pA2 estimates obtained in uteri from oestrogen‐treated and pregnant animals, respectively, indicates that pregnancy does not affect myometrial muscarinic receptors in the rat.

British Journal of Pharmacology (1998) 123, 1639–1644; doi:10.1038/sj.bjp.0701794
Comparative, general pharmacology of SDZ NKT 343, a novel, selective NK1 receptor antagonist
Authors: Walpole C S J , Brown M C S , James I F , Campbell E A , McIntyre P , Docherty R , Ko S , Hedley L , Ewan S , Buchheit K‐H , Urban L A 
Published: January 2005

The in vitro and in vivo pharmacology of SDZ NKT 343 (2‐nitrophenyl‐carbamoyl‐(S)‐prolyl‐(S)‐3‐(2‐naphthyl)alanyl‐N‐benzyl‐N‐methylamide), a novel tachykinin NK1 receptor antagonist was investigated.
SDZ NKT 343 inhibited [3H]‐substance P binding to the human NK1 receptor in transfected Cos‐7 cell membranes (IC50=0.62±0.11 nM). In comparison, in the same assay Ki values for FK888, CP 99,994, SR 140,333 and RPR 100,893 were 2.13±0.04 nM, 0.96±0.20 nM, 0.15±0.06 nM and 1.77±0.41 nM, respectively. SDZ NKT 343 showed a markedly lower affinity at rat NK1 receptors in whole forebrain membranes (IC50=451±139 nM).
SDZ NKT 343 caused an increase in EC50 as well as reduction in the number of binding sites (Bmax) determined for [3H]‐substance P, suggesting a non‐competitive interaction at the human NK1 receptor. SDZ NKT 343 also caused a reduction in the maximum elevation of [Ca2+]i evoked by substance P (SP) in human U373MG cells and depressed the maximum [Sar9]SP sulphone‐induced contraction of the guinea‐pig isolated ileum. The antagonism of SP effects on U373MG cells by SDZ NKT 343 was reversible.
SDZ NKT 343 showed weak affinity to human NK2 and NK3 receptors in transfected Cos‐7 cells (Ki of 0.52±0.04 μM and 3.4±1.2 μM, respectively). SDZ NKT 343 was inactive in a broad array of binding assays including the bradykinin B2 receptor the histamine H1 receptor, opiate receptors and adrenoceptors. SDZ NKT 343 only weakly inhibited the voltage‐activated Ca2+ and Na+currents in guinea‐pig dorsal root ganglion neurones. The enantiomer of SDZ NKT 343, (R,R)‐SDZ NKT 343 was about 1000 times less active at human NK1 receptors expressed in Cos‐7 cell membranes.
Contractions of the guinea‐pig ileum by [Sar9]SP sulphone were inhibited by SDZ NKT 343 in a concentration‐dependent manner, with an IC50=1.60±0.94 nM, while the enantiomer (R,R)‐SDZ NKT 343 was 100 times less active (IC50=162±26 nM). In comparison, in the same assay IC50 values for other NK1 receptor antagonists CP 99,994, SR 140,333, RPR 100,893 and FK 888 were 2.90±07 nM, 0.14±0.02 nM, 11.4±2.9 nM and 2.4±0.83 nM, respectively.
In anaesthetized guinea‐pigs i.v. administered SDZ NKT 343 antagonized [Sar9]SP sulphone‐evoked bronchoconstriction (70% reduction at 0.4 mg kg−1, i.v.). Basal airway resistance, mean arterial blood pressure and heart rate were not affected.
In conclusion, SDZ NKT 343 is a highly selective NK1 receptor antagonist with high potency at the human and guinea‐pig receptors. SDZ NKT 343 may be used as a potential novel therapeutic agent in human diseases where NK1 receptor hyperfunction is involved.