bluuebunny/crossref_metadata_2025_split huggingface dataset:
Desensitization of ETA endothelin receptor‐mediated negative chronotropic response in right atria–species difference and intracellular mechanisms
Authors: Ono Kageyoshi , Sakamoto Aiji , Masaki Tomoh , Satake Motoyoshi 
Published: January 2005

Desensitization of ETA endothelin receptor (ETAR) was compared between the rat and guinea‐pig with regard to negative chronotropic response (NC) in the right atria (RA).
ET‐1 (100 nM) produced distinct NC in the presence of BQ788 (300 nM), and positive chronotropic response (PC) in the presence of BQ123 (1 μM) in both species, showing that ETAR and ETB endothelin receptor (ETBR) mediate NC and PC, respectively.
Repetitive applications of ET‐1 (50 nM) desensitized PC, and the second application only induced a strong NC in both species. Later applications of ET‐1 produced virtually no response in the rat RA, whereas they produced BQ123‐sensitive NCs repetitively in guinea‐pig RA, exhibiting marked species difference in desensitization of ETAR‐mediated NC.
Pretreatment with staurosporine (100 nM) prevented desensitization of ETAR in the rat RA altogether. However, phorbol 12‐myristate 13‐acetate (PMA, 300 nM) failed to induce, but rather hampered, desensitization of ETAR.
Partial amino acid sequencing of ETARs, spanning from the 2nd through the 4th intracellular loops, revealed that all the potential Ser/Thr phosphorylation sites, including a protein kinase C (PKC) site, are conserved among guinea‐pigs, rats, rabbits, bovines and humans.
In guinea pig RA, pretreatment with okadaic acid (1 μg ml−1) and PMA did not facilitate desensitization of ETAR whereas these agents successfully desensitized ETAR during combined stimulation of β‐adrenoceptor and ETAR by isoproterenol (300 nM) and ET‐1 (100 nM).
These results suggest that species differences in desensitization of ETAR are not caused by differences in the site(s) of, but caused by differences in the environment for phosphorylation of the receptor. Desensitization of ETAR appears to require phosphorylation of the receptor by PKC as well as a kinase stimulated by β‐adrenoceptor activation.

British Journal of Pharmacology (1998) 125, 787–797; doi:10.1038/sj.bjp.0702125
The role of A3 adenosine receptors in central regulation of arterial blood pressure
Authors: Stella Luigi , de Novellis Vito , Marabese Ida , Berrino Liberato , Maione Sabatino , Filippelli Amelia , Rossi Francesco 
Published: January 2005

Pharmacological studies have suggested that A3 receptors are present on central neurons. Recently this adenosine receptor subtype has been identified in the rat and its presence in the central nervous system has been confirmed.
In this study we investigated the effects of acute intracerebroventricular (i.c.v.) injections of N6‐2‐(4‐aminophenyl)‐ethyladenosine (APNEA), a non‐selective A3 adenosine receptor agonist, on arterial blood pressure (ABP) and heart rate (HR), after treatment with 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX), a selective antagonist of A1 adenosine receptors.
Anaesthetized rats, after DPCPX (12 μg−1 kg i.c.v.), were treated with APNEA (0.4–4 μg kg−1 i.c.v.) resulting in a transitory and dose‐dependent decrease in arterial blood pressure without a change in heart rate. APNEA also induced hypotensive responses after i.c.v. pretreatment with aminophylline, at a dose of 20 μg kg−1. In contrast, pretreatment 48 h before, with 4 μg kg−1 i.c.v. of pertussis toxin reduced the hypotensive effect induced by APNEA. Administration of APNEA at a higher dose (20 μg kg−1 i.c.v.), after DPCPX, induced a decrease in ABP of −66±5.4 mmHg and after 3 min a decrease in heart rate of −62±6.0 beats min−1. Transection of the spinal cord abolished this significant fall in ABP, but not the decrease of HR.
These results suggest that a population of A3‐receptors is present in the CNS, whose activation induces a decrease in blood pressure with no change of heart rate.

British Journal of Pharmacology (1998) 125, 437–440; doi:10.1038/sj.bjp.0702126
Investigation of oxidant stress and vasodepression to glyceryl trinitrate in the obese Zucker rat in vivo
Authors: Laight David W , Kengatharan K M , Gopaul Nitin K , Änggård Erik E , Carrier Martin J 
Published: January 2005

We examined the relationship between oxidant stress and the vasodepressor activity of glyceryl trinitrate (GTN) in vivo, including rapid GTN tolerance development, in 13‐week old obese and age‐matched lean Zucker rats which had been maintained for 4 weeks on either control diet or diets enriched with the lipophilic, chain‐breaking antioxidants vitamin E (0.5% w w−1) or probucol (0.5% w w−1) or the superoxide anion scavenger tiron (1% w v−1 in drinking water).
The basal plasma level of the isoprostane 8‐epi‐PGF2α, an in vivo marker of lipid peroxidation, was elevated by approximately 5 fold in the obese Zucker rat and markedly reduced by dietary lipophilic antioxidants and depressed by dietary tiron.
Vasodepression to bolus does GTN (0.1–100 μg kg−1 i.v.), but not endothelium‐dependent vasodepression to bolus dose acetylcholine (ACh, 0.02–2.0 μg kg−1 i.v.), was impaired in obese animals and completely restored by dietary antioxidants.
Nitrate tolerance developed in vivo during a 1 h infusion of GTN (40 μg kg−1 min−1 i.v.) appeared more severe in obese animals. However, rapid nitrate tolerance was not affected by dietary antioxidants in either the obese or lean Zucker rat.
We therefore provide evidence that elevated oxidant stress in the obese Zucker rat is associated with an impairment in nitrate vasodepressor activity. However, our data are not consistent with either a role for oxidant stress in rapid nitrate tolerance development in the anaesthetized Zucker rat or the aggravation of this tolerance by pre‐existing oxidant stress.

British Journal of Pharmacology (1998) 125, 895–901; doi:10.1038/sj.bjp.0702132
On the inhibition of voltage activated calcium currents in rat cortical neurones by the neuroprotective agent 619C89
Authors: Stefani A , Hainsworth A. H. , Spadoni F , Bernardi G 
Published: January 2005

The lamotrigine analogue 619C89, utilised to reduce postischaemic and posttraumatic neuronal injury, has been shown to inhibit sodium channels and cloned N‐type calcium channels. To verify whether this neuroprotective agent also blocked native calcium channels, we have tested its action in cortical pyramidal neurones, acutely isolated from the adult rat brain.
619C89 inhibited more than 90% of the high voltage‐activated calcium currents recorded in the whole‐cell configuration. The response was relatively slow in onset (30–60 s), recovered incompletely (96%), but showed no consistent desensitization.
This inhibitory effect was not selective for any calcium channel subtype, being largely unaffected by ω‐conotoxin‐GVIA, ω‐agatoxin‐IVA, ω‐conotoxin‐MVIIC and dihydropyridine antagonists.
Saturating responses to 619C89 were detected for concentrations 50 μM. Dose‐response curves revealed that 619C89 have an approximately 8 μM binding site.
The effect of 619C89 was dependent on the divalent concentrations in that its potency was reduced on increase of the charge carrier up to 20 mM barium. Since the lamotrigine analogue shifted to the right the dose‐dependence of the cadmium block, the 619C89‐mediated inhibition of calcium currents seemed to rely on a direct interaction with the channel pore. Functional implications are discussed.

British Journal of Pharmacology (1998) 125, 1058–1064; doi:10.1038/sj.bjp.0702134
Pharmacological characterization of endothelin‐induced contraction in the guinea‐pig oesophageal muscularis mucosae
Authors: Uchida Kohsuke , Yuzuki Rika , Kamikawa Yuichiro 
Published: January 2005

In the oesophageal muscularis mucosae, we examined the effects of endothelin‐1 (ET‐1), endothelin‐2 (ET‐2), endothelin‐3 (ET‐3) and sarafotoxin S6c (SX6c) as agonists, and FR139317, BQ‐123 and RES‐701‐1 as endothelin receptor antagonists.
All of the endothelins produced tonic contractions which were frequently superimposed on rhythmic motility in a concentration‐dependent manner. The order of potency (−log EC50) was ET‐1 (8.61)=SX6c (8.65)>ET‐2 (8.40)>ET‐3 (8.18).
FR139317 (1–3 μM) and BQ‐123 (1 μM) caused parallel rightward shifts of the concentration‐response curve to ET‐1, but at higher concentrations caused no further shift. RES‐701‐1 (3 μM) caused a rightward shift of the concentration‐response curve to ET‐1, while RES‐701‐1 (10 μM) had no additional effect. RES‐701‐1 (0.1–1 μM) concentration‐dependently caused a rightward shift of the concentration‐response curve to SX6c. The contraction to ET‐1 (10 nM) in preparations desensitized to the actions of SX6c was greatly inhibited by pretreatment with FR139317 (10 μM).
Modulation of the Ca2+ concentration in the Krebs solution caused the concentration‐response curve to ET‐1 or SX6c to shift to the right and downward as external Ca2+ concentrations decreased. Verapamil (30 μM) abolished rhythmic motility induced by ET‐1 or SX6c. Ni2+ (0.1 mM) weakly inhibited ET‐1‐ or SX6c‐induced tonic contraction. SK&F 96365 (60 μM) completely inhibited ET‐1‐induced contractions.
We conclude that there are two types of ET‐receptors, excitatory ETA‐ and ETB‐receptors in the oesophageal muscularis mucosae. These receptors mediate tonic contractions predominantly by opening receptor‐operated Ca2+ channels (ROCs) and partly by opening T‐type Ca2+ channels, and mediate rhythmic motility by opening L‐type Ca2+ channels.

British Journal of Pharmacology (1998) 125, 849–857; doi:10.1038/sj.bjp.0702140
Excitatory motor and electrical effects produced by tachykinins in the human and guinea‐pig isolated ureter and guinea‐pig renal pelvis
Authors: Patacchini Riccardo , Santicioli Paolo , Zagorodnyuk Vladimir , Lazzeri Massimo , Turini Damiano , Alberto Maggi Carlo 
Published: January 2005

In isolated tissue experiments, neurokinin A (NKA) produced concentration‐dependent contraction of human and guinea‐pig ureter (pD2=6.7 and 7.2, respectively); an effect greatly reduced (>80% inhibition) by the tachykinin NK2 receptor‐selective antagonist MEN 11420 (0.1 μM). The tachykinin NK1 and NK3 receptor agonists septide and senktide, respectively, were ineffective.
Electrical field stimulation (EFS) of the guinea‐pig isolated renal pelvis produced an inotropic response blocked by MEN 11420 (0.01–1 μM). In the same preparation MEN 11420 (0.1 μM) blocked (apparent pKB=8.2) the potentiation of spontaneous motor activity produced by the NK2 receptor‐selective agonist [βAla8]NKA(4–10).
In sucrose‐gap experiments, EFS evoked action potentials (APs) accompanied by phasic contractions of human and guinea‐pig ureter, which were unaffected by tetrodotoxin or MEN 11420 (3 μM), but were blocked by nifedipine (1–10 μM). NKA (1–3 μM) produced a slow membrane depolarization with superimposed APs and a tonic contraction with superimposed phasic contractions. NKA prolonged the duration of EFS‐evoked APs and potentiated the accompanying contractions. MEN 11420 completely prevented the responses to NKA in both the human and guinea‐pig ureter.
Nifedipine (1–10 μM) suppressed the NKA‐evoked APs and phasic contractions in both human and guinea‐pig ureter, and slightly reduced the membrane depolarization induced by NKA. A tonic‐type contraction of the human ureter in response to NKA persisted in the presence of nifedipine.
In conclusion, tachykinins produce smooth muscle excitation in both human and guinea‐pig ureter by stimulating receptors of the NK2 type only. NK2 receptor activation depolarizes the membrane to trigger the firing of APs from latent pacemakers.

British Journal of Pharmacology (1998) 125, 987–996; doi:10.1038/sj.bjp.0702147
Dual pathway for angiotensin II formation in human internal mammary arteries
Authors: Voors Adriaan A. , Pinto Yigal M. , Buikema Hendrik , Urata Hidenori , Oosterga Margreeth , Rooks Gerrit , Grandjean Jan G. , Ganten D , Van Gilst Wiek H. 
Published: January 2005

Angiotensin converting enzyme (ACE) is thought to be the main enzyme to convert antiotensin I to the vasoactive angiotensin II. Recently, in the human heart, it was found that the majority of angiotensin II formation was due to another enzyme, identified as human heart chymase. In the human vasculature however, the predominance of either ACE or non‐ACE conversion of angiotensin I remains unclear.
To study the effects of ACE‐ and chymase‐inhibition on angiotensin II formation in human arteries, segments of internal mammary arteries were obtained from 37 patients who underwent coronary bypass surgery.
Organ bath experiments showed that 100 μM captopril inhibited slightly the response to angiotensin I (pD2 from 7.09±0.11–6.79±0.10, P<0.001), while 100 μM captopril nearly abolished the response to [pro10] angiotensin I, a selective substrate for ACE, and the maximum contraction was reduced from 83±19%–23±17% of the control response (P=0.01). A significant decrease of the pD2 of angiotensin I similar to captopril was observed in the presence of 50 μM chymostatin (pD2 from 7.36±0.13–6.99±0.15, P<0.039), without influencing the maximum response. In the presence of both inhibitors, effects were much more pronounced than either inhibitor alone, and a 300 times higher dose was needed to yield a significant contraction response to angiotensin I.
These results indicate the presence of an ACE and a non‐ACE angiontensin II forming pathway in human internal mammary arteries.

British Journal of Pharmacology (1998) 125, 1028–1032; doi:10.1038/sj.bjp.0702150
Use‐dependent block of Ih in mouse dorsal root ganglion neurons by sinus node inhibitors
Authors: Raes A , Van de Vijver G , Goethals M , van Bogaert P P 
Published: January 2005

The sinus node inhibitors UL–FS 49 and DK–AH 269 reduce heart rate by slowing diastolic depolarization rate in the sino‐atrial (SA) node, which might originate from the use‐dependent blockade of a hyperpolarization‐activated current If. A hyperpolarization‐activated current Ih, which is present in many types of neurons, is similar to If. We studied the effects of these drugs on Ih in cultured mouse dorsal root ganglion (DRG) neurons.
With the whole‐cell patch‐clamp technique use‐dependent block of Ih was observed. The steady‐state block following a voltage‐clamp pulse train (1‐s steps from −38 to −108 mV applied at 0.5 Hz) was dependent on drug concentration and showed an apparent Kd of 0.1 and 0.79 μM with DK–AH 269 and UL–FS 49 respectively.
The rate of block increased linearly with drug concentration. The rate of recovery from block was, however, much slower compared to cardiac tissue.
There was no significant effect of UL–FS 49 on the activation curve.
At high concentrations of UL–FS 49 a clear association of the drug with the open channel was observed.
When the cell was stimulated at a frequency of 3 Hz, a distinct hyperpolarization was observed in the presence of extracellular Cs+ or when Ih was blocked with UL–FS 49, but not in the absence of Cs+ and UL–FS 49.
These results indicate that Ih protects the cell against hyperpolarizations and subsequent inexcitability. The action of the drugs on the hyperpolarization‐activated current in cardiac and neuronal tissue show some similarities; however, some pronounced differences indicate that different subtypes of the channel might exist.

British Journal of Pharmacology (1998) 125, 741–750; doi:10.1038/sj.bjp.0702153
Endothelium‐dependent and ‐independent responses to protease‐activated receptor‐2 (PAR‐2) activation in mouse isolated renal arteries
Authors: Moffatt J D , Cocks T M 
Published: January 2005

Protease‐activated receptors (PARs) are receptors which require proteolytic cleavage to be self‐activated by newly exposed N‐terminal ‘tethered ligands’, and hence serve as sensors for protelytic enzymes. While both the thrombin receptor (PAR‐1) and PAR‐2 (activated by tryptic enzymes) have been shown to mediate endothelium‐dependent vasorelaxation, only PAR‐1 has been shown to cause direct vascular smooth muscle contraction. In this study, we report that trypsin and the PAR‐2 selective peptide ligand SLIGRL‐NH2 not only caused endothelium‐dependent relaxation of mouse renal arteries but also direct smooth muscle contraction if endothelial nitric oxide synthase was inhibited or if the endothelium was removed.British Journal of Pharmacology (1998) 125, 591–594; doi:10.1038/sj.bjp.0702157
Examination of somatostatin involvement in the inhibitory action of GIP, GLP‐1, amylin and adrenomedullin on gastric acid release using a new SRIF antagonist analogue
Authors: Rossowski Wojciech J. , Cheng Beng‐L , Jiang Ning‐Y , Coy David H. 
Published: January 2005

The effect of a new type 2 selective somatostatin (SRIF) receptor antagonist (DC‐41‐33) on somatostatin‐induced inhibition of pentagastrin‐stimulated gastric acid secretion in conscious, chronic gastric fistula equipped rats was studied.
Infused intravenously, DC‐41‐33 dose‐dependently inhibits SRIF‐induced inhibition of pentagastrin‐stimulated gastric acid secretion with an IC50 of 31.6±1.2 nmol kg−1 versus 10 nmol kg−1 SRIF and blocks the inhibitory effects of SRIF when simultaneously co‐infused. Its effectiveness provides additional evidence that SRIF‐inhibition of gastric acid release is a SRIF type 2 receptor‐mediated process.
DC‐41‐33 is able to completely reverse the inhibitory effect of glucose‐dependent insulinotropic polypeptides, GIP and GIP‐(1–30)NH2, and glucagon‐like polypeptide, GLP‐1(7‐36)NH2, on pentagastrin‐stimulated gastric acid secretion thus confirming that they exert these effects through stimulation of endogenous SRIF release.
DC‐41‐33 only partially blocks potent amylin and adrenomedullin‐induced inhibition of gastric acid secretion, therefore suggesting that somatostatin may not function as a primary mediator in the action of these peptides.
Our results indicate that DC‐41‐33, is a potent in vivo inhibitor of exogenous and endogenous SRIF in rats. It represents a new class of SRIF analogues which should eventually provide excellent tools for further evaluating the many physiological roles of SRIF and its five receptor subtypes.

British Journal of Pharmacology (1998) 125, 1081–1087; doi:10.1038/sj.bjp.0702160
The 5‐HT4 receptor antagonist ML10375 inhibits the constitutive activity of human 5‐HT4(c) receptor
Authors: Blondel Olivier , Gastineau Monique , Langlois Michel , Fischmeister Rodolphe 
Published: January 2005

Transient expression in COS‐7 cells of the recombinant human 5‐hydroxytryptamine (5‐HT) h5‐HT4(c) receptor isoform led to constitutive activity of the receptor. The 5‐HT4 receptor antagonist 2‐(cis‐3,5‐dimethylpiperidino)ethyl 4‐amino‐5‐chloro‐2‐methoxybenzoate (ML10375) at 1 μM completely abolished the 5‐HT (1 μM)‐mediated increase in adenylyl cyclase activity in COS‐7 cells expressing the h5‐HT4(c) receptor. Moreover, ML10375 also reduced basal cAMP levels in cells over‐expressing the receptor, even in the absence of agonist. The inhibitory effect of ML10375 on basal adenylyl cyclase activity was not modified by pre‐treatment of the cells with pertussis toxin, indicating that ML10375 acts through inactivation of spontaneously active h5‐HT4(c) receptors rather than through a Gi/Go regulatory pathway. We conclude that ML10375 acts as an inverse agonist on the h5‐HT4(c) receptor.British Journal of Pharmacology (1998) 125, 595–597; doi:10.1038/sj.bjp.0702163
Differential role of vasoactive prostanoids in porcine and human isolated pulmonary arteries in response to endothelium‐dependent relaxants
Authors: Lawrence R N , Clelland C , Beggs D , Salama F D , Dunn W R , Wilson V G 
Published: January 2005

The pig is increasingly being used in medical research, both as a model of the human cardiovascular system, and as a possible source of organs for xenotransplantation. However, little is known about the comparative functions of the vascular endothelium between porcine and human arteries. We have therefore compared the effects of two endothelium‐dependent vasorelaxants, acetylcholine (ACh) and the Ca2+‐ATPase inhibitor, cyclopiazonic acid (CPA) on the porcine and human isolated pulmonary artery using isometric tension recording.
ACh and CPA produced endothelium‐dependent relaxations of both the human and porcine pulmonary arteries.
In the porcine pulmonary artery, the cyclo‐oxygenase inhibitor, flurbiprofen had no effect on relaxations to ACh (Emax: control 67.8±8.8% versus 72.4±9.5% (n = 11)) or CPA (Emax: control 79.6±5.0% versus 94.0±10.6% (n = 7)). The nitric oxide synthase inhibitor, l‐NAME converted relaxations to both ACh and CPA into contractile responses (maximum response: ACh 30.0±11.1% (n = 10); CPA 80.4±26.2% (n = 8) of U46619‐induced tone). These contractile responses in the presence of l‐NAME were abolished by flurbiprofen.
In the human pulmonary artery, l‐NAME and flurbiprofen partly attenuated relaxations to ACh (Emax: control: 45.1±12.1%; flurbiprofen: 33.4±13.5%; l‐NAME: 10.1±7.2%) and CPA (Emax: control: 78.1±5.5%; flurbiprofen: 69.6±7.2%; l‐NAME 37.9±10.7% of U46619‐induced tone). These responses were abolished by the combination of both inhibitors.
We have demonstrated that while the release of nitric oxide is important in responses to endothelium‐dependent vasorelaxants in both human and porcine pulmonary arteries, in the human arteries, there is an important role for vasorelaxant prostanoids whilst in the porcine arteries, vasoconstrictor prostanoids are released.

British Journal of Pharmacology (1998) 125, 1128–1137; doi:10.1038/sj.bjp.0702168
Functional response of the rat kidney to inhibition of nitric oxide synthesis: role of cytochrome P450‐derived arachidonate metabolites
Authors: Oyekan Adebayo O. , McGiff J. C. 
Published: January 2005

We tested the hypothesis that nitric oxide (NO) exerts a tonic inhibitory influence on cytochrome P450 (CYP450)‐dependent metabolism of arachidonic acid (AA).
Nω‐nitro‐L‐Arginine methyl ester (L‐NAME), an inhibitor of nitric oxide synthase (NOS), increased mean blood pressure (MBP), from 91±6 to 137±5 mmHg, renal vascular resistance (RVR), from 9.9±0.6 to 27.4±2.5 mmHg ml−1 min−1, and reduced renal blood flow (RBF), from 9.8±0.7 to 6.5±0.6 ml min−1) and GFR from 1.2±0.2 to 0.6±0.2 ml 100 g−1 min−1) accompanied by diuresis (UV, 1.7±0.3 to 4.3±0.8 μl 100 g−1 min−1), and natriuresis (UNaV, 0.36±0.04 to 1.25±0.032 μmol 100 g−1 min−1).
12, 12 dibromododec‐enoic acid (DBDD), an inhibitor of ω hydroxylase, blunted L‐NAME‐induced changes in MBP, RVR, UV and UNaV by 63±8, 70±5, 45±8 and 42±9%, respectively, and fully reversed the reduction in GFR by L‐NAME. Clotrimazole, an inhibitor of the epoxygenase pathway of CYP450‐dependent AA metabolism, was without effect.
BMS182874 (5‐dimethylamino)‐N‐(3,4‐dimethyl‐5‐isoxazolyl)‐1‐naphthalenesulfonamide), an endothelin (ET)A receptor antagonist, also blunted the increases in MBP and RVR and the diuresis/natriuresis elicited by L‐NAME without affecting GFR.
Indomethacin blunted L‐NAME‐induced increases in RVR, UV and UNaV. BMS180291 (1S‐(1α,2α,3α.4α)]‐2‐[[3‐[4‐[(pentylamino)carbonyl]‐2‐oxazolyl] ‐ 7 ‐ oxabicyclo[2.2.1]hept ‐ 2 ‐yl]methyl]benzenepropanoic acid), an endoperoxide receptor antagonist, attenuated the pressor and renal haemodynamic but not the renal tubular effects of L‐NAME.
In conclusion, the renal functional effects of the CYP450‐derived mediator(s) expressed after inhibition of NOS with L‐NAME were prevented by inhibiting either CYP450 ω hydroxylase or cyclo‐oxygenase or by antagonizing either ETA or endoperoxide receptors. 20‐hydroxyeicosatetraenoic acid (20‐HETE) fulfils the salient properties of this mediator.

British Journal of Pharmacology (1998) 125, 1065–1073; doi:10.1038/sj.bjp.0702171