bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potentiation of the vasorelaxant activity of nitric oxide by hydroxyguanidine: implications for the nature of endothelium‐derived relaxing factor
Authors: Zembowicz Artur , Swierkosz Tomasz A. , Southan Garry J. , Hecker Markus , Vane John R. 
Published: July 2012

We recently demonstrated that NG‐hydroxy‐l‐arginine (l‐HOArg) is a substrate for the constitutive nitric oxide (NO) synthase present in bovine aortic endothelial cells cultured on microcarrier beads (EC). Furthermore, l‐HOArg reacts chemically with NO released from these cells to form a potent and more stable vasodilator. This is most likely through a reaction with the hydroxyguanidino group.
Here, we studied the interaction of a simpler molecule, hydroxyguanidine (HOG) with NO.
HOG (10 μm), like l‐HOArg (10 μm) or NG‐hydroxy‐d‐arginine (d‐HOArg, 10 μm), potentiated and stabilized the relaxant activity of authentic NO.
When NO was bubbled through the solution of HOG, a new compound was formed. It had similar physicochemical properties to those of the previously described l‐HOArg/NO adduct. It was also a potent vasodilator and its action was inhibited by oxyhaemoglobin (10 μm), indicating formation of a NO‐containing substance.
Moreover, HOG (10 μm) was not a substrate for the constitutive NO synthase present in the microsomal fraction of EC and did not affect the flow‐induced or bradykinin‐stimulated generation of prostacyclin, as measured by 6‐ketoPGF1α.
We also studied the effect of HOG on the endothelium‐derived relaxing factor (EDRF) released from the column of EC. HOG (10 μm) potentiated and stabilized the relaxations of rabbit aortic strips induced by EDRF released by bradykinin (5–20 pmol) or ADP (5–10 nmol). These relaxations were inhibited by NG‐nitro‐l‐arginine methyl ester (l‐NAME, 10 μm) and l‐arginine (l‐Arg, 1 mm) reversed the inhibitory effects of l‐NAME.
HOG (10 μm) augmented the basal (flow‐induced) EC‐dependent relaxations which were also inhibited by l‐NAME (10 μm) and the effects of l‐NOArg were reversed by l‐Arg (1 mm).
Thus, the hydroxyguanidino moiety of l‐HOArg is involved in the reaction with NO. Moreover, the comparable reaction of the hydroxyguanidino compounds with NO on the one hand and with flow‐induced and agonist‐triggered EDRF on the other, strongly supports their common identity.
Analysis of the agonist activity of fenoldopam (SKF 82526) at the vascular 5‐HT2 receptor
Authors: Christie Mark I. , Harper Diane , Smith George W. 
Published: July 2012

The 5‐HT2 receptor agonist activity of fenoldopam (SKF 82526) was characterized in the rabbit isolated aorta preparation.
Fenoldopam was an agonist at the vascular 5‐HT2 receptor with lower affinity and efficacy than the naturally occurring agonist 5‐hydroxytryptamine (5‐HT). Fenoldopam had an affinity (pKA) of 5.84 ± 0.04 and efficacy (τ) of 0.57 ± 0.04, whereas 5‐HT had a pKA of 6.65 ± 0.12 and τ of 2.66 ± 0.41.
The constrictor effects of fenoldopam and 5‐HT were competitively antagonized by the 5‐HT2 antagonist, ketanserin, with pKB values of 8.81 ± 0.11 and 8.83 ± 0.10 respectively.
Prior incubation with fenoldopam produced a concentration‐related rightward shift of a subsequent 5‐HT concentration‐response curve. This inhibition was specific for 5‐HT since constrictor responses to angiotensin II were unaffected.
This study indicates that the D1 receptor agonist, fenoldopam, acts as an agonist at the vascular 5‐HT2 receptor, but with an affinity and efficacy less than that of the naturally occurring agonist, 5‐HT.
Mechanisms of the biphasic responses to endothelin‐3 in dog coronary arteries
Authors: Okamura Tomio , Matsumoto Tetsuya , Ikemoto Fumihiko , Toda Noboru 
Published: July 2012

Endothelin‐3 (ET‐3) elicited relaxations at low concentrations (up to 10−8 m) and contractions at higher concentrations in dog isolated coronary arteries precontracted with prostaglandin F2α (PGF2α). The relaxation by ET‐3 was not affected by endothelium denudation nor treatment with NG‐nitro‐l‐arginine, but was abolished or reversed to a contraction by treatment with indomethacin and markedly suppressed by tranylcypromine, a PGI2 synthetase inhibitor, or diphloretin phosphate, a prostaglandin receptor antagonist. ET‐1 produced only concentration‐dependent contractions.
BQ‐123, a new selective ETA receptor antagonist, caused relaxation of the strips contracted with ET‐3 in a dose‐dependent manner and prevented the ET‐3‐induced contraction but did not affect the contraction produced by PGF2α. The relaxation caused by ET‐3 was enhanced by treatment with BQ‐123.
It is concluded that the relaxations elicited by ET‐3 in dog coronary arteries are mediated via liberation of PGI2 by activation of non‐ETA receptors, located in subendothelial tissues, possibly smooth muscle cells, whereas the peptide‐induced contractions are mediated via ETA receptors.
Potassium channel openers, NIP‐121 and cromakalim, enhance the relaxation induced by sodium nitroprusside in the guinea‐pig isolated trachea
Authors: Shikada Ken‐ichi , Tanaka Sakuya 
Published: July 2012

The effect of the potassium channel openers, NIP‐121 and cromakalim, on agonist‐induced relaxation of the guinea‐pig isolated trachea was investigated and the results were compared with those in the epithelium‐denuded trachea.
Tracheal strips were incubated with a potassium channel opener or vehicle for 30 min in the presence of 5 μm indomethacin and then contracted with 30 nm leukotriene D4 (LTD4). Relaxant agents were added to the organ bath after the LTD4‐elicited contraction had reached a plateau.
In epithelium‐intact trachea, NIP‐121 0.1 μm and cromakalim 1 μm, which did not modify the LTD4 (30 nm)‐induced contraction, significantly enhanced the sodium nitroprusside (SNP)‐induced relaxation. This enhancement of relaxation was not seen in the case of relaxation induced by the cyclic AMP‐dependent bronchodilators isoprenaline, vasoactive intestinal peptide or prostaglandin E2. The enhancement of SNP‐induced relaxation by NIP‐121 and cromakalim was abolished in the presence of the ATP‐sensitive potassium channel blocker, glibenclamide (1 μm). NIP‐121 and cromakalim did not produce any significant changes in the relaxation induced by 8‐bromoguanosine‐cyclic monophosphate (8‐Br‐cyclic GMP), a cyclic GMP analogue.
In epithelium‐denuded trachea, SNP‐induced relaxation alone was significantly enhanced but that induced by 8‐Br‐cyclic GMP was not changed. Neither NIP‐121 nor cromakalim enhanced SNP‐induced relaxation in denuded trachea.
These results suggest that in the presence of an intact epithelium the enhancement by NIP‐121 and cromakalim of the relaxation of guinea‐pig tracheal smooth muscle induced by SNP may be associated with the opening of glibenclamide‐sensitive potassium channels.
Effects of cicletanine on haemodynamics, arrhythmias and extent of necrosis during coronary ligation in rabbits
Authors: Burton T. , Chakrabarty S. , Fluck D.S. , Flores N.A. , Sheridan D.J. 
Published: July 2012

The effects of cicletanine on arrhythmias, haemodynamics and extent of necrosis during myocardial ischaemia were investigated in rabbits subjected to coronary ligation.
Cicletanine increased cardiac output prior to coronary occlusion (P < 0.01) but had no other significant haemodynamic effects at this time and did not significantly alter heart rate, blood pressure or cardiac output during 30 min of ischaemia or 30 min of reperfusion.
Ventricular fibrillation and mortality were greater in control (65% and 60% respectively) than treated animals (15.4% and 15.4%, P < 0.01).
The extent of myocardial necrosis expressed as a percentage of the area at risk was also reduced by cicletanine from 61 ± 8% in controls to 37 ± 6% (P < 0.05).
These findings indicate that cicletanine attenuates arrhythmias and preserves myocardium in the early phase of ischaemia and this effect appears to be independent of an established antihypertensive action.
Involvement of nitric oxide in the regional haemodynamic effects of perindoprilat and captopril in hypovolaemic Brattleboro rats
Authors: Gardiner Sheila M. , Bennett Terence 
Published: July 2012

Male, homozygous Brattleboro (i.e. vasopressin‐deficient) rats were chronically instrumented with pulsed Doppler flow probes and intravascular catheters, and were studied 5 h after a subcutaneous injection of an hyperoncotic solution of polyethylene glycol to render them hypovolaemic, and hence dependent on the renin‐angiotensin system for maintenance of haemodynamic status. Pilot experiments showed that, in this model, primed infusion of perindoprilat (0.05 mg kg−1 bolus, 0.05 mg kg−1 h−1 infusion) or captopril (0.2 mg kg−1 bolus, 0.2 mg kg−1 h−1 infusion) just abolished the pressor effect of angiotensin I (120 pmol), and had similar initial hypotensive and renal hyperaemic vasodilator effects.
Perindoprilat had more sustained hypotensive, and mesenteric and hindquarters vasodilator effects than captopril in the presence of saline. In the presence of NG‐nitro‐l‐arginine methyl ester (l‐NAME 3 mg kg−1 h−1), the renal vasodilator effects of perindoprilat were unchanged, whereas the other haemodynamic effects of perindoprilat and captopril were reduced. Hence, in the presence of l‐NAME, all haemodynamic effects of perindoprilat were greater than those of captopril.
The renal hyperaemic vasodilator effects of acetylcholine were abolished by l‐NAME and by perindoprilat, and were markedly reduced by captopril. However, since perindoprilat and captopril caused such marked renal hyperaemic vasodilatation themselves, it is feasible this change in baseline status contributed to their effects. It is unlikely this could be a full explanation of the results, because the haemodynamic effects of lemakalim were unchanged under any experimental conditions.
Bradykinin alone, or in the presence of saline, caused mesenteric hyperaemic vasodilatation whereas, in the presence of perindoprilat or captopril, bradykinin caused marked renal and mesenteric vasoconstrictions. However, in the additional presence of l‐NAME, the mesenteric vasoconstriction was reduced, yet the hypotensive effect of bradykinin was augmented. One possible explanation of these observations is that, in the presence of l‐NAME and either perindoprilat or captopril, bradykinin caused marked coronary vasoconstriction, leading to a reduction in cardiac output.
Neither perindoprilat nor captopril impaired the pressor, or renal, mesenteric, or hindquarters vasoconstrictor effects of l‐NAME. Indeed, in their presence, the effects of l‐NAME were generally enhanced, consistent with perindoprilat and captopril causing activation of nitric oxide‐dependent mechanisms that were subsequently inhibited by l‐NAME.
Characteristics of the contractile response of rabbit aorta produced by cromakalim in calcium‐free solution
Authors: Duty S. , Weston A.H. 
Published: July 2012

The effect of potassium channel opening compounds has been investigated in the smooth muscle of rabbit aorta under Ca‐free conditions. Examination of the characteristics of the response has been performed using cromakalim as the prototype compound.
In order of potency, Ro 31–6930, cromakalim, minoxidil sulphate and pinacidil each produced a contraction in rabbit aortic strips bathed in Ca‐free MOPS‐buffered physiological salt solution (PSS). In contrast, forskolin, glyceryl trinitrate and nifedipine each failed to increase tension under identical conditions. Cromakalim also evoked contraction of bovine trachealis muscle bathed in Ca‐free PSS.
The contractile response to cromakalim in rabbit aortic strips was of delayed onset (15–20 min) and reached a plateau after approximately 120 min (1.8 g maximum with 1 μm cromakalim). No cromakalim‐induced tension changes were observed in either 1 mm or 2.5 mm Ca‐containing PSS.
Raising the [KCl] of the Ca‐free PSS to 65.9 mm fully inhibited the cromakalim‐induced contraction in rabbit aortic strips. In addition, pretreatment of aortic strips with the sulphonylurea glibenclamide antagonized the subsequent mechanical response to cromakalim.
In Ca‐free PSS, cromakalim (1 μm) stimulated 42K‐efflux with a time‐course corresponding to the contractile event. Glibenclamide (1 μm) inhibited this cromakalim‐induced 42K‐efflux.
In sharp microelectrode studies in bovine trachealis, cromakalim (10 μm) produced a sustained membrane hyperpolarization in normal PSS. In contrast, the cromakalim‐induced hyperpolarization in Ca‐free PSS was not sustained. The fading of the hyperpolarization was temporally correlated with the increase in tension under these experimental conditions.
It is concluded that the K‐channel opener‐induced smooth muscle contractile response revealed in Ca‐free PSS is the consequence of K‐channel opening. The nature of the detailed mechanism which underlies this contractile phenomenon remains to be determined.
Effects of acromelic acid A on the binding of [3H]‐kainic acid and [3H]‐AMPA to rat brain synaptic plasma membranes
Authors: Smith Adam L. , McIlhinney R.A. Jeffrey 
Published: July 2012

The ability of acromelic acid A to inhibit [3H]‐kainic acid and [3H]‐(RS)‐α‐amino‐3‐hydroxy‐5‐methyloxazole‐4‐propionic acid ([3H]‐AMPA) binding to rat brain synaptic plasma membranes was investigated by equilibrium radioligand binding assay.
Kinetic analysis of [3H]‐kainic acid binding demonstrated the existence of two kainate binding sites in this tissue preparation and yielded equilibrium dissociation constants for [3H]‐kainic acid of KD = 0.4 nm and KD = 20.8 nm.
Kainic acid and domoic acid both appeared to displace [3H]‐kainic acid from a single binding site with equilibrium binding constants of KD = 19.4 nm and Ki= 14.5 nm respectively. Acromelic acid A exhibited a biphasic inhibition of [3H]‐kainic acid binding to synaptic membranes with binding affinities of Ki = 15.1 nm and Ki = 1.49 μm.
In the absence of chaotropic ions, the order of potency of inhibition of [3H]‐AMPA binding was acromelic acid A (Ki = 26 nm) > AMPA (KD = 184 nm) > domoic acid (Ki = 499 nm).
The inclusion of 100 mm thiocyanate ion in the [3H]‐AMPA binding assay resulted in a change in the order of potency to: AMPA (KD = 160 nm) > acromelic acid A (Ki = 289 nm) > domoic acid (Ki = 9.02 μm).
These results show that acromelic acid A distinguishes two kainate binding sites in rat brain synaptic plasma membranes and in addition, that in the absence of chaotropic ions, acromelic acid A is the most potent displacer of [3H]‐AMPA binding yet described.
Subtype classification of the presynaptic α‐adrenoceptors which regulate [3H]‐noradrenaline secretion in guinea‐pig isolated urethra
Authors: Alberts Pèteris 
Published: July 2012

The following experiments were carried out to investigate the presence and type of functional presynaptic receptors in adrenergic nerves of the guinea‐pig urethra.
The urethra from male guinea‐pigs was incubated with [3H]‐noradrenaline and superfused with Tyrode solution in vitro. The fractional secretion of [3H]‐noradrenaline evoked by 300 electrical pulses was measured.
The [3H]‐noradrenaline secretion was positively frequency‐dependent, yielding a half‐maximal secretion at 8 ± 5 Hz. Stimulation was usually applied at 5 Hz.
The [3H]‐noradrenaline secretion was not altered by noradrenaline (1 or 100 μm), norephedrine (1 μm), isoprenaline (0.1 μm), 5‐hydroxytryptamine (10 μm), oxotremorine (10 μm), adenosine (0.2 mm), propranolol (1 μm), atropine (1 μm) or 8‐phenyltheophylline (10 μm).
The [3H]‐noradrenaline secretion was enhanced by clonidine (3 μm), chlorpromazine (10 μm), metitepine (1 μm), 4‐aminopyridine (0.5 mm), tetraethylammonium (2 mm), 3‐isobutyl‐1‐methylxanthine (4 mm), 8‐bromo cyclic AMP (1 mm) and forskolin (25 μm).
The α‐adrenoceptor antagonists rauwolscine, yohimbine, phentolamine, prazosin and AR‐C 239 maximally enhanced the [3H]‐noradrenaline secretion to about 300% of control. The partial α‐adrenoceptor agonist oxymetazoline maximally enhanced the secretion to about 200% of control. The order of apparent EC50 values was rauwolscine < yohimine < phentolamine < oxymetazoline < prazosin < AR‐C 239.
The enhancing effects of yohimbine (1 μ m) with tetraethylammonium (2 mm), 8‐bromo cyclic AMP (1 mm), or forskolin (25 μm) were additive, but not those of yohimbine (1 μm) with prazosin (10 μm), 4‐aminopyridine (0.5 mm), or 3‐isobutyl‐1‐methylxanthine (4 mm).
These results suggest that the [3H]‐noradrenaline secretion in the guinea‐pig urethra is regulated by presynaptic α2A‐adrenoceptors which may, in a cyclic AMP‐independent manner, be coupled to a 4‐aminopyridine‐sensitive potassium channel. The secretion is not influenced by compounds acting at β‐adrenoceptors, muscarinic cholinoceptors or adenosine receptors.
Responses to vasodilator drugs on pulmonary artery preparations from pulmonary hypertensive rats
Authors: Wanstall Janet C. , O'Donnell Stella R. 
Published: July 2012

Relaxant responses to six vasodilator drugs, with different mechanisms of action, were examined on noradrenaline (0.1 μm)‐contracted ring preparations of pulmonary artery and aorta taken from rats with pulmonary hypertension induced by monocrotaline or chronic hypoxia.
On pulmonary artery preparations from monocrotaline‐treated rats, compared with controls, (a) the maximum relaxation to pinacidil and cromakalim was significantly increased, but their potency (negative log EC50) was unchanged, (b) the potencies of nitroprusside and sodium nitrite were significantly reduced (10 fold and 3 fold respectively), but there was no change in the maxima, (c) for nicorandil there was an increase in maximum relaxation and a decrease in potency (3 fold), and (d) for atriopeptin II there was no change in potency or maximum.
The increase in maximum relaxation for pinacidil and the decrease in potency for nitroprusside were also demonstrated in pulmonary artery preparations from rats with chronic hypoxic pulmonary hypertension. The other four drugs were not examined in preparations from hypoxic rats.
In both models of pulmonary hypertension, no change in maximum response or potency was seen on aortic preparations for any of the vasodilator drugs.
In control preparations, none of the drugs was more potent on pulmonary artery than on aorta (i.e. they were not pulmonary‐selective). In preparations from pulmonary hypertensive rats, pinacidil was selective for pulmonary artery, in contrast to nitroprusside which was selective for aorta.
It is concluded that the development of pulmonary hypertension in rats is accompanied by changes in the responsiveness of the pulmonary arteries to some vasodilator drugs; whether or not these changes occur depends on the mechanism of action of the vasodilator drug; but they are independent of the method of inducing pulmonary hypertension.
It is postulated that the reduction in potency seen for nitroprusside, sodium nitrite and nicorandil may be due to desensitization of soluble guanylate cyclase in pulmonary vascular smooth muscle in pulmonary hypertension.
Interference of cetirizine with the late eosinophil accumulation induced by either PAF or compound 48/80
Authors: Martins Marco A. , Pasquale Claudia P. , e Silva Patrícia M.R. , Pires Ana L.A. , Ruffié Claude , Rihoux Jean P. , Cordeiro Renato S.B. , Vargaftig B. Boris 
Published: July 2012

The effect of topical or systemic treatment with the histamine H1‐receptor antagonist, cetirizine, on the rat pleural eosinophil accumulation induced by PAF or compound 48/80 was investigated. The number of pleural resident eosinophils increased 6 h after the intrathoracic (i.t.) injection of PAF (1 μg/cavity), peaked within 24 h and persisted significantly augmented for at least 96 h. Compound 48/80 (25 μg/cavity) also produced a long lasting pleural eosinophilia but this was first noted only 24 h after stimulation.
Intraperitoneal pretreatment with cetirizine inhibited eosinophilia induced by either PAF (ED50 = 19 mg kg−1) or compound 48/80 (ED50 = 14 mg kg−1) whereas meclizine, another histamine H1‐receptor antagonist, was inactive.
Administered locally, cetirizine (5 and 15 μg/cavity) also dose‐dependently inhibited both PAF‐ and compound 48/80‐induced eosinophilia, providing evidence that its inhibitory effect is not due to any action upon circulating eosinophils. Consistent with this result, incubation of isolated peritoneal eosinophils with cetirizine failed to modify in vitro eosinophil migration caused by PAF.
Since the late eosinophilia induced by PAF may depend on the synthesis of a transferable protein mediator, cetirizine was administered to donor or recipient rats in order to determine whether it interferes with the generation or with the expression of this protein. We showed that only the treatment of recipient rats abolished the transfer of the eosinophilotactic activity, indicating that cetirizine does not modify the generation but inhibits the expression of this activity.
Our findings indicate that cetirizine is able to inhibit eosinophil accumulation by acting locally. The mechanism is neither related to its recognized ability to antagonize histamine H1‐receptors nor to a direct action upon circulating eosinophils.
Effects of inhibiting nitric oxide biosynthesis on the systemic and splanchnic circulation of rats with portal hypertension
Authors: Pizcueta M.P. , Piqué J.M. , Bosch J. , Whittle B.J.R. , Moncada S. 
Published: July 2012

The effects of inhibiting endogenous nitric oxide (NO) synthesis with NG‐monomethyl‐l‐arginine (l‐NMMA) on the systemic and splanchnic circulation have been investigated in rats with experimental chronic portal hypertension, anaesthetized with ketamine.
Portal hypertension was induced by partial portal vein ligation, 2 weeks prior to study. This procedure induced a reduction in systemic arterial blood pressure (MAP), an increase in cardiac output as measured by radiolabelled microspheres, a reduction in peripheral and splanchnic vascular resistance and an increased portal venous inflow (PVI) and portal pressure, as compared to control non‐ligated rats.
l‐NMAA (6.25 and 50 mg kg−1, i.v.) dose‐dependently increased MAP, reduced cardiac output and PVI, and increased peripheral and splanchnic vascular resistance. With l‐NMMA (50 mg kg−1), PVI and the vascular resistances returned to values comparable to those determined in control non‐ligated anaesthetized rats under resting conditions.
Porto‐collateral resistance was also increased by these doses of l‐NMMA, whereas portal pressure was unchanged. The increase in renal blood flow and decrease in renal vascular resistance also seen in portal‐hypertensive rats was reversed by l‐NMMA (50 mg kg−1).
These effects of l‐NMMA (50 mg kg−1) were inhibited by prior administration of l‐arginine (300 mg kg−1, i.v.).
These findings indicate that the chronic hyperdynamic circulatory characteristics following portal vein stenosis can be attenuated by l‐NMMA. Thus, the excessive formation of endogenous NO may be implicated in the pathogenesis of the haemodynamic disturbances and splanchnic vasodilatation associated with chronic portal hypertension.