bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological specificity of novel, synthetic, cyclic peptides as antagonists at tachykinin receptors
Authors: McKnight A.T. , Maguire J.J. , Elliott N.J. , Fletcher A.E. , Foster A.C. , Tridgett R. , Williams B.J. , Longmore J. , Iversen L.L. 
Published: July 2012

The interaction at tachykinin receptors of a series of novel cyclic hexapeptides has been examined by use of radioligand binding assays (NK1 and NK3 sites in rat cortex, NK2 sites in hamster urinary bladder) and functional pharmacological assays (guinea‐pig ileum, rat vas deferens and rat portal vein for NK1, NK2 and NK3 receptors, respectively).
The compounds cyclc(GlnTrpPhe(R)Gly[ANC‐2]LeuMet) (L‐659,837) and cyclo(GlnTrpPheGlyLeuMet) (L‐659,877) were powerful and selective displacers of NK2 binding (pIC50 6.9 and 8.0, respectively), and were competitive antagonists of responses to stimulation of NK2 receptors in rat vas deferens (pKB for antagonism of responses to eledoisin 6.7 and 8.1, respectively). Responses in the NK1 and NK3 pharmacological assays were blocked only weakly, if at all.
In the longitudinal muscle of the small intestine of the rat, responses to stimulation of the putative NK2 receptor by eledoisin, neurokinin A or neurokinin B were antagonized by both cyclo(GlnTrpPhe(R)Gly[ANC‐2]LeuMet) and cyclo(GlnTrpPheGlyLeuMet) in a manner consistent with the presence in this tissue of a uniform population of receptors, indistinguishable from the NK2 receptor of the rat vas deferens.
The compounds cyclo(GlnTrpPheGlyLeuMet) and the lactam‐containing analogue are among the most selective antagonists for the NK2 receptor that have been described; their availability should be of value in the characterization of the receptors mediating responses to tachykinins, and in elucidating the physiological functions of the tachykinin receptors.
Modulation of agonist‐induced calcium mobilisation in bovine aortic endothelial cells by phorbol myristate acetate and cyclic AMP but not cyclic GMP
Authors: Buchan Kevin W. , Martin William 
Published: July 2012

In bovine aortic endothelial cells (BAEC), thrombin (1 u ml−1), bradykinin (1–10 nm) and adenosine triphosphate (ATP) (0.3 μm–100 μm) each induced a biphasic elevation of cytosolic calcium ([Ca2+]i), consisting of an initial transient followed by a sustained plateau phase.
Pretreatment of BAEC with 4β‐phorbol 12‐myristate 13‐acetate (PMA; 100 nm) reduced the magnitude of the initial transient elevation of [Ca2+]i, induced by thrombin (1 u ml−1), low concentrations of bradykinin (1 nm) or ATP (0.3 μm, 3 μm), but not by higher concentrations of the latter two agonists. Addition of PMA (100 nm) during the plateau phase of the increase in [Ca2+]i induced by thrombin (1 u ml−1), bradykinin (10 nm) or ATP (30 μm) resulted in a fall in [Ca2+]i.
The inhibitory effects of PMA (100 nm) were inhibited by staurosporine (100 nm) but not mimicked by the inactive phorbol ester, 4α‐phorbol 12, 13‐didecanoate (4α‐PDD; 100 nm). Furthermore, staurosporine (100 nm) increased [Ca2+]i when added during the plateau phase of the increase in [Ca2+]i induced by thrombin or bradykinin. In contrast, staurosporine (100 nm) reduced [Ca2+]iWhen added during the plateau phase of the increase in [Ca2+]i induced by ATP (30 μm).
Pretreatment with forskolin (10 μm) had no effect on the magnitude of the initial transient elevation of [Ca2+]i induced by thrombin (1 u ml−1), bradykinin (1 nm and 10 nm) or ATP (30 μm). In contrast, forskolin (10 μm) and isoprenaline (10 μm) each induced biphasic elevations of [Ca2+]i when added during the plateau phase of the increase in [Ca2+]i induced by the three agonists. Furthermore, in the presence of the inhibitor of calcium influx, nickel chloride (4 mm), these biphasic elevations were reduced to monophasic transient elevations.
8 Bromo cyclic GMP (30 μm), a membrane‐permeant analogue of guanosine 3′: 5′‐cyclic monophosphate (cyclic GMP), had no effect on the magnitude of the initial transient elevation of [Ca2+]i induced by thrombin (1 u ml−1), bradykinin (10 nm) or ATP (3 μm). Furthermore, 8 bromo cyclic GMP (30 μm) and sodium nitroprusside (1 μm), had no effect when added during the plateau phase of the increase in [Ca2+]i induced by the three agonists.
NG‐nitro‐l‐arginine (50 μm), an inhibitor of nitric oxide synthase, had no effect on the magnitude of the initial transient elevation of [Ca2+]i induced by thrombin (1 u ml−1), bradykinin (1 nm) or ATP (3 μm), and had no effect on the plateau phase of the increase in [Ca2+]i induced by these agents.
These findings suggest that while activation of protein kinase C inhibits and elevation of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) augments calcium mobilisation in bovine aortic endothelial cells, elevation of cyclic GMP appears to have no effect.
Different pharmacological profiles of big‐endothelin‐3 and big‐endothelin‐1 in vivo and in vitro
Authors: D'Orléans‐Juste Pedro , Télémaque Sabine , Claing Audrey 
Published: July 2012

Human big‐endothelin‐1 (big‐ET‐1) and endothelin‐1 (ET‐1) are equipotent as pressor agents and produce a significant change in mean arterial blood pressure (MAP) in anaesthetized guinea‐pigs (2 nmol kg−1: peak Δ MAP: 23 ± 6 mmHg and 26 ± 5 mmHg, respectively).
Unlike big‐ET‐1, big‐endothelin‐3 (big‐ET‐3) (10 and 20 nmol kg−1) induces no pressor responses whereas endothelin‐3 (ET‐3) at 2 nmol kg−1induces a significant increase of blood pressure in anaesthetized guinea‐pigs (peak Δ MAP: 27 ± 5 mmHg) with a shorter duration than ET‐1 and big‐ET‐1.
Big‐ET‐1 at concentrations 40 times higher than those required for ET‐1 (2.5 nm) releases prostacyclin (PGI2) (maximal release: 2.7 ± 0.8 ng ml−1; 2.9 ± 0.9 ng ml−1, respectively) and thromboxane B2 (TxB2) (maximal release: 6.7 ± 1.3 ng ml−1; 6.8 ± 1.1 ng ml−1, respectively) from guinea‐pig perfused lungs. ET‐3 (2.5 nm) is also a potent releaser of PGI2 and TxB2 from the guinea‐pig lungs (maximal release: PGI2: 2.4 ± 1.0 ng ml−1; TxB2: 3.8 ± 0.6 ng ml−1). Conversely, big‐ET‐3 (100 nm) does not increase basal release of eicosanoids.
Phosphoramidon (50 μm), a metalloprotease inhibitor, markedly reduced the eicosanoid releasing properties of big‐ET‐1 (n = 4, P < 0.01) in guinea‐pig perfused lungs without affecting the release stimulated by ET‐1.
Our results suggest that big‐ET‐1 is converted to ET‐1 via a phosphoramidon‐sensitive endothelin converting enzyme (ECE) to release eicosanoids. The ECE is present in the guinea‐pig pulmonary vasculature. Furthermore, our results suggest that the ECE activity is specific for big‐ET‐1 and may not convert big‐ET‐3 to its active metabolite, ET‐3.
l‐Glutamate diethyl ester and deaminated analogues as excitatory amino acid antagonists in rat cerebral cortex
Authors: Turner J.P. , Meldrum B.S. 
Published: July 2012

The effects of l‐glutamate diethyl ester (GDEE) HCl, glutarate diethyl ester (GlrDEE) and glutarate dimethyl ester (GlrDME) on depolarizing responses to α‐amino‐3‐hydroxy‐5‐methyl‐4‐iso‐xazolepropionate (AMPA), kainate (Kain), N‐methyl‐d‐aspartate (NMDA) and quisqualate (Quis), and spontaneous paroxsymal discharges (SPDs) were examined. Experiments were performed on slices of rat cingulate cortex using the in vitro grease gap recording technique in nominally Mg2+‐free Krebs medium.
GDEE HCl (3–14 mm) caused a concentration‐dependent depolarization of the d.c. baseline potential. l‐Glutamate (0.1–0.5 mm), HCl (15 mm) and sucrose (30 mm) also depolarized the baseline. GlrDEE (3–12 mm) and GlrDME (4–26 mm) had no consistent effect on baseline potential.
GDEE HCl (10 mm) had no effect on depolarizing responses to AMPA, Kain and NMDA, but caused potentiation of those to Quis with a dose‐ratio of 0.53 (0.44–0.63) (n = 4). In two other experiments, where the depolarization of the baseline induced by GDEE HCl was large, a depression of Quis response amplitude was observed.
GlrDEE (10 mm) antagonized depolarizing responses to Kain, and to a lesser extent NMDA, with dose‐ratios of 2.14 (1.92–2.38) and 1.61 (1.39–1.87), respectively. This concentration of GlrDEE had no effect on AMPA responses, but potentiated Quis responses, with a dose‐ratio of 0.64 (0.58–0.71).
GlrDME (10 mm) antagonized depolarizing responses to Kain and to Quis, with dose‐ratios of 1.66 (1.48–1.85) and 1.22 (1.15–1.29), respectively, and had no effect on responses to NMDA.
The SPDs were inhibited by GDEE HCl (IC50 6.7 ± 0.37 mm), GlrDEE (IC50 5.6 ± 0.38 mm) and GlrDME (IC50 10.4 ± 0.73 mm).
In conclusion, there is little evidence that GDEE HCl is an antagonist of the postsynaptic excitatory amino acid receptors in the rat neocortex, and its effects may result from its contamination with l‐glutamate and increased osmolarity of the bathing medium at high concentrations. The deaminated analogues of GDEE are very weak Kain antagonists.
Effect of nedocromil sodium on allergen‐, PAF‐, histamine‐ and bradykinin‐induced airways vasodilatation and pulmonary obstruction in the pig
Authors: Alving K. , Matran R. , Lundberg J.M. 
Published: July 2012

The influence of nedocromil sodium on the nasal and bronchial effects induced by allergen, platelet‐activating factor (PAF), capsaicin, histamine and bradykinin aerosol challenge in ascaris‐sensitized and pentobarbitone‐anaesthetized pigs was studied. Blood flow changes in the bronchial and nasal circulation were measured with ultrasonic flow probes around the supplying arteries, and vascular resistance was calculated. Changes in pulmonary resistance (Rpulm), dynamic compliance (Cdyn), mean arterial pressure (MAP) and heart rate (HR) were also determined.
Allergen and PAF aerosol challenge in the lung produced similar effects consisting of both bronchial and nasal vasodilatation, bronchoconstriction (increase in Rpulm and decrease in Cdyn) and increases in MAP and HR. Local pretreatment with nedocromil sodium (80 mg, aerosol) reduced the peak and duration of both the bronchial vasodilatation and increase in Rpulm, while only the duration of the change in Cdyn was significantly decreased. Nedocromil sodium did not alter the increases in MAP and HR. The nasal vasodilatation evoked by PAF, but not allergen, challenge in the lung was reduced by nedocromil sodium.
Allergen challenge in the nose induced vasodilatation of long duration which was reduced by local nedocromil sodium pretreatment (50 μg kg−1, intra‐arterially).
The vasodilator response to histamine aerosol was attenuated in the nasal, but not the bronchial circulation by local nedocromil sodium pretreatment. Histamine‐induced bronchoconstriction was not altered by nedocromil sodium.
Bradykinin aerosol‐induced vasodilatation in the nasal and bronchial circulation was markedly and equally reduced by local nedocromil sodium and systemic capsaicin (50 mg kg−1, s.c. 2 days before) pretreatment. The vasodilatation caused by i.v. bradykinin challenge was not reduced by capsaicin pretreatment. Capsaicin aerosol‐induced vasodilatation in the nasal and bronchial circulation was not affected by local nedocromil sodium pretreatment.
In conclusion, nedocromil sodium blocks some local vascular and bronchial effects, but not increases in MAP and HR, induced by allergen and PAF aerosol in the pig. Bradykinin‐induced vasodilatation in the airways, which seems to be largely dependent on capsaicin‐sensitive sensory nerves, is markedly inhibited by nedocromil sodium pretreatment, whereas capsaicin‐induced vasodilatation is not affected by nedocromil sodium. It may be suggested that nedocromil sodium acts by inhibiting some common process involved in the release of mediators from inflammatory cells (when stimulated by allergen and PAF) and sensory nerves (when stimulated by bradykinin and histamine, but not capsaicin).
Characterization of the interaction of R 56865 with cardiac Na‐ and L‐type Ca channels
Authors: Wilhelm D. , Himmel H. , Ravens U. , Peters T. 
Published: July 2012

In isolated cardiac muscle, submicromolar concentrations of R 56865 (N‐[1‐[4‐(4‐fluorophenoxy)‐butyl]‐4‐piperidinyl]‐N‐methyl‐2‐benzothiazolamine) have been shown to attenuate the toxicity of cardiac glycosides.
We studied the influence of R 56865 on calcium and sodium currents in single isolated ventricular cardiomyocytes. The effect of R 56865 on action potential and contractile force in the presence of increased sodium load was also tested by exposing papillary muscles to veratridine or Anemonia sulcata toxin ATX II.
The calcium current was not affected by R 56865 as assessed in slow action potentials of papillary muscles and current measurements in ventricular cardiomyocytes.
In papillary muscles, R 56865 (1 μmol l−1) abolished veratridine‐induced aftercontractions and afterdepolarizations without affecting the profound prolongation of the action potential. When pretreated with R 56865, the occurrence of afterdepolarizations was prevented and the decline of the resting membrane potential was attenuated.
Pretreatment with R 56865 (1 μmol l−1) did not counteract the ATX II‐induced prolongation of the action potential.
The sodium current (Nao 30 mmol l−1) was concentration‐dependently decreased by R 56865 (0.1–10 μmol l−1). The blocking effect was more pronounced at less negative holding potentials.
Our results demonstrate that the protective effect of R 56865 against veratridine‐induced electrical and mechanical oscillations is not due to a direct effect on the calcium current. A potential‐dependent inhibition of the sodium current may contribute. Additional sites of action, like interference with intracellular calcium release and inhibition of potassium currents, remain to be investigated.
Non‐adrenergic, non‐cholinergic neural activation stabilizes smooth‐muscle tone independently of eicosanoid factors in guinea‐pig isolated airways
Authors: Lindén A. , Ullman A. , Löfdahl C‐G. , Skoogh B‐E. 
Published: July 2012

We examined the effect of variations in resting smooth‐muscle tone induced by eicosanoid inhibitors on the direction and magnitude of the non‐adrenergic, non‐cholinergic (NANC) nervous response in guinea‐pig isolated airways.
NANC responses (in the presence of 1 μm atropine, 10 μm guanethidine) to electrical field stimulation (1200 mA; 0.5 ms; 240 s; 3 Hz) were studied in guinea‐pig isolated airway preparations (n = 4–7) taken from the proximal trachea, the distal trachea and the main bronchus. Tissues were treated with either the cyclo‐oxygenase‐blocker, indomethacin (10 μm), or the leukotriene receptor antagonist, FPL 55712 (11.5 μm), to modulate the resting tone.
Depending on the level of resting tone prior to electrical field stimulation, NANC activation induced either a contraction or a relaxation converging towards a similar level of tone, a ‘tonus equilibrium’. This tonus equilibrium displayed an increasing level towards the periphery (3 ± 3 (s.e.mean) % for the proximal trachea, 28 ± 3% for the distal trachea and 54 ± 4% for the main bronchus, in % of maximum active tension). After NANC activation, the tonus returned to a level similar to the resting tone.
We conclude that changes in resting smooth‐muscle tone not only affect the magnitude but also the direction of the NANC response. It is suggested that the NANC nervous system is a stabilizing factor in the regulation of airway smooth‐muscle tone, independent of eicosanoid factors. An increasing contractile component and a decreasing relaxant component of the NANC system towards the peripheral airways is indicated.
A comparative study of the prostanoid receptor profile of 9α11β‐prostaglandin F2 and prostaglandin D2
Authors: Giles H. , Bolofo M.L. , Lydford S.J. , Martin G.R. 
Published: July 2012

The aim of this study was to determine the receptor profile of 9α11β‐prostaglandin F2 (PGF2) and compare it with that of its parent, prostaglandin D2 (PGD2). The experiments were designed to overcome the problems associated with the presence of multiple prostanoid receptor sub‐types in most tissues; the lack of selective antagonists for each receptor means that conclusions regarding efficacy at FP and EP2 receptors must remain provisional.
At DP receptors in human platelets and rabbit jugular vein, PGD2 was a full agonist, p[A50] 7.02 ± 0.09 and 6.60 ± 0.12 respectively. 9α11β‐PGF2 was approximately 30–60 fold less potent than PGD2.
9α11β‐PGF2 was a full agonist in the FP receptor containing preparation, cat iris sphincter (p[A50] 7.35 ± 0.09) comparable in potency to PGD2 (p[A50] 7.15 ± 0.19). Likewise the two prostanoids showed similar potency at the TP receptor in guinea‐pig aorta (9α11β‐PGF2 p[A50] 6.00 ± 0.07; PGD2 6.24 ± 0.08).
9α11β‐PGF2 and PGD2 had efficacy but low potency at EP1 receptors (guinea‐pig oesophageal muscularis mucosa) and demonstrated 2000–3000 fold lower potency than PGE2 (p[A50] 8.35 ± 0.09). Similarly, in the EP2 receptor‐containing preparation, cat trachea, 9α11β‐PGF2 was 3500 fold less potent and PGD2 700 fold less potent than PGE2 (p[A50] 8.06 ± 0.26).
9α11β‐PGF2 and PGD2 (10 μm) were without affinity at the IP receptors on human platelets and had no agonist action in the EP3 receptor containing preparation, guinea‐pig vas deferens.
9α11β‐PGF2 is a major metabolite of PGD2 in vivo and this conversion clearly represents an inactivation step since 9α11β‐PGF2 is of considerably lower potency than PGD2 at DP receptors. However, it is of similar potency to PGD2 at TP, FP, EP1 and EP2 receptors and it may, therefore, contribute to the biological effects which follow PGD2 administration or endogenous synthesis; its actions at these receptors are likely to be similar to those of PGD2 itself.
Dissociation between the effects of zymosan on the systemic and pulmonary vessels of the rat
Authors: Damas Jacques , Lagneaux Denise 
Published: July 2012

Zymosan, an activator of the alternative complement pathway, (2 to 16 mg kg−1) injected intravenously via the tail vein of anaesthetized rats, dose‐dependently increased the vascular permeability of lung parenchyma, as measured by the accumulation of 125I‐labelled albumin in lungs.
Pretreatment of the animals with cyclo‐oxygenase inhibitors, indomethacin or ketoprofen (3 mg kg−1) or with the lipoxygenase and cyclo‐oxygenase inhibitor, BW755C (40 mg kg−1) abolished the vascular permeability changes induced by zymosan (16 mg kg−1). Neither, the PAF antagonist, WEB 2086 (10 mg kg−1) nor the antagonists of mast cell amines, mepyramine and methysergide (3 mg kg−1) affected the plasma exudation in lungs. Zymosan did not induce any accumulation of labelled albumin in lungs of rats made leucopenic by rabbit anti‐neutrophil serum.
Zymosan (16 mg kg−1) increased the haematocrit. This increase was not modified by indomethacin but reduced by WEB 2086.
Intravenous injection of zymosan (3 and 8 mg kg−1) in anaesthetized rats transiently increased right ventricular blood pressure and pulmonary arterial pressure, accelerated respiratory rate and decreased systemic blood pressure.
WEB 2086 largely reduced the systemic hypotension but did not affect the increase of pulmonary vascular resistance. Indomethacin inhibited the increase of blood pressure in the right ventricle and the modification of the respiratory rate. This drug did not inhibit but increased the systemic hypotension induced by zymosan.
Zymosan (16 mg kg−1) reduced serum complement haemolytic activity by 46%.
These data suggest that the pulmonary vascular changes induced by intravascular complement activation with zymosan in rats are mediated by neutrophils and prostanoids while the systemic vascular effects depend mainly on PAF.
Cardiovascular actions of the κ‐agonist, U‐50,488H, in the absence and presence of opioid receptor blockade
Authors: Pugsley M.K. , Penz W.P. , Walker M.J.A. , Wong T.M. 
Published: July 2012

The cardiovascular actions of U‐50,488H, a κ‐receptor agonist, were studied in rat isolated perfused hearts, and in anaesthetized rats, over concentrations or doses generally above those required to produce κ‐receptor‐mediated effects.
U‐50,488H dose‐dependently decreased left‐ventricular peak systolic pressure and beating rate in vitro and reduced blood pressure and heart rate in vivo.
Over the concentration range of 1–30 μm in vitro, and the dose‐range of 0.5–32 μmol kg−1 in vivo, U‐50,488H prolonged the P—R, QRS and Q—T intervals of the ECG.
The effects of U‐50,488H were not antagonized by an opioid receptor antagonist, naloxone (1 μm or 8 μmol kg−1). Similarly, the opioid receptor antagonist, MR 2266, at 8 μmol kg−1 did not significantly reduce the cardiovascular actions of U‐50,488H in vivo.
The actions of U‐50,488H on responses to electrical stimulation were also studied. Over the dose range of 0.5–32 μmol kg−1, U‐50,488H altered thresholds and effective refractory period. It had a biphasic action on thresholds for induction of ventricular fibrillation. Thresholds were decreased at lower doses (0.5–4 μmol kg−1) but increased at higher doses (8–32 μmol kg−1). The effects of lower doses were blocked by naloxone. Effective refractory period and threshold pulse width only increased with dose.
In conclusion, U‐50,488H at high concentration, had direct depressant actions on cardiac contractility, electrical excitability and the ECG. These depressant effects were not antagonized by the opioid receptor antagonists, naloxone and MR 2266, and probably do not involve opioid receptors. Furthermore, some of the observed effects were those expected to result from sodium channel blockade.
Inhibition of endothelium‐dependent vasorelaxation by arginine analogues: a pharmacological analysis of agonist and tissue dependence
Authors: Martin G.R. , Bolofo M.L. , Giles H. 
Published: July 2012

Isolated rings of rabbit external jugular vein (RbJV) and rat thoracic aorta (RA) were used to study the effect of the NO synthase inhibitor l‐NG‐nitroarginine methyl ester (l‐NAME) on muscarinic and 5‐hydroxytryptamine (5‐HT) receptor‐stimulated, endothelium‐dependent vascular relaxations.
In RbJV relaxations produced by the endothelial 5‐HT receptor agonist α‐methyl‐5‐HT were potently and non‐surmountably inhibited by l‐NAME (10 μm), whereas acetylcholine relaxations in this tissue were unaffected by this concentration of inhibitor. By contrast, acetylcholine relaxations in RA were virtually abolished by 10 μm l‐NAME. In each case an equivalent concentration of d‐NAME was without effect on agonist‐induced relaxations.
The different effect of l‐NAME on acetylcholine relaxations in RbJV and RA was not due to muscarinic receptor differences. Affinity estimates for acetylcholine (pKA = 6.12 ± 0.09; 6.09 ± 0.08 respectively) and for 4‐diphenyl‐acetoxy‐N‐methylpiperidine methobromide (4‐DAMP, pKB = 9.01 ± 0.12; 9.24 ±0.16 respectively) indicated that the receptors in both tissues belong to the same M3 class. Tissue differences resulting from the release of a cyclo‐oxygenase product or a glibenclamide‐sensitive K+‐channel‐linked hyperpolarizing factor were also ruled out by selective inhibition of these pathways.
When phenoxybenzamine was used to reduce the efficacy of acetylcholine in RbJV so that it behaved as a partial agonist in this tissue, l‐NAME (10 μm) now produced non‐surmountable inhibition of relaxation responses. In untreated tissues the same concentration of l‐NAME also profoundly inhibited responses produced by butyrylcholine and pilocarpine, both of which behave as partial agonists at the M3 receptor in RbJV.
A simple model was developed which describes the theoretical behaviour of receptor‐stimulated synthesis and release of NO. The model predicts that competitive inhibition of NO formation results in parallel displacements of the agonist response curve in the case of high efficacy agonist, but right‐shift with concomitant depression of the curve maximum in the case of low efficacy agonists. Simulations based on the model showed reasonable agreement with the experimental data.
It is concluded that analogues of l‐arginine demonstrate tissue‐ and agonist‐dependence in terms of their ability to inhibit receptor‐mediated events involving the liberation of NO. This behaviour can reflect differences in agonist efficacy in the receptor systems being studied, a possibility that should be ruled out before apparent resistance to inhibition is taken as evidence for the involvement of heterogeneous endothelium‐derived relaxing factors (EDRFs).