bluuebunny/crossref_metadata_2025_split huggingface dataset:
[3H]‐verapamil binding to rat cardiac sarcolemmal membrane fragments; an effect of ischaemia
Authors: Dillon J. S. , Nayler W.G. 
Published: July 2012

The [3H]‐verapamil binding activity of rat cardiac sarcolemmal fragments was studied, using membranes harvested from non‐perfused, aerobically‐perfused and ischaemic hearts.
Glass‐fibre filters were found to contain specific, high affinity ‐(KD 38 ± 3.1 nm) [3H]‐verapamil binding sites‐making them unsuitable for use in [3H]‐verapamil binding studies.
Incubation of membranes from non‐perfused hearts in a medium containing 150 mm NaCl, 1 mm CaCl2 and 50 mm Tris revealed two populations of [3H]‐verapamil binding sites. When centrifugation instead of filtration was used to separate bound and free [3H]‐verapamil, high affinity sites with a KD of 0.57 ± 0.19 μm and a Bmax of 38 ± 5.2 pmol mg−1 protein, and low affinity sites with a KD of 78 ± 27.5 μm and a Bmax of 2.9 ± 1.3 nmol mg−1 protein were detected. However, only low affinity binding sites could be detected in membranes which had been incubated in a cation‐free medium containing 50 mm Tris.
[3H]‐verapamil binding to the low and high affinity sites was saturable, reversible, stereospecific and displaceable by D600>diltiazem>Ca2+ but not by nifedipine, nitrendipine, nisoldipine or prazosin.
The two populations of binding sites survived aerobic perfusion and 60 min ischaemia at 37°C. Ischaemia reduced the Bmax and KD but selectivity was maintained.
Differential effect of temperature on histamine‐ and carbachol‐stimulated inositol phospholipid breakdown in slices of guinea‐pig cerebral cortex
Authors: Carswell Heather , Galione A.G. , Young J.M. 
Published: July 2012

Slices of guinea‐pig cerebral cortex were incubated with [3H]‐inositol at 37°C before exposure to histamine or carbachol at 37°C or 25°C. Histamine‐stimulated accumulation of [3H]‐inositol 1‐phosphate ([3H]‐IP1) at 25°C was only 5–7% of that at 37°C, whereas for carbachol the response at 25°C was 45–49% of that at 37°C.
The affinity of benzilylcholine, obtained from inhibition of carbachol‐induced accumulation of [3H]‐IP1 was similar at 25°C and 37°C, but the EC50 for carbachol was lower at 25°C (20 ± 2 μm) than at 37°C(42 ± 2 μm).
The IC50 for histamine inhibition of [3H]‐mepyramine binding to homogenates of guinea‐pig cerebral cortex did not differ significantly at 25°C and 37°C.
Histamine‐induced accumulations of [3H]‐IP2 and [3H]‐IP3 at 25°C, expressed as a percentage of the accumulation at 37°C, were also much less than the corresponding value for carbachol.
These observations imply that the locus or pathway(s) of agonist‐induced formation of([3H]‐IP1) are not the same for histamine and carbachol.
Effects of tachykinins on inositol phospholipid hydrolysis in slices of hamster urinary bladder
Authors: Bristow D.R. , Curtis N.R. , Suman‐Chauhan N. , Watling K.J. , Williams B.J. 
Published: July 2012

Tachykinin‐stimulated inositol phospholipid hydrolysis was examined in slices of hamster urinary bladder.
In the presence of lithium, to inhibit inositol monophosphatase activity, substance P, eledoisin and related tachykinins induced large, dose‐dependent increases in [3H]‐inositol monophosphate accumulation.
The responses to substance P and eledoisin were not antagonized by the cholinoceptor antagonist, atropine.
The rank order of potency for various tachykinins was kassinin ≫ neurokinin A ≫ neurokinin B ≫ eledoisin ≫ physaelamin ≫ substance P ≫ substance P methyl ester.
The synthetic analogue [p‐Glu6, D‐Pro9] SP (6–11) was considerably more potent than its L‐prolyl stereoisomer at stimulating inositol phospholipid hydrolysis.
These results suggest that in the hamster urinary bladder, tachykinin‐induced inositol phospholipid breakdown is mediated via tachykinin receptors of the SP‐E type, as opposed to the SP‐P type.
Celiprolol: a positive inotropic β‐adrenoceptor blocking agent in conscious dogs
Authors: Nganele David M. , DeLeonardis V. Maria , Hintze Thomas H. 
Published: July 2012

β‐Adrenoceptor blocking agents are used to manage various cardiovascular disorders. A limiting factor in their use is the suppression of the cardiac contractile state. In our study, we examined the cardiac effects of celiprolol, a new β‐adrenoceptor blocking agent with reported positive inotropic effects.
Dogs were instrumented by use of sterile surgical techniques for the study of myocardial inotropic state, heart rate and internal left ventricular dimensions. Following complete recovery from surgery, experiments were conducted in the conscious state.
Intravenous injection of celiprolol (3 mg kg−1) in nine dogs, increased LV dP/dt by 13 ± 2.6%, velocity of shortening (LV dD/dt) by 9.2 ± 3.4%, and heart rate by 19 ± 4.6% and decreased LV end‐diastolic diameter by 1.8 ± 0.8%, all significantly (P < 0.05). Celiprolol blocked the inotropic actions of isoprenaline (0.5 μg kg−1) but only partially reduced its hypotensive effects. Propranolol, in contrast, reduced LV dP/dt by 17 ± 3.3% and heart rate by 8.1 ± 2.7% (P < 0.05) while totally abolishing the hypotension, tachycardia and increase in LV dP/dt caused by isoprenaline. Following β‐adrenoceptor blockade with propranolol and with heart rate held constant by electrical pacing, celiprolol increased LV dP/dt by 16 ± 4.0%, LV dD/dt by 12 ± 3.0% and reduced LV end‐diastolic diameter by 3.5 ± 0.5% (P < 0.05).
Thus, in conscious dogs, celiprolol increases inotropic state and reduces preload independently of β‐adrenoceptor mechanisms and the Bowditch phenomenon, while effectively blocking β‐receptors in the heart. These properties would make celiprolol useful in patients where a conventional β‐adrenoceptor blocking agent might lead to pump failure.
Secretion, pain and sneezing induced by the application of capsaicin to the nasal mucosa in man
Authors: Geppetti Pierangelo , Fusco Bruno M. , Marabini Simone , Maggi Carlo Alberto , Fanciullacci Marcello , Sicuteri Federigo 
Published: July 2012

Topical application of capsaicin to the human nasal mucosa induced a burning sensation and sneezing. A dose‐dependent seromucous nasal secretion was also observed. Capsaicin (75 μg) was more potent than methacholine (50 mg) in producing nasal secretion, while topical histamine (200 μg), substance P (135 μg) and calcitonin gene‐related peptide (36 μg) did not induce rhinorrhea.
Pretreatment with either topical ipratropium bromide, systemic dexchlorpheniramine or indomethacin did not influence the effects induced by capsaicin. Topical pretreatment with lidocaine inhibited the painful sensation but failed to block the rhinorrhea. Desensitization to the effects of capsaicin occurred following 4–5 subsequent applications, and full recovery was observed within 30–40 days.
It is proposed that the effects of capsaicin in human nasal mucosa are due to excitation of primary afferent neurones that (a) convey burning and painful sensation, (b) evoke a sneezing reflex and (c) induce nasal secretion by releasing transmitter(s) from their peripheral terminals.
Evidence that inhibitory factor extracted from bovine retractor penis is nitrite, whose acid‐activated derivative is stabilized nitric oxide
Authors: Martin William , Smith Jerry A. , Lewis Malcolm J. , Henderson Andrew H. 
Published: July 2012

Unactivated extracts of bovine retractor penis (BRP) contain 3–7 μm nitrite. Acid‐activation of these extracts at pH 2 for 10 min followed by neutralization generates the active form of inhibitory factor (IF; assayed by its vasodilator action on rabbit aorta), and is associated with partial loss of nitrite.
Increasing the time of acid‐activation at pH 2 from 10 to 60 min with intermittent vortex mixing generates greater vasodilator activity and increases nitrite loss.
When acid‐activated and neutralized extracts are incubated at 37°C or 30 min or boiled for 5 min, vasodilator activity is lost and nitrite content increased. Reactivation of these samples at pH 2 for 10 min followed by neutralization leads to partial recoveries of vasodilator activity with loss in nitrite content.
Addition of sodium nitrite to BRP extracts increases acid‐activatable vasodilator activity pro rata.
Acid‐activation of aqueous sodium nitrite solutions results in less loss of nitrite and generation of less vasodilator activity than BRP extracts. Vasodilatation is only transient and is rapidly abolished on neutralization, whereas responses to acid‐activated BRP extracts are more prolonged and activity is stable on ice.
Bovine aortic endothelial cells yield vasodilator activity that is indistinguishable from that isolated from BRP. It is activated by acid, stable on ice, abolished by boiling or by haemoglobin, and appears to be due to the generation of nitric oxide (NO) from nitrite.
The data provide confirmatory evidence that nitrite in BRP extracts is IF, that acid‐activation of BRP extracts yields NO which is responsible for its vasodilator action, and that inactivation occurs by decay of NO to nitrite and nitrate. They further suggest that BRP extracts contain a NO‐stabilizing agent which favours conversion of nitrite to NO.
The finding that bovine aortic endothelial cells yield an agent indistinguishable from IF suggests that nitrite in endothelial cells may likewise be the precursor of endothelium‐derived relaxing factor (EDRF), itself identified as NO.
Endothelium‐derived relaxing factor (EDRF) and resistance vessels in an intact vascular bed: a microangiographic study of the rabbit isolated ear
Authors: Griffith T.M , Edwards D.H. , Davies R. Ll , Harrison T.J. , Evans K.T. 
Published: July 2012

Microradiographic techniques have been used to show that endothelium‐derived relaxing factor (EDRF), which is believed to be nitric oxide, influences vasomotor responses in small arteries and arterioles down to 25 μm in diameter in an isolated, intact, buffer‐perfused ear preparation of the rabbit. Arteries down to 75 μm in diameter, i.e. the central ear artery (G0) and its first three generations of branch vessels (G1, G2 and G3) were studied quantitatively.
Relative constrictor responses to 1 μm 5‐hydroxytryptamine (5‐HT) and the combination of 1 μm 5‐HT and 1 μm histamine diminished progressively from G0 to G3. Constrictor responses to 5‐HT were doubled in all generations by 1 μm haemoglobin which abolishes EDRF activity.
Relative dilator responses to acetylcholine or to substance P in preconstricted arteries were, in contrast, equal in the different generations. Mean —log (IC50) values calculated from diameter measurements were 7.63 ± 0.10 m and 9.80 ± 0.11 m, respectively. These dilator responses were abolished by 1 μm haemoglobin, implying that they were EDRF‐mediated. Spatial homogeneity of relative dilator responses was found also with glyceryl trinitrate (10 or 50 μm) whose activity is thought to depend on biotransformation to nitric oxide, in both the presence and the absence of haemoglobin.
This finding of spatial homogeneity of the diameter response to changes in EDRF activity (or to glyceryl trinitrate) implies that EDRF influences hydrodynamic resistance more in vessels where constrictor tone is high.
Benoxaprofen activates membrane‐associated oxidative metabolism in human polymorphonuclear leucocytes by apparent modulation of protein kinase C
Authors: Lukey Pauline T. , Anderson Ronald , Dippenaar Ursula H. 
Published: July 2012

The non‐steroidal anti‐inflammatory drug (NSAID) benoxaprofen at concentrations of 15, 30 and 60 μg ml−1 caused a dose‐related activation of superoxide generation by human polymorphonuclear leucocytes (PMNL) in vitro.
The protein kinase C (PKC) inhibitor H‐7 prevented benoxaprofen‐mediated activation of superoxide generation by PMNL.
Benoxaprofen, by apparent substitution for phosphatidylserine, caused a dose‐related activation of purified PKC from rat brain and in cytosolic extracts from human platelets.
Benoxaprofen‐mediated stimulation of PMNL membrane‐associated oxidative metabolism is due to apparent activation of PKC by this NSAID. These findings establish the molecular basis of the pro‐oxidative properties of benoxaprofen.
Zn2+ stimulates spontaneous transmitter release at mouse neuromuscular junctions
Authors: Nishimura Masakazu 
Published: July 2012

Experiments were carried out to examine the effect of Zn2+ on the rate of spontaneous release of transmitter at the neuromuscular junction of the mouse diaphragm muscle, in the presence and absence of external Ca2+. Miniature endplate potentials (m.e.p.ps) were measured in vitro.
Zn2+ markedly elevated the frequency of m.e.p.ps without affecting the resting membrane potential of muscle fibres. This effect was time‐ and concentration‐dependent but was independent of the presence of external Ca2+. In a Ca2+‐free bathing solution, Zn2+ frequently produced twitching in several fibres. The twitching dislodged the microelectrode. Replacement of the 10 mm NaCl in the Ca2+‐free solution with equimolar KCl overcame this difficulty. The experiments summarized below were done in the Ca2+‐free bathing solution which contained 10 mm KCl instead of 10 mm NaCl.
The effect of Zn2+ was transient and required a latent period of many minutes. Low temperature (24°C) increased the length of this latent period and reduced the maximum effect of Zn2+.
Zn2+ increased the frequency of m.e.p.ps in K+‐free (replaced with NaCl) solution. The effect appeared with shorter latency in this solution compared to the standard Krebs‐Ringer solution.
The effect of Zn2+ was partially antagonized by dantrolene sodium or by neomycin. Both agents also reduced the effect of external Ca2+ on m.e.p.ps in depolarizing solution.
Cd2+ and 2,3‐bisphosphoglycerate also elevated the frequency of m.e.p.ps in a manner independent of external Ca2+, but the latter compound was much less potent than Cd2+.
These experiments provide evidence for a role of intracellularly stored Ca2+ in the release of transmitter at the motor nerve terminal. The release of Ca2+ from the storage site may be coupled with the metabolism of phosphatidylinositol.
14β‐Hydroxyprogesterone binds to the digitalis receptor, inhibits the sodium pump and enhances cardiac contractility
Authors: Bose D. , Elliott D. , Kobayashi T. , Templeton J.F. , Kumar V.P.S. , LaBella F.S. 
Published: July 2012

Certain derivatives of progesterone are potent inhibitors of high affinity, specific binding of 3H‐cardiac glycosides. The steroids interact at the cardiac glycoside site on Na,K‐ATPase and inhibit the enzyme (the sodium pump) in cardiac and other tissues. However, the active congeners identified previously have been, unlike the cardiac glycosides, predominantly cardiodepressant.
Because a 14β‐hydroxy substituent is an important determinant of activity of the cardiotonic cardiac glycosides, we synthesized 14β‐hydroxyprogesterone. This derivative has about one‐tenth the potency of the aglycone, ouabagenin, in a [3H]‐ouabain binding assay.
Like ouabagenin, but in contrast to the cardiodepressant congeners of progesterone, 14β‐hydroxyprogesterone consistently elicited positive inotropy in isolated cardiac muscle and enhanced both the magnitude and frequency of fluctuations in scattered light (an index of oscillatory intracellular release of calcium).
Thus, at least one hydroxylated derivative (and putative endogenous metabolite) of progesterone, mimics the cardiac effects of cardiac glycosides including enhanced contractility.
The inhibitory effect of somatostatin peptides on the rat anococcygeus muscle in vitro
Authors: Priestley T. , Woodruff G.N. 
Published: July 2012

Electrically evoked contractions of the rat anococcygeus muscle were inhibited in a concentration‐dependent manner by somatostatin‐14 (SS14), −28 (SS28) and two synthetic hexapeptide analogues: L‐363,301 and L‐363,586 , with pIC50 values of 7.41, 7.38, 7.07 and 8.34, respectively.
The inhibitory effects of SS14 were dependent on stimulation frequency and external calcium ion concentration. Calcium behaved as a non‐competitive antagonist of SS14, it reduced the maximal inhibitory effect of the peptide and at a concentration of 5.08 mm it significantly affected the pIC50 value.
SS14 (3 times 10−7 m) did not affect the tonic actions of bath‐applied noradrenaline in the absence of field stimulation.
The effects of SS14 persisted in naloxone (10−5 m) and were, therefore, not due to an action at opiate receptors. Furthermore, experiments involving the lyophilisation of bath contents, showed no evidence to support an indirect mechanism involving the release of an endogenous inhibitory substance.
High concentrations (10−5 m) of SS14 or L‐363,301 inhibited the relaxation response evoked by electrical stimulation of guanethidine (3 times 10−4 m)‐treated preparations.
These results are consistent with similar actions of SS14 on other smooth muscle preparations and are presumed to reflect a presynaptic inhibition of transmitter release by a direct action on somatostatin receptors. The antagonistic effect of calcium on this response is discussed with reference to a possible role in receptor desensitization.
Blockade of vasopressor and vas deferens responses by α, β‐methylene ATP in the pithed rat
Authors: Bulloch J.M. , McGrath J.C. 
Published: July 2012

The pressor responses produced by the intravenous administration of α,β‐methylene ATP were tachyphylactic.
α,β‐Methylene ATP can attenuate pressor responses to sympathetic nerve stimulation both in the presence and in the absence of α‐adrenoceptor blocking agents.
α,β‐Methylene ATP has no effect on the pressor responses produced by bolus injections of noradrenaline.
In the presence of α‐adrenoceptor blocking agents, α,β‐methylene ATP further attenuates contractions of the vas deferens produced by nerve stimulation.
The results, together with previous data, suggest that the vasopressor response to stimulation of the sympathetic outflow in the rat is partly purinergic and partly α‐adrenergic and that this occurs as co‐transmission. The same applies to rat vas deferens, confirming in vitro data. The pithed rabbit had an α‐blocker‐resistant vasopressor nerve‐mediated response but this was resistant to α,β‐methylene ATP.
Effects of atropine and tetrodotoxin on neurotensin‐induced ileal sodium transport in the dog
Authors: Mailman David 
Published: July 2012

Neurotensin was infused intravenously, in the presence or absence of intravenous atropine or intraarterial tetrodotoxin, into dogs anaesthetized with sodium pentobarbitone. Net and unidirectional fluxes of sodium and blood flows in the ileum were measured. Arterial and mesenteric venous blood pressures, haematocrits and plasma total solids were also determined.
Neurotensin caused a transient increase in net sodium absorption which was not associated with significant changes in unidirectional fluxes. This was followed by prolonged net secretion which was associated with an increase in unidirectional sodium secretion and a smaller decrease in sodium absorption. Potassium secretion was also increased when net sodium secretion increased.
Neurotensin increased haematocrit and total solids and decreased arterial pressure at the same time that secretion occurred.
Atropine blocked all the cardiovascular effects of neurotensin and reduced its early effects on both absorption and secretion but not the later effects on secretion. Tetrodotoxin only blocked the increase in absorption but not the secretion or the cardiovascular effects.
It was concluded that there is a cholinergic step in the cardiovascular effects of neurotensin and that the early effects of neurotensin on secretion are due to active secretion supported by fluid leakage from the plasma. The later effects of neurotensin on secretion do not have a cholinergic step and are due primarily to an active secretion. The increased absorption is mediated partly through intrinsic nerves of the gut.
Neurokinin3‐receptors are linked to inositol phospholipid hydrolysis in the guinea‐pig ileum longitudinal muscle‐myenteric plexus preparation
Authors: Guard S. , Watling K.J. , Watson S.P. 
Published: July 2012

Tachykinin‐stimulated inositol phospholipid hydrolysis was examined in slices of longitudinal muscle from guinea‐pig ileum.
Substance P, neurokinin A and neurokinin B induced a concentration‐dependent accumulation of total [3H]‐inositol phosphates in the presence of 12 mm lithium with similar maximal responses and EC50 values.
The selective NK1‐receptor agonist, substance P methyl ester, and the selective NK3‐receptor agonist succ‐[Asp6, MePhe8]‐SP(6–11) (senktide) also stimulated [3H]‐inositol phosphate formation with maximum responses of 50.69 ± 0.96 and 45.64 ± 1.17% relative to 10 μm substance P, respectively. Substance P methyl ester was approximately equipotent with substance P, whereas senktide was approximately 100 times more potent.
When added together, maximally effective concentrations of substance P methyl ester and senktide gave responses that were fully additive. In contrast, responses to substance P and neurokinin B were not additive.
The stimulation of [3H]‐inositol phosphate formation by substance P, neurokinin B and senktide was not affected by atropine (2 μm) or tetrodotoxin (TTX, 0.3 μm).
The contractile effect of senktide was inhibited completely by TTX and partially blocked by atropine. Contractions induced by substance P methyl ester were not changed in the presence of TTX or atropine.
[d‐Pro4, d‐Trp7,9,10]‐SP(4–11) competitively antagonized the action of substance P methyl ester on inositol phospholipid hydrolysis and contraction, but had no significant effect on senktide‐induced inositol phospholipid breakdown or contraction.
These results suggest that NK3‐receptors in the guinea‐pig ileum are coupled to inositol phospholipid hydrolysis.
Correlation between log POCT/H2O and pKB estimates for a series of muscarinic and histamine H2‐receptor antagonists
Authors: Shankley N.P. , Black J.W. , Ganellin C.R. , Mitchell R.C. 
Published: July 2012

With histamine used as agonist, pKB values were estimated for seventeen histamine H2‐receptor antagonists on assays involving acid secretion by the mouse isolated stomach and contraction frequency of the guinea‐pig right atrium.
With the exception of oxmetidine, SK&F 94,826 and SK&F 94,206 on the right atrium assay, the compounds behaved as simple competitive antagonists on both assays. Although the former three compounds produced concentration‐dependent, parallel, displacement of the histamine concentration‐effect curves, subsequent analysis indicated Schild plot slope parameters significantly less than unity. However, the application of a combined dose‐ratio analysis indicated that their antagonistic behaviour did not differ from expectations for simple competition at dose‐ratios of approximately 20, and pKB values were estimated on this basis.
In accordance with previously reported data, pKB values were found to be consistently lower on the stomach than atrial assays. The pKB value for tiotidine was underestimated to the same extent on the stomach assay when impromidine was used as agonist.
The removal of the serosal muscle from the mouse stomach, achieved by using an isolated, perfused, mucosal sheet preparation, did not significantly affect the underestimation of the pKB value for metiamide.
Linear regressional analysis indicated a significant, positive, correlation between lipophilicity (log POCT/H2O) of the antagonists and the degree of antagonist pKB value underestimation on the gastric secretion assay.