bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of β2‐adrenoceptor‐mediated mechanisms in the cardiovascular responses to α1‐ and α2‐adrenoceptor antagonism in conscious, unrestrained, Long Evans and Brattleboro rats
Authors: Gardiner Sheila M. , Bennett Terence 
Published: July 2012

Intra‐arterial blood pressures and heart rates were recorded in conscious, unrestrained, Long Evans and Brattleboro rats receiving sequential, continuous administrations of selective α1‐ (prazosin) and α2‐ (idazoxan) adrenoceptor antagonists. The same protocols were also run in the presence of ICI 118551 (a selective antagonist of β2‐adrenoceptors).
Prazosin and idazoxan caused large, but transient, hypotensions in Long Evans and Brattleboro rats. In the continued presence of both drugs there were marked, intermittent, depressor episodes and tachycardias in both strains of rat.
In the presence of low or high doses of ICI 118551 the hypotensive responses to prazosin and idazoxan were markedly reduced in both strains of rat and blood pressures showed little variability, although intermittent tachycardias still occurred.
In adrenal‐demedullated Long Evans rats, the hypotensive responses to prazosin and idazoxan were attenuated and in the presence of both drugs, blood pressure was relatively steady, although intermittent tachycardias still occurred.
In the presence of prazosin and idazoxan, when a depressor episode was not occurring, administration of captopril caused hypotension in Long Evans and Brattleboro rats. In the latter, the reduction in blood pressure was sustained, whereas there was a recovery in blood pressure in Long Evans rats. This recovery was punctuated by depressor episodes, and was abolished by a V1‐receptor antagonist (d(CH2)5DAVP).
Long Evans rats given two primed doses of the non‐selective α‐adrenoceptor antagonist, phentolamine, exhibited variation in blood pressure similar to that seen in the presence of prazosin and idazoxan. As in the latter case, blood pressure variability was inhibited by the β2‐adrenoceptor antagonist, ICI 118551.
Administration of idazoxan into a lateral ventricle in Long Evans rats receiving phenoxybenzamine intravenously did not cause blood pressure instability. However, intravenous administration of idazoxan in the same animals produced intermittent depressor episodes and tachycardias similar to those seen in the presence of prazosin and idazoxan.
The simplest explanation of the results is that β2‐adrenoceptor‐mediated depressor mechanisms contribute to the hypotensive responses to α1‐ and α2‐adrenoceptor antagonism. Furthermore, in the presence of adequate peripheral α1‐ and α2‐adrenoceptor antagonism, blood pressure may be maintained by the renin‐angiotensin system and vasopressin (although it is only when the former system has been antagonized that a clear‐cut pressor action of vasopressin is apparent). Under these conditions, blood pressure maintenance is interrupted by intermittent depressor episodes that are largely due to adrenal medullary activation.
Highly potent and stereoselective effects of the benzoic acid derivative AZ‐DF 265 on pancreatic β‐cells
Authors: Garrino M.G. , Henquin J.C. 
Published: July 2012

Mouse islets were used to define the characteristics and study the mechanisms of the stimulation of insulin release by compound AZ‐DF 265, 4‐[[N‐(α‐phenyl‐2‐piperidino‐benzyl) carbamoyl]methyl] benzoic acid, a substituted benzoic acid with an asymmetric carbon atom.
At a non‐stimulatory concentration of glucose (3 mm), (‐)‐AZ‐DF 265 reversibly inhibited 86Rb efflux from islet cells, depolarized the β‐cell membrane, induced electrical activity, stimulated 45Ca efflux, and triggered insulin release. Maximum inhibition of 86Rb efflux occurred at 0.03 μm (‐)‐AZ‐DF 265, whereas the threshold concentration for stimulation of release was 0.1 μm. Omission of extracellular Ca2+ abolished all effects of the drug but the inhibition of 86Rb efflux.
At a stimulatory concentration of glucose (10 mm), (‐)‐AZ‐DF 265 reversibly increased 86Rb efflux, potentiated electrical activity, augmented 45Ca efflux, and increased insulin release. Maximum stimulation of 86Rb efflux and insulin release was obtained with 0.03 μm (‐)‐AZ‐DF 265. Omission of extracellular Ca2+ abolished all effects of the drug.
The potency of (‐)‐AZ‐DF 265 was similar to that of glibenclamide, whereas the (+)‐enantiomer was about 10 times less potent on 86Rb efflux and insulin release.
It is concluded that, like sulphonylureas, compound AZ‐DF 265 decreases K+ permeability of the β‐cell membrane and thereby causes depolarization. This activates voltage‐dependent Ca channels, permits Ca2+ influx and eventually stimulates insulin release. Its stereoselectivity may help to elucidate the mechanisms of K channel blockade and, hence, lead to the design of more potent and specific insulinotropic drugs.
Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea‐pig
Authors: Adcock J.J. , Schneider C. , Smith T.W. 
Published: July 2012

Antitussive, antinociceptive and respiratory depressant effects of codeine, morphine and H.Tyr.d>‐Arg.Gly.Phe(4‐NO2) Pro.NH2 (compound BW443C) were investigated in unanaesthetized guinea‐pigs. Antagonism of the antitussive and antinociceptive effects was investigated by the use of nalorphine and N‐methylnalorphine. Naloxone was used to antagonize respiratory depression.
Antitussive ED50s (with 95% confidence limits) for inhibition of cough induced by citric acid vapour were for codeine, morphine and BW443C respectively, 9.1(5.8‐15), 1.3(0.7‐2.4) and 1.2(0.6‐2.6) mg kg−1 s.c. and 8.7(4.2‐12), 1.6(1.2‐1.9) and 0.67(0.002‐3.3) mg kg−1, i.v. The antitussive effects of subcutaneous codeine (25 mg kg−1) morphine (8.1 mg kg−1) and BW443C (2.5 mg kg−1) were significantly antagonized by subcutaneous nalorphine (3.0 mg kg−1) and N‐methylnalorphine (3.0 mg kg−1).
In the multiple toe‐pinch test, the antinociceptive ED50s (with 95% confidence limits) of codeine and morphine were 18(16–22) and 2.3(0.4‐4.3) mg kg−1, s.c., respectively. Compound BW443C was ineffective in doses of 2.5 and 10 mg kg−1 s.c., a result consistent with its lacking penetration into the CNS. Subcutaneous nalorphine (3.0 mg kg−1) antagonized the antinociceptive action of codeine (25 mg kg−1) and morphine (8.1 mg kg−1). In contrast, N‐methylnalorphine (3.0 mg kg−1) had no significant effect on the antinociceptive action of codeine and morphine, suggesting lack of penetration of the CNS by N‐methylnalorphine.
At doses near to the i.v. ED50 values for the antitussive activity, morphine (1.5 mg kg−1, i.v.) and codeine (10 mg kg−1, i.v.) caused small but significant depressions of ventilation (7.0 ±2.3% and 16.5 ± 8.4% respectively). Higher doses of morphine (10, 30 and 60 mg kg−1, i.v.) caused further dose‐related depression of ventilation (9.6 ± 5.3%, 22.4 ± 6.2% and 36.2 ± 9.6% respectively) whereas codeine (30 and 60 mg kg−1 i.v.) caused stimulation of ventilation which was marked (191.3 ± 43.9%) at 60 mg kg−1.
Compound BW443C in doses of 1 or 10 mg kg−1, i.v. (approximately equal to, and 10 times the ED50 for antitussive activity) did not cause significant depression of ventilation. Only at higher doses of 30 and 60 mg kg−1, i.v. was there a significant decrease in minute volume (13.1 ±6.8% and 15.9 ± 1.89% respectively). The depression of ventilation caused by either BW443C (60 mg kg−1, i.v.) or morphine (60 mg kg−1, i.v.) was prevented by pretreatment with naloxone (3 mg kg−1, i.v.) administered 15 min before morphine or BW443C.
These results in the guinea‐pig support the hypothesis that the antitussive action of the opiates codeine and morphine and the opioid pentapeptide BW443C do not require penetration of these drugs into the CNS.
A comparison of fast and slow depolarizations evoked by 5‐HT in guinea‐pig coeliac ganglion cells in vitro
Authors: Wallis D.I. , Dun N.J. 
Published: July 2012

5‐Hydroxytryptamine (5‐HT) was applied by pressure ejection to coeliac ganglion cells of the guinea‐pig maintained in vitro and responses measured intracellularly.
Cells responded in one of three ways to 5‐HT: by (a) a fast, transient depolarization (43%), (b) a fast transient followed by a slow depolarization (biphasic response, 30%) or (c) a slow sustained depolarization (25%).
Fast depolarizations (response (a) above)) were graded according to the duration of the ejection pulse. Maximal responses had a mean amplitude of 12 ± 0.8 mV, a duration of 6.4 ± 1.0 s, a latency of 0.4 ± 0.1 s, were associated with a fall in membrane input resistance, increased in amplitude by hyperpolarization and probably mediated by an increased conductance to Na and K. The estimated reversal potential was −22.8 ± 2.4 mV (n = 14). The maximal fast response seen in biphasically‐responding cells (b) appeared similar to fast response (a).
Fast depolarizations (a) showed marked tachyphylaxis and were abolished by superfusion of the ganglion with 5‐HT (100 μm). They were reduced in amplitude by tubocurarine (10–100 μm, pIC50 4.4), MDL 72222 (1–5 μm, pIC50 5.8), quipazine (1 μm reduced responses by 65 ± 15%, n = 3), ICS 205–930 (1 μm reduced responses by 64 ± 14%, n = 7) and metoclopramide (10 μm reduced responses by about 45%), but were unaffected by methysergide (up to 1 μm) or hexamethonium (up to 1 mm).
Slow depolarizations (c) varied in amplitude with the duration of the ejection pulse. Maximal responses had a mean amplitude of 6.4 ± 0.7 mV, a duration of 62 ± 6 s, a latency of 3.5 ± 0.8 s and were reduced in amplitude by methysergide (0.1–1 μm, pIC50 6.5) but not by MDL 72222 (1 μm). The maximal slow component in biphasically‐responding cells (b) was similar in amplitude and duration to slow response (c), was partially blocked by methysergide (1–5 μm) in 4 of 6 cells and was enhanced by tubocurarine (50 μm) which reduced the fast component.
Slow depolarizations (b,c) were associated with either a small reduction or no change in membrane input resistance depending on the cell studied. Hyperpolarization had variable effects on slow depolarization amplitude.
It was concluded that the fast, phasic depolarization is mediated by an ionic mechanism and by receptors both of which are distinct from those involved in the slow depolarization. The receptor mediating the fast depolarization is a 5‐HT3 receptor while that mediating the slow depolarization has yet to be identified.
Catecholamines released from the adrenal medulla exert a compensatory, protective effect at β2‐adrenoceptors against Paf‐induced death in mice
Authors: Criscuoli Marco , Subissi Alessandro 
Published: July 2012

The effects of a number of drugs and experimental conditions, which inhibit or stimulate adrenergic function, were evaluated on platelet‐activating factor (Paf)‐induced death in conscious mice.
Adrenalectomy markedly potentiated Paf toxicity, while guanethidine and reserpine did not. However, reserpine, which produced a virtually complete depletion of cathecolamines (CA) in cardiac tissue, was not able to reduce adrenal CA by more than 58%. Drugs which release noradrenaline from the adrenergic nerve terminals, such as tyramine and amphetamine, did not protect mice from Paf toxicity, while drugs or conditions which favour the release of CA from the adrenal medulla, such as urethane and cold‐induced stress, did.
β2‐ and β1 + β2‐adrenoceptor antagonists (ICI 118551, propranolol and nadolol), but not β1‐ antagonists (atenolol, practolol, metoprolol and CGP 20712 A), potentiated Paf toxicity at low doses; β2‐ and β1 + β2‐agonists (salbutamol, fenoterol and isoprenaline), but not β1‐agonists (prenalterol and tazolol) were potent inhibitors of Paf toxicity. α1‐ and α2‐adrenoceptor agonists and antagonists did not exert significant effects. Propranolol did not appear to enhance the hypotensive action of Paf in pentobarbitone‐anaesthetized mice.
It is concluded that manipulation of the release of CA from the adrenal medulla, but not from adrenergic nerves, has profound effects on Paf toxicity in mice. A number of considerations support the hypothesis that bronchoconstriction is a major determinant of Paf‐induced death in mice.
Release of tissue‐type plasminogen activator is induced in rats by leukotrienes C4 and D4, but not by prostaglandins E1, E2 and I2
Authors: Tranquille N. , Emeis J.J. 
Published: July 2012

Acute release of plasminogen activator (PA) was studied in rat isolated hindleg system perfused with Tyrode solution.
Leukotriene C4 (LTC4) and LTD4 dose‐dependently induced the release of PA, which plateaued at 160 nmol l−1 and 200 nmol l−1, respectively. The amount of PA released was about 1 iu ml−1. The effects of LTC4 and LTD4 were not additive.
The PA released was identified as tissue‐type PA (t‐PA) by quenching experiments using anti‐human t‐PA IgG, by fibrin autography, and by the dependence of its activity on the presence of soluble fibrin.
LTE4 (300 and 450 nmol l−1) and 5‐hydroxy‐eicosatetraenoic acid (600 nmol l−1) did not induce any t‐PA release in the perfusion system used.
Release of t‐PA induced by LTC4 and LTD4 was inhibited by the leukotriene‐receptor antagonist FPL 55712 (10 μmol l−1), whereas FPL 55712 did not inhibit t‐PA release induced by platelet‐activating factor (Paf‐acether).
In vivo LTC4 and LTD4 (2 μg kg−1 i.v.) also induced an acute increase of t‐PA activity in rat blood as evidenced by decreased blood clot lysis times.
Prostaglandin E1 and E2, prostacyclin and the stable prostacyclin analogue ZK 36374 at concentrations of 0.1–3.0 μmol l−1 induced little or no t‐PA release.
Cardiovascular effects of two new calcium antagonists, PY 108‐068 and PN 200‐110, in conscious spontaneously hypertensive rats
Authors: Barrès Christian , Cerutti Catherine , Morin Benoît , Sassard Jean 
Published: July 2012

The acute cardiovascular effects of PY 108‐068 and PN 200‐110 were studied by means of a computerized analysis of the intra‐aortic blood pressure (BP) recorded continuously for 26 h in conscious unrestrained spontaneously hypertensive rats. Both compounds were studied at three doses (50, 100 and 200 μg kg−1) and each dose was administered intravenously 5 times (09 h 00 min, 14 h 00 min, 19 h 00 min, 24 h 00 min and 09 h 00 min). Baroreflex sensitivity was measured 1 h following the last injection.
The two compounds were found to induce rapid (3 min) and dose‐dependent falls in BP. After the first administration, these decreases reached −20% and −35% for systolic BP (SBP) and diastolic BP (DBP) respectively with PY 108‐068 (200 μg kg−1) and −25% and −45% for SBP and DBP respectively with PN 200‐110 (200 μg kg−1).
The duration of the reduction in BP increased with the dose and was much longer for PN 200‐110 (180 min for SBP) than for PY 108‐068 (20 min for SBP).
A tachycardia was associated with the decrease in BP which did not differ at 200 μg kg−1 between PY 108‐068 (+ 108 beats min−1) and PN 200‐110 (+ 103 beats min−1). Baroreflex sensitivity was not significantly increased by either drug.
The 5 repeated injections of PY 108‐068 and PN 200‐110 evoked similar responses.
In conclusion, both compounds exhibited marked hypotensive properties. PN 200‐110 appeared to be more suitable for further development since its effects were found to be greater and much longer lasting than those of PY 108‐068.
Importance of magnesium and potassium concentration on basal tone and 5‐HT‐induced contractions in canine isolated coronary artery
Authors: Murakawa Toshisuke , Altura Bella T. , Carella Anthony , Altura Burton M. 
Published: July 2012

In vitro studies were undertaken to investigate the effects of external potassium ([K+]o) and magnesium ([Mg2+]o) concentration on canine coronary arterial basal tone and on 5‐hydroxytryptamine (5‐HT)‐induced contractions.
Acute withdrawal of, or reduction in, [K+]o produced relaxation of basal tone in isolated coronary arteries, whereas acute withdrawal (but not reduction) of [Mg2+]o produced contraction of these blood vessels.
The magnitude of coronary contraction obtained on withdrawal of [Mg2+]o was dependent upon the [K+]o; the higher the [K+]o, the greater the contraction.
The precise ratio of [K+]o/[Mg2+]o appeared to be important in dictating the degree of contraction (maximum response) and sensitivity (EC50) of canine coronary vascular smooth muscle cells to 5‐HT. The EC50 to 5‐HT was enhanced by increases in the [K+]o/[Mg2+]o ratio, whereas the ability of 5‐HT to induce a maximal contraction was attenuated by decreases in the [K+]o; the latter being modulated by [Mg2+]o. Small changes in [Mg2+]o could effect large changes in the EC50 as [K+]o was lowered.
These actions took place over patho‐physiological ranges of [K+]o and [Mg2+]o.
Maintenance of a constant [K+]o/[Mg2+]o ratio, irrespective of the exact [K+]o and [Mg2+]o, produced similar degrees of maximum tension.
Use of intact vascular ring preparations and helically‐cut vascular strips produced similar results with varying [K+]o/[Mg2+]o.
A variety of pharmacological receptor antagonists (phentolamine, propranolol, atropine, diphenhydramine, cimetidine), as well as a prostaglandin cyclo‐oxygenase inhibitor, did not modify the altered contractile responses or basal tone evoked by varying [K+]o/[Mg2+]o ratios.
These results suggest: (1) that basal tone and contractility of canine coronary vascular smooth muscle cells appear to be exquisitely sensitive to alterations in extracellular K+ and Mg2+; and (2) 5‐HT receptor‐operated Ca2+ channels, as well as those Ca2+ channels involved in generation of coronary arterial basal tone are modulated and controlled by the precise concentrations of [K+]o and [Mg2+]o.
Positive inotropic effects induced by carbachol in rat atria treated with islet‐activating protein (IAP) — association with phosphatidylinositol breakdown
Authors: Imai Shoichi , Ohta Hideo 
Published: July 2012

To elucidate the functional consequences of phosphatidyl inositol (PI) breakdown produced by activation of the muscarinic receptor of the atrial muscle, and to clarify the subtypes of the muscarinic receptor involved, the effects of muscarinic agonists and antagonists on mechanical function were studied in atria isolated from rats given intravenous islet‐activating protein (IAP; 50 μg kg−1 body weight) 48–72 h before the experiments.
The negative chronotropic and inotropic actions of carbachol (CCh) were attenuated and positive inotropic effects (62.5 ± 5.8% above basal level) were observed with 10−5‐10−3 m CCh. Oxotremorine did not produce positive inotropic effects even in doses as high as 3 × 10−4 m. High doses of carbachol produced positive chronotropic effects, although the effects were weak.
Propranolol (10−7 m) did not modify the positive inotropic effect of carbachol observed in IAP‐treated atria, nor was there any change in the tissue cyclic AMP levels after carbachol.
High doses (10−5‐10−3m) of carbachol produced PI breakdown in the absence and presence of IAP. Oxotremorine (3 × 10−4 m) did not produce PI breakdown. In the presence of oxotremorine, the positive inotropic effects and PI breakdown by carbachol were abolished.
The positive inotropic effect of carbachol was readily antagonized by atropine but pirenzepine and gallamine exhibited only weak antagonist effects.
These results suggest that a muscarinic agonist such as carbachol can produce a positive inotropic effect in IAP‐treated atria, in association with PI breakdown, through activation of a muscarinic receptor which shows some similarity to that previously identified in smooth muscles.
Effects of calcium channel blockade in canine saphenous veins after storage at −190°C
Authors: Ebeigbe Anthony B. , Müller‐Schweinitzer Else , Vogel Arnold 
Published: July 2012

Canine saphenous veins were investigated in vitro either within 24 h after removal or after storage at −190°C for 4–5 weeks in foetal calf serum containing 1.8 m dimethyl sulphoxide.
Contractions and 45Ca2+ uptake in response to both depolarization and guanfacine were studied in the absence and presence of the calcium channel antagonists diltiazem, verapamil, nifedipine and the two stereoisomers of a 1,4‐dihydropyridine derivative, namely the (+)−(S) enantiomer and the (−)−(R) enantiomer of 202–791 (isopropyl 4‐(2,1,3‐benzoxadiazol‐4‐yl)‐l,4‐dihydro‐2, 6‐dimethyl‐5‐nitro‐3‐pyridinecarboxylate).
Comparison of the data obtained on unfrozen and frozen/thawed veins revealed a good preservation of both contractile responsiveness and 45Ca2+ uptake mechanisms after storage at −190°C.
It is suggested that cryopreservation is a useful technique for storing venous smooth muscle for pharmacological studies.
Inhibitory effect of sodium cromoglycate on pulmonary responses to histamine administered after indomethacin in anaesthetized guinea‐pigs
Authors: Mitchell H.W. 
Published: July 2012

Histamine (2–4 μg kg−1 i.v.) increased airways resistance (Raw) and decreased dynamic lung compliance (Cdyn) in urethane‐anaesthetized guinea‐pigs. The effects on Raw were almost abolished by atropine (0.1 mg kg−1 i.v.) and reduced by vagal cooling (11–16°C).
Histamine‐induced changes in Raw and Cdyn were significantly (P < 0.05) enhanced by indomethacin (1 mg kg−1 i.v.).
In animals not treated with indomethacin, exposure to an aerosol containing sodium cromoglycate (0.01–2% for 30 s) failed to affect subsequent (3 min) histamine‐induced bronchoconstriction.
Administration of an aerosol containing low (0.01–0.2%) concentrations of sodium cromoglycate had no effect on the enhanced responses (i.e. hyperreactivity) seen after indomethacin. However, more concentrated sodium cromoglycate aerosols (>0.2%) reduced or abolished the hyperreactivity to histamine seen after indomethacin.
It was concluded that sodium cromoglycate can prevent the development of hyperreactivity to histamine, possibly by interacting with some mechanism utilized by both histamine and indomethacin in this model.
Blockade of the inotropic effect of Bay K 8644 by cytochalasin‐B and phloretin
Authors: Dresel Peter E. , Ogbaghebriel Azieb 
Published: July 2012

The positive inotropic effect in rabbit atria and papillary muscles of Bay K 8644 is blocked by cytochalasin‐B (Cyto‐B) and phloretin, two compounds known to block the facilitated diffusion of glucose. These compounds do not change the concentration‐response curve of calcium.
Cyto‐B is more potent in atria than in papillary muscles, 10−7 m having a maximal effect in atria whereas 2 × 10−5m was required for a maximal effect in papillary muscles. Phloretin was fully effective at 10−4m, the only concentration tested.
The inotropic effect of Bay K 8644 was virtually abolished in atria bathed in a glucose‐free medium or one containing 5 mM pyruvate. The contractile response to Bay K 8644 of papillary muscles was not changed significantly in glucose‐free or in pyruvate‐containing medium.
Cyto‐B (2 × 10−5 m) caused a slight but significant increase in the KD for the binding of nitrendipine to a crude sarcolemnal preparation from rabbit ventricles. The Bmax was unchanged.
These results may best be explained by the hypothesis that there is a metabolic requirement for the inotropic effect of Bay K 8644.
Involvement of central α‐ and β‐adrenoceptors in the pressor response to electrical stimulation of the rostral ventrolateral medulla in rats
Authors: Ward‐Routledge C. , Marshall P. , Marsden C.A. 
Published: July 2012

Electrical stimulation of the C1 area of the rostral ventrolateral medulla in rats elicits an increase in mean arterial pressure (MAP).
This increase in MAP is attenuated by intra‐hypothalamic and intradsternal administration of the non‐selective β‐adrenoceptor antagonist (±)‐propranolol and the β2‐selective antagonist ICI 118551.
The selective β1‐antagonist atenolol and (+)‐propranolol, which is inactive on β‐adrenoceptors, did not alter the increase in MAP produced by stimulation of the C1 area.
The α2‐adrenoceptor antagonist idazoxan enhanced the effects of C1 stimulation on MAP when administered either into the posterior hypothalamus or intradsternally.
The results indicate that β2‐ and α2‐receptors both have a role in the mediation of the rise in MAP during stimulation of the C1 area and that the receptors involved are located both within the hypothalamus and the spinal cord.