British Journal of Pharmacology
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Impairment of endothelium‐dependent relaxation and changes in levels of cyclic GMP in aorta from streptozotocin‐induced diabetic rats
Acetylcholine (ACh)‐induced relaxation of aortic strips with endothelium and production of cyclic GMP between streptozotocin‐induced diabetic and age‐matched control rats were compared. The concentration‐response curve for ACh‐induced relaxation was shifted to the right in diabetic rats. IC50 values for ACh were 4.57 ± 0.67 × 10−8 m and 1.00 ± 0.87 × 10−7 m in aortic strips from age‐matched control and diabetic rats, respectively (n = 6, P < 0.05). Relaxations produced by atrial natriuretic peptide (ANP) in diabetic aortae were similar to those in age‐matched vessels. Relaxations produced by sodium nitroprusside (SNP) in diabetic aortae were similar to those in age‐matched vessels. Basal levels of cyclic GMP and ACh‐induced production of cyclic GMP were significantly decreased in diabetic rats. These results suggest that functional changes in endothelium but not in guanylate cyclase activity in the aorta may occur in diabetes, and, thus, spontaneous and ACh‐induced formation of cyclic GMP may be decreased. This decrease in production of cyclic GMP may be responsible for the decreased response of the aorta to the relaxant effect of ACh.
British Journal of Pharmacology - Tập 97 Số 2 - Trang 614-618 - 1989
Attenuated 5‐hydroxytryptamine receptor‐mediated responses in aortae from streptozotocin‐induced diabetic rats
British Journal of Pharmacology - Tập 111 Số 1 - Trang 370-376 - 1994
Identification of a novel nicotinic binding site in mouse brain using [<sup>125</sup>I]‐epibatidine
[125 I]‐Epibatidine binds to multiple nicotinic acetylcholine receptor (nAChR) subtypes with high affinity. In this study, [125 I]‐epibatidine was used to label and characterize a novel nAChR subtype found in mouse brain inferior colliculus, interpeduncular nucleus, and olfactory bulb homogenates. Binding of [125 I]‐epibatidine was saturable and apparently monophasic in each brain region (K D M mean±s.e.mean across regions) but inhibition of [125 I]‐epibatidine binding (200 pM ) by A85380, cytisine and (−)‐nicotine was biphasic, indicating the presence of multiple binding sites. The sites with lower agonist affinity comprised 30.0±2.2, 58.6±0.1 and 48.7±3.3% of specific [125 I]‐epibatidine (200 pM ) binding in inferior colliculus, interpeduncular nucleus, and olfactory bulb homogenates, respectively. The affinity difference between A85380‐sensitive and ‐resistant binding sites was particularly marked (approximately 1000 fold). Thus A85380 was used to differentiate agonist‐sensitive and ‐resistant sites. The pharmacological profiles of the A85380‐resistant sites in each region were assessed with inhibition binding experiments, using 14 agonists and five antagonists. The profiles were indistinguishable across regions, implying that A85380‐resistant [125 I]‐epibatidine binding sites in inferior colliculus, interpeduncular nucleus, and olfactory bulb represent a single nAChR subtype. The pharmacological profile of the A85380‐resistant sites is very different from that previously reported for high affinity (−)‐[3 H]‐nicotine‐, [125 I]‐α‐bungarotoxin‐, or [125 I]‐α‐conotoxin MII‐binding sites, suggesting that they represent a novel nAChR population in mouse brain.
British Journal of Pharmacology (2000) 131 , 729–739; doi:10.1038/sj.bjp.0703616
British Journal of Pharmacology - Tập 131 Số 4 - Trang 729-739 - 2000
The mechanism of action of maitotoxin in relation to Ca<sup>2+</sup> movements in guinea‐pig and rat cardiac muscles
British Journal of Pharmacology - Tập 86 Số 2 - Trang 385-391 - 1985
Contraction and increase in tissue calcium content induced by maitotoxin, the most potent known marine toxin, in intestinal smooth muscle Maitotoxin (MTX), the most potent known marine toxin, isolated from toxic dinoflagellates and poisonous fish, caused a dose‐dependent contraction of the guinea‐pig isolated ileum and taenia caeci at concentrations of 100 pg to 30 ng/ml. These contractile responses to MTX (3 ng/ml) in both tissues were abolished by incubation in Ca2+ ‐free solution and were markedly inhibited by treatment with methoxyverapamil (D600), but were not affected by tetrodotoxin and atropine. Furthermore, MTX markedly elevated tissue Ca2+ content of the taenia caeci. These results suggest that MTX activates Ca2+ channels in the smooth muscle membrane of both tissues to increase Ca2+ influx and thus induces contractions.
British Journal of Pharmacology - Tập 79 Số 1 - Trang 3-5 - 1983
<i>In vitro</i> cardiac models of dog Purkinje fibre triggered and spontaneous electrical activity: effects of nicorandil
The effects of nicorandil (30 μm and 100 μm ) on two models of triggered activity [early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs)] and on spontaneous automaticity occurring from both normal and depolarized levels of membrane potential were examined in isolated cardiac Purkinje fibres of the dog. Standard intracellular microelectrode techniques were used. Nicorandil (30 μm ) abolished EADs provoked by superfusion with Tyrode solution containing 2.7 mm K+ and 3 mm Cs. DADs were induced by 0.2 μm acetylstrophanthidin in Tyrode solution containing 5.4 mm K+ . Nicorandil (30 μm ) significantly reduced the amplitude of these DADs from 12.5 ± 2.5 mV to 5.5 ± 0.2 mV (P > 0.02, n = 6), while DADs were fully abolished by 100 μm nicorandil. In unstimulated Purkinje strands, superfused with 2.7 mm K+ containing Tyrode solution having a pH of either 7.4 or 6.8, spontaneous depolarizations developed with a mean maximum diastolic potential (MDP) of −84.6 ± 1.6 mV (n = 9) or −54.0 ± 1.2 mV (n = 9), respectively. Nicorandil significantly reduced the frequency of this automatic activity and caused its cessation, at either level of MDP. Nicorandil, however, produced significant hyperpolarization only when automaticity occurred from the depolarized level of potential. These results suggest that nicorandil may exert significant antiarrhythmic actions in vivo by abolishing both spontaneous and triggered electrical activity.
British Journal of Pharmacology - Tập 99 Số 1 - Trang 119-123 - 1990
Rat arterial smooth muscle devoid of ryanodine receptor function: effects on cellular Ca<sup>2+</sup> handling
The roles of intracellular Ca2+ stores and ryanodine (Ry) receptors for vascular Ca2+ homeostasis and viability were investigated in rat tail arterial segments kept in organ culture with Ry (10 – 100 μM ) for up to 4 days. Acute exposure to Ry or the non‐deactivating ryanodine analogue C10 ‐Oeq glycyl ryanodine (10 μM ) eliminated Ca2+ release responses to caffeine (20 mM ) and noradrenaline (NA, 10 μM ), whereas responses to NA, but not caffeine, gradually returned to normal within 4 days of exposure to Ry. Ry receptor protein was detected on Western blots in arteries cultured either with or without Ry. Brief Ca2+ release events (sparks) were absent after culture with Ry, whereas Ca2+ waves still occurred. The propagation velocity of waves was equal (∼19 μm s−1 ) in tissue cultured either with or without Ry. Inhibition of Ca2+ accumulation into the sarcoplasmic reticulum (SR) by culture with caffeine (5 mM ), cyclopiazonic acid or thapsigargin (both 10 μM ) decreased contractility due to Ca2+ ‐induced cell damage. In contrast, culture with Ry did not affect contractility. Removal of Ca2+ from the cytosol following a Ca2+ load was retarded after Ry culture. Thapsigargin reduced the rate of Ca2+ removal in control cultured rings, but had no effect after Ry culture. It is concluded that intracellular Ca2+ stores recover during chronic Ry treatment, while Ry receptors remain non‐functional. Ry receptor activity is required for Ca2+ sparks and for SR‐dependent recovery from a Ca2+ load, but not for Ca2+ waves or basal Ca2+ homeostasis.
British Journal of Pharmacology (2001) 132 , 1957–1966; doi:10.1038/sj.bjp.0703986
British Journal of Pharmacology - Tập 132 Số 8 - Trang 1957-1966 - 2001
Mechanisms of relaxation by urocortin in renal arteries from male and female rats
Urocortin is a peptide recently identified, which is structurally related to the corticotropin‐releasing factor (CRF). To analyze the mechanisms that could be involved in its effect on renal arteries from male and female rats, the response to urocortin was studied in isolated segments, 2 mm long, of renal arteries from male and female rats. In renal artery segments precontracted with endothelin‐1 (1 nM ), urocortin (1 pM –10 nM ) produced concentration‐dependent relaxation, which was similar in the arteries from male and female rats. This relaxation was reduced by the antagonists of urocortin receptors astressin (1 μ M ) and α ‐helical CRF(9–41) (1 μ M ) in arteries from both male and female rats. In renal arteries from female rats, the relaxation to urocortin was reduced by the inhibitor of adenyl cyclase SQ22536 (300 μ M ), by 8‐bromo‐cyclic‐ADP‐ribose (cADPR; 30 μ M ), an antagonist of the endogenous activator of sarcoplasmic Ca2+ channel cADPR and by ryanodine (1 μ M ), which produces depletion of sarcoplasmic Ca2+ . In renal arteries from male rats, the relaxation to urocortin was increased by ryanodine, and was not modified by SQ22536 or 8‐bromo‐cADPR. These results suggest that the mechanisms involved in the relaxation to urocortin in renal arteries differ between female and male rats. In female rats, this relaxation may be mediated by the production of cyclic AMP (cAMP), synthesis of cADPR and release of sarcoplasmic Ca2+ , whereas in male rats it is not mediated by cAMP.
British Journal of Pharmacology (2003) 140 , 1003–1007. doi:10.1038/sj.bjp.0705516
British Journal of Pharmacology - Tập 140 Số 5 - Trang 1003-1007 - 2003
The superficial buffer barrier in venous smooth muscle: sarcoplasmic reticulum refilling and unloading
The interaction of Ca2+ transport in the plasmalemma and the sarcoplasmic reticulum (SR) was investigated in smooth muscle of the rabbit inferior vena cava. We tested the possibility of direct refilling of the SR with extracellular Ca2+ and of the existence of a vectorial Ca2+ extrusion pathway from the SR lumen to the extracellular space suggested by earlier results. After depletion with caffeine the SR was loaded with Ca2+ to increasing levels by incubation in a high potassium 1.5 mm Ca2+ solution and a 10 mm Ca2+ zero Na+ solution, respectively. Thapsigargin, 2 μm , (a specific SR Ca2+ ‐ATPase blocker) completely blocked refilling of the SR in either of the above solutions, indicating that the SR Ca2+ ‐ATPase is essential for this process. Three different agents, caffeine, ryanodine and thapsigargin, which inhibit Ca2+ accumulation by the SR, increased the steady state intracellular Ca2+ concentration in the rabbit inferior vena cava. Measurements of Mn2+ induced quenching of the intracellular fura‐2 signal during pharmacological manipulation of the SR content showed that these three agents did not stimulate divalent cation entry. On the other hand, stimulation with noradrenaline caused a marked increase in Mn2+ influx, which was blocked by 2 mm Ni2+ . Mn2+ entry stimulated by high K+ solution was blocked by 1 μm diltiazem. We conclude that the SR refilling has to be mediated by the SR Ca2+ ‐ATPase. Inhibition of Ca2+ accumulation by the SR causes an increase in the steady state intracellular Ca2+ concentration. This observation cannot be explained by an increase in Ca2+ influx into the smooth muscle cells of the rabbit inferior vena cava. Alternatively these results suggest the existence of a continuous vectorial release of Ca2+ from the SR lumen to the extracellular space.
British Journal of Pharmacology - Tập 109 Số 2 - Trang 336-343 - 1993
Characterization of action potential‐triggered [Ca<sup>2+</sup>]<sub>i</sub> transients in single smooth muscle cells of guinea‐pig ileum
To characterize increases in cytosolic free Ca2+ concentration ([Ca2+ ]i ) associated with discharge of action potentials, membrane potential and [Ca2+ ]i were simultaneously recorded from single smooth muscle cells of guinea‐pig ileum by use of a combination of nystatin‐perforated patch clamp and fura‐2 fluorimetry techniques. A single action potential in response to a depolarizing current pulse elicited a transient rise in [Ca2+ ]i . When the duration of the current pulse was prolonged, action potentials were repeatedly discharged during the early period of the pulse duration with a progressive decrease in overshoot potential, upstroke rate and repolarization rate. However, such action potentials could each trigger [Ca2+ ]i transients with an almost constant amplitude. Nicardipine (1 μM ) and La3+ (10 μM ), blockers of voltage‐dependent Ca2+ channels (VDCCs), abolished both the action potential discharge and the [Ca2+ ]i transient. Charybdotoxin (ChTX, 300 nM ) and tetraethylammonium (TEA, 2 mM ), blockers of large conductance Ca2+ ‐activated K+ channels, decreased the rate of repolarization of action potentials but increased the amplitude of [Ca2+ ]i transients. Thapsigargin (1 μM ), an inhibitor of SR Ca2+ ‐ATPase, slowed the falling phase and somewhat increased the amplitude, of action potential‐triggered [Ca2+ ]i transients without affecting action potentials. In addition, in voltage‐clamped cells, the drug had little effect on the voltage step‐evoked Ca2+ current but exerted a similar effect on its concomitant rise in [Ca2+ ]i to that on the action potential‐triggered [Ca2+ ]i transient. Similar action potential‐triggered [Ca2+ ]i transients were induced by brief exposures to high‐K+ solution. They were not decreased, but rather increased, after depletion of intracellular Ca2+ stores by a combination of ryanodine (30 μM ) and caffeine (10 mM ) through an open‐lock of Ca2+ ‐induced Ca2+ release (CICR)‐related channels. The results show that action potentials, discharged repeatedly during the early period of a long membrane depolarization, undergo a progressive change in configuration but can each trigger a constant rise in [Ca2+ ]i . Intracellular Ca2+ stores have a role, especially in accelerating the falling phase of the action potential‐triggered [Ca2+ ]i transients by replenishing cytosolic Ca2+ . No evidence was provided for the involvement of CICR in the action potential‐triggered [Ca2+ ]i transient.
British Journal of Pharmacology (1997) 122 , 477–486; doi:10.1038/sj.bjp.0701407
British Journal of Pharmacology - Tập 122 Số 3 - Trang 477-486 - 1997
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