Prejunctional Modulation by Prostaglandin E2 of Noradrenaline Release from Sympathetic Neurones in Rabbit Aorta

Abstract: The modulating effect of prostaglandin E₂ (PGE₂) on the electrically-evoked ³H-overflow from rabbit isolated aorta preloaded with ³H-noradrenaline was examined. PGE₂ (3x10^-9-3x10^-7M) inhibited the stimulation-evoked ³H-overflow (maximum inhibition: 81%; pIC₅₀: 8.1). The inhibition was reversible and inversely related to stimulation frequency (1-30 Hz). Cocaine (3x10^-5M) and corticosterone (4x10^-5M) did not alter the inhibitory effect of PGE₂ (3x10^-9-10^-7M). Rauwolscine (10^-6M) enhanced the reduction caused by PGE₂ (3x10^-9-10^-7M). Rauwolscine (10^-6M) alone enhanced the ³H-overflow by 360%. Indomethacin (3x10^-6M) and suprofen (4x10^-5M) did not alter the PGE₂ (3x10^-9-10^-7M)-induced reduction of the ³H-overflow. Indomethacin (3x10^-6M) and suprofen (4x10^-5M) alone had no effect. We conclude that in the rabbit aorta (1) PGE₂ modulates noradrenaline release from sympathetic neurones through a prejunctional inhibitory receptor mechanism; (2) that there is an interaction between α₂-adrenoceptors and EP-receptors; (3) that uptake inhibition does not affect the effect of PGE₂; and (4) that the influence of endogenous prostaglandins on the noradrenaline release can be excluded.     

Calcium Channels Involved in Noradrenaline Release from Sympathetic Neurones in Rabbit Carotid Artery*

Abstract: Transmitter release from nerve terminals is dependent on the entry of Ca²⁺ through neuronal voltage‐gated calcium channels. In sympathetic neurones both N‐ and L‐type calcium channels are present. Potassium channel blockade increases Ca²⁺ entry into sympathetic neurones. We examined the participation of N‐ and L‐type calcium channels in the stimulation‐evoked release of noradrenaline from vascular sympathetic neurones. Rings of rabbit carotid artery were preincubated with [³H]‐noradrenaline. Electrical field stimulation was used to evoke ³H overflow. The selective N‐type calcium channel blocking agent ω‐conotoxin GVIA (single concentrations: 3×10^?10–10^?8 M) caused a slowly developing reduction of the stimulation‐evoked ³H overflow. At 3×10^?8 M, ω‐conotoxin GVIA caused an equilibrium block with a rapid (15 min.) onset. After 2 hr exposure to ω‐conotoxin the inhibition was steady (pIC₅₀ (‐log M): 9.43; E_max: 91%). The selective L‐type calcium blocking agents nifedipine (10^?7–10^?5 M) and nimodipine (10^?8–10^?5 M) had no effect on the stimulation‐evoked ³H overflow. The calcium channel opener Bay K 8644 (10^?6 M) likewise had no effect. The potassium channel blocking agent 4‐aminopyridine (10^?5–10^?3 M) enhanced the stimulation‐evoked ³H overflow up to 5 times. 4‐Aminopyridine (10^?4 M) did not alter the inhibitory effect of ω‐conotoxin GVIA (3×10^?8 M). In the presence of 4‐aminopyridine (10^?4 M), nifedipine (10^?5 M) and nimodipine (10^?6 M) enhanced the ³H overflow. We conclude that the stimulation‐evoked release of noradrenaline from sympathetic neurones in rabbit carotid artery is mediated by N‐type calcium channels and that L‐type channels are not involved even when potassium channels are blocked by 4‐aminopyridine.     

Effect of ω‐Conotoxin GVIA on Noradrenaline Release from Postganglionic Sympathetic Neurones in Rabbit Aorta

Abstract: The aim of the present work was to examine the effect of the selective N‐type calcium blocking agent ω‐conotoxin GVIA on stimulation‐evoked release of noradrenaline from sympathetic nerves in rabbit isolated aorta with regard to stimulation frequency, extracellular Ca²⁺ concentration, and transmitter uptake. Rings of rabbit isolated aorta were preloaded with (‐)‐³H‐noradrenaline and the fractional ³H‐overflow evoked by electrical‐field stimulation was determined by liquid scintillation spectrometry. ω‐Conotoxin GVIA (3×10^?10– 3×10^?8 M) did not alter the spontaneous ³H‐outflow. ω‐Conotoxin GVIA (3×10^?10– 3×10^?8 M) caused a slowly developing reduction of stimulation‐evoked ³H‐overflow at 1 and 30 Hz. The Emax for the ω‐conotoxin‐induced inhibition was less (70%) at 30 Hz than that (96%) seen at 1 Hz. Short‐term incubation with ω‐conotoxin GVIA caused a subsequent steady‐state inhibition. The inhibitory action of ω‐conotoxin GVIA (3×10^?10– 3×10^?9 M) was inversely related to the extracellular Ca²⁺ concentration (6.5×10^?4– 2.7×10^?3 M). Cocaine (3×10^?5 M) plus corticosterone (4×10^?5 M), neuronal and extraneuronal uptake inhibitors, respectively, did not alter the inhibitory effect of ω‐conotoxin GVIA (3×10^?9 M) on ³H‐overflow evoked by stimulation at a frequency of either 1 or 30 Hz. It is concluded that ω‐conotoxin GVIA acts on prejunctional N‐type calcium channels to inhibit stimulation‐evoked noradrenaline release from sympathetic neurone terminals in rabbit aorta. At a high frequency, another subtype calcium channel may possibly be involved. The action of ω‐conotoxin GVIA is independent of neuronal and extraneuronal uptake mechanisms for noradrenaline, but dependent on the amount of Ca²⁺ to be transported across the neurilemma from the extracellular space into the neurone.     

Modulation of Noradrenaline Release in Human Cardiovascular Tissues*

Abstract: 2,6‐Dichlorophenyl methylsulphone (2,6‐diClPh‐MeSO₂) induces persistent olfactory mucosal metaplasia and a strong glial fibrillary acidic protein increase in the olfactory bulb of mice. Furthermore, 2,6‐diClPh‐MeSO₂ gives rise to a long‐lasting hyperactivity along with an impaired radial arm maze performance. To study cause‐effect relationships, olfactory mucosal histopathology, glial fibrillary acidic protein induction and neurobehavioural deficits were re‐examined in mice and rats of both sexes given a single intraperitoneal dose of 2,6‐diClPh‐MeSO₂ (16 and 65 mg/kg). There was a clear difference in the character of the olfactory mucosal lesions in the two species. In mice, an extensive metaplasia characterised by severe fibrosis, cartilage and bone formation accompanied with large polyps filling the nasal lumen was confirmed. In rats, a dose‐dependent weak metaplasia with patchy loss of olfactory epithelium was observed three weeks after dosing, preferentially at the dorsal meatus, nasal septum, and the tips of the middle ethmoturbinates. Large areas of intact olfactory epithelium remained in all animals, particularly in the low dose rats. In both species, 2,6‐diClPh‐MeSO₂ gave rise to significantly increased motor‐activities, impaired performance in the radial arm maze, and glial fibrillary acidic protein‐induction. Only rats showed hyperactivity at the low dose. Performance in the Morris water maze was unaffected in rats of both sexes indicating that a general impairment in spatial learning could not be supported. We propose that the observed hyperactivity and radial arm maze acquisition deficits originated from a direct effect of 2,6‐diClPh‐MeSO₂ in the brain rather than being a consequence of the olfactory mucosal lesion.     

Release of 3H-5-Hydroxytryptamine from Isolated Rabbit Aorta

Abstract: The main aim of the present investigation was to study systematically the passive and stimulation-evoked release of ³H-5-hydroxytryptamine (³H-5-HT) from rabbit isolated aorta. This was accomplished by preloading rings of aorta with ³H-5-HT (10^–6M) and then monitoring by fractional collection the basal ³H-outflow and stimulation-evoked ³H-overflow. The basal ³H-outflow from aorta preloaded with 10^–6M of either ³H-5-HT or (-)-³H-noradrenaline (³H-NA) leveled off about 100 min. after the onset of wash-out and remained almost constant thereafter (100–240 min.). The basal ³H-outflow from tissue preloaded with ³H-5-HT was almost 3-fold higher (70–240 min.) than that seen after preloading with ³H-NA. Cocaine (3x10^–5M) did not alter the basal ³H-outflow (15–240 min.) from tissue preloaded with ³H-5-HT, while pargyline (5X10^–4M) decreased it by about 66% (100–240 min.). Electrical-field stimulation (S₁S₇, 200 mA, 600 pulses, 0.5 msec, 3 Hz) were applied to the tissue. The initial stimulation-evoked ₃H-overflow from aorta preloaded with ³H-5-HT was higher than the subsequent ones (S₁-S₇: 100, 35, 35, 35, 35, 37, and 40%). Similar results to these were obtained with tissues preloaded with ³H-NA. The stimulation (S₁-S₇; 200 mA; 600 pulses, 0.5 msec, 3 Hz)-evoked ³H-overflow increased in an apparent linear manner with the amount of current used (50–200 mA). This was also the case for number of pulses (100–900) in the stimulus. The stimulation-evoked ³H-overflow depended in part on the stimulation frequency: unchanged at 2–4 Hz; small increase at 8 Hz; and a 15-fold increase at 16 Hz relative to 2 Hz. Tetrodotoxin (10^–6M) decreased the stimulation-evoked ³H-overflow from aorta preloaded with ³H-5-HT (S₂-S₆) by about 60%, while S₁ was not affected. The inhibitory effect of tetrodotoxin was fully reversed by washing the aorta with drug-free salt solution. Omission of Ca²⁺ from the salt solution reduced the stimulation ³H-overflow by 47–57% (S₂-S₆) while S₁ was unaffected. 6-Hydroxydopamine markedly increased the stimulation-evoked ³H-overflow from ³H-5-HT preloaded rings (180–323% of control). Pargyline (5x10^–4M), cocaine (3x10^–5M) and removal of endothelium did not alter the stimulation-evoked ³H-overflow evoked by stimulation (S₁-S₆) of aorta preloaded with ³H-5-HT. It is concluded that ³H-5-HT can be released by electrical-field stimulation as a “false transmitter'’from rabbit isolated aorta. Most of the release is probably of neuronal origin. However, some of the stimulation-evoked ³H-overflow is derived from extraneuronal sites.     

Multiple Muscarinic Receptor Subtypes Mediating Pulmonary Oedema in the Rabbit

Summary: The effects of various muscarinic antagonists on acetylcholine (ACh)-induced pulmonary oedema were studied in isolated perfused rabbit lungs. ACh induced a dose-dependent increase in the capillary filtration coefficient (Kf,c). This effect has been previously related to the activation of the capsaicin-sensitive nerve fibres and the release of substance P. Atropine, pirenzepine (M₁-selective antagonist) and 4-DAMP (M₃-selective antagonist) altered this response, producing a dose-dependent shift to the right of the ACh concentration-Kf,c response curve. By contrast, the M₂-selective antagonist AFDX-116 shifted the ACh concentration-response curve to the left. Atropine, pirenzepine and 4-DAMP also significantly reduced the capsaicin-induced increase in the Kf,c, while AFDX-116 enhanced it. We conclude that multiple muscarinic receptor subtypes are present in the rabbit lung, located on the C-fibres, and are involved in the ACh-induced pulmonary oedema. M₁ and M₃ receptors seem to stimulate the release of neuropeptides from C-fibres, whereas M₂ receptors have an inhibitory effect on these fibres.     

Muscarinic Receptor Density in the Rat Urinary Bladder after Denervation,Hypertrophy and Urinary Diversion *

Abstract: Parasympathetic denervation of the urinary bladder results in supersensitivity to muscarinic agonists and in bladder hypertrophy. In the present study, the effects of denervation on the muscarinic receptors in the rat bladder were investigated, using a receptor binding technique with (-)³H-QNB as radioligand. The density of muscarinic receptors was increased in denervated, hypertrophied bladders but it was decreased, below that in control bladders, when the development of hypertrophy was prevented by urinary diversion. A decreased receptor density was also found in innervated bladders after urinary diversion, whereas the receptor density was unaffected by hypertrophy alone. Competition experiments with methacholine revealed no changes in the agonist binding properties of the receptors. When the present data are combined with those in previous functional studies, it seems unlikely that the muscarinic receptors in the bladder are involved in the development of supersensitivity. It is suggested that the density of muscarinic receptors in the bladder may be related to the bladder function.     

益母草水提液对兔胸主动脉条收缩反应的影响

目的研究益母草水提液(WELLS)对血管平滑肌收缩反应的影响。方法以体外兔胸主动脉条为标本，观察不同浓度WELLS对去甲 肾上腺素(NE)、氯化钾(KCl)和氯化钙(CaCl2)量效曲线的影响。结果对于NE ，25 mg·mL 1WELLS为激动剂，可使NE最大反应增加(6± 4)% ，50和75 mg·mL 1 WELLS为部分激动剂；对于KCl，25 mg·mL 1WELLS为部分激动剂；对于CaCl2，50 mg·mL 1WELL为部分激动 剂。结论WELLS对血管平滑肌的收缩反应与浓度有关，高浓度时可能主要阻滞电压依赖性钙通道，而低浓度时可能主要激动受体调控 性钙通道。     

Pilocarpine Treatments Differentially Affect α2-Adrenoceptors which Modulate the Firing Rate of Locus coeruleus Neurones and the Synthesis and Release of Noradrenaline in Rat Brain

Abstract: We have investigated the effect of treatments with the muscarinic acetylcholine receptor agonist, pilocarpine, on the sensitivity of central α₂-adrenoceptors that regulate the firing activity of rat locus coeruleus, the tyrosine hydroxylase activity in the rat cortex, hippocampus and hypothalamus, and the K⁺-evoked release of [³H]noradrenaline from rat cortical and hippocampal synaptosomes. Short-term (4 days), but not acute, treatment with pilocarpine caused a small but statistically significant increase in the inhibitory effect of the α₂-adrenoceptor agonist clonidine on the firing rate of locus coeruleus neurones, with a decrease in the ED₅₀ of 29% (P<0.001). However, no change in the effect of clonidine on the locus coeruleus was observed after longer pilocarpine (11 days) treatment. In the rat cerebral cortex, but not in hippocampus or hypothalamus, chronic (19 days) treatment with pilocarpine caused a decrease in the inhibitory effect of clonidine on tyrosine hydroxylase activity (55%, P<0.05), but did not change the stimulatory effect of the α₂-adrenoceptor antagonist idazoxan. Moreover, treatments (4, 11 and 19 days) with pilocarpine did not alter the inhibitory effect of clonidine [10^?8-10^?5 M] on the K⁺-evoked release of [³H]noradrenaline from rat cortical and hippocampal synaptosomes. These results indicate that administration of pilocarpine slightly potentiates some but not all the functional responses mediated by brain presynaptic α₂-adrenoceptors. In conclusion, these results do not support the hypothesis that chronic treatments with pilocarpine lead to a suitable model of α₂-adrenoceptor supersensitivity.     

Modulation of Venlafaxine Hydrochloride Release from Press Coated Matrix Tablet

The aim of present study was to prepare novel modified release press coated tablets of venlafaxine hydrochloride. Hydroxypropylmethylcellulose K4M and hydroxypropylmethylcellulose K100M were used as release modifier in core and coat, respectively. A 3² full factorial design was adopted in the optimization study. The drug to polymer ratio in core and coat were chosen as independent variables. The drug release in the first hour and drug release rate between 1 and 12 h were chosen as dependent variables. The tablets were characterized for dimension analysis, crushing strength, friability and in vitro drug release. A check point batch, containing 1:2.6 and 1:5.4 drug to polymer in core and coat respectively, was prepared. The tablets of check point batch were subjected to in vitro drug release in dissolution media with pH 5, 7.2 and distilled water. The kinetics of drug release was best explained by Korsmeyer and Peppas model (anomalous non-Fickian diffusion). The systematic formulation approach enabled us to develop modified release venlafaxine hydrochloride tablets.     

Rabbit Aorta GlutathioneS-Transferases and Their Role in Bioactivation of Trinitroglycerin

The pharmacological action of glyceryl trinitrate (GTN), a widely used drug for the treatment of angina pectoris, is thought to be mediated through release of nitric oxide (NO) during its biotransformation. Since glutathioneS-transferases (GST) can utilize GTN as substrate and GST inhibitors can attenuate GTN-induced relaxation of rabbit aortain vitroit has been suggested that these enzymes are involved in the bioactivation of GTN in rabbit aorta. Because GSTs are multifunctional enzymes and a multitude of GST isozymes with varying substrate preferences are present in mammalian tissues, the role of specific GST isozymes in bioactivation of GTN in rabbit aorta needs to be established. Therefore, during the present studies we have purified and characterized GST isozymes from rabbit aorta and evaluated their possible roles in the biotransformation of GTN. The results of these studies showed that rabbit aorta contained three GST isozymes having pI values of 9.4, 7.7, and 5.4. Structural, immunological, and kinetic studies showed that GST 9.4, GST 7.7, and GST 5.4 belonged to the α-, π-, and μ-classes, respectively. The relative abundance of these enzymes in rabbit aorta was α > π > μ. The α- and μ-class GST isozymes had similar activities toward GTN (0.71 U/mg and 0.86 U/mg, respectively) while the π-class GST showed much lower activity toward GTN. The catalytic efficiencyk_cat/K_mof the μ- and α-class GSTs toward GTN were similar but these activities were differentially inhibited by ethacrynic acid, its GSH conjugate, bromosulfophthalein (BSP), and hematin. These results suggest that in rabbit aorta GSTs may be involved in bioactivation of GTN, and because of their higher abundance the α-class GSTs may be more important for the pharmacological effects of GTN than the μ-class GSTs. The results on kinetics of inhibition by various inhibitors suggest that hematin may be an effective inhibitor to delineate the role of specific GST isozymes in the bioactivation of GTN.     

Cold-storage of Rabbit Thoracic Aorta in University of Wisconsin Solution Reduces Endothelium-independent Vasodilation

Optimum preservation conditions for storage of donor livers and blood vessels are essential for successful transplantation. The blood vessels are used as vascular conduits to facilitate anastomosis of the liver to the recipient's systemic vasculature. Failure of some transplants has been ascribed to thrombosis of these vascular conduits possibly because of alterations in vascular reactivity owing to inadequate storage techniques. To restrict data variability previously associated with studies using a heterogeneous sample of vessels from man, this study investigated changes in vascular reactivity in segments of rabbit thoracic aorta from male, age-matched, New Zealand White rabbits stored at 4°C in either University of Wisconsin solution (UW; Du Pont Pharmaceuticals, UK) or Krebs-Bülbring buffer (KB). Percent vasodilation to acetylcholine remained significantly greater in UW than in KB at –log (m ) concentrations of 70 (UW = 47.05 ± 4.26 compared with KB = 13.20 ± 7.20%; P < 0.001), 6.5 (UW = 66.82 ± 4.83 compared with KB = 26.60 ± 9.48%; P < 0.01), and 60 (UW = 83.68 ± 5.26 compared with KB = 31.20 ± 9.83%; P < 0.001). This was not significantly different to relaxation in unstored arteries and suggested improved endothelial function and structure, confirmed by electron microscopy. Percent vasodilation to sodium nitroprusside was significantly lower in UW than in unstored (D₀) arteries at –log (M) concentrations of 7.5 (D₀ = 28.27 ± 4.02 compared with UW = 15.21 ± 1.82%; P < 0.01), 7.3 (D₀ = 52.58 ± 5.05 compared with UW = 29.23 ± 1.94%; P < 001), 70 (D₀ = 69.70 ± 4.85 compared with UW = 49.72 ± 2.49%; P < 005), and 6.4 (D₀ = 93.16 ± 2.93 compared with UW = 71.29 ± 5.20%; P < 0.05). Percent vasodilation was also lower in UW- compared with KB-stored arteries at –log (m ) sodium nitroprusside concentrations of 7.0 (UW = 49.72 ± 2.49 compared with KB = 64.11 ±5.03%; P < 0.05) and 6.4 (UW = 71.29 ± 5.20 compared with KB = 96.91 ± 5.96; P < 0.05). Electron microscopy confirmed that this was not a result of degradation of smooth muscle structure. The nitric oxide synthase inhibitor l -N^G-nitro-l -arginine methyl ester (100 μm ) did not significantly modulate sodium nitroprusside-induced vasodilation in unstored arteries, when endothelial function was maximum, or in UW-stored arteries, suggesting that the reduced responses in UW-stored arteries were not because of increased synthesis of nitric oxide. This reduced relaxation to sodium nitroprusside was therefore nitric oxide-independent and not a result of competition between sodium nitroprusside and endothelial ‘nitric oxide donation’ for cGMP. In summary, cold-storage preservation with UW reduced endothelium-independent vascular relaxation by mechanisms other than competition with NO; this requires further evaluation.     

Effects of NIK-247 and Tacrine on Muscarinic Receptor Subtypes in Rats

• 1.The purpose of this study was to compare the effect of NIK-247 on muscarinic receptor subtypes with that of tacrine (THA) in rats.
• 2.NIK-247 and tacrine dose dependently inhibited the binding of [³H]pirenzepine (M₁), [³H]AF-DX 384 (M₂), and [³H]4-DAMP (M₃). The IC₅₀ values for NIK-247 were 4.4×10⁻⁶ M, 1.1×10⁻⁵ M, and 1.5×10⁻⁵ M, respectively, whereas those for tacrine were 5.8×10⁻⁷ M, 2.0×10⁻⁶ M, and 5.8×10⁻⁶ M, respectively.
• 3.Gpp[NH]p, a GTP analogue, slightly shifted the curve of displacement of [³H]AF-DX 384 binding for NIK-247 to the right. However, Gpp[NH]p did not shift the curve of displacement of [³H]pirenzepine and [³H]4-DAMP binding to the right.
• 4.NIK-247 moderately decreased the rate of beating in right atrial preparations, but did not decrease it below 50% of control level.
• 5.These findings indicate that NIK-247 is an M₁ antagonist, M₂ partial agonist, and M₃ antagonist.

     

Role of Cyclic AMP in Stimulation-Evoked Release of 3H-Noradrenaline from Rabbit Isolated Ear Artery

Abstract: The possible involvement of cyclic AMP in the stimulation-evoked ³H-overflow from rabbit isolated ear artery preloaded with ³H-noradrenaline was studied. Cyclic AMP (10^–5–3x10^–4M), 8–bromo-cyclic AMP (3x10^–4M) and adenosine (10^–5–3X10^–4M) enhanced stimulation-evoked ³H-overflow. Dibutyryl-cyclic AMP (10^–5–3x10^–4M) had no effect. Theophylline (3X10^–5M) and the phosphodiesterase inhibitor AH 21–132 (3X10^–5M) did not alter the enhancement of ³H-overflow caused by either cyclic AMP or adenosine. Forskolin (3X10^–6M) and the phosphodiesterase inhibitors ICI 63 197 (10^–4M) and AH 21–132 (3x10^–6–3x10^–5M) increased stimulation-evoked ³H-overflow. Forskolin (10^–6M) enhanced the effect of ICI 63 197 (3x10^–5M) but it did not alter the effect of AH 21–132. It is concluded that cyclic AMP is involved in the stimulation-evoked release of noradrenaline from postganglionic sympathetic nerves in the rabbit ear artery.     

Effect of Dopexamine Hydrochloride on Sympathetic Neuroeffector Transmission in Rabbit Isolated Pulmonary Artery

Abstract: The effects of dopexamine hydrochloride on sympathetic neuroeffector transmission were studied in rabbit isolated pulmonary artery. Short-term exposure of dopexamine (10-⁸x10^-7 M) and cocaine (10^-6-3x10^-5 M), but not desipramine (3x10^-9-3x10^-7 M), to the artery enhanced the contractions evoked by electrical-field stimulation. Corticosterone (4x10^-5 M), corticosterone (4x10^-5 M) plus cocaine (3x10^-8 M), but not cocaine (3x10^-5 M), attenuated the enhancement seen with dopexamine. High concentrations of dopexamine (10^-5-3x10^-5 M), cocaine (10^-4 M), and desipramine (10^-6-10^-5M) decreased the stimulation-evoked contractions. Dopexamine (10^-7-3x10^-5 M), but neither cocaine nor desipramine, caused an increase in resting tension that waned with time. Corticosterone (4x10^-5 M), but not cocaine (3x10^-5 M), attenuated the increase in resting tension. Propranolol (10^-6 M) did not alter the enhancing and inhibitory effects of dopexamine. A single concentration (10^-7 and 10^-6 M) of either dopexamine or desipramine caused a time-dependent biphasic response as regards the repetitive stimulation-evoked contractions of pulmonary artery: initial enhancement followed by inhibition. The inhibitory effect of dopexamine (10^-6 M) and desipramine (3x10^-6 M) seen after prolonged exposure was almost irreversible and partially reversible, respectively, by washing the preparations with drug-free salt solution. Cocaine caused a monophasic steady-state response: either enhancement (10^-5 M) or inhibition (2x10^-4 M). In both cases, the onset was rapid. The reduction caused by cocaine (2x10^-4 M) and by prazosin (10^-9 M) was fully reversed. Dopexamine (10^-5 M) antagonized competitively the contractions evoked by noradrenaline (3x10^-9-10^-4 M). It is concluded that (1) the dopexamine-induced enhancement of neurogenic contractions is not due to either inhibition of neuronal and extraneuronal uptake of noradrenaline or an agonist action on prejunctional β₂-adrenoceptors; (2) that the dopexamine-induced inhibition of stimulation-evoked contraction is due to an inhibition of postjunctional α₁-adrenoceptors; and (3) that the dopexamine-induced increase in resting tension is due to its metabolite methyldopexamine.     

Inhibition by (−)-Deprenyl of Agonist-Evoked Contractions in Rabbit Aorta

Abstract: The effect of (?)-deprenyl, a relatively selective MAO-B inhibitor, was examined for its ability to inhibit the contractions of rabbit isolated aorta evoked by various agonists and potassium. (?)-Deprenyl (10^?5?3 × 10^?4 M) antagonized the contractions evoked by noradrenaline (10^?8?3 × 10^?4 M); pA₂: 5.10. The antagonism was reversible. It was attenuated by cocaine (3x M); pA₂: 4.38, unchanged by corticosterone (4 × 10^?5 M); pA₂ 4.79 and enhanced by cocaine (3 × 10^?5 M) plus corticosterone (4 × 10^?5 M); pA₂: 5.48. (+)-Deprenyl (10^?6?10^?4 M) did not alter the contractions evoked by noradrenaline (3 × 10^?9?10^?4 M). Clorgyline (10^?5 and 10^?4 M) antagonized the noradrenaline-evoked contractions. Pargyline (10^?4 and 3 × 10^?4 M) had no effect. (?)-Deprenyl (10^?5?3 × 10^?4 M) antagonized the contractions evoked by phenylephrine (10^?8?10^?4 M); pA₂: 5.10. Removal of the endothelium did not alter the antagonism; pA₂: 5.35. (?)-Deprenyl (10^?5?3 × 10^?4 M) antagonized the contractions evoked by either 5-hydroxytryptamine (3 × 10^?8?3 × 10^?4 M); pA₂: 4.61 or by histamine (10^?6?3 × 10^?2 M); pA₂: 4.84. (?)-Deprenyl (3 × 10^?4 M) caused a non-competitive antagonism of the contractions evoked by potassium (1.5-5.5 × 10^?2 M). It is concluded that (?)-deprenyl is a weak inhibitor of postjunctional α-adrenoceptors, 5-hydroxytryptamine (5-HT₂) receptors, and histamine (H₁) receptors.     

Inhibition by Diphenylhydantoin of Vasopressin Release from Isolated Rat Neurohypophyses*

Abstract: Diphenylhydantoin (40 μg/ml) inhibited vasopressin release from isolated hemilobes of rat neurohypophyses, both during resting conditions and after electrical stimulation.