Prostaglandin I2 and thromboxane A2production in relation to α1 and α2-adrenoreceptor activation in the normotensive and hypertensive rat

1 The perfused mesenteric arterial bed (MAB) from normotensive (WKY) and hypertensive (SHR) rats was used as a model to investigate the relationship between α₁ and α₂-adrenoreceptor activation and prostanoid release. 2 Prostaglandin I₂ (PGI₂) and small amounts of thromboxane A₂ (TXA₂) are released from this preparation and can be monitored in the perfusate under basal and stimulated conditions. 3 Noradrenaline (NA) caused a significant increase in the release of PGI₂ from the MAB of both WKY and SHR. Both basal and NA-stimulated PGI₂ release were lower in the SHR, whereas pressor responses to NA were higher. Noradrenaline caused a very small increase in TXA₂ release in the WKY only and the basal release of this prostanoid was again lower in the SHR. 4 Prazosin, an α₁-selective antagonist (10^?10, 10^?9, 10^?8M) was more effective in blocking pressor responses to NA in the SHR than in the WKY, did not affect the NA-induced release of PGI₂ in either group and abolished the small increase of TXA₂ release in WKY. 5 Rauwolscine, an α₂-selective antagonist (10^?8, 10^?7, 10^?6 M) was more effective in reducing pressor responses to NA in the SHR than in the WKY. It abolished, from 10^?7M upwards, the NA-induced release of PGI₂ in the WKY and reduced it in the SHR. The NA-induced release of TXA₂ was abolished in WKY. 6 The observed differences in the effects of rauwolscine and prazosin do not correlate with the effects of these antagonists on pressor responses since both reduce the latter but only rauwolscine abolishes the stimulated PGI₂ release. 7 These results indicate that in the SHR, the mechanisms mediating the release of PGI₂ from the MAB may be similar but not identical to those in the WKY. The observation that an increase in adrenergically induced pressor responses is not followed by an increase in PGI₂ release, which is in fact reduced in the SHR, suggests a more complex regulation of this relationship which may have pathophysiological implications.     

Arrhythmogenesis in isolated rat hearts with enhanced α‐adrenoceptor‐mediated responsiveness

1 It has been postulated that stimulation of myocardial α‐adrenoceptors is one of the primary mediators of the dysrhythmias which occur during periods of myocardial ischaemia and reperfusion. This study examines arrhythmogenesis during coronary artery occlusion and reperfusion in isolated perfused rat hearts from control animals and from rats with enhanced myocardial α‐adrenoceptor responsiveness. 2 Rats were administered propylthiouracil (PTU) in their drinking water for 8 weeks. This treatment resulted in an enhanced responsiveness of isolated left atria to the α‐adrenoceptor agonist phenylephrine compared with atria from control animals. 3 In Langendorff‐perfused isolated hearts, the spontaneous rate of contraction was significantly lower in the PTU‐pretreated group than in either age‐matched or weight‐matched controls. Occlusion of the left anterior descending artery (LAD) for 25 min resulted in ventricular tachycardia (VT) of similar incidence and duration in all groups and ventricular fibrillation (VF) in both control groups but not the PTU‐pretreated group. 4 Following the 25‐min ischaemic period the myocardium was reperfused for 10 min. The incidence and duration of VT and VF during this period was similar in all groups except that the duration of VF in the PTU‐pretreated group was significantly lower than in controls. 5 In perfused hearts paced at 4 Hz, the incidence and duration of dysrhythmias during ischaemia and reperfusion was again similar in all groups, only the duration of VF being affected (reduced) by PTU‐pretreatment. 6 In conclusion, this study does not lend support to the hypothesis that myocardial α‐adrenoceptors have a primary role in arrhythmogenesis, but the data would support a role for these receptors in myocardial protection.     

Differential blockade of α,β-methylene-ATP,noradrenaline and electrically evoked contractions of the rat vas deferens

1 The present study was carried out compare the effects of nifedipine, verapamil, papaverine and chloroethylclonidine (CEC) on the electrically-induced contractions and on the contractions produced by exogenous noradrenaline and α,β methylene-ATP in the epidydimal portion of rat vas deferens. 2 Nifedipine inhibited in a concentration-dependent fashion the purinergic component (phase I) of the electrically evoked response. Verapamil (10^??7 M?10^??5 M) did not inhibit significantly or even potentiated phase I of the contractile response to single-pulse field stimulation but inhibited the response to α,β methylene-ATP. Papaverine left unaffected phase I but depressed the response to α,β methylene-ATP. CEC significantly potentiated the purinergic component of the electrically-evoked response and the response induced by α,β methylene-ATP. 3 Nifedipine was devoid of any inhibitory action on the noradrenergic component (phase II) of the response to single shock. Verapamil at the highest concentration used (10^??5 M) was able to partially inhibit phase II. Papaverine abolished in a concentration-dependent manner the noradrenergic component of the response to single shock. CEC abolished the phase II of single shock while was devoid of any inhibitory action on exogenous noradrenaline. 4 The implications of these differences among the compounds studied in the present work are discussed in relation to roles of calcium channels.     

The metabolism of 16α-ethylprogesterone by rat liver in vitro

The metabolism of 16α-ethylprogesterone by rat liver homogenate at different steroid to tissue ratios has been examined. The products, identified by thin-layer chromatography, gas-liquid chromatography and combined gas-liquid chromatography-mass spectrometry were 16α-ethyl-5α-pregnane-3, 20-dione and 16α-ethyl-3α-hydroxy-5α-pregnan-20-one. The yield of these metabolites was 14 and 48% respectively. The results are discussed in relation to the liver in vitro metabolism of progesterone and 16α-hydroxyprogesterone.     

The α‐adrenoceptor antagonist,zolertine, inhibits α1D‐ and α1A‐adrenoceptor‐mediated vasoconstriction in vitro

1 The antagonist effect of zolertine (4‐phenyl‐1‐[2‐(5‐tetrazolyl)ethyl]piperazine trihydrochloride), on vascular contraction elicited by noradrenaline in aorta, carotid (α1D‐adrenoceptors), mesenteric (α1A/D‐adrenoceptors) and caudal arteries (α1A‐adrenoceptors) from Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats and rabbit aorta (α1B‐adrenoceptors), was investigated in endothelium‐denuded arterial rings.
2 The selective α1D‐adrenoceptor agonist, noradrenaline, elicited concentration‐dependent contractions in all arterial rings from both species. Noradrenaline selectivity was: carotid=aorta>>.Gt;mesenteric=rabbit aorta>caudal arteries.
3 The contractile responses induced by noradrenaline were competitively antagonized by zolertine in rat carotid and aorta arteries, yielding pA2 values of WKY, 7.48±0.18; SHR, 7.43±0.13 and WKY, 7.57±0.24; SHR, 7.40±0.08, respectively. Zolertine was a non‐competitive antagonist in some blood vessels as Schild plot slopes were lower than unity. The pKb estimates for zolertine were WKY, 6.98±0.16; SHR, 6.81±0.18 in the mesenteric artery, WKY, 5.73±0.11; SHR, 5.87±0.25 in the caudal artery and 6.65±0.09 in rabbit aorta.
4 Competition binding experiments using the α1‐adrenoceptor antagonist [³H]prazosin showed a zolertine pKi of 6.81±0.02 in rat liver (α1B‐adrenoceptors) and 6.35±0.04 in rabbit liver (α1A‐adrenoceptors) membranes.
5 Zolertine showed higher affinity for α1D‐adrenoceptors compared to α1A‐adrenoceptors, while it had an intermediate affinity for α1B‐adrenoceptors. The ability of the α1‐adrenoceptor antagonist zolertine to block α1D‐adrenoceptor‐mediated constriction in different vessels of WKY and SHR rats may explain its antihypertensive efficacy despite its low order of potency.     

No evidence for more than one type of α1-adrenoreceptor in rabbit pulmonary artery

1 The effects of the α-adrenoreceptor antagonists, prazosin and yohimbine, have been examined on the isometric contraction of the rabbit pulmonary artery produced by α₁-adrenoreceptor agonists. Cocaine, corticosterone and propranolol were present throughout and either a single or two concentration-response curve method was used. 2 Prazosin and yohimbine competitively antagonized the responses to agonists but did not reveal differences between agonists. 3 Using the single concentration-response curve method, prazosin had pA₂ values of 9.06 against clonidine and 8.76 against methoxamine. 4 Using the two concentration-response curve method the absolute pA₂ values of prazosin (8.65 against phenylephrine, 8.78 against clonidine) and yohimbine (5.73 against phenylephrine, 5.72 against clonidine), as well as the relative potencies of the two antagonists (prazosin approximately 1000 times more potent than yohimbine), suggest that both agonists act on α₁-adrenoreceptors. 5 There is no evidence from this study to support the suggestion that the rabbit pulmonary artery contains two subtypes of of α₁-adrenoreceptor.     

Agonist function of the recombinant α4β3δ GABAA receptor is dependent on the human and rat variants of the α4‐subunit

1. It is known that the α₄‐subunit is likely to occur in the brain predominantly in α₄β₃δ receptors at extrasynaptic sites. Recent studies have revealed that the α₁‐, α₄‐, γ₂‐ and δ‐subunits may colocalize extrasynaptically in dentate granule cells of the hippocampus. In the present study, we characterized a series of recombinant GABA_A receptors containing human (H) and rat (R) α₁/α₄‐, β₂/β₃‐ and γ_2S/δ‐subunits in Xenopus oocytes using the two‐electrode voltage‐clamp technique. 2. Both Hα₁β₃δ and Hα₄β₃γ_2S receptors were sensitive to activation by GABA and pentobarbital. Contrary to earlier findings that the α₄β₃δ combination was more sensitive to agonist action than the α₄β₃γ_2S receptor, we observed extremely small GABA‐ and pentobarbital‐activated currents at the wild‐type Hα₄β₃δ receptor. However, GABA and pentobarbital activated the wild‐type Rα₄β₃δ receptor with high potency (EC₅₀ = 0.5 ± 0.7 and 294 ± 5 μmol/L, respectively). 3. Substituting the Hα₄ subunit with Rα₄ conferred a significant increase in activation on the GABA and pentobarbital site in terms of reduced EC₅₀ and increased I_max. When the Hα₄ subunit was combined with the Rβ₃ and Rδ subunit in a heteropentameric form, the amplitude of GABA‐ and pentobarbital‐activated currents increased significantly compared with the wild‐type Hα₄β₃δ receptor. 4. Thus, the results indicate that the Rα₄β₃δ, Hα₁β₃δ and Hα₄β₃γ_2S combinations may contribute to functions of extrasynaptic GABA_A receptors. The presence of the Rα₄ subunit at recombinant GABA_A receptors containing the δ‐subunit is a strong determinant of agonist action. The recombinant Hα₄β₃δ receptor is a less sensitive subunit composition in terms of agonist activation.     

α-Alkylmercapto- und α-Arylmercapto-alkylisocyanate

α-Alkylmercapto- and α-Arylmercapto-alkylisocyanates α-Alkylmercapto- and α-arylmercapto-alkylisocyanates 2 were prepared from α-halosulfides 1 by reaction with silver cyanate. With ammonia, primary or secondary amines they give the corresponding α-mercaptoalkyl-ureas 4 ; with alcohols, the α-mercaptoalkylurethans 3.     

Stereoselective binding of β-blockers to purified rat α1-acid glycoprotein

Abstract— The stereoselectivity of binding of four β-blockers, pindolol, propranolol, oxprenolol and acebutolol, to purified rat α₁-acid glycoprotein (AAG) was examined using equilibrium dialysis. Pindolol and propranolol were bound stereoselectively to AAG, whereas binding of oxprenolol was non-stereospecific. Neither of the enantiomers of acebutolol bound to either AAG or any other plasma protein. The affinity of (+)-pindolol was 25 times that of (–)-pindolol, as determined in a single enantiomer experiment. Both enantiomers of propranolol demonstrated two classes of binding sites in AAG, the total binding for the high affinity site for (+)-propranolol being double that of (–)-propranolol, which could explain the higher binding of the (+)-enantiomer in racemate experiments. These results further showed that stereoselective binding to a rat AAG is not a property common to all β-blockers.     

Ventral hippocampal α7 nicotinic receptor blockade and chronic nicotine effects on memory performance in the radial-arm maze

Chronic nicotine administration has been shown to significantly improve working memory. Nicotinic involvement in memory function critically involves the ventral hippocampus. Local ventral hippocampal infusions of the nicotinic antagonists mecamylamine, dihydro-β-erythroidine (DHβE) and methyllycaconitine (MLA) significantly impair working memory. The impairment caused by hippocampal infusion of the α4β2 antagonist DHβE is reversed by chronic systemic nicotine. This study determined the interaction of chronic systemic nicotine with acute ventral hippocampal infusions of the α7 antagonist MLA. Adult female Sprague–Dawley rats were trained on an 8-arm radial maze working memory task. Then they underwent ventral hippocampal cannulation and received sc implants of minipumps delivering nicotine (0 or 5 mg/kg/day for 28 days). Acute ventral hippocampal infusions of MLA (0, 4.88, 14.64 and 43.92 μg/side) were given during 3–4 weeks of chronic nicotine. MLA caused a significant dose-related memory impairment. In the rats not receiving nicotine, the 14.64 and 43.92 μg/side MLA doses caused significant memory impairment. Chronic systemic nicotine exposure did not block the MLA-induced memory impairment. Comparing the current results with MLA with previous results with DHβE, equimolar ventral hippocampal DHβE more effectively impaired memory than MLA, but the DHβE-induced impairment was more effectively reversed by chronic systemic nicotine administration.     

In vivo and in vitro binding of α- and γ-hexachlorocyclohexane to mouse liver macromolecules

α-Hexachlorocyclohexane (α-HCH) but not γ-HCH, produces a strong neoplastic response in HPB strain mouse liver. In vivo and in vitro binding studies with ¹⁴C-labelled HCH isomers showed no preferential binding of the α-HCH isomer to protein or DNA. Moreover, the binding of both isomers to DNA in vivo or in vitro occurred only at very low levels, a result consistent with the lack of mutagenic activity associated with these compounds. The results suggest that the neoplastic response observed with α-HCH results from a non-genotoxic mechanism.