巴马汀的α肾上腺素受体阻断作用

用大鼠肛尾肌、兔主动脉和门静脉条观察巴马汀(Pal)的α_1受体阻断作用,用大鼠输精管观察其α_2受体阻断作用。在前三种标本中,Pal的pA_2值分别为5.8,5.9,5.3;在大鼠输精管中,其pA_2值为5.1。Pal能分别降低[~3H]Pra及[~3H]CLN与大鼠脑细胞膜α_1及α_2受体的特异性结合量,竞争抑制常数K_I分别为4.53μM及2.0μM。提示Pal能竞争性阻断α_1和α_2的受体。     

苄基四氢巴马汀对α受体的作用

本实验表明苄基四氢巴马汀(BTHP)具有阻断α-肾上腺素受体的作用。它能竞争性拮抗苯肾上腺素所致大鼠肛尾肌和兔主动脉条的收缩反应,其pA_2值分别为5.86和5.8;也能浓度依赖性地使可乐定和B-HT920的量效曲线平行右移,最大反应不变,其pA_2值分别为5.2和5.3。放射配基结合测定表明,BTHP对α_1和α_2受体均有亲和力,其竞争抑制常数(K_i)分别为3.52μmol/L和8.1μmol/L。     

Different subtypes of alpha 1A-adrenoceptor mediating contraction of rat epididymal vas deferens, rat hepatic portal vein and human prostate distinguished by the antagonist RS 17053.

1. The alpha 1-adrenoceptor subtype mediating contraction of the rat hepatic portal vein to phenylephrine was characterized by use of competitive antagonists previously shown to have selectivity between the expressed alpha 1-subtype clones. Prazosin competitively antagonized the phenylephrine contractions with a pA2 value of 9.2, as did WB 4101 (pA2 9.4), 5-methyl urapidil (pA2 8.6), indoramin (pA2 8.4) and BMY 7378 (pA2 6.5). 2. The pA2 values on the rat portal vein correlated highly with their previously published pA2 values for the alpha 1A-adrenoceptors mediating contraction of the rat epididymal vas deferens and human prostate and poorly with those for the alpha 1B- and alpha 1D-adrenoceptors mediating contraction of the rat spleen and aorta, respectively. The antagonist pA2 values on the rat portal vein correlated highly with their previously published pK1 values for the expressed alpha 1a-clone and poorly with those for the expressed alpha 1b- and alpha 1d-clones. Therefore the results show that contraction of the rat portal vein to phenylephrine is mediated by alpha 1A-adrenoceptors. 3. The novel alpha 1-adrenoceptor antagonist RS 17053 had a relatively high affinity for the alpha 1A-adrenoceptors mediating contraction of the rat epididymal vas deferens (pA2 9.5) compared with the alpha 1B-adrenoceptors in the rat spleen (pA2 7.2) or the alpha 1D-adrenoceptors in the rat aorta (pKB 7.1), in agreement with its selectivity for the expressed alpha 1a-clone. However, RS 17053 had over 100 fold lower affinity for the alpha 1A-adrenoceptors mediating contraction of the rat portal vein (pKB 7.1) and human prostate (pKB 7.1) compared with its affinity for the alpha 1A-adrenoceptors in the rat epididymal vas deferens or the expressed alpha 1a-clone. 4. The difference in affinity of RS 17053 between the rat epididymal vas deferens and rat portal vein cannot be explained by a species difference in the receptor. Therefore RS 17053 may distinguish between subtypes of the alpha 1A-adrenoceptor in the rat portal vein and human prostate compared with those in the rat epididymal vas deferens or the expressed alpha 1a-clone.     

Effects of St-587 on the alpha-adrenoceptors in the bisected rat vas deferens

The effects of the alpha-adrenoceptor agonist St-587 have been studied on the twitch responses induced by field stimulation in the prostatic portion of rat vas deferens. Moreover the drug's influence on the unstimulated prostatic and epididymal halves of rat vas deferens has also been determined. Alone and after addition of yohimbine (0.3 microM) it enhanced in a concentration-dependent manner the twitch responses in the prostatic half. Prazosin competitively antagonized (pA2 = 8.41 +/- 0.03) this effect. The enhancing effect of St-587 was not reduced in reserpinized animals. These results suggest that post-synaptic alpha 1-adrenoceptors are involved in the potentiation of twitch responses induced by St-587. When alpha 1-adrenoceptors were blocked by prazosin (0.1 microM), St-587 partially inhibited the twitch responses of the prostatic portion of rat vas deferens (Emax = 49.5 +/- 3.5%). Yohimbine completely reversed the inhibitory effects of both St-587 and clonidine. Furthermore St-587 antagonized the inhibitory effects of clonidine on twitch responses. Thus it appears that St-587 also behaves as a partial agonist of presynaptic alpha 2-adrenoceptors in this portion of rat vas deferens, but it did not induce contractions in the unstimulated prostatic half of the vas deferens. However, it competitively antagonized the alpha 1-adrenoceptor agonist phenylephrine by acting as an antagonist of prostatic postsynaptic alpha 1 adrenoceptors. These alpha 1-adrenoceptors are probably different from those that mediate the twitch enhancing response to St-587 in that portion. On the other hand, St-587 was a partial agonist of alpha 1-adrenoceptors in the epididymal half.(ABSTRACT TRUNCATED AT 250 WORDS)     

4种异喹啉类衍生物对α-肾上腺素受体的阻断作用

4种异喹啉类化合物(Isoquinoline derivative IQ_(85029),Q_(85030),IQ_(86034),IQ_(86035)的抗α_1及α_2肾上腺素受体的作用在大鼠肛尾肌及输精管标本上进行了比较,在肛尾肌标本上,IQ_(86034)抗α_1受体的作用最强(pA_2=6.5),IQ_(85030)最弱(pA_2=5.1),而IQ_(85020)及IQ_(86035)的效价强度相近(pA_2=6.0～6.1)。在输精管前列腺端,它们拮抗α_2受体的效价强度依次为IQ_(86035)(pA_2=6.75)>IQ_(85030)(6.69)>IQ_(85029)(6.34)>IQ_(86034)(5.3)。     

Studies on RX 781094: a selective, potent and specific antagonist of alpha 2-adrenoceptors.

1 The selectivity and specificity of RX 781094 [2-(2-(1,4 benzodioxanyl))2-imidazoline HCl] for alpha-adrenoceptors have been examined in peripheral tissues. 2 In isolated tissue experiments RX 781094 was a competitive antagonist at prejunctional alpha 2-adrenoceptors situated on the sympathetic nerve terminals of the rat (pA2 = 8.56) and mouse (pA2 = 7.93) vas deferens and on the parasympathetic nerve terminals of the guinea-pig ileum (pA2 = 8.55). 3 Although RX 781094 was also a competitive antagonist at the postjunctional alpha 1-adrenoceptors of the rat anococcygeus muscle (pA2 = 6.10) its affinity for these receptors was markedly less than that displayed for prejunctional sites. From pA2 values obtained in the rat vas deferens and anococcygeus muscle the calculated alpha 2/alpha 1-adrenoceptor selectivity ratio for RX 781094 was 288. 4 The rank order of alpha 2/alpha 1-adrenoceptor selectivities for the antagonists studied was RX 781094 greater than RS 21361 greater than yohimbine greater than piperoxan greater than phentolamine greater than WB 4101 greater than prazosin. 5 RX 781094 had extremely low affinity for beta-adrenoceptors, histamine receptors, cholinoceptors, 5-hydroxytryptamine and opiate receptors in vitro. 6 In pithed rats, intravenous administration of RX 781094 antagonized the prejunctional alpha 2-adrenoceptor agonist effects of clonidine and guanabenz on electrically-induced contractions of the vas deferens and anococcygeus muscle respectively. 7 In the vas deferens the rank order of alpha 2-adrenoceptor antagonist potencies was RX 781094 greater than phentolamine greater than piperoxan greater than yohimbine greater than RS 21361 greater than WB 4101. Only RX 781094, yohimbine and RS 21361 were active against guanabenz in the anococcygeus muscle. 8 In the pithed rat, RX 781094 preferentially antagonized the pressor responses evoked by postjunctional alpha 2-adrenoceptor activation by UK 14,304 although higher doses also inhibited the effects of phenylephrine and cirazoline at postjunctional alpha 1-adrenoceptors. 9 RX 781094 had little effect on the cardiovascular responses to 5-hydroxytryptramine, angiotensin II, histamine, acetylcholine and isoprenaline in pithed rats and rats anaesthetized with pentobarbitone. 10 These results demonstrate that RX 781094 is a potent and selective alpha 2-adrenoceptor antagonist with a high degree of specificity for these receptors.     

1-(α-萘甲基)2-甲基-6,7-二甲氧基-四氢异喹啉对大鼠α-肾上腺素受体的阻断作用

1—(α—萘甲基)2—甲基—6,7—二甲氧基—四氢异喹啉;;α—肾上腺素受体;;肛尾肌输精管     

Study of the mechanism of the relaxant action of (+)-glaucine in rat vas deferens.

1. Effects of the aporphinoid alkaloid, (+)-glaucine, on rat vas deferens were investigated. 2. (+)-Glaucine (2-18 microM) competitively inhibited contractions induced by noradrenaline and methoxamine with a pA2 value of about 6. 3. (+)-Glaucine (2 and 18 microM) did not change the accumulation of tritium during incubation of the vas deferens with [3H]-noradrenaline. 4. (+)-Glaucine (0.3 nM-0.1 mM) inhibited specific [3H]-prazosin binding to membranes from rat vas deferens with a pKi value of 6.63, which is close to the pA2 value obtained against noradrenaline and methoxamine in functional studies. 5. In electrically-stimulated rat vas deferens, (+)-glaucine (0.3-10 microM) enhanced twitch contractions and competitively antagonized the inhibitory effect of clonidine with a pA2 value of 5.91. 6. In tissues incubated in depolarizing calcium-free high-potassium medium, (+)-glaucine (30-80 microM) inhibited Ca(2+)-induced contractions with depression of the maximal response at higher doses and with a pD'2 value of 3.65. Furthermore, (+)-glaucine (50 microM) did not modify basal 45Ca uptake but strongly inhibited the influx of 45Ca induced by K+. 7. These results suggest that (+)-glaucine has non-selective alpha 1- and alpha 2-adrenoceptor blocking properties. At higher doses, (+)-glaucine shows calcium antagonist activity which may be responsible, at least in part, for the inhibition of the contractions induced by Ca2+ in calcium-free high-potassium medium.     

Effects of raubasine stereoisomers on pre- and postsynaptic alpha-adrenoceptors in the rat vas deferens.

The actions of raubasine, tetrahydroalstonine and akuammigine were studied on pre- and postsynaptic alpha-adrenoceptors of the rat vas deferens. These three drugs competitively antagonized the effect of noradrenaline on postsynaptic alpha-adrenoceptors, yielding pA2 values of 6.57, 4.56 and 4.68 respectively. The presynaptic alpha-adrenoceptor antagonist activity of the drugs was quantitatively determined by studying the effect of increasing concentrations on the clonidine dose-response curve in the electrically stimulated vas deferens. The inhibitory effect of clonidine could be competitively blocked by these three compounds and the pA2 values for raubasine, tetrahydroalstonine and akuammigine were 6.02, 7.71 and 5.64 respectively. These results indicate that: akuammigine is a very weak antagonist at pre- and postsynaptic sites; raubasine acts preferentially at postsynaptic sites; tetrahydroalstonine is a highly selective presynaptic alpha-adrenoceptor blocking agent. The ratio of the pre/postsynaptic potency declines in the order tetrahydroalstonine greater than akuammigine greater than raubasine.     

Occupancy of alpha 1-adrenergic receptors and contraction of rat vas deferens

The interaction of agonists and antagonists with alpha 1-adrenergic receptors in rat vas deferens was examined using radioligand binding assays and contractility measurements. 125I-Labeled BE 2254 (125IBE) was found to bind rapidly and reversibly to a single class of high-affinity binding sites in homogenates of rat vas deferens. The k1 for association was 3.8 X 10(7) 1/mole-sec, the k-1 for dissociation was 2.3 X 10(-3) sec-1, and the KD was 105 pM. The order of potency for antagonists inhibiting 125IBE binding was prazosin greater than indoramin greater than phentolamine greater than yohimbine. Norepinephrine, phenylephrine, and other alpha-adrenergic agonists produced dose-dependent contractions of whole vas deferens in vitro. This contractile response was competitively inhibited by alpha-adrenergic blocking drugs with the same potency order observed for inhibition of specific 125IBE binding. Comparison of pA2 values for alpha 1- and alpha 2-selective antagonists competitively inhibiting contractile responses to norepinephrine, epinephrine, or phenylephrine suggested that these drugs caused their contractile effects solely through alpha 1-adrenergic receptors, and that there were no alpha 2-adrenergic receptors mediating contraction in this tissue. The pA2 values for antagonist inhibition of alpha-adrenergic receptor-mediated contractile responses were highly correlated (r = 0.995) with the KD values for antagonist inhibition of 125IBE binding in this tissue. The EC50 values for partial agonists were also highly correlated with the KD values for inhibition of 125IBE binding in vas deferens. However, the EC50 values of full agonists in causing contraction were in general 10- to 100-fold lower than the KD values for inhibiting 125IBE binding, possibly representing a substantial "spare receptor" population in this tissue. The results suggest that rat vas deferens contains a homogeneous population of alpha 1-adrenergic receptors mediating the contractile response to norepinephrine, that these receptors can be directly labeled with 125IBE, and that there may be a nonlinear relationship between agonist occupancy of alpha 1-adrenergic receptors and the functional response of this tissue.