Effects of 1, 4-bis-(3-(3, 4, 5-trimethoxy benzoyl oxy)-propyl) perhydro-1, 4-diazepine (dilazep) on the isolated smooth muscles]

The effects of a new coronary vasodilator (dilazep) on isolated intestine, taenia coli, trachea, vas deferens, uter, aorta and coronary arteries were investigated in rats, guinea pigs, rabbits and dogs. Dilazep showed relaxant effects on isolated smooth muscle in a concentration of 10(-5) 3 X 10(-4) M and non-competitive inhibition on contraction induced by agonists (pD'2: 4.405.05). In guinea pig taenia coli, dilazep had a relaxant effect on K-contracture. The effect was qualitatively similar to that of papaverine. In guinea pig taenia coli, dilazep showed a Ca++ antagonistic effect in a concentration as high as 3 X 10(-6)M. The potency was stronger than dipyridamole, NaNO2 and aminophylline and equalled that of papaverine and hexobendine. In guinea pig taenia coli, dilazip potentiated relaxant effects induced by adenosine and adenine nucleotides in a concentration as high as 10(-8)M. The potency was stronger than that of dipyridamole. From these results, it is suggested that the potentiating effect of both adenosine and adenine nucleotides and Ca++ antagonistic effect of dilazep may play an important role in producing the coronary vasodilating effect.     

Pharmacological Activity of Prunus spinosa on Isolated Tissue Preparations.

The pharmacological action of the aqueous extract of PRUNUS SPINOSA L. branches has been studied in tissue preparation IN VITRO. The influence of the extract on rat vas deferens and duodenum was tested using norepinephrine and acetylcholine on spasmogens as well as on guinea pig ileum and taenia coli using histamine and calcium chloride, respectively. The extract reduced responses to norepinephrine, epinephrine and histamine. Responses to cumulative increased Ca (2+) concentrations in depolarizing bathing medium were also blocked. The P. SPINOSA L. extract had effects PER SE on rat vas deferens and guinea pig ileum.     

Indications for P2-purinoceptor subtypes in guinea pig smooth muscle

The effects of ADP, ATP, 2-methylthio ATP, alpha,beta-methylene ADP (alpha,beta meADP) and alpha,beta meATP on smooth muscle tone and the responses to transmural nerve stimulation were studied in isolated longitudinal ileum muscle, in vas deferens and in taenia coli of the guinea pig. The nucleotides evoked contractile responses in the ileum and vas deferens preparations which were blocked by p-chloromercuribenzene sulfonic acid (PCMBS) and evoked relaxation in the taenia which was not affected by PCMBS. The potency order of the agonists in the ileum (2-methylthio ATP was more potent than ATP which was equipotent with ADP) is consistent with the suggestion that there are P2Y receptors in the taenia. The antagonist pattern, including the inefficacy of reactive blue 2, instead suggests a similarity between the ileum receptors and the P2X receptors in vas deferens. However, alpha,beta meATP did not antagonize the contractile effect of ATP in the ileum, in contrast to its effect in the vas deferens where alpha,beta meATP did abolish the contractile effect of ATP. The possibilities for classification of a new receptor/site of purine nucleotide action, P2S, are considered.     

(+/-)-CP-96,345, a selective tachykinin NK1 receptor antagonist, has non-specific actions on neurotransmission.

1. The non-specific effects of the non-peptide tachykinin receptor antagonist (+/-)-CP-96,345, were assessed in several smooth muscle-nerve preparations. The preparations were the iris sphincter muscle of the rabbit and the taenia coli, vas deferens and seminal vesicle of the guinea-pig. 2. (+/-)-CP-96,345 concentration-dependently inhibited the electrically evoked, tachykinin-mediated contractile responses of the iris sphincter and the taenia coli. The pIC50 values were 5.4 +/- 0.2 (mean +/- s.e.mean) and 5.7 +/- 0.08 respectively. 3. (+/-)-CP-96,345 also inhibited non-tachykinin-mediated contractile responses to electrical stimulation of the iris sphincter, taenia coli, vas deferens and seminal vesicle. The pIC50 values were 4.3 +/- 0.02, 4.8 +/- 0.03, 4.7 +/- 0.02 and 4.4 +/- 0.05 respectively. These values differ significantly from the pIC50 values of the inhibition of the tachykinin-mediated response in the iris sphincter and taenia coli. 4. (+/-)-CP-96,345 was without effect on carbachol- and noradrenaline-evoked contractions of the iris sphincter but inhibited carbachol- and prostaglandin F2 alpha (PGF2 alpha)-evoked contractions of the taenia coli. 5. We suggest that (+/-)-CP-96,345, apart from its NK1 receptor blocking activity, induces non-specific suppression of neurotransmission, exerted at both pre- and post-junctional sites.     

Pharmacological analysis of effects of perimetazine on isolated smooth muscle]

Effects of perimetazine on the motility of the isolated smooth muscle of guinea pig (ileum, taenia coli, uterus, vas deferens and trachea) and the ileum of rabbit were studied. The results obtained are as follows: Perimetazine showed a specific antihistamine, antiadrenaline and antiserotonin action. Moreover, antiacetylcholine and anti-BaC12 actions were observed with high doses of perimetazine as well as chlorpromazine and such actions were attributed to the nonspecific direct action on the smooth muscle. Both the spontaneous movement and the tonus of guinea pig taenia coli were also inhibited by a high concentration of perimetazine. The spontaneous membrane action potentials of the taenia coli recorded by the use of the sucrose-gap method were inhibited by a high concentration of perimetazine both in frequency and in amplitude with relaxation of the tonus. The action potentials were abolished however and change in the resting membrane level was not clearly observed.     

Prompt effect of progesterone on the adrenergic response of smooth muscles

The contractile effects of epinephrine on the uterus and ductus deferens of the rabbit and the ductus deferens of the monkey were inhibited by the preincubation with progesterone (6.4 X 10(-5) M) for 1 or 3 min in Locke-Ringer solution. Epinephrine relaxed the guinea pig uterus and taenia caecum. The relaxant effects were enhanced by preincubation with progesterone. Their effects were in a dose-dependent manner. There was no apparent change in the number and affinity of alpha-adrenergic receptors in the uterus of rabbits and the ductus deferens of guinea pigs during the incubation with progesterone. Progesterone has no direct effect on alpha-adrenergic receptors. All smooth muscles yielded reproducible contractile reactions to Ca2+ when maintained in depolarizing Tyrode's solution containing K+ (40 mmol/l). Their concentration-response curves were inhibited by preincubation with progesterone (6.4 X 10(-5) M), and they were shifted to the right in a concentration-dependent manner. Established Ca2+-induced contractions were rapidly relaxed by the addition of progesterone (6.4 X 10(-5) M). It suggests that progesterone directly affects the plasma membrane and inhibits the voltage-dependent Ca2+ channel and then inhibits smooth muscle contraction.     

Adenosine 5'-(2-fluorodiphosphate) is a selective agonist at P2-purinoceptors mediating relaxation of smooth muscle

The pharmacological effects of ATP and of an adenine nucleotide analogue, adenosine 5'-(2-fluorodiphosphate) (ADP-beta-F) on various guinea-pig isolated smooth muscle preparations were investigated. ATP relaxed the taenia coli and the aorta, and contracted the urinary bladder and vas deferens. ADP-beta-F mimicked the effects of ATP on the taenia coli and aorta, but did not contract the bladder or vas deferens. The lack of potency of ADP-beta-F on the bladder was not due to its rapid degradation by ectonucleotidases, as it was degraded more slowly than ATP by both the bladder and the taenia coli. These results are consistent with the suggestion that the P2-purinoceptors mediating contraction of smooth muscle (P2X) are different from those mediating inhibitory effects (P2Y), and suggest that ADP-beta-F is a specific agonist at the P2Y-purinoceptor.     

Tissue specificity of endothelin binding sites.

A measurement was made of the binding of 125I-labeled endothelin (125I-ET) to crude membrane fractions prepared from rat aorta, atrium, ventricle, portal vein, trachea, lung parenchyma, vas deferens, ileum, bladder, and guinea-pig taenia coli and lung parenchyma. Scatchard analysis of 125I-ET binding in all tissues indicated binding to a single class of saturable sites. The affinity and density of 125I-ET binding sites varied between tissues. The Kd of 125I-ET binding was approximately 0.5 nM for rat aorta, trachea, lung parenchyma, ventricle, bladder, and vas deferens, and guinea-pig taenia coli and lung parenchyma, 1.8 nM for rat portal vein and atrium, and 3.3 nM for ileum. The Bmax of 125I-ET binding had the following rank order of density in rat tissues: trachea greater than lung parenchyma = vas deferens much greater than aorta = portal vein = atrium greater than bladder greater than ventricle = ileum. The properties of 125I-ET endothelin binding were characterized in rat ventricular membranes. 125I-ET binding was time dependent, reaching a maximum within 45-60 min at 25 degrees C. The calculated microassociation constant was 9.67 x 10(5) s-1 M-1. Only 15-20% of 125I-ET dissociated from its binding site even when dissociation was studied as long as 3 h. Preincubation of ventricular membranes with ET prevented binding of 125I-ET. 125I-ET binding was destroyed by boiling of ventricular membranes and was temperature, pH, and cation (Ca2+, Mg2+, and Na+) dependent.(ABSTRACT TRUNCATED AT 250 WORDS)     

硫酸锌对离体血管平滑肌的作用

硫酸锌是体内一种重要的微量元素,它使离体动物心脏动作电位振幅降低,有效不应期延长,并能显著降低家兔窦房结自律性。本文采用离体豚鼠胸主动脉条和犬门静脉环标本,观察硫酸锌对KCl,CaCl_2和去甲肾上腺素(NE)诱发血管平滑肌收缩的影响。进一步探讨硫酸锌与Ca~(2 )的作用关系。     

Effects of the calcium channel facilitator, CGP 28,392, on different modes of contraction in smooth muscle of rabbit and rat aortae and guinea-pig taenia caeci.

Effects of a Ca2+ channel facilitator, CGP 28,392, on smooth muscle contractions were examined in order to delineate characteristics of Ca2+ channels in rabbit and rat aortae and guinea-pig taenia caeci. Application of increasing concentrations of KCl induced contractile responses in these smooth muscles and CGP 28,392 shifted the concentration-response curve for KCl to the left. The maximum response was also increased in rat aorta and guinea-pig taenia. CGP 28,392 also shifted the concentration-response curves for noradrenaline in rat aorta and for histamine in taenia to the left and increased the maximum response in rat aorta. However, the corresponding curve for noradrenaline in rabbit aorta was not affected by CGP 28,392. The sustained contractions induced by KCl were inhibited by cumulative application of verapamil in these smooth muscles. Pretreatment of the muscle with CGP 28,392 decreased the inhibitory effect of verapamil. The noradrenaline-induced contraction in rat aorta and the histamine-induced contraction in taenia were also inhibited by verapamil, and CGP 28,392 antagonized the effect of verapamil. The noradrenaline-induced contraction in rabbit aorta was only slightly inhibited by verapamil, and CGP 28,392 did not modify the effect of verapamil. In these smooth muscles, cumulative application of Ca2+ to the Ca2+-depleted, KCl-treated muscle induced contraction, and the concentration-response curve for Ca2+ was shifted to the left by CGP 28,392 and to the right by verapamil. The concentration-response curves for Ca2+ in Ca2+-depleted, noradrenaline-treated rabbit and rat aortae and in Ca2+-depleted, histamine-treated taenia were also shifted to the left by CGP 28,392 and to the right by verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological effects of flurazepam and diazepam on isolated canine arteries

The effects of flurazepam and diazepam, benzodiazepine derivatives, on contractions (or contractures) induced by Ca++, K+ or norepinephrine were examined in the isolated canine coronary artery and thoracic aorta. Ca++-Induced contraction was evoked by cumulative addition of CaCl2 to Ca++-depleted K+-depolarizing solution; K+: and norepinephrine-induced contractions were evoked by cumulative addition of KCl and norepinephrine, respectively, to the medium. Flurazepam and diazepam (1 X 10(-5), 3 X 10(-5) and 1 X 10(-4) M for coronary artery; 3 X 10(-5) and 1 X 10(-4) M for thoracic aorta) shifted the dose-response curves for KCl downwards in a non-competitive manner, and shifted the dose-response curves for CaCl2 to the right in a competitive manner. Ca++-Induced contracture was inhibited completely by addition of flurazepam or diazepam (1 X 10(-4) M), and the inhibition was reversed dose-dependently by addition of CaCl2. Flurazepam and diazepam (3 X 10(-5) and 1 X 10(-4) M) shifted the dose-response curves for norepinephrine both rightwards and downwards in the thoracic aorta. These findings suggest that flurazepam and diazepam inhibit Ca++-influx into the cells (Ca++-antagonistic effect), causing relaxation and inhibition of K+-, Ca++-, or norepinephrine-induced contraction (or contracture) of the vascular smooth muscle.     

The inhibitory effects of N2-dansyl-L-arginine-4-t-butylpiperidine amide (TI233) on contraction of vascular and intestinal smooth muscle.

Effects of N2-dansyl-L-arginine-4-t-butylpiperidine amide (TI233) on the contractions in vascular and intestinal smooth muscles were examined. High K-induced sustained contractions in the smooth muscles were inhibited by TI233 with an IC50 of 2.1 X 10(-5) M for rabbit aorta and 3.6 X 10(-6) M for guinea-pig taenia coli in a solution containing 1.5 mM Ca. Initial transient contraction induced by K in taenia coli was less sensitive to the inhibitory effect of TI233. When the Ca concentration in the medium was decreased to 0.3 mM, the concentration-inhibition curves for TI233 shifted to the left in both aorta and taenia coli. Increasing the Ca concentration to 7.5 mM shifted the curve to the right in the aorta. TI233 also inhibited the noradrenaline-induced contraction in the aorta (IC50 = 2.1 X 10(-5 M). In a hypoxic solution without added glucose, the inhibitory effect of TI233 on the K-induced contraction in aorta was augmented. In the presence of high concentrations (40 mM) of glucose in hypoxia, TI233 did not inhibit the noradrenaline-induced contraction of the aorta. Hypoxia and a high concentration of glucose also decreased the inhibitory effect of TI233 on the K-induced contraction in taenia coli. TI233 inhibited the K-induced increase in cellular Ca content measured by a modified lanthanum method. TI233 decreased oxygen consumption and ATP content of resting and K-stimulated aorta and taenia coli. It was concluded that TI233 inhibits the vascular and intestinal smooth muscle contraction by a Ca antagonistic action and also by inhibition of aerobic metabolism.     

Temperature dependency of P2 receptor-mediated responses

The P2 receptor-mediated responses of isolated guinea pig urinary bladder and vas deferens (P2X receptors) and taenia caeci (P2Y receptors) were registered at the three temperature conditions of 30, 37 and 42 degrees C. The contractile responses of both urinary bladder and vas deferens to a P2X receptor agonist alpha,beta-methylene ATP (alpha,beta-meATP; 0.01-30 microM) and to electrical field stimulation (1-64 Hz, 0.1 ms, supramaximal voltage) in the presence of atropine (0.1 microM) and phentolamine (1 microM) were markedly more prominent at a temperature of 30 degrees C than at 37 or 42 degrees C. Similarly, relaxation of carbachol-precontracted taenia caeci caused by electrical field stimulation (0.5-8 Hz, 0.1 ms, supramaximal voltage) temperature-dependently increased with decrease of temperature, while relaxation of this tissue by exogenous ATP (1-100 microM) was not affected by the temperature. A P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 1-30 microM) at all three temperature conditions concentration-dependently antagonised contractile responses to alpha,beta-methylene ATP and electrical field stimulation in both urinary bladder and vas deferens. PPADS, even at the highest concentration tested (30 microM), had no effect on the relaxant responses of the taenia caeci either to electrical field stimulation or ATP and its action was not affected by the change of temperature. It is concluded from this study that the effectiveness of P2 receptor-mediated responses in guinea pig urinary bladder, vas deferens and taenia caeci increases by decrease of temperature.     

一种新的阿片受点不可逆激动剂7α-二(β-氯乙基)胺甲基-6,14-乙烯撑基四氢奥利文的药理研究

α-CAM是一新的阿片受点不可逆激动剂,在离体组织(GPI,MVD,RVD和RbVD)及大鼠脑P₂膜制备上均表现不可逆作用。对小鼠镇痛(icv)ED₅₀为0.12 nmol/鼠,镇痛作用可持续2～3 d,是迄今所知镇痛时间最长的化合物。一次注射(icv)即可使小鼠成瘾,可作为研究成瘾机理的工具药。     

Structure activity relationships for derivatives of adenosine-5′-triphosphate as agonists at P2 purinoceptors: Heterogeneity within P2x and P2y subtypes

The structure-activity relationships for a variety of adenine nucleotide analogues at P_2X and P_2Y-purinoceptors were investigated. Compounds formed by structural modifications of the ATP molecule including substitutions of the purine ring (C2, C8, N1, and N⁶-substituents, and a uridine base instead of adenine), the ribose moiety (2′ and 3′-positions), and the triphosphate group (lower phosphates, bridging oxygen substitution, and cyclization) were prepared. Pharmacological activity at P_2Y-purinoceptors was assayed in the guinea pig taenia coli, endothelial cells of the rabbit aorta, smooth muscle of the rabbit mesenteric artery, and turkey erythrocyte membranes. Activity at P_2X-purinoceptors was assayed in the rabbit saphenous artery and the guinea-pig vas deferens and urinary bladder. Some of the analogues displayed selectivity, or even specificity, for either the P_2X- or the P_2Y-purinoceptors. Certain analogues displayed selectivity or specificity within the P_2X- or P_2Y-purinoceptor superfamilies, giving hints about possible subclasses. For example, 8-(6-aminohexylamino)ATP and 2′,3′-isopropylidene-AMP were selective for endothelial P_2Y-purinoceptors over P_2Y-purinoceptors in the guinea pig taenia coli, rabbit aorta, and turkey erythrocytes. These compounds were both inactive at P_2X-purinoceptors. The potent agonist N⁶-methyl ATP and the somewhat less potent agonist 2′-deoxy-ATP were selective for P_2Y-purinoceptors in the guinea pig taenia coli, but were inactive at P_2X-purinoceptors and the vascular P_2Y-purinoceptors. 3′-Benzylamino-3′-deoxyATP was very potent at the P_2X-purinoceptors in the guinea pig vas deferens and bladder, but not in the rabbit saphenous artery and was inactive at P_2Y receptors. These data suggest that specific compounds can be developed that can be utilized to activate putative subtypes of the P_2X- and P_2Y-purinoceptor classes. © 1994 Wiley-Liss, Inc.     

Receptor interactions of a series of imidazolines: comparison of the alpha 2-adrenoceptors between the rabbit vas deferens and guinea pig ileum

A series of imidazolines and norepinephrine were used to characterize and differentiate the presynaptic alpha 2-adrenoceptors in the rabbit vas deferens and the guinea pig ileal longitudinal muscle using pharmacological procedures. Based on pEC50-values (the negative log of the 50% effective concentration) for each imidazoline, a rank order of potency of p-aminoclonidine greater than oxymetazoline greater than or equal to clonidine greater than naphazoline greater than phentolamine was obtained in the rabbit vas deferens and an order of p-aminoclonidine greater than clonidine greater than naphazoline greater than oxymetazoline was obtained in the guinea pig ileum. In the rabbit vas deferens, phentolamine, which is generally considered to be a competitive alpha 1- and alpha 2-adrenoceptor antagonist, acted as a full alpha 2-adrenoceptor agonist. The dissociation constants of oxymetazoline and yohimbine were significantly lower in the rabbit vas deferens than in the guinea pig ileum. These results suggest that the presynaptic alpha 2- adrenoceptors in these tissues are different. Furthermore, the pKB-value of yohimbine against norepinephrine was significantly one log unit lower than those obtained using a series of imidazolines. Data from our studies add to increasing evidence of the existence of high and low affinity binding sites on the alpha 2-adrenoceptors in the rabbit vas deferens.     

P2-receptor antagonists: IV. Blockade of P2-receptor subtypes and ecto-nucleotidases by compounds related to reactive blue 2

Effects of reactive blue 2 and twelve structurally related compounds were studied on contractions of the rat vas deferens elicited by α,β-methylene ATP (α,β-MeATP; mediated by P2X-receptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5′-O-(2-thiodiphosphate) (ADPβS; mediated by P2Y-receptors), and the degradation of ATP by rat vas deferens tissue. All compounds, except acid blue 41 and acid blue 129 (at up to 100μM), shifted the concentration-response curve of α,β-MeATP in the rat vas deferens to the right. Most increased, but uniblue A greatly decreased, the maximum of the curve. In the case of cibacron blue 3GA and reactive blue 19, of which three concentrations were tested, the Arunlakshana-Schild regression was linear, and the slope did not differ from unity. The apparent K_d values of the effective substances ranged between 0.7 and 111μM. Most compounds increased the contraction of the rat vas deferens elicited by high K⁺. In the guinea-pig taenia coli, all compounds, except uniblue A and reactive blue 19 (at up to 100μM), shifted the concentration-response curve of ADPβS to the right in a parallel manner. In the case of acid blue 129 and acid blue 80, of which three concentrations were tested, the slope of the Arunlakshana-Schild regression did not differ from unity. The apparent K_d values of the effective substances were between 0.7 and 69μM. Most compounds also reduced the relaxation of the guinea-pig taenia coli elicited by noradrenaline. The removal of ATP from the medium by vas deferens tissue was decreased only by reactive blue 2, cibacron blue 3GA, uniblue A and reactive blue 19, with IC_25% values between 17 and 62μM. The structure-activity relationships for P2X- and P2Y-receptor blockade in this series are strikingly dissimilar. In reactive blue 2 and its isomers, for example, both the 1-amino-anthraquinone-2-sulphonate core and the ‘side-chain’ of the molecule are involved in P2X-receptor binding; P2Y-receptor affinity, in contrast, resides largely or totally in the anthraquinone core. The most promising antagonists are uniblue A which is P2X- versus P2Y-selective and acid blue 129 which is P2Y- versus P2X-selective, both with few, if any, non-P2-receptor effects at concentrations blocking the respective P2-subtype. Received: 23 July 1997 / Accepted: 4 November 1997     

Glycopyrronium bromide blocks differentially responses mediated by muscarinic receptor subtypes

Summary To analyse the potency of glycopyrronium bromide in blocking responses mediated via subtypes of muscarinic receptors in vitro, we tried to determine its equilibrium dissociation constants at prejunctional muscarinic receptors inhibiting the twitch response of rabbit vas deferens (presumed M₁ type), at M₂ (paced rat left atria), M₃ (guinea pig ileum) muscarinic receptor subtypes and at the muscarinic receptor of the rabbit iris sphincter (not M₁–M₄, not m₅). Glycopyrronium bromide shifted to the right the curve for inhibition of the twitch response induced by the agonist McN-A-343, and the methacholine-induced curves for inhibition of rat atrial contraction, and for tonic contraction of guinea pig ileum and rabbit iris sphincter.Glycopyrronium bromide blocked with very high potency (> 11, apparent -log K_B) the response in rabbit vas deferens. Its affinity was low (9.09) for the M₂ subtype, and intermediate (10.31 or 10.13) for the ileal M₃ and the atypical iris muscarinic receptor subtype, respectively. Except at the receptors in rabbit vas deferens, the blockade of agonist effect appeared to be of simple competitive type.In conclusion, glycopyrronium bromide is about 10 or 100fold more potent in preventing a response to activation of the prejunctional receptor in rabbit vas deferens than in blocking an M3 or M2 muscarinic receptor subtype, respectively, in vitro. The low affinity for M₂ receptors may, in part, explain the low incidence of unwanted tachycardia in therapy. The drug failed to discriminate between an M3 receptor and the atypical rabbit iris sphincter receptor.Correspondence to H. Fuder at the above address     

Further comparison of contractions of the smooth muscle of the guinea-pig isolated vas deferens induced by ATP and related analogs

Some structural requirements which are important for the contractile activity of adenine nucleotides at P2-purinergic receptors in the guinea-pig isolated vas deferens were examined. The consequences of deletions, substitutions and isosteric rearrangements in 1-N, C-2, C-8, N-9 and N6 of adenine, in the ribose hydroxyls, and in the polyphosphate chain were examined. Several kinds of effects on activity were observed, including potentiation of responses, losses in activity, modifications of response duration, and transitions from biphasic concentration-response curves, which are characteristic of ATP, to monophasic curves. Generally, deletions and substitutions to adenine reduced activity. Ribose modifications were better-tolerated. The presence of 5'-phosphate or phosphorothioate moieties was required for maximum activity. A comparison of the present results with previous reports indicates that certain modifications to ATP result in similar effects in both the vas deferens and urinary bladder, which are opposite those which occur in the taenia coli.     

Activation of P1- and P2Y-purinoceptors by ADP-ribose in the guinea-pig taenia coli, but not of P2X-purinoceptors in the vas deferens.

1. The activity of adenosine 5'-diphosphoribose (ADP-ribose), a ribosylated purine nucleotide, was investigated on the carbachol-contracted taenia coli, a tissue possessing P1- (A2) and P2Y-purinoceptors and on the guinea-pig vas deferens which possesses P2X-purinoceptors. 2. In the vas deferens, where ATP (1 microM-1 mM) produced concentration-dependent contractions, ADP-ribose was without effect at concentrations up to 1 mM. 3. In the taenia coli, ADP-ribose (0.1 microM-1 mM) produced concentration-dependent relaxations with a potency similar to that of adenosine, but less than that of ATP. The pD2 values for ADP-ribose, adenosine and ATP were 4.5 +/- 0.07 (27), 4.4 +/- 0.10 (9) and 5.5 +/- 0.14 (21), respectively. The time-course of the relaxations elicited by ADP-ribose was found to be significantly longer than that for ATP and significantly shorter than that for adenosine. 4. The P1-purinoceptor antagonist, 8-phenyltheophylline (5 microM), produced parallel rightward shifts in the concentration-response curves of the relaxations of the taenia coli elicited by ADP-ribose and adenosine but not ATP. 5. Dipyridamole (0.3 microM), a purine nucleoside uptake inhibitor, potentiated the responses to adenosine and ADP-ribose in the taenia coli. These potentiations were sensitive to 8-phenyltheophylline (5 microM). 6. Reactive blue 2, a P2Y-purinoceptor antagonist, antagonized the inhibitory responses of ADP-ribose and ATP in the taenia coli, without significantly altering the inhibitory responses of either adenosine or noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)