Topological signatures of globular polymers.

Simulations in which a globular ring polymer with delocalized knots is separated in two interacting loops by a slipping link, or in two noninteracting globuli by a wall with a hole, show how the minimal crossing number of the knots controls the equilibrium statistics. With slipping link the ring length is divided between the loops according to a simple law, but with unexpectedly large fluctuations. These are suppressed only for unknotted loops, whose length distribution always shows a fast power-law decay. We also discover and explain a topological effect interfering with that of surface tension in the globule translocation through a membrane nanopore.

Lyn-mediated SHP-1 recruitment to CD5 contributes to resistance to apoptosis of B-cell chronic lymphocytic leukemia cells.

In B-cell chronic lymphocytic leukemia (B-CLL) cells, Lyn, a tyrosine kinase belonging to the Src family, is overexpressed and atypically localized in an aberrant cytosolic complex in an active conformation, contributing to the unbalance between cell survival and pro-apoptotic signals. In this study, we demonstrate that Lyn constitutively phosphorylates the immunoreceptor tyrosine inhibitory motifs of the inhibitory cell surface co-receptor CD5, a marker of B-CLL. As a result, CD5 provides an anchoring site to Src homology 2 domain-containing phosphatase 1 (SHP-1), a known negative regulator of hematopoietic cell function, thereby triggering the negative B-cell receptor (BCR) signaling. The subsequent segregation of SHP-1 into two pools, one bound to the inhibitory co-receptor CD5 in an active form, the other in the cytosol in an inhibited conformation, proves crucial for withstanding apoptosis, as shown by the use of phosphotyrosine phosphatase-I-I, a direct inhibitor of SHP-1, or SHP-1 knockdown. These results confirm that Lyn exhibits the unique ability to negatively regulate BCR signaling, in addition to positively regulating effectors downstream of the BCR, and identify SHP-1 as a novel player in the deranged signaling network and as a potential attractive target for new therapeutic strategies in B-CLL.

Volumetric MRI analysis of hippocampal subregions in Cushing's disease: a model for glucocorticoid neural modulation.

Several preclinical studies have demonstrated neuronal effects of glucocorticoids on the hippocampus (HC), a limbic structure with anterior-posterior anatomical and functional segmentation. We propose a volumetric magnetic resonance imaging analysis of hippocampus head (HH), body (HB) and tail (HT) using Cushing's disease (CD) as model, to investigate whether there is a differential sensitivity to glucocorticoid neuronal damage in these segments. We found a significant difference in the HH bilaterally after 12 months from trans-sphenoidal surgical selective resection of the adrenocorticotropic hormone (ACTH)-secreting pituitary micro-adenomas. This pre-post surgery difference could contribute to better understand the pathopysiology of CD as an in vivo model for stress-related hypercortisolemic neuropsychiatric disorders.

Isolated porcine bronchi provide a reliable model for development of bronchodilator anti-muscarinic agents for human use.

BACKGROUND AND PURPOSE: In human airways, muscarinic acetylcholine receptors (mAChRs) exert a predominant role in the control of airways resistance and anti-muscarinic agents are currently included in the pharmacological treatment of chronic obstructive pulmonary disease (COPD). However, the development of more effective mAChR antagonists is hampered by considerable species variability in the ultrastrucural and functional control of airway smooth muscle, making extrapolation of any particular animal model questionable. This study was designed to characterize the mAChRs in a bronchial preparation from pigs, animals considered to provide close models of human biology. EXPERIMENTAL APPROACH: Smooth muscle bronchial strips were examined by electron microscopy in order to compare their neuromuscular structure with that of human bronchi and used to study the affinity of a series of selective mAChR antagonists, estimated as pKis in competition binding assays with NMS and pA2, by Schild analysis, in contractile experiments. KEY RESULTS: Pharmacodynamic binding parameters and affinity profiles of a series of antagonists were consistent with the presence of a majority of M2 mAChRs along with a minor population of M3 mAChRs. Functionally, the highly significant correlation between postjunctional pA2 affinities and corresponding affinity constants at human recombinant M1-M5 subtypes indicated that smooth muscle contraction in porcine bronchi, as in human bronchi, was dependent on the M3 subtype. CONCLUSION AND IMPLICATIONS: Based on the characterization of mAChRs, isolated porcine bronchi provide an additional experimental model for development of mAChR antagonists for the treatment of human airway dysfunctions.

Size of knots in ring polymers.

We give two different, statistically consistent definitions of the length l of a prime knot tied into a polymer ring. In the good solvent regime the polymer is modeled by a self avoiding polygon of N steps on cubic lattice and l is the number of steps over which the knot "spreads" in a given configuration. An analysis of extensive Monte Carlo data in equilibrium shows that the probability distribution of l as a function of N obeys a scaling of the form p(l,N) approximately l(-c)f(l/N(D)) , with c approximately equal to 1.25 and D approximately equal to 1. Both D and c could be independent of knot type. As a consequence, the knot is weakly localized, i.e., approximately N(t) , with t=2-c approximately equal to 0.75 . For a ring with fixed knot type, weak localization implies the existence of a peculiar characteristic length l(nu) approximately N(tnu) . In the scaling approximately N(nu) (nu approximately equal to 0.58) of the radius of gyration of the whole ring, this length determines a leading power law correction which is much stronger than that found in the case of unrestricted topology. The existence of this correction is confirmed by an analysis of extensive Monte Carlo data for the radius of gyration. The collapsed regime is studied by introducing in the model sufficiently strong attractive interactions for nearest neighbor sites visited by the self-avoiding polygon. In this regime knot length determinations can be based on the entropic competition between two knotted loops separated by a slip link. These measurements enable us to conclude that each knot is delocalized (t approximately equal to 1) .

Liver ischemia modifies the concentration of plasmatic catecholamines after reperfusion in the rat.

Pulmonary hypertension is one of the most frequent and severe consequences of liver ischemia. The aim of this study is to evaluate the presence of humoral vasoactive mediators, generated during liver ischemia, which could be able to determine the onset of pulmonary hypertension. Thus, we evaluated the plasmatic concentration of catecholamines (adrenaline, noradrenaline, dopamine) during the immediate reperfusion period. Wistar rats were used. Animals (n = 89) were divided into four groups. Group 1 served as control (sham-operated). In group 2 animals underwent 60 min of left hepatic exclusion. In group 3 animals underwent to bilateral adrenectomy. In group 4 animals had both bilateral adrenectomy and liver ischemia. Ischemia in group 2 and 4 was induced by interrupting the vascular supply to the left and median lobes, so avoiding the use of a portal shunt. Blood samples were collected from the suprahepatic inferior caval vein immediately after reperfusion. Strips of the main pulmonary artery were put into an isolated organ bath and tested for the response to noradrenaline, adrenaline and plasma samples. Plasma samples collected after ischemia caused a significantly greater (p < 0.01) contraction of the pulmonary artery compared to controls. Plasma samples collected after adrenectomy caused a weak contraction which was not different from that obtained in the adrenectomy + ischemia group. Plasma concentrations of catecholamines after liver ischemia were significantly increased in the control group (p < 0. 01). In adrenectomized rats only the adrenaline level was greatly reduced. However ischemia did not increase plasma catecholamines as it occurred in sham-operated rats.

[The hemodynamic effects of the in-vivo administration of insulin-like growth-factor I]. / Effetti emodinamici della somministrazione in vivo dell'Insulin-like Growth Factor-I.

BACKGROUND: Recent studies have demonstrated that IGF-I has several biological activities that correlate with the GH axis, by acting as a cell protecting factor and a promoting compound in different tissues and organs. Our latest findings have demonstrated a potential application of IGF-I in the treatment of postischemic renal injury, which frequently appears after a kidney transplant. The beneficial effect of the renal postoperative recovery probably correlates with the regulation of the vascular tone, in which IGF-I plays a role with other cytokines. However, this rises the question whether IGF-I has any effect on the general hemodynamic status. This study was designed to underline the intraoperative hemodynamic effect of exogenous IGF-I in an experimental setting of renal transplantation in swine. METHODS: Twelve female swine underwent a left renal autotransplantation. At the reperfusion the animals were separated in two groups. Group one served as control. Group two received 400 micrograms of IGF-I (added to the flushing solution). The animals were kept under complete hemodynamic monitoring over the operation. RESULTS: Among the different parameters studied (mean arterial pressure, mean pulmonary arterial pressure, pulmonary wedge pressure, central venous pressure, cardiac output, oxygen extraction ratio, systemic vascular resistance, oxygen delivery and oxygen consumption), any statistically significant difference between group one and two were observed. CONCLUSIONS: While the clinical administration of IGF-I requires further studies, the in vivo administration of this peptide is apparently well tolerated, and does not cause any hemodynamic instability to the operation.

Quantitative changes in pharmacodynamic parameters of noradrenaline in different rat aorta preparations: influence of endogenous EDRF.

1. The aim of the present study was to assess the role of endothelial cells in the modulation of vasocontractile responses to noradrenaline in rat isolated aorta when cut as standard helical strips or as ring segments. 2. Noradrenaline-potency in helical strip preparations evaluated as -logEC50 was greater than that obtained in endothelium-intact ring preparations (9.45 +/- 0.28 versus 8.69 +/- 0.09, respectively) (P < 0.05). The maximum contractile response of helical strips was significantly higher than the response of ring preparations (P < 0.05). 3. Subsequent experiments were performed on helical strips and ring preparations where the endothelium was removed by rubbing the luminal surface of the aorta with filter paper. Removal of the endothelium potentiated the noradrenaline-induced contraction in ring preparations, but not in the helical strips. 4. The nitric oxide synthase inhibitors L-NAME (3 x 10(-5)-3 x 10(-4) M) or L-NNA (1 x 10(4)-3 x 10(-4) M) which were added to the tissue bath potentiated the noradrenaline-induced contraction in the endothelium-intact ring preparations, although only L-NNA induced a statistically significant potentiation. Both L-NAME and L-NNA had no effect on the noradrenaline-contraction induced in rings without endothelium, or in helical strips with or without endothelium. 5. Vascular acetylcholine-induced relaxation is dependent on endothelium derived relaxing factor (nitric oxide). Acetylcholine (10(-9)-10(-6) M) induced a concentration-dependent relaxation in noradrenaline preconstricted intact rings. The relaxant response was strongly reduced by L-NAME (3 x 10(-5)-1 x 10(-4) M). The relaxant response to acetylcholine was very weak in ring and helical strip preparations without endothelium, but also, surprisingly, in unrubbed standard helical strips. 6. The present results suggest that the endothelium of standard helical strip preparations may be greatly damaged, a view confirmed by morphological studies. The structural and functional damage of the endothelium induced very important changes in pharmacodynamic parameters such as in the potency and the maximal responses of vascular preparations to noradrenaline. Therefore, caution must be observed when the potency and intrinsic activity of agonists evaluated on different preparations are compared, even if these come from the same vascular segment.

Pharmacological characterization of alpha-adrenoceptors that mediate contraction in splenic artery strips from the pig.

The alpha-adrenoceptors that mediate contractions in strips of splenic artery from the pig were characterized by the use of selective agonists and subtype-selective antagonists. Noradrenaline, the alpha1-selective agonist phenylephrine and the alpha1-/alpha2-agonist oxymetazoline caused the preparations to contract with potency (pD2) values of 6.94, 6.14 and 7.27, respectively. Compared to noradrenaline, phenylephrine and oxymetazoline induced 93% and 78% of noradrenaline maximum effect. Conversely, the two alpha2-selective agonists clonidine and B-HT 920 induced only 31% and 13% of noradrenaline maximum effect. B-HT 920 only marginally contracted the tissue even when it was precontracted with phenylephrine. The alpha2-selective antagonist yohimbine antagonized oxymetazoline- and phenyleprine-induced contractions with affinity (pA2) values (6.80 and 6.74, respectively) consistent with alpha1-adrenoceptor interaction. This suggests that the pig splenic artery possesses only functional alpha1-adrenoceptors. The alpha1-adrenoceptor antagonists of varying subtype selectivities like WB-4101, 5-methylurapidil, benoxathian and BMY 7378 competitively antagonized phenylephrine-induced contractions with affinity values of 9.46, 8.26, 9.06 and 6.91, respectively. These values correlated highly with published affinity values for functional alpha1A-adrenoceptors (r=0.92) and alpha1a-clones (r=0.94) and less well with affinity values for functional alpha1B-adrenoceptors (r=0.84) and alpha1b-clones (r=0.87). Conversely, correlation with functional alpha1D-adrenoceptors (r=0.26) and alpha1d-clones (r=0.33) was poor. In addition the alpha1D-selective antagonist BMY 7378 had a low affinity value compared to that reported for alpha1D-adrenoceptors. Therefore, based on correlation studies, the plot that resembled the line of equal values most closely was that for the alpha1A-subtype. The alpha1A-selective antagonist RS-17053 antagonized phenylephrine-induced contractions in an apparently non-competitive manner and gave an apparent pA2 value of 7.06 which is similar to the "low" affinity values reported in other alpha1A-containing tissues. Exposure to the irreversible alpha1B/D-antagonist chloroethylclonidine slightly decreased maximum response to phenylephrine without significantly affecting its potency value, indicating that the phenylephrine response is substantially chloroethylclonidine-insensitive. It is concluded that splenic artery strips from the pig contract in response to phenylephrine through activation of alpha1-adrenoceptors which display the pharmacological profile of the alpha1A-subtype for which the recently reported alpha1A-selective antagonist RS-17053 shows low affinity. Evidence for contribution of the alpha1B-subtype in the overall contractile response is elusive while no evidence was obtained for the involvement of the alpha1D-subtype. The contribution of functional alpha2-adrenoceptors to the contractile response was ruled out.

Insulin-like growth factor-I ameliorates delayed kidney graft function and the acute nephrotoxic effects of cyclosporine.

BACKGROUND: Delayed graft function (DGF) is a relatively common complication after cadaveric renal transplantation. The adverse effect of DGF on long-term graft survival has lead to intensive efforts to reduce ischemic graft injury. In this study we examined the effects of a new protective treatment based on insulin growth factor (IGF)-I. We evaluated the impact of the treatment on renal recovery and on the nephrotoxicity that is a common side effect of mainstream immunosuppressants. Because therapy with IGF-I or the analog des(1-3)IGF-I is effective in treating experimental ischemic renal failure, these peptides may be useful as perspective clinical treatments. METHODS: We have addressed three areas relating to the potential use of IGF-I and its analog des(1-3)IGF-I. First, because of the immunogenic properties of IGF-I, we assessed the effect of des(1-3)IGF-I on the rejection of skin allografts in Lewis rats. Next we determined whether treatment with des(1-3)IGF-I influences the early function of transplanted kidneys in a model of DGF induced by a combination of warm and cold ischemia. Finally we tested whether IGF-I protects against acute cyclosporine nephrotoxicity. RESULTS: Des(1-3)IGF-I did not accelerate the rejection of the skin grafts (P=0.57). The administration of this peptide in a model of syngenic renal transplant improved the early function of the graft. Postoperative values of creatinine and blood urea nitrogen were significantly better (P<0.05) in treated animals. IGF-I also ameliorated the nephrotoxicity of cyclosporine, with better values of creatinine and blood urea nitrogen (P<0.05). CONCLUSIONS: In evaluating this study it should be recognized that the animal models studied, although widely used, differ from the human condition. However, IGF-I and des(1-3)IGF-I exhibit properties that strongly suggest their value in preventing clinical DGF, and they deserve further studies.

Evaluation of the reperfusion syndrome after liver ischemia in the rat.

Hepatic surgery in man often requires a transient interruption of the blood flow to the liver. After the vascular declamping the hepatic reperfusion induces a group of phenomena commonly called "reperfusion injuries." The aim of this study was to evaluate the presence and effect of vasoactive agents that could induce the acute pulmonary arterial hypertension which contributes to reperfusion injury. Wistar rats were used. The hepatic ischemia was induced by crossclamping the whole hepatic hilus for 20, 40, and 60 min. In control experiments a sham operation was performed. Blood samples were collected from the suprahepatic inferior vena cava. Strips of the main pulmonary artery were set up in an isolated organ bath and tested for the response to noradrenaline, adrenaline, KCl, and plasma samples. Plasma levels of catecholamines were determined by high-performance liquid chromatography. Plasma concentration of noradrenaline significantly increased from 1.6 +/- 0.4 (control) to 10.8 +/- 2.9 ng.ml-1 and adrenaline concentration rose from 2.7 +/- 0.7 to 38.7 +/- 7.6 ng.ml-1 after ischemia. Noradrenaline potency, compared to control values, significantly increased after prolonged liver ischemia. The plasma samples collected after prolonged liver ischemia caused a greater contraction of the pulmonary artery than from control plasma. This contraction is partially inhibited by phentolamine. We conclude that hepatic ischemia modifies the response of the pulmonary artery to exogenous noradrenaline. At the same time it induces an increase in the plasma levels of adrenaline and noradrenaline. The resulting combined effect may cause the pulmonary hypertension which has been observed in reperfusion injury.

High-performance liquid chromatographic profiles of aloe constituents and determination of aloin in beverages, with reference to the EEC regulation for flavouring substances.

Characteristic HPLC profiles of fresh and aged aloe solutions, detected at 360 and 220 nm, are presented and compared. Several aloe constituents (aloesin, aloeresin A, hydroxyaloin, aloin A and B and aloinoside A and B) were simultaneously separated and identified. The determination of aloin is described (detection limit 0.15 ppm) and discussed. In aloe-based alcoholic beverages, the aloins could not be detected, owing to their instability and degradation in solution; this is discussed in relation to the EEC Council Directive 88/388, which fixed the values of maximum allowable concentrations for aloin in food and beverages. Instead of aloin, other aloe compounds (e.g., aloeresin A or aloesin) should perhaps be used as an index of the presence of aloe in alcoholic beverages.

Selectivity of LG50643 for postjunctional muscarinic-receptor subtype in the guinea-pig trachea.

The effects of (+/-)-LG50643, a new N-quaternary tropinic ester of phenylcyclohexene carboxylic acid, endowed with a potent antimuscarinic activity, have been investigated on muscarinic receptor-mediated responses of the guinea-pig trachea to electrical field stimulation. An isolated preparation which allows the simultaneous measurement of tritiated acetylcholine release (prejunctional effect) and smooth muscle contraction (postjunctional effect) was used. The guinea-pig epithelium-deprived trachea was stimulated with 500 pulses (20 Hz, 1 ms, 9 V for 5 s, 30 s apart) in the presence of indomethacin (1 microM). Three successive pre- and postjunctional responses were observed. The potencies (-logEC50) of (+/-)-LG50643 for pre- and postjunctional muscarinic receptors were determined and compared with those of selective muscarinic antagonists. In addition, the affinity values of (+/-)-LG50643 for muscarinic-receptor subtypes were determined in radioligand binding experiments in cerebral cortex, heart and salivary glands of rat as target tissues for M1, M2 and M3 receptors, respectively. The results obtained in both functional and binding assays indicate (+/-)-LG50643 is a potent and selective antagonist for the M3-receptor subtype.

Synthesis and muscarinic activity of some muscarone analogs.

The synthesis of some muscarone analogs has been accomplished and their muscarinic activity has been assayed in three in vitro functional tests. The results of such an investigation put in evidence the active role played by the methylene moiety, placed exocyclic to the pentaatomic ring, on the interaction of the ligands with the different muscarinic receptor subtypes. Worth noting is the ileum-atria selectivity displayed by methylene derivative 7.

The inhibitory effect of differently classified calcium antagonists on the calcium- and epinephrine-induced responses of isolated guinea-pig atria.

The effects of calcium antagonists diltiazem, flunarizine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W7) were investigated on the calcium- and epinephrine-induced responses of guinea-pig spontaneously beating atria. All these calcium antagonists showed negative chronotropic and inotropic effects. Diltiazem (3 x 10(-8) M to 1.8 x 10(-7) M) antagonized both the action of epinephrine and calcium in a different manner but at the same concentrations. Flunarizine (1 x 10(-6) M to 1 x 10(-5) M) also antagonized both the action of epinephrine and calcium; but flunarizine weakly inhibits the calcium response at concentrations which have considerable antiadrenergic action. Only at the highest concentrations did both calcium antagonists show a decrease of the epinephrine maximum effect. W7 (1 x 10(-5) M to 1 x 10(-4) M) showed a mainly non-competitive antagonism against epinephrine but was practically ineffective against calcium. The results obtained suggest that a pharmacological prerequisite exists for classifying a calcium antagonist as a calcium entry blocker in the atrial muscle. Such a drug does not produce selective inhibition to calcium- and epinephrine-induced responses. The ability or inability to inhibit the response to calcium represents the discriminant parameter for the action site of the calcium antagonist which are transmembranal fluxes or intracellular mechanisms respectively.

Synthesis and pharmacological investigation of the enantiomers of muscarone and allomuscarone.

A strategy based on the use of (R)- and (S)-lactic ester as starting materials allowed the synthesis of the two enantiomers of muscarone [(-)-1 and (+)-1] and allomuscarone [(-)-5 and (+)-5] in greater than 98% enantiomeric excess. The compounds were examined for their ability to bind to membranes from cerebral cortex (M1), heart (M2), and salivary glands (M3) and to recognize affinity agonist states of the muscarinic receptors. The two pairs of enantiomers were also tested in five functional assays, and their muscarinic potency was determined. In both binding and functional tests, (-)-1 (2S,5S) and (-)-5 (2R,5S) were the eutomers of muscarone and allomuscarone, respectively. The eudismic ratio of muscarone, evaluated in the functional tests, spanned a range of 280-440. These values are substantially different from ones (2.4-10.1) reported in the literature. From a stereochemical point of view, muscarone behaves as muscarine and all other major muscarinic agonists; as a consequence, the hypotheses advanced to account for the anomalies of muscarone no longer have reason to exist.

Synthesis and pharmacological investigation of stereoisomeric muscarines.

The synthesis of the eight stereoisomers of muscarine has been efficiently accomplished by utilizing the two enantiomers of lactic esters as starting material. The synthetic strategy is based on a SnCl4-catalyzed addition of allyltrimethylsilane to O-protected lactic aldehydes followed by an iodocyclization process. All the final derivatives possess an enantiomeric excess higher than 98%. The four pairs of enantiomers bound to M1, M2, and M3 muscarinic receptor subtypes in membranes from cerebral cortex, heart, and salivary glands, respectively, and recognized heterogeneous states of the receptors. Of the eight isomers, only natural muscarine (+)-1 recognized three affinity states of the M2 receptor. The compound was also the only one to show selectivity in the binding study, demonstrating 37- to 44-fold higher affinity for the M2 than for the M1 or M3 receptors. In addition, the compounds were tested in functional assays on isolated guinea pig atria (M2 receptors) and ileum (mixed population of M2 and M3 receptors) and their muscarinic potencies were determined. Among the eight isomers, again only (+)-1 enantiomer was found to be very active on both tissues. Its potency was more than two orders of magnitude higher than that of its enantiomer (-)-1 as well as the other six isomers. The eudismic ratios (E.R.) deduced from the two functional tests were 324 and 331.

A novel class of cholinergic agents structurally related to 2-morpholinol.

A series of esters and ethers of N-alkylmorpholin-2-ols, and their methiodides, which can be considered cyclic analogues of acetylcholine, were synthesized. The amines were obtained by acylation or etherification of morpholinols with the appropriate acyl chlorides and alcohols. All compounds were tested for their ability to interact with the muscarinic receptor M2 (guinea-pig atria) or M3 (rat ileum and urinary bladder) subtype. Some compounds, although endowed with relatively low potency, proved interesting for their organ selectivity. Some considerations on the structure-activity relationship are made and the results obtained with reference agonists and antagonists are also shown.

Potentiating actions of tranylcypromine and moclobemide on the sympathomimetic activity of dopamine.

Ex vivo investigations were carried out to study the potentiating actions of the MAOIs moclobemide and tranylcypromine on peripheral alpha- and beta-adrenergic effects of dopamine. Isolated rat vas deferens and atria were used. Preliminary experiments showed that both moclobemide and tranylcypromine did not affect the response to noradrenaline, while they enhanced the response to tyramine. By comparison of the responses to dopamine in control and reserpinized rats, it was shown that dopamine acts in a direct and indirect manner on both the tissues tested. Two concentrations (20, 40 mg/kg, i.p.) of moclobemide were tested and administered at different time periods (2, 5 or 24 h) before the animals were sacrificed. Two concentrations (2, 20 mg/kg, i.p.) of tranylcypromine were tested at different intervals of time (2, 24 h). The results obtained pointed out that: (1) Moclobemide 20 mg/kg potentiated the alpha-adrenergic response to dopamine only 2 h after administration while 40 mg/kg exerted a potentiation which was evident not only 2 but also 5 h after administration. Both doses were ineffective 24 h after administration. (2) Moclobemide 20 and 40 mg/kg potentiated the beta-adrenergic response to dopamine. The effect was present 2 and 5 h after administration but it was absent 24 h after. (3) Tranylcypromine 20 mg/kg potentiated the alpha-adrenergic response to dopamine: this effect was present after 2 h from pretreatment and was still evident after 24 h. The lower concentration of tranylcypromine (2 mg/kg) enhanced the response to dopamine only after 24 h from pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition by glibenclamide of the effects of cromakalim on responses of rat vas deferens to naphazoline.

Cromakalim has been shown to inhibit naphazoline-induced contractions and spontaneous activity induced by exposure to naphazoline in the rat isolated vas deferens. Glibenclamide 10(-6) M blocked both these effects of cromakalim. Our data add to the list of data derived mainly from experiments on vascular smooth muscle; they suggest that the same glibenclamide-sensitive K+ channel is present in vascular and non-vascular smooth muscle and that it may be involved in the relaxant actions of cromakalim.