A small-conductance charybdotoxin-sensitive,apamin-resistant Ca2+-activated K+ channel in aortic smooth muscle cells (A7r5 line and primary culture)

A small conductance K⁺ channel was identified in smooth muscle cells of the rat aortic cell line A7r5 and also in rat aortic smooth muscle cells in primary culture, using conventional single-channel recording techniques. The single-channel conductance shows no rectification, either in the range –70 to +40 mV under asymmetrical conditions (9.1 pS), or in the range –100 to +50 mV in symmetrical 150 mM K⁺ (37 pS). Channel activity is reversibly inhibited by extracellular application of charybdotoxin, with a concentration of 8 nM producing half-maximal inhibition. It is unaffected by apamin or scyllatoxin. Channel activity depends on the presence of free Ca²⁺ on the cytosolic face of the membrane, with an activation zone between 0.1 and 1 rc="/content/k636tr5m43133m20/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">M. This small-conductance, charybdotoxin-sensitive, Ca²⁺-regulated K⁺ channel is activated by vasoconstrictors such as vasopressin and endothelin.     

The effect of denervation of Merkel cells in cats

The morphology of Merkel cells in sinus hair follicles of the upper lip (vibrissae with a circular blood sinus), and in touch domes of the glabrous skin of the nose, was investigated in cats up to 12 weeks after resection of the infraorbital nerve. Even 12 weeks after denervation there was neither an ultrastructural alteration of Merkel cells nor a reduction of their number in sinus hair follicles. Also in touch domes the Merkel cells did not disappear.     

Use of λgt11 and monoclonal antibodies to map the gene for the 60,000 dalton glycoprotein of infectious laryngotracheitis virus

To localize the gene encoding the 60 kD glycoprotein (gp60) of infectious laryngotracheitis virus (ILTV), a library of the ILTV genome was constructed in the rc="/content/m4k82g0n39440r26/xxlarge955.gif" alt="lambda" align="BASELINE" BORDER="0">gt11 expression vector. Twelve recombinant bacteriophages expressing gp60 epitopes as fusion products with rc="/content/m4k82g0n39440r26/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-galactosidase were detected by immunoscreening with monoclonal antibodies specific for gp60. The ILTV DNA sequence contained in one of these recombinants rc="/content/m4k82g0n39440r26/xxlarge955.gif" alt="lambda" align="BASELINE" BORDER="0">24-4 was used as a hybridization probe for mapping the insert sequence on the viral genome. The gene for the gp60 was located at map unit 0.72–0.77 in the unique long region (U_L) of the ILTV genome. The DNA sequence of the 1.2 kb insert of rc="/content/m4k82g0n39440r26/xxlarge955.gif" alt="lambda" align="BASELINE" BORDER="0">24-4 containing the gp60 epitope was determined. The majority of deduced gp60 amino acid sequence has no homology with any of the known alphaherpesvirus glycoproteins.The nucleotide sequence data reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned the accession number X 121209.     

Effects of guanabenz and guanfacine on postsynaptic α2-adrenoceptors in the rat submaxillary and parotid glands

Summary The effects of two rc="/content/fw373207r334q734/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-agonists (guanfacine and guanabenz) on both the submaxillary and parotid gland of the rat were studied. Whereas guanfacine in doses ranging between 1,000 and 30,000 rc="/content/fw373207r334q734/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">g/kg i.v. produced an immediate and persistent secretion of saliva from the submaxillary gland, guanabenz in doses as high as 40,000 rc="/content/fw373207r334q734/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">g/kg did not induce measurable secretion either from the parotid or the submaxillary gland. Secretion clicited by guanfacine was not modified by yohimbine (300 rc="/content/fw373207r334q734/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">g/kg) but was abolished by prazosin (100 rc="/content/fw373207r334q734/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">g/kg).In both glands, low doses of either guanabenz (10 rc="/content/fw373207r334q734/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">g/kg) or guanfacine (100 rc="/content/fw373207r334q734/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">g/kg) markedly inhibited the secretory responses induced by noradrenaline, methacholine and substance P, but not that induced by isoprenaline. The inhibition caused by the rc="/content/fw373207r334q734/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-agonists was greater for noradrenaline than for either methacholine or substance P. Blockade of rc="/content/fw373207r334q734/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptors with yohimbine (300 rc="/content/fw373207r334q734/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">g/kg) did not modify the response to noradrenaline, methacholine or substance P in either gland. However, the same dose of yohimbine injected 5 min before the rc="/content/fw373207r334q734/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-agonists prevented the inhibitory effects of guanfacine and guanabenz on the response induced by either one of the three sialagogic agents. Guanabenz (10 rc="/content/fw373207r334q734/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">g/kg) did not modify the increase in mean blood pressure observed after the different doses of noradrenaline employed to induce salivary secretion. Guanabenz (10 rc="/content/fw373207r334q734/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">g/kg) and guanfacine (100 rc="/content/fw373207r334q734/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">g/kg) did not change the time course of the secretion elicited by either noradrenaline, methacholine or substance P, since the degree of inhibition was of similar magnitude at all the periods of time analyzed.The results obtained give further support to the hypothesis that activation of rc="/content/fw373207r334q734/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptors in the submaxillary as well as parotid gland of the rat inhibits secretory responses which are mediated by either muscarine, substance P and rc="/content/fw373207r334q734/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₁-receptors and not those elicited by rc="/content/fw373207r334q734/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptors.Partially supported by grants no. 3111 k/83 CONICET and Res 40-5/4/84 SUBCYT     

Interactions of the enantiomers of 3-O-methyldobutamine with α- and β-adrenoceptors in vitro

Summary The enantiomers of 3-O-methyldobutamine, a metabolite of dobutamine, were evaluated for their rc="/content/f107tx2q82j51h7r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">- and rc="/content/f107tx2q82j51h7r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptor mediated effects in vitro in a variety of isolated organs and in radioligand binding studies. Neither enantiomer of 3-O-methyldobutamine possessed rc="/content/f107tx2q82j51h7r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₁-adrenoceptor agonist activity in isolated guinea pig aorta. However, both enantiomers of 3-O-methyldobutamine were competitive rc="/content/f107tx2q82j51h7r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₁-adrenoceptor antagonists, with the (+)-enantiomer being approximately 10-fold more potent than the (-)-enantiomer as assessed either in guinea pig aorta or by displacement of ³H-prazosin binding from rc="/content/f107tx2q82j51h7r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₁-adrenoceptors in rat cerebral cortex. The rc="/content/f107tx2q82j51h7r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₁-adrenoceptor blocking activity of (+)-3-O-methyldobutamine was relatively potent and corresponded to a pA₂ of 7.33 in guinea pig aorta and a-log K _i of 7.72 in radioligand binding studies. Neither enantiomer of 3-O-methyldobutamine possessed rc="/content/f107tx2q82j51h7r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptor agonist activity in field-stimulated guinea pig ileum. Although (+)-3-O-methyldobutamine weakly inhibited the twitch response in field-stimulated guinea pig ileum, the response was not blocked by the selective rc="/content/f107tx2q82j51h7r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptor antagonist, yohimbine, and was found to result from weak anticholinergic activity (pA₂=5.06). Neither enantiomer of 3-O-methyldobutamine possessed rc="/content/f107tx2q82j51h7r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₁-adrenoceptor agonist activity in guinea pig atria, however the (+)-enantiomer was a weak noncompetitive antagonist at rc="/content/f107tx2q82j51h7r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₁-adrenoceptors. In contrast, both enantiomers of 3-O-methyldobutamine were weak rc="/content/f107tx2q82j51h7r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₂-adrenoceptor agonists in rat uterus, however these weak effects were not highly stereoselective, which was also confirmed in radioligand binding studies. The results of the present study indicate that 3-O-methyldobutamine is a potent and highly selective rc="/content/f107tx2q82j51h7r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₁-adrenoceptor antagonist, with minimal activity at rc="/content/f107tx2q82j51h7r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-, rc="/content/f107tx2q82j51h7r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₁- and rc="/content/f107tx2q82j51h7r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₂-adrenoceptors. It is hypothesized that the potent rc="/content/f107tx2q82j51h7r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₁-adrenoceptor antagonist activity of 3-O-methyldobutamine, which resides predominantly in the (+)-enantiomer, may play a role in the hemodynamic effects of dobutamine, by contributing, in part, to the decrease in total peripheral vascular resistance observed following administration of dobutamine.     

An analysis of theα-adrenoceptor modulation of vasomotor tone at the level of lateral medullary pressor area (LMPA)

Summary Microinjection of noradrenaline and clonidine into lateral medullary pressor area (LMPA) of chloralose anaesthetized cats produced dose dependent decrease in blood pressure without affecting heart rate, while phenylephrine did not elicit any cardiovascular response. Selectiverc="/content/r1w804032138705w/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0"> ₂-adrenoceptor, antagonists idazoxan and piperoxan, microinjected locally, blocked the effects of the agonists but prazosin and phenoxybenzamine, which are relatively selective forrc="/content/r1w804032138705w/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0"> ₁-adrenoceptors, failed to do so. Clonidine did not elicit any response in guanethidine pretreated cats but noradrenaline microinjected into LMPA of these animals induced a pressor response which was blocked by prazosin pretreatment. It is concluded that catecholaminergic fibres impinging upon this are inhibit the activity of the inhibitory second order baroreceptor neurone by activatingrc="/content/r1w804032138705w/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0"> ₁-adrenoceptors whilerc="/content/r1w804032138705w/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0"> ₂-adrenoceptors situated presynaptically on these inhibitory catecholaminergic nerve terminals are responsible for the manifestation of the hypotensive effect of clonidine and exogenously administered noradrenaline.     

138. Zum Krankheitsbild der primären chronischen intestinalen Pseudoobstruktion (CIPSO) im Kindesalter

Zusammenfassung Bei der primären CIPSO besteht eine Ileussymptomatik ohne mechanische Occlusion aufgrund fehlender bzw. ineffektiver Peristaltik trotz normaler Darmwandstruktur. Es werden die neonatale und adulte Form unterschieden. Die Pathogenese ist ungeklärt. Bei den neonatalen Krankheitsbildern der CIPSO (neonatale CIPSO, MMIHS, congenitales rc="/content/r87648lj427g502r/xxlarge8222.gif" alt="ldquor" align="MIDDLE" BORDER="0">short-bowel-Syndromrc="/content/r87648lj427g502r/xxlarge8221.gif" alt="rdquo" align="MIDDLE" BORDER="0">) besteht ein progredienter Ileus, bei der adulten Form ein chronischer, letztlich aber auch letaler Verlauf. Anhand von 5 Kindern mit einer primären CIPSO wird die Problematik von Diagnostik und Therapie besprochen.     

Effects of pentagastrin and carbachol on the gastric histamine level in α-fluoromethylhistidine-treated mice and rats

Summary The gastric mucosal histamine level in mice increased by about 80% and 100% after fasting for 24 and 48 h, respectively. In non-fasted mice, rc="/content/r30847u231803118/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-fluoromethylhistidine (rc="/content/r30847u231803118/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-FMH), a specific histidine decarboxylase inhibitor, significantly decreased the histamine level, the reduction amounting to 35% and 49%, 2 h and 4 h after treatment, respectively. In mice fasted for 24 h, a significant decrease of 42% was observed 4 h after treatment. However, in mice fasted for 48 h, no significant decrease was seen even 4 h after rc="/content/r30847u231803118/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-FMH treatment. Therefore, the histamine-releasing effect of re-feeding and drugs on the gastric mucosa was examined in vivo, using animals fasted for 48 h and subsequently treated with rc="/content/r30847u231803118/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-FMH. Food given simultaneously with rc="/content/r30847u231803118/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-FMH to 48-h fasted mice significantly decreased the histamine level 4 h later. Pentagastrin and carbachol administered alone (0.25–2.0 mg/kg, i.p.) had no significant effect on the histamine level. However, the combined treatment with these drugs significantly decreased the histamine level. In rats fasted for 48 h and treated with rc="/content/r30847u231803118/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-FMH, pentagastrin (0.25 and 0.5 mg/kg, i.p.) but not carbachol (0.125 – 0.5 mg/kg, i. p.) caused a significant decrease in the mucosal histamine level. In contrast to mice, the effect of the combined treatment with pentagastrin and carbachol was not synergistic in rats. These findings suggest that gastrin acts synergistically with acetylcholine in the histamine release from the gastric mucosa in mice, whereas such synergism may not occur in rats. Send offprint requests to K. Saeki     

Hairy cell leukemia: clinical features and therapeutic advances

Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder which has been extensively studied over the past decade. Much has been learned regarding the diagnosis, natural history, biology, and treatment of this unique neoplasm. The disease most commonly affects middle aged men and characteristic clinical features include splenomegaly, cytopenias, and usually the presence in the peripheral blood of distinctive thairy cells with irregular cytoplasmic projections. Diagnosis can usually be confirmed by bone marrow biopsy. Although the natural history can be extremely variable among patients, complications are usually referable to the cytopenias, with anemia and infection being most frequent. In addition to pyogenic infections, patients are susceptible to unusual organisms including atypical mycobacterium, legionella, and fungi. The requirement of red blood cell transfusion, severe granulocytopenia or thrombocytopenia, frequent infections, or painful splenomegaly are all indications for treatment. Splenectomy is the standard initial treatment of choice. However, in the past few years there have been exciting major advances in the therapeutic modalities for HCL. Recombinant alfa-interferon is highly effective, with beneficial responses occurring in close to 90% of patients. The Food and Drug Administration has recently approved the use the interferon for HCL. This represents the first time a biological response modifier has been approved for the treatment of human disease. In addition, preliminary results with the adenosine deaminase inhibitor, 2rc="/content/r03637g54253k016/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0"> deoxycoformycin (def), have been encouraging. Further clinical trials are required in order to determine the optimal sequential treatment strategy for HCL. The exact mechanisms of action of both interferon and def in HCL remain to be elucidated. A better understanding of the unusual features of the hairy cell and the underlying biological effect of these two agents in HCL may have important applications in other hamatologic and non-hematologic malignancies.