Effect of the K+ efflux stimulating vasodilator BRL 34915 on 86Rb+ efflux and spontaneous activity in guinea‐pig portal vein

Quast, Ulrich

doi:10.1111/j.1476-5381.1987.tb11250.x

Cited by 103 publications

(77 citation statements)

References 18 publications

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“…It is thought that the ability of cromakalim to open smooth muscle cell membrane K+ channels underlies its relaxant effect not only in rabbit, rat and guinea-pig isolated blood vessels (Coldwell & Howlett, 1986;Hamilton et al, 1986;Quast, 1987), but also in rat isolated uterus (Hollingsworth et al, 1987), guineapig trachealis (Allen et al, 1986) and guinea-pig and pig urinary bladder (Foster & Brading, 1987).…”

Section: Introductionmentioning

confidence: 99%

Inhibition by glibenclamide of the vasorelaxant action of cromakalim in the rat

Buckingham

Hamilton

Howlett

et al. 1989

British J Pharmacology

117

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In rat isolated thoracic aortic rings pre‐contracted with noradrenaline (10−6 m), cromakalim (3 × 10−7‐3 × 10−5 m) produced concentration‐related relaxation. This effect was progressively inhibited by increasing concentrations of the anti‐diabetic sulphonylurea drug, glibenclamide (10−6‐10−5 m). In rat isolated portal veins, cromakalim (3 × 10−8‐10−6 m) produced concentration‐related inhibition of the spontaneous contractive activity and glibenclamide (3 × 10−7‐3 × 10−6 m) prevented this inhibitory action in a concentration‐dependent manner. In both rat aortic rings and portal veins, cromakalim (10−5 m) stimulated 86Rb efflux. Prior exposure to glibenclamide (10−7‐10−6 m) produced a concentration‐related inhibition of this response. In conscious rats, cromakalim, 0.075 mg kg−1 i.v., produced a rapid and sustained fall in arterial blood pressure which was not influenced by pretreatment (2 h) with a large oral dose of glibenclamide (100 mg kg−1). In conscious rats, the hypotensive action of cromakalim, 0.075 mg kg−1 i.v., was abolished by pretreatment (30 min) with glibenclamide, 20 mg kg−1, given by the intravenous route. The results suggest that the vasorelaxant and hypotensive actions of cromakalim involve a K+ channel which can be inhibited by glibenclamide, but which may be distinct from the ATP‐sensitive K+ channel of the pancreatic β‐cell.

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Section: Introductionmentioning

confidence: 99%

Inhibition by glibenclamide of the vasorelaxant action of cromakalim in the rat

Buckingham

Hamilton

Howlett

et al. 1989

British J Pharmacology

117

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“…This may indicate that the effects of R 56865 in a concentration of 10-6 and 10- In a variety of mammalian smooth muscles, BRL 34915 produces relaxation by opening 6Rb permeable Keg channels leading to membrane hyperpolarisation (Weir & Weston, 1986a,b;Quast, 1987;Allen et al, 1986). The nature of the Ki channels opened by BRL 34915 is as yet unknown, although they do not appear to require Ca2m entry through dihydropyridine-sensitive channels nor are they sensitive to apamin.…”

Section: 'mentioning

confidence: 99%

“…At higher concentrations, the spontaneous mechanical activity was abolished and the simultaneous measurement of "6Rb efflux (Quast, 1987) This response does not require intact endothelium and is prostaglandin-mediated (F8rstermann et al, 1986).…”

Section: 'mentioning

confidence: 99%

“…(Hamilton et al, 1986). Evidence for an increase in Pk was obtained by measuring membrane potential (Hamilton et al, 1986) or 0GRb' efflux (Hamilton et al 1986 ;Quast, 1987); however, these effects were observed only at concentrations of BRL 34915 considerably higher than those required to elicit the vasorelaxing response. One possible reason for the inability to detect stimulation of 0Rb' efflux at low concentrations of BRL 34915 might be that the K' channels opened by the drug are highly selective for K' over Rb'.…”

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confidence: 99%

“…Strips from rat aorta or guinea-pig portal veins (gppv) were incubated in HEPESbuffered PSS (pH 7.2) supplemented with 42K' (5 pCi/ml) or 8Rb' (5 pCi/ml) or both (double labelling experiments). Efflux of radioactivity was measured in a superfusion capillary (Quast, 1987) at 37*C (rat aorta) or 32*C (gppv), the latter in the presence of 0.3 or 0.5 pM of the dihydropyridine Ca2' antagonist PN 200-110 (Hof et al, 1984) in order to abolish myogenic activity . 42K' data were corrected for the short half life of the isotope; double labelling experiments were evaluated essentially as described by Smith et al (1986).…”

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confidence: 99%

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1988

British J Pharmacology

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We have considerable evidence that increased amounts of an endogenous monoamine oxidase inhibitor, which we have called tribulin (Sandler, 1982), are generated in conditions of stress and anxiety. In this study we have investigated the effects of the anxiogenic drugs pentylenetetrazole (PTZ) and ephedrine on tribulin levels in rat brain and heart. Female Wistar ra~ts (approximately 250g) were injected (i.p.) with PTZ (20mg/kg), ephedrine (20mg/kg) or water, 30 min prior to death, or diazepam (1 and 2.5mg/kg) or propranolol (5mg/kg) 60 min before death. When two drugs were administered, a 30 min preadministration period was employed. Rat brains and hearts were rapidly removed, weighed and homogenised (20% w/v) in cold 2M HCl, using an Ultraturrax homogenizer. Homogenates were centrifuged for 10 min at 3,000g and the supernatant extracted into two volumes of redistilled ethyl acetate. The organic layer was removed and dried under nitrogen. Acid blanks were run in parallel throughout the procedure. Residues were reconstituted in 100V1 of 100mM phosphate buffer, pH 7.4 and incubated with 20p1 MAO preparation (1% w/v rat liver homogenate) and 10P1 14C-tyramine (New England Nuclear Corporation); diluted with unlabelled tyramine to give a final concentration of 83pM for 30 min at 37 C. MAO inhibitory activity in rat brain. Diazepam, which had no intrinsic activity, was able to prevent this. Similarly, ephedrine adminiistration brought about raised MAO inhibitory activity in rat brain which could be prevented by prior administration of propranolol. Similar results were found in the heart, although ephedrine did not cause increased MAO I in the heart. We have shown previously that rat urinary tribulin is increased by cold restraint stress, an effect attenuated by benzodiazepines (Glover et al., 1981). These results show that anxiogenic agents can also increase levels of this endogenous MAO inhibitor in rat brain and heart, an effect similarly attenuated by anxiolytic agents. [4,5]decan-7,9-dione methane sulphonate) evolved frpm a programme aimed at the rational design of 5-HTlA receptor ligands using graphics computer assisted technology (Hibert et al., 1986). This report describes the characterisation of MDL 73005EF as a potent and highly selective ligand for 5-HTIA receptors and its activity in a variety of in vitro and in vivo test systems.In a variety of radioligand binding assays (for details see Fozard et al., 1987) MDL 73005EF proved a highly selective displacer of binding to the 5-HTlA recognition site (Table 1). In functional tests the agonist and antagonist activity of MDL 73005EF has been evaluated by its ability to either mimic or reverse the effects of the selective 5-HTIA receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin . On the transmurally stimulated guinea-pig ileum (Fozard and Kilbinger, 1985), MDL 73005EF blocked the 8-OH-DPAT-induced inhibition of the contractile response with a -log KB value of 8.5. The compound was a weak inhibitor of the contractile response (pICl5, 6.7) but achieve...

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Electrophysiological and antiarrhythmic effects of the K‐channel opener, BRL 34915, in cardiac purkinje fibers

Liu

Golyan

McCullough³

et al. 1988

Drug Development Research

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The effects of BRL 34915 (6-cyano-3,4-dihydro-2,2-dimethyl-frans-4-[2-oxo-l-pyrrolidyl]-2H-benzo [b]pyran-3-oI, to be referred to as BRL) on the electromechanical properties of superfused dog and sheep ventricular Purkinje fibers were studied in vitro. At 5 pM, BRL shortened the action potential and decreased contractile force; these effects were greater in dog than in sheep Purkinje fibers. BRL reduced the slope and amplitude of diastolic depolarization measured during interruptions of drive. BRL suppressed spontaneous activity and antagonized the enhancement of automatic discharge induced by norepinephrine (0.5 pM), barium (50 pM), or strophanthidin (0.5 pM). BRL reduced or abolished the oscillatory potentials induced by high [Ca2+], (10.8 mM). It also antagonized the spontaneous responses in low [K+], (1 mM) and hyperpolarized fibers depolarized in a K-free solution. It is concluded that BRL modifies the action potential and force and has antiarrhythmic actions as it antagonizes abnormal pacemaker activity in Purkinje fibers by modifying potassium conductance and secondarily reducing intracellular calcium.

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Effect of the K⁺ efflux stimulating vasodilator BRL 34915 on ⁸⁶Rb⁺ efflux and spontaneous activity in guinea‐pig portal vein

Cited by 103 publications

References 18 publications

Inhibition by glibenclamide of the vasorelaxant action of cromakalim in the rat

Inhibition by glibenclamide of the vasorelaxant action of cromakalim in the rat

Untitled

Electrophysiological and antiarrhythmic effects of the K‐channel opener, BRL 34915, in cardiac purkinje fibers

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