摘要:

The effect of cromakalim, a K+ channel opener, on the growth of human brain tumor cells was investigated. Cromakalim inhibited the growth of SK-N-MC human neuroblastoma and U-373 MG human astrocytoma cell lines in a dose-dependent manner. This effect of cromakalim was significantly blocked by the co-treatment with sulfonylureas (glibenclamide or tolbutamide) which are known as specific blockers for ATP-sensitive K+ channels. In addition, cromakalim significantly inhibited agonist-induced intracellular Ca2+ mobilization in the astrocytoma cells. This inhibition induced by cromakalim was also reversed by pretreatment with glibenclamide. These results suggest that the antitumor activity of cromakalim may be due to the activation of ATP-sensitive K+ channels leading to the inhibition of the intracellular Ca2+ signalling mechanism.

ISSN:0031-7012    

DOI:10.1159/000139218

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Cromakalim, an agent that opens ATP-modulated potassium channels, has recently been reported to reduce skeletal muscle contractile force during anoxia in vitro. To determine whether this activity occurs in vivo, cromakalim was tested for its ability to influence muscle function and blood flow in a model of skeletal muscle ischemia. In anesthetized ferrets the muscles of the hindlimb were stimulated electrically via the sciatic nerve and isometric force of contraction was measured. Under normal perfusion conditions, contractile force peaked (324 ± 33 g) within 1 or 2 min and gradually declined to about 85% of the peak over 20 min. Following this initial period, the abdominal aorta was partially occluded to reduce femoral blood pressure to 35-40 mm Hg, and infusion of cromakalim or vehicle was started. After 60 min of treatment, a second exercise challenge was performed. In the vehicle-treated group, peak force was reduced by 33% (p < 0.05), and over the 20-min stimulation period, the area under the force-time curve (AUC) was 22.8 ± 2.6% of that seen during the normal flow period. Compared to vehicle, cromakalim infusions of 1.33 or 3.0 µg/kg/min reduced mean arterial blood pressure by 7 and 45%, but had no significant effect on either peak force or AUC. Although the higher dose of cromakalim significantly reduced vascular resistance in resting, normally perfused skeletal muscle of the forelimbs, neither dose affected blood flow in the ischemic skeletal muscles of the hindlimb during exercise. These results suggest that cromakalim does not influence skeletal muscle blood flow or function during an acute ischemic insu

ISSN:0031-7012    

DOI:10.1159/000139219

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

ATP-sensitive potassium (K+Atp) channel openers such as cromakalim and pinacidil exhibit both potent vasodilatory and anti-ischemic properties. U-89232, a cyanoguanidine analog of cromakalim, has recently been found to exhibit myocardial protection during ischemia without altering in vivo hemodynamics. We examined the effects of U-89232, cromakalim and pinacidil in isolated vascular and cardiac tissue and tested whether glyburide, a Katp channel blocker, could antagonize their effects. All three compounds produced concentration-dependent relaxation in isolated vascular segmentswith cromakalim being approximately 100-fold more potent than either pinacidil or U-89232. Glyburide completely antagonized the effects of pinacidil but merely blunted the effects of cromakalim and U-89232. In an isolated rabbit cardiac tissue preparation, U-89232 had little effect on maximum tension in cardiac muscle, whereas cromakalim and pinacidil significantly decreased maximum developed tension in a concentration-dependent manner. Glyburide effectively antagonized the effects of cromakalim and pinacidil in cardiac tissue. These data suggest that U-89232, although chemically related to cromakalim, possesses activity which is not common to known potassium channel openers.

ISSN:0031-7012    

DOI:10.1159/000139220

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

We have previously reported that cromakalim and U-89232 reduce infarct size in a rabbit model of myocardial ischemia. Because U-89232 appeared to lack activity in the vasculature, we tested its reversibility with glibenclamide. Twenty-eight ketamine-xylazine anesthetized open-chest, New Zealand White rabbits were instrumented for regional coronary occlusion and reperfusion. Study animals received either cromakalim, U-89232 or vehicle. In some animals, glibenclamide was administered. All animals were then subjected to ischemia (30 min) and reperfusion (120 min), and necrosis was determined using tetrazolium. With comparable hemodynamics and myocardium at risk, infarct size in control animals was 35.5 ± 4.6% of risk region, and was not different from glibenclamide-treated animals (37.7 ± 5.8%). Cromakalim alone has been shown to be protective, however when combined with glibenclamide necrosis amounted to 35.1 ± 3.8% of the risk region (p = NS vs. control). In contrast, U-89232 was protective in the presence of glibenclamide (17.2 ± 4.9% of the risk region). We conclude that U-89232 produces myoprotection independent of K-ATP channel inhibition, indicating that this compound possesses novel anti-ischemic characterist

ISSN:0031-7012    

DOI:10.1159/000139221

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

In isolated pancreatic islets of mice, the relationships between free glimepiride concentration and membrane binding or inhibition of ATP-sensitive K+ channels were examined. Microsomal membrane binding and K+ channel inhibition were half-maximal at 0.7 and 0.3 nmol/l glimepiride, respectively. The corresponding concentrations for glibenclamide were 0.4 and 0.6 nmol/l. Administration of glimepiride (10 nmol/l) or glibenclamide (10 nmol/l) to isolated mouse islets perifused with albumin-containing media induced a slow increase in insulin secretion. The kinetics of the secretory responses to glimepiride and glibenclamide were identical. Determination of albumin binding revealed that the free glimepiride and glibenclamide concentrations applied in our investigation were in the range of therapeutic serum concentrations of the free drugs. It is concluded that the effects of glimepiride and glibenclamide are very similar in mouse β-cells

ISSN:0031-7012    

DOI:10.1159/000139222

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

We studied the action of β-adrenergic agonists on Japanese quail erythrocyte carbonic anhydrase (CA) in vitro. Earlier we had reported that epinephrine increased CA activity by 14%; the present study focused on an attempt to increase the size of this response. Washed erythrocytes from reserpine-treated (1 mg/kg daily i.m. for 3 days) and control birds were incubated for 40 min in the presence of isoproterenol 10–6 mol/l. The activity of CA expressed as Wilbur-Anderson units/mg hemoglobin was increased by as much as 42% in reserpine-treated birds over the control depending on the conditions. Addition of 10–5 mol/l of the β-adrenergic antagonist propranolol inhibited the isoproterenol-induced effect in nonreserpinized birds. We conclude that pretreatment with reserpine, which was accompanied by a fall in plasma catecholamine levels, particularly epinephrine levels, enhanced the activation of CA by isoprote

ISSN:0031-7012    

DOI:10.1159/000139223

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

To find a δ-opioid receptor preferring peptide structure containing an Asp residue in a potentially interacting position, Tyr-Pro-Phe-Asp, Tyr-D-Ala-Phe-Asp, Tyr-D-Ala-Gly-Phe-Asp, Tyr-D-Ala-Gly-Phe-Asp α- and β-methyl ester and Tyr-Gly-Gly-Phe-Asp peptides were synthesized and their biological activities were analyzed in vitro in mouse vas deferens and longitudinal muscle strip of guinea pig ileum. Changing the β-methyl ester for an alkylating chloromethyl ketone moiety in the δ-receptor-selective agonist Tyr-D-Ala-Gly-Phe-Asp-β-methyl ester enhanced further the δ-receptor preference. The δ-receptor selective chloromethyl ketone but not the β-methyl ester gave a very slow washout after prolonged incubation in the mouse vas deferens bioassay; however, it was still readily displaceable by naloxone. The washout pattern of µ-specific Tyr-D-Ala-Gly-(Me)Phe chloromethyl ketone did not differ in the bioassays from that of the corresponding Gly5-ol derivative. Both chloromethyl ketones gave irreversible characteristics in the receptor bind

ISSN:0031-7012    

DOI:10.1159/000139224

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Experimental studies have suggested that ambroxol, a drug clinically used to enhance pulmonary surfactant production, may also exert some anti-inflammatory effects, though specific mechanisms are not yet fully understood. Thus, potential scavenging properties of ambroxol towards the most toxic neutrophil-arising prooxidants hypochlorous acid and monochloramine were investigated. We have found that the drug at 25, 50 and 100 µmol/l exerted a significant, concentration-related antagonizing effect on both chlorine species, with a maximal specific activity detected against hypochlorous acid. These new pharmacological properties of ambroxol may play a role in vivo in disease entities characterized by white blood cell activation and uncontrolled oxidant generation, such as inflammatory/ischemic conditions

ISSN:0031-7012    

DOI:10.1159/000139225

出版商:S. Karger AG    

年代:1994

数据来源: Karger

ISSN:0031-7012    

DOI:10.1159/000139226

出版商:S. Karger AG    

年代:1994

数据来源: Karger