1,289 research outputs found

    A K<sub>ATP</sub> channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias

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    Low concentrations of certain K&lt;sub&gt;ATP&lt;/sub&gt; channel openers have been reported to exert a moderate inhibitory effect on arrhythmias during post-ischaemic early myocardial reperfusion, but the accompanying effects on the time course of changes in action potentials in intact hearts have not yet been studied. We report that in rat isolated hearts, reperfusion following 10 min of regional no-flow ischaemia was associated with both an acute, marked, but transient, shortening of ventricular repolarisation (by 63%) during reperfusion, and a high incidence (90%) of ventricular tachyarrhythmias. The K&lt;sub&gt;ATP&lt;/sub&gt; channel opener Ro 31-6930 [2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-pyridine 1-oxide], delivered prior to ischaemia at a relatively low concentration (0.5 Ī¼M), significantly reduced the incidence and duration of reperfusion arrhythmias, and prevented the associated acute action potential shortening during reperfusion, each in a glibenclamide (1 Ī¼M)-sensitive manner (P&lt;0.05, &lt;i&gt;n&lt;/i&gt;=10ā€“15 hearts). This was associated with a moderate and non-arrhythmogenic action potential shortening during ischaemia (a potentially ā€œcardioprotectiveā€ effect). However, these data highlight the potential harm these drugs may cause, since a higher concentration of Ro 31-6930 caused marked shortening of action potentials and significant pro-arrhythmia during ischaemia

    Do K<sub>ATP</sub> channels open as a prominent and early feature during ischaemia in the Langendorff-perfused rat heart?

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    The objective was to investigate whether myocardial adenosine triphosphate-sensitive K&lt;sup&gt;+&lt;/sup&gt; (K&lt;sub&gt;ATP&lt;/sub&gt;) channels open during the first 10 min of regional ischaemia in Langendorff-perfused rat hearts. Changes in monophasic action potentials and arrhythmias were studied during myocardial ischaemia in both the presence and absence of pharmacological K&lt;sub&gt;ATP&lt;/sub&gt; modulation. Ligation of the left main coronary artery for 10 min did not shorten the action potential duration (APD). The APD&lt;sub&gt;50&lt;/sub&gt; and APD&lt;sub&gt;80&lt;/sub&gt; (15.5 +/- 1.0 and 38.1 +/- 2.3 ms, respectively [mean +/- S.E., n = 15 hearts], immediately prior to ligation) increased transiently during the first 4 min of ligation (by 160 and 79% respectively, P &#60; 0.05), before returning to pre-ligation values, but without a significant below-baseline-shortening. The cardiac electrogram showed no accompanying ventricular tachyarrhythmia (VT). These results raised the possibility that the myocardial K&lt;sub&gt;ATP&lt;/sub&gt; channels had not opened during the ligation. The K&lt;sub&gt;ATP&lt;/sub&gt; opener Ro 31-6930 (0.5 and 5 microM) shortened the APD50 and APD80 during coronary ligation, to significantly below both their control and pre-occlusion values (P &#60; 0.05), and caused a concentration-dependent increase in both the incidence and duration of VT during the ligation. Ro 31-6930 at 5 microM also shortened APD50 and APD80 even before ligation (by 50 and 62% respectively, P &#60; 0.05), and abolished the normal APD-lengthening seen during ischaemia. The K&lt;sub&gt;ATP&lt;/sub&gt; blocker glibenclamide (1 &#956;M) abolished both the APD-shortening and pro-arrhythmic effects of the K&lt;sub&gt;ATP&lt;/sub&gt; opener, both before and during coronary ligation, yet when delivered on its own, at the same concentration which abolished the effects of K&lt;sub&gt;ATP&lt;/sub&gt; activation, it had no significant effect on the APD changes seen during the coronary ligation alone. These results suggest that, in Langendorff-perfused rat hearts in the absence of drugs, K&lt;sub&gt;ATP&lt;/sub&gt; channels do not open during early myocardial ischaemia

    Inhibition of NO-synthase and degranulation of rat omental mast cells in vitro

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    Mast cell amines, platelet-activating factor (PAF), thromboxanes and leukotrienes have been shown to be released during nitric oxide-synthase inhibition in the rat intestine. Mast cells in rat isolated omentum (OMCs) or isolated from the rat peritoneal cavity (PMCs) have been used here to investigate the relationship(s) between these agents. N-nitro-L-arginine methyl ester (L-NAME, 100 Ī¼M) caused some degranulation of OMCs, but no enhancement of histamine release from PMCs. PAF (5 Ī¼M) and U46619 (1 Ī¼M) degranulated OMCs and enhanced histamine release from PMCs. Pre-treatment of the omentum with BN52021 (10 Ī¼M) inhibited degranulation of OMCs in response to L-NAME, PAF or U46619. Pretreatment with 1-benzylimidazole (5 or 50 Ī¼M) inhibited the effect of L-NAME but not that of PAF. Indomethacin (1 Ī¼M) or sodium nitroprusside (10 Ī¼M) also inhibited the effects of L-NAME, but nordihydroguaiaretic acid (30 Ī¼M) did not. In PMCs BN52021 inhibited PAF-induced, but not U46619-induced, release of histamine. These results suggest that inhibition of nitric oxidesynthase in the omentum by L-NAME allows thromboxanes to release PAF, which in turn degranulates and releases histamine from OMCs

    Possible bi-directional link between ETA receptors and protein kinase C in rat blood vessels

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    Possible links have been investigated between activation of protein kinase C (PKC) and endothelin (ET) production by small blood vessels. Perfusion pressures were recorded from rat isolated mesenteric artery, with or without the small intestine attached, before and after addition to the perfusate of either ET-1, ET-3 or the PKC activator 12-deoxyphorbol 13-phenylacetate (DOPPA). Rises in perfusion pressure in response to ET-1 (10āˆ’8 M)or DOPPA (10āˆ’6 M) were reduced significantly by pre-treatment with either the ETA receptor antagonist PD151242 (10āˆ’6 M) or the PKC inhibitor Ro 31-8220 (10āˆ’6 M). ET-3 (10āˆ’8 M) had a significant, albeit small, effect only when the gut was still attached to the mesentery. Inthis latter preparation ET-1 and DOPPA increased the permeability of villi microvessels to colloidal carbon in the perfusate. This effect of DOPPA was reduced by pre-treatment with either PD151242 or Ro 31-8220, but the effects of ET-1 were reduced significantly only by Ro 31-8220. ET-3 (10āˆ’8 M) was without effect. The results suggest a possible bi-directional link between ETA receptors and PKC in the intestinal vasculature
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