Glibenclamide enhances but pinacidil reduces attenuation in sympathetic responsiveness after acute coronary artery occlusion

Makoto Ito, Harald P. Pride, Douglas P. Zipes

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

To investigate the role of ATP-sensitive K+ channels in modulating the efferent autonomic response following acute myocardial ischemia/infarction, we examined the effects of a blocker (glibenclamide) and an opener (pinacidil) of ATP-sensitive K+ channels on the time course and extent of the attenuation in efferent cardiac sympathetic responsiveness in anesthetized dogs. We measured the effective refractory periods (ERPs) at nonischemic sites basal and apical to the area of myocardial ischemia/infarction in the baseline state and during bilateral stimulation of the ansae subclaviae before and after each drug administration and 5, 30, 60, 120, and 180 minutes after latex injection of a diagonal branch of the left anterior descending coronary artery. Animals received either vehicle (n=12), glibenclamide (0.3 mg · kg-1, n=10), pinacidil (0.15 mg · kg-1 +0.2 mg · kg-1 infusion, n=10), or a combination of these two drugs (n=9) intravenously. In another group of dogs receiving just pinacidil (n=10), an intra-aortic balloon was inflated distal to the renal arteries to prevent pinacidil-induced hypotension. Another group of dogs received either high- dose glibenclamide (0.3 mg · kg-1+0.15 mg · kg-1, n=4), low-dose glibenclamide (0.06 mg · kg-1, n=4), medium-dose pinacidil (0.03 mg · kg-1+0.04 mg · kg-1 infusion, n=4), or low-dose pinacidil (0.0075 mg · kg-1+0.01 mg · kg-1 infusion, n=4). In all dogs, basal sites exhibited no attenuation of sympathetically induced shortening of the ERP throughout the period of acute myocardial ischemia/infarction. Cumulative attenuation in sympathetic responsiveness (shortening of ERP ≤2 milliseconds induced by bilateral stimulation of the ansae subclaviae) at nonischemic test sites apical to the area of ischemia/infarction during a 3-hour period was greater in the glibenclamide group (26 of 44 sites, P=.008) and less in the pinacidil (2 of 44 sites, P=.002) and pinacidil-balloon (1 of 48 sites, P<.001) groups compared with the vehicle group (14 of 46 sites). Glibenclamide abolished the protective effect of pinacidil so that 10 of 45 sites had <2-millisecond shortening during a 3-hour period in the glibenclamide+pinacidil group (P=.018 versus pinacidil group, P=.286 versus vehicle group). Such effects of glibenclamide and pinacidil on sympathetic attenuation were dose dependent. Maintaining the blood glucose level during glibenclamide administration did not affect the sympathetic attenuation after acute coronary artery occlusion. Infarct size using triphenyltetrazolium staining and measured as the ratio of the width of subepicardial infarction to the left ventricular circumference was similar (P>.9) among the five groups. Glibenclamide and pinacidil did not affect the attenuation of the ERP response to stimulation of the ansae subclaviae during pericardial superfusion with combined (12 mmol/L K+, pH 6.8, plus 10 μmol/L adenosine) Tyrode's solution, suggesting no direct effects of glibenclamide and pinacidil on sympathetic neural function. We interpret these data to indicate that pinacidil helps preserve the ERP response to sympathetic stimulation during acute myocardial ischemia/infarction, whereas glibenclamide worsens it.

Original languageEnglish (US)
Pages (from-to)379-392
Number of pages14
JournalCirculation research
Volume75
Issue number2
DOIs
StatePublished - Aug 1994

Keywords

  • denervation
  • efferent sympathetic nerve
  • glibenclamide
  • myocardial infarction
  • pinacidil

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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