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Inhibition of lactate‐producing glycolysis increases antidiabetic drug‐induced vasorelaxations and blocks sildenafil's attenuation of them
Author(s) -
Peuler Jacob D.,
Phelps Laura E.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.571.7
Subject(s) - sildenafil , metformin , rosiglitazone , pharmacology , glycolysis , medicine , vascular smooth muscle , contraction (grammar) , drug , endocrinology , chemistry , diabetes mellitus , metabolism , smooth muscle
Sildenafil is used to treat erectile dysfunction in men with type 2 diabetes (T2D). Hypertension is common in T2D but sildenafil attenuates vasorelaxant actions of metformin, pioglitazone and rosiglitazone: 3 antidiabetic (AD) drugs often used to improve glucose metabolism in T2D. Previously, to assess the glucose dependence of this effect, vascular rings from rat tail arteries were treated with each AD drug ± sildenafil. After 4 hours, all rings were contracted with norepinephrine (NE). With extracellular glucose present, all 3 AD drugs relaxed NE contractions and sildenafil attenuated such relaxations. With glucose omitted, relaxant actions of the AD drugs were notably increased and sildenafil failed to attenuate them. More recently, specific inhibition of only lactate‐producing glycolysis pathways with iodoacetate (30 micromolar) exerted similar results. We conclude that, in addition to vascular smooth muscle relaxant mechanisms, these 3 AD drugs also activate contraction‐enhancing mechanisms, which are dependent on specific glycolysis pathways and mask the full potential of the relaxant mechanisms. Thus, sildenafil's attenuation of AD drug‐induced vasorelaxations may not only involve interference with their relaxant mechanisms but also facilitation of specific glycolysis‐dependent contraction‐enhancing mechanisms. Support: Midwestern University