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Schild Analysis of In Vivo Theophylline Antagonism of Adenosine in Fetal Sheep Coronary Arteries
Author(s) -
Jonker Sonnet,
Giraud George,
Louey Samantha
Publication year - 2015
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.29.1_supplement.lb594
Subject(s) - theophylline , adenosine , adenosine receptor , medicine , adenosine receptor antagonist , blood flow , coronary vessel , endocrinology , chemistry , receptor , agonist
Adenosine causes near‐maximal vasorelaxation of fetal coronary arteries but adenosine receptor antagonism in this bed has not been characterized. We performed Schild analysis of theophylline (adenosine antagonist with similar affinity for receptors A1, A2a and A2b) in near‐term fetal sheep coronaries. Fetuses (n=4) were instrumented with vascular catheters and a circumflex transit‐time flow probe. Vascular pressures (corrected to amniotic pressure) and coronary flow (corrected to driving force) were recorded continuously. Heart rate was controlled with propranolol and atropine. Theophylline (bolus then continuous infusion) was given into the right atrium. Graded infusions of adenosine into the left atrium stimulated increased coronary flow. Theoretical adenosine concentrations were calculated from infusion rates and assumed left ventricular output; theophylline concentrations were measured in arterial blood. The plateau was constrained at 100% of adenosine‐stimulated coronary flow, while the floor was unconstrained, allowing for theophylline suppression of baseline flow due to endogenously produced adenosine. Log(EC50), pA 2 , Schild and Hill slopes were constrained to share values within one fetal experiment. Schild analysis yielded a mean global R 2 =0.98, EC50=0.88±0.41uM(sd), Hill slope=2.5±0.4, Schild slope=0.94±0.63 and pA 2 =4.8±0.4. A Schild slope close to 1 indicates theophylline acts as a competitive antagonist of adenosine in the fetal coronaries in this dose range, thus pA 2 =pK b . These data suggest that maternal methylxanthine consumption may alter fetal coronary perfusion. Supported by NICHD R01HD071068 and P01HD034430.