title: Effects of gestational age and cortisol treatment on ovine fetal heart function in a novel biventricular Langendorff preparation.
abstract: Structural and functional maturation of a number of fetal organs and physiological systems occurs in the immediate period prior to term, in association with the prepartum increase in fetal plasma cortisol concentration. At present, little is known about how myocardial sensitivity to adrenergic and muscarinic cholinergic stimulation changes as the fetus approaches term, nor the role of the prepartum increase in plasma cortisol concentration in mediating these changes. This study used a novel Langendorff, biventricular, ovine fetal heart preparation to investigate the effects of advancing gestation and cortisol treatment on myocardial sensitivity to adrenergic (isoprenaline) and muscarinic cholinergic (carbachol) stimulation. It was hypothesized that cortisol infusion would fully mimic developmental changes in myocardial responsiveness to adrenergic and cholinergic stimulation. Sixteen Welsh Mountain sheep fetuses were surgically prepared under general anaesthesia with vascular catheters. At 125 +/- 1 days gestational age (dGA; term, 145 dGA) fetuses were infused with saline vehicle (n= 7; Premature Control) or with cortisol (n= 4; 2-3 mg kg(-1) d(-1)i.v.; Premature Cortisol) for 5 days. The Term Control group (n= 5) comprised fetuses that were surgically prepared at 130 dGA and infused with vehicle for 5 days prior to delivery (n= 2), or that received no surgery (n= 3). Under terminal anaesthesia, Premature Control and Premature Cortisol fetuses were delivered at 130 dGA and Term Control fetuses between 135 and 143 dGA. Following exsanguination under anaesthesia, fetal hearts were mounted in the Langendorff preparation, allowing measurement of left ventricular (LV) developed pressure and right ventricular (RV) developed pressure, heart rate (HR), coronary perfusion pressure and perfusate distribution to the myocardium. Cortisol infusion elevated fetal plasma cortisol concentrations to values similar to those measured close to term (45.0 +/- 7.1 ng ml(-1)). Advancing gestational age, but not cortisol treatment, enhanced fetal LV developed pressure, RV developed pressure and HR responses to carbachol (P < 0.05). Advancing gestational age, but not cortisol treatment, suppressed fetal LV developed pressure, RV developed pressure and HR responses to isoprenaline (P < 0.05). Maximum doses of either carbachol or isoprenaline had no effect on coronary perfusate distribution. Changes in myocardial responsiveness to adrenergic and muscarinic cholinergic stimulation with advancing gestation provide mechanisms that contribute to the maturation of the cardiovascular system as the ovine fetus approaches term. These changes in myocardial responsiveness are not solely dependent on preparturient elevations in fetal plasma cortisol concentration.
authors.affiliation: Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Andrew J W
authors.initials: AJ
authors.lastname: Fletcher
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Forhead
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Fowden
authors.forename: Will R
authors.initials: WR
authors.lastname: Ford
authors.forename: Peter W
authors.initials: PW
authors.lastname: Nathanielsz
authors.forename: Dino A
authors.initials: DA
authors.lastname: Giussani
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D003326:Coronary Circulation / Q000502:physiology; D036861:Delivery, Obstetric; D004305:Dose-Response Relationship, Drug; D005260:Female; D005456:Fluorescent Dyes; D005865:Gestational Age; D006321:Heart / Q000187:drug effects* / Q000196:embryology; D006339:Heart Rate / Q000502:physiology; D006854:Hydrocortisone / Q000097:blood / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D010477:Perfusion; D011247:Pregnancy; D012756:Sheep
chemical_list: D000318:Adrenergic beta-Agonists; D005456:Fluorescent Dyes; D018721:Muscarinic Agonists; D002217:Carbachol; D007545:Isoproterenol; D006854:Hydrocortisone