Presented at the Neonatal Society 2004 Summer Meeting.

Thakor AS, Giussani DA (introduced by Alison Forhead)

Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK.

Introduction: There has been a long-standing clinical and physiological interest in haemodynamic changes in the umbilical vascular bed during pregnancy, due to its functional importance in representing feto-placental blood flow and, hence, fetal well-being. Novel and potent vasodilator peptides, like CGRP, are rapidly gaining interest in cardiovascular regulation in the adult. However, its role in fetal cardiovascular function is largely unknown. This study tested the hypothesis that CGRP has a vasodilator role in the umbilical vascular bed during basal and hypoxaemic conditions in late gestation.

Methods: Under halothane anaesthesia, 5 sheep fetuses were instrumented with catheters and a Transonic flow probe around an umbilical artery, inside the fetal abdomen, at 0.8 of gestation. Five days later, animals were subjected to a 2.5 h protocol: 1 h normoxia, 0.5 h hypoxaemia and 1 h recovery, during either saline I.V. or fetal treatment with a CGRP antagonist (50 μg.kg^-1 I.A. bolus + 10 μg.kg^-1.min^-1 I.V. infusion). Hypoxaemia during saline or antagonist treatment occurred on separate days in a randomised order. Antagonist treatment started 30 min before hypoxaemia and ran continuously until the end of the challenge. Two days later, all fetuses also received 2 and 5 μg bolus doses of exogenous CGRP I.A. Both doses were then repeated after the NO clamp, a technique that permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function (Gardner & Giussani. Circulation 2003, 108:331-5). Umbilical vascular conductance (UVC) was calculated by dividing umbilical blood flow (UBF) by supra-amniotic fetal arterial blood pressure (BP).

Results: Fetal treatment with the CGRP antagonist did not alter basal blood gas status or basal cardiovascular variables. A similar fall in PaO2 occurred in fetuses during either saline (21±0.8 to 9±0.9) or antagonist treatment (20±0.9 to 9±1.2 mmHg). Acute hypoxaemia during saline infusion led to significant increases in BP (64±1.3 to 81±2.6 mmHg), UBF (134±10 to 196±16 ml.min^-1) and UVC (2.1±0.2 to 2.7±0.3 (ml.min^-1).mmHg^-1). In marked contrast, acute hypoxaemia during fetal treatment with the CGRP antagonist led to pronounced falls in both UBF (140±13 to 90±10 ml.min^-1) and UVC (Fig.1A) without affecting the magnitude of the hypertensive response. Exogenous treatment of the fetuses with 2 and 5 µg of CGRP during saline produced similar increases in UVC. Remarkably, this vasodilator effect of CGRP was reversed to constriction following NO blockade (Fig.1B).

Conclusion: Combined, the results support the hypothesis and suggest an important role for CGRP in pregnancy, maintaining UBF via NO-dependent mechanisms during basal and hypoxaemic conditions.

Acknowledgements: Supported by The Journal of Experimental Pathology & The Lister Institute for Preventive Medicine.