With the onset of ventilation at birth, pulmonary blood flow (PBF) increases 8- 10-fold with a concomitant fall in pulmonary vascular resistance. Although recent physiological advances have highlighted the role of the vascular endothelium in contributing to these changes, of primary importance in this respect are nitric oxide (NO) and PGI2, both of which are pulmonary vasodilators produced by endothelium in response to a variety of stimuli, a complete understanding of the regulatory mechanisms involved remains unachieved. Exogenous endothelin-1 (Et-1), which in endogenous form also is produced by endothelium, vasoconstricts adult pulmonary arteries (predominantly via EtA subtype receptors) whereas it vasodilates in the perinatal period (via EtB subtype receptors). I propose that this difference relates to the ontogenetic differences in Et receptor subtypes.
In specific aim 1 I will examine the role of the 2 receptor subtypes in the regulation of basal vascular tone, by specific receptor inhibition or stimulation; I will examine the ontogeny of these receptors by studying fetuses at 2 different gestational ages. I also will evaluate, using the in utero ventilation model we have developed, the role of endogenous Et-1 in affecting the perinatal changes in PBF and finally I will examine the mechanisms by which Et-1 might produce vasodilation, by examining the possible secondary role of NO production or of ATP-dependent K+ channel activation influence. Since angiotensin II (AII) concentrations increase dramatically at birth, and since AII has been shown in other systems to stimulate PGI2 and NO production, in specific aim 2 I will examine with the in utero ventilation model, the role of endogenous AII in affecting the increase in PBF at birth. Since 2 specific AII receptor subtypes are known, AT1 and AT2, specific blockers will be used to assess their relative importance in the increase in PBF. I also will evaluate the potential mechanisms whereby AII may be acting (PGI2 or NO stimulation) by using selective inhibitors of PGI2 and NO production. Calcitonin gene-related peptide (CGRP) is a potent vasodilator that in adults also produces pulmonary vasodilation. Recent availability of a specific C1 receptor blocker, now affords the opportunity to evaluate the possible role of this highly important peptide in the fetal circulation, and particularly in the transitional period.
In specific aim 3, I will examine the role of CGRP in the regulation of basal pulmonary vascular tone, the role of CGRP in affecting the increase in PBF at birth, using the in utero ventilation model, and by selective blockade the role of NO production or ATP-dependent K+ channel activation in producing the changes in PBF.
In specific aim 4 I will examine whether platelet activating factor (PAF), which with exogenous administration produces fetal pulmonary vasodilation, also plays a functional role in the increase in PBF at birth. These studies will provide further information on the mechanisms involved in the regulation of basal pulmonary vascular tone in the fetus, on the mechanisms involved in the dramatic increase in PBF at the time of birth and on some of the secondary mechanisms stimulated at this increase in PBF occurs.
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