Regulation of Cardiovascular Function During Fetal and Newborn Life

Ontogeny of Baroreflex Function

Short-term changes in vascular stretch related to arterial pressure modify the discharge of afferent baroreceptors fibers located in the carotid sinus and aortic arch. This, in turn, results in alterations in parasympathetic and sympathetic nerve activities that influence heart rate and peripheral vascular resistance and serve to buffer changes in arterial pressure. ^, Studies in sheep demonstrate the arterial baroreflex is functional during fetal and early postnatal life. ^{, , ,} Investigators disagree, however, about the magnitude of the baroreflex early in development and the influence of these reflexes on controlling heart rate and arterial pressure. Early studies indicated that the threshold for baroreceptor activity is above the normal range of arterial pressure during fetal and neonatal life, and that baroreceptors may not be loaded during fetal life. ^, Other studies in fetal sheep demonstrate that sino-aortic denervation (SAD) produces marked fluctuations in fetal arterial pressure and heart rate, ^, suggesting that the arterial baroreflex plays an important role in maintaining cardiovascular homeostasis. Evidence for the presence of functional baroreceptors in the immature animal is provided by single fiber recordings of baroreceptor afferents in the carotid sinus and aortic depressor nerves. In fetal and newborn animals carotid sinus nerve activity is phasic and pulse synchronous while activity increases with a rise in arterial or carotid sinus pressure. ^{, ,} Basal discharge of baroreceptor afferents does not change during fetal and postnatal maturation, despite a considerable increase in mean arterial pressure during this time. These findings are consistent with those demonstrated in developing rabbits and indicate that baroreceptors reset during development, such that they continue to function within the physiologic range for arterial pressure. Furthermore, the response of carotid baroreceptor activity to increases in carotid sinus pressure is greater in fetal than in newborn and 1-month-old lambs. The threshold for carotid baroreceptor discharge is lower and the sensitivity of the baroreceptor is also greater in newborn, compared to adult, rabbits. Although parasympathetic influence on heart rate early during development is limited, ^, results obtained from direct recording of baroreceptor afferents ^, demonstrate that the sensitivity of the baroreceptors is greater during early development and resets at a lower level as arterial pressure increases during fetal and postnatal life. These findings suggest that reduced heart rate responses to changes in arterial pressure during fetal life are not due to underdeveloped afferent activity of baroreceptors but to differences in central integration and efferent parasympathetic nerve activity.

The mechanisms regulating the changes in sensitivity of the baroreceptors early in development have not been investigated, but may be similar to those proposed in the adult. In younger animals, the carotid sinus is more distensible, resulting in an increase in the degree of mechanical deformation of nerve endings and, ultimately, in a greater strain sensitivity. Alternatively, ionic mechanisms, ^, such as activation of the sodium pump that may operate at the receptor membrane to cause hyperpolarization of the endings, and substances released from the endothelium, including prostacyclin and NO, may modulate baroreceptor activity during development. Blockade of cyclooxygenase with indomethacin reduces carotid baroreceptor sensitivity in newborn, but not adult, sheep. Along these lines, prostaglandin E ₂ and I ₂ levels within carotid sinus tissues are sixfold higher in newborn than adult sheep. Whether such influences on baroreceptor activity are present during fetal development has not been investigated.

Arterial baroreflex function and sensitivity are equally dependent on the efferent limb of the reflex, including sympathetic and parasympathetic nerve activity and end organ neuroeffector responsiveness. The arterial baroreflex during fetal and postnatal maturation has primarily been investigated by examining the relationship between the increase in arterial pressure and the fall in heart rate. ^{, , , ,} Baroreflex control of fetal heart rate is dominated by changes in cardiac vagal tone, although integrity of the reflex is dependent upon both sympathetic and parasympathetic pathways. A number of studies describe a relatively reduced heart rate response to alterations in arterial pressure in fetal and newborn animals, and in human infants. ^{, , ,} Recording reflex bradycardia in response to increased blood pressure induced by balloon inflation, Shinebourne and colleagues found that baroreflex activity is present as early as 0.6 gestation in fetal lambs, and that the sensitivity of the reflex increased up to term. Studies in sheep and other species ^, have similarly found increasing baroreflex sensitivity with postnatal age. In addition to changes in the sensitivity, or slope of the relationship between change in blood pressure and change in heart rate that occur with maturation, the response time of heart rate changes to hypotension are markedly slower in preterm compared to term fetus. Maturational changes continue to occur during postnatal life. For example, reflex bradycardia in response to carotid sinus stimulation is absent during the first week of life in the piglet, although vagal efferents exert a tonic action on the heart at this stage of development. Age-related changes in heart rate in response to phenylephrine are also greater in 2-month old piglets than in 1-day old animals. On the other hand, several studies suggest that the sensitivity of the cardiac baroreflex is, in fact, greater in the fetus than in the newborn and decreases with maturation. ^, For example, studies in the fetal horse have reported that fetal cardiac baroreflex sensitivity decreased with advancing gestational age.

Developmental changes in control of efferent RSNA in response to increases and decreases in blood pressure over the last third of gestation and after birth have been examined. ^{, ,} These studies demonstrate that baroreceptor activity regulates sympathetic outflow as well as heart rate during fetal life, that functional baroreflex control of RSNA shifts toward higher pressures during development, and that the sensitivity of the RSNA baroreflex function curve is greatest in the late term fetus and decreases following the transition from fetal to newborn life ( Fig. 50.1 ). Although cardiac baroreflex function is present in the preterm sheep fetus (0.7 of gestation), there is no significant baroreflex control of RSNA at this stage of development. It is likely that attenuated cardiac and RSNA responses to hypotension described in these animal studies may contribute to blood pressure instability in the preterm infant.

Several reasons for reported differences in the sensitivity of baroreflex function early in development are apparent. First, there is interspecies variability in the maturation of sympathetic and parasympathetic activity and function, including maturity of the central and efferent components of the reflex. For example, a functional baroreflex is not present in rats until three weeks of age, while baroreceptor sensitivity in newborn pigs and dogs is low, increasing with postnatal age. ^, Second, there have been differences in experimental design and analysis of baroreflex responses. Investigators have studied baroreflex responses to alterations in blood pressure using either pharmacologic agents ^, or intravascular balloon inflation, ^, and analyzed responses using derived sigmoidal baroreflex curves or linear slopes. These considerations are important, particularly as it has now become clear that—in addition to interspecies differences—there may be differential maturation of the vagal and sympathetic components mediating cardiac baroreflex responses that would not be appreciated from complete sigmoidal autonomic baroreflex curve analysis.

Resetting of the arterial baroreflex is defined as a change in the relation between arterial pressure and heart rate; or between pressure and sympathetic and parasympathetic nerve activities. ^, As noted earlier, a number of studies demonstrate that the sensitivity of the baroreflex changes with maturation and shifts or resets toward higher pressures. ^{, ,} This shift occurs during fetal life, is present immediately after birth, and continues with postnatal maturation, paralleling the naturally occurring increase in blood pressure. The mechanisms regulating developmental changes in baroreflex sensitivity and controlling the resetting of the baroreflex are poorly understood. Changes in the relationship between arterial pressure and sympathetic activity or heart rate can occur at the level of the baroreceptor itself (peripheral resetting) or from altered coupling within the central nervous system of afferent impulses from baroreceptors to efferent sympathetic or parasympathetic activities (central resetting). Locally produced factors, such as NO; circulating hormones and neuropeptides such as angiotensin II (ANG II), vasopressin (AVP), and serotonin; and activation of additional neural reflex pathways likely modulate the changes in arterial baroreflex set-point and sensitivity during development. ^{, ,}