Maternal and fetal adaptations during pregnancy: lessons in regulatory and integrative physiology.

PREGNANCY IS A COMPLEX PHYSIOLOGICAL condition that involves the integration of a variety of regulatory and organ systems. Many aspects of maternal and fetal adaptations during pregnancy have been addressed by recent publications in the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. Articles include investigations on cardiac, vascular, endothelial (1, 7), renal (17), respiratory, gastrointestinal (39), uteroplacental (12, 36, 38, 48, 55, 56, 63, 68, 71–74), and neuroendocrine changes during pregnancy. Cardiovascular (19) and neurohumoral (41, 49, 66) and metabolic (3, 4, 8, 18) adaptations in the fetus have also been a subject of great interest. Much attention has also been given to the impact of hypoxia, glucocorticoids, and other stressors on the development of the fetus and newborn. Normal pregnancy is associated with marked hemodynamic alterations within the maternal circulation, including increases in cardiac output and plasma volume and reductions in vascular resistance and arterial pressure. Associated with these changes are marked alterations in the activity of various neurohumoral systems and in vascular and endothelial function. Hines and colleagues (33–35) recently reported that stimulation of volume-sensitive cardiac mechanoreceptors elicits an attenuated reflex effect on blood pressure and renal function. Furthermore, these investigators reported baroreceptor afferent as well as cardiac receptor afferent discharge is reduced during pregnancy (33–35). These investigators postulate these changes in reflex function are an important adaptation that allows plasma volume expansion during pregnancy. The reduction in arterial pressure in the face of marked increases in cardiac output during pregnancy is due to a considerable decrease in vascular tone. An increase in nitric oxide (NO) during normal pregnancy has been suggested to mediate decreases in vascular resistance by direct actions and by blunting the vascular responsiveness to vasoconstrictors such as angiotensin II and norepinephrine (16, 57). This concept is supported by recent reports that the expression (2) and activity of NO synthases are elevated during normal pregnancy and that the plasma level and urinary excretion of cGMP, a second messenger of NO and a mediator of vascular smooth muscle relaxation, are increased during pregnancy. Moreover, pharmacological blockade or targeted disruption of NO synthases markedly attenuates the reduction in vascular resistance and blood pressure during pregnancy (11, 32). Inhibition of NO synthesis has also been recently shown to modulate the reduction in vascular smooth muscle intracellular calcium concentration (52) and protein kinase C activity (40) that normally occurs during pregnancy. Furthermore, the vascular responsiveness to vasoconstrictors such as angiotensin II is markedly enhanced during pregnancy when NO synthase is inhibited. Finally, recent studies in American Journal of Physiology-Regulatory, Integrative and Comparative Physiology have reported that the vascular actions of NO during pregnancy are attenuated by hyperlipidemia (53) and alcohol intake (15). The renal circulation is particularly affected during normal pregnancy. Both renal plasma flow and glomerular filtration rate increase to 40–80% above normal in humans and 20–40% in pregnant rats. Mechanisms underlying the marked renal vasodilation during pregnancy have been a subject of intensive investigation. Although numerous factors may be involved in this renal hyperemia, recent studies have implicated NO as an important mediator of the renal hyperfiltration during pregnancy (27, 45). Pregnancy is associated with enhanced renal expression and activation of NO synthase (2). Nonselective and selective inhibition of NO synthase isoforms also attenuate the renal hemodynamic changes during pregnancy (1). Recent studies have suggested that the hormone relaxin is an important factor that mediates the enhanced renal hyperemia and production of NO during pregnancy (17). It