Development of baroreflex influences on heart rate variability in preterm infants.

To investigate developmental changes in autonomic cardiovascular reflexes in preterm infants, we used autoregressive power spectral analysis to analyze the effect of upright tilting on heart rate variability in preterm infants. Twenty-eight infants were studied in a longitudinal fashion beginning at 28-32 weeks postconceptional age (postnatal age 1-5 weeks). Each week, heart rate variability in the supine position and after 45 degrees head-up tilt was analyzed by spectral analysis. With the initial study of each infant, there was no significant change in heart rate following head-up tilt compared with baseline (-0.5+/-0.9 bpm). However, linear regression analysis revealed that with increasing postnatal age, the change in heart rate in response to tilting became more positive (mean slope of regressions 0.45+/-0.12 bpm/week, P<0.005). The power spectral density of R-R interval variability in the low-(LF; 0.02-0.15 Hz) and high-(HF; 0.15-1.5 Hz) frequency ranges were obtained and the values normalized by dividing each component by the total power. For measurements obtained in the supine position, the LF/HF ratio progressively decreased with increasing postnatal age, indicating a maturational change in sympathovagal balance. We used the difference in the LF/HF ratio between tilt and the recumbent position as a measure of the change in autonomic input to the heart in response to unloading of the arterial baroreceptors. No significant change in these ratios were observed when infants were first studied between 28 and 32 weeks postconceptional age, suggesting that the cardiac baroreflex is poorly developed at this stage of development. However, with postnatal maturation, the LF component of the power spectrum became progressively larger with tilt relative to the basal state, such that the difference between LF/HF(tilt) and LF/HF(base) became progressively more positive (P <0.006). These findings suggest that in premature infants, cardiac baroreceptor reflexes become more functional with postnatal development.

Glucocorticoid modulation of cardiovascular and autonomic function in preterm lambs: role of ANG II.

The mechanisms by which antenatal glucocorticoids facilitate postnatal circulatory function in preterm infants are uncertain but may be related to augmented angiotensinergic functions. To test the hypothesis that the effects of glucocorticoids on postnatal cardiovascular and sympathetic activity are mediated via the renin-angiotensin system, we studied the effects of AT(1) receptor blockade on postnatal changes in heart rate (HR), mean arterial blood pressure (MABP), renal sympathetic nerve activity (RSNA), and baroreflex control of HR in prematurely delivered lambs. After maternal administration of betamethasone (12 mg im 48 and 24 h before delivery), chronically instrumented preterm lambs (118- to 123-day gestation, term 145 days) were studied before and after delivery by cesarean section; fetuses received either the AT(1) receptor antagonist losartan (10 mg iv, n = 6) or saline (n = 6) 1 h before delivery. A third group of animals (n = 6) received losartan without prior exposure to betamethasone. Compared with fetal values, betamethasone-treated animals demonstrated significant increases (P < 0.05) in MABP (47 +/- 2 to 58 +/- 2 mmHg) and RSNA (181 +/- 80% of fetal value) 1 h after delivery. Betamethasone + losartan-treated lambs also displayed increases in MABP (48 +/- 1 to 55 +/- 3 mmHg) and RSNA (198 +/- 96% of fetal value) 60 min after birth, similar to betamethasone alone lambs. Losartan alone treated animals had no postnatal increase in either MABP or RSNA, responses similar to those seen in nontreated sheep delivered at the same gestational age. The sensitivity of baroreflex-mediated changes in HR in response to increases in MABP was less in both groups of betamethasone-treated animals; no effect was seen with losartan. These results suggest the postnatal increases in MABP and RSNA seen with antenatal glucocorticoid treatment are not mediated by stimulation of peripherally accessible AT(1) receptors. We speculate that augmented cardiovascular function in glucocorticoid-treated premature lambs is dependent, in part, on a generalized sympathoexcitatory response and that this effect of glucocorticoids is mediated by central mechanisms.

Angiotensin II in cardiac pressure-overload hypertrophy in fetal sheep.

We previously demonstrated in fetal sheep that blockade of ANG II type 1 (AT(1)) receptors did not attenuate an increase in right ventricle (RV) mass resulting from partial occlusion of the pulmonary artery (PA). We have now determined the effects of AT(2)-receptor blockade (PD-123319, 10 mg. kg(-1). day(-1) continuous iv) on the response of the fetal RV to PA banding for 7 days. Four groups of fetuses (each n = 7) were studied beginning at 126 +/- 1 days gestation (term 145 days). RV weight-to-body weight ratio (RV wt/body wt) increased (P < 0.05) in PA-banded (6.00 +/- 0.09 g/kg) and PA-banded + PD-123319 (6.19 +/- 0.27 g/kg) compared with control (5.17 +/- 0.17 g/kg) and PD-123319-infused (5.27 +/- 0.35 g/kg) fetuses (means +/- SE). Blood pressure and heart rate were similar in all groups. PD-123319 produced a decrease (P < 0.05) in AT(1) but not AT(2) mRNA levels in both fetal ventricles. To examine the effect of ANG II on fetal heart growth, twin fetal sheep were infused with either ANG II (twin received vehicle) or phenylephrine (Phe) (twin received vehicle) continuously for 7 days. Mean arterial blood pressure was 20-25 mmHg higher in ANG II and Phe fetuses compared with controls. The rate-pressure product was similar in ANG II and Phe fetuses and 40-50% greater than controls. Phe resulted in no change in RV wt/body wt or left ventricle-to-body weight ratio (LV wt/body wt) compared with controls. In contrast, ANG II produced a selective increase (27 +/- 5%, P < 0.05) in LV wt/body wt; no effect was seen on the RV. ANG II produced a decrease (P < 0.05) in LV but not RV AT(1) mRNA levels compared with controls; no effect was seen with Phe. The data demonstrate that in the ovine fetus, AT(2) receptors do not contribute to the maintenance of blood pressure or the development of pressure-overload RV hypertrophy. Elevated ANG II levels produce a selective increase in LV mass in the fetal sheep that is, in part, independent of increased systolic load.

Angiotensin AT1 receptor blockade fails to attenuate pressure-overload cardiac hypertrophy in fetal sheep.

We examined the hypothesis that endogenous angiotensin II and angiotensin type 1 (AT1) receptors participate in the development of fetal right ventricular hypertrophy by studying the effects of AT1 receptor blockade on cardiac growth in fetal sheep subjected to constrictive banding of the pulmonary artery (PA). Seven pairs of twin fetuses were studied beginning at 126 +/- 1 days gestation (term = 145 days). One twin was given losartan (10 mg kg(-1) x day(-1) i.v.) for 7 consecutive days after PA banding, and the other twin served as a saline-treated, PA-banded control. Four additional pairs of twins served as sham-operated controls. Fetal heart rate (HR) and mean arterial blood pressure (MABP) were similar in the two groups of PA-banded animals before treatment and remained unchanged in the PA-banded control group. Losartan resulted in a significant decrease (P < 0.05) in MABP between days 0 and 7, whereas HR was not affected. Total body weight of the losartan-treated animals was significantly less (P < 0.05) than twin PA-banded controls and nonbanded fetuses. Right ventricle weight-to-body weight ratios were similar in saline (2.29 +/- 0.34 g/kg) and losartan-treated (2.11 +/- 0.15 g/kg) PA-banded animals and significantly greater than that in nonbanded fetuses (1.52 +/- 0.07 g/kg). Similar differences were seen in the right ventricle weight-to-left ventricle weight ratios. Right and left ventricle AT1 receptor mRNA and protein expression were also similar among the three groups, as were AT2 receptor mRNA levels. These data suggest that endogenous angiotensin II does not contribute to the development of pressure overload-induced right ventricular hypertrophy during fetal life and that expression of angiotensin receptors is not altered by increased afterload in the ovine fetus.

Ontogeny and regulation of cardiac angiotensin types 1 and 2 receptors during fetal life in sheep.

Previous studies have shown that the expression of cardiac angiotensin II (ANG II) type 1 (AT1) and type 2 (AT2) receptors are developmentally regulated, although factors modulating these receptors have not been well investigated. The present study was designed 1) to characterize the ontogeny of cardiac AT1 and AT2 gene expression during the last third trimester of gestation in fetal sheep and newborn lambs, 2) to determine the influence of ANG II on modulating cardiac AT1 and AT2 gene expression during fetal life, and 3) to investigate the role of AT1 receptor activity on the regulation of AT1 and AT2 mRNA levels during fetal cardiac development. Using sheep AT1 and AT2 cDNA probes, we demonstrated that cardiac AT1 gene expression is relatively unchanged during fetal (90-135 d of gestation, term 145 d) and newborn life. In contrast, cardiac AT2 mRNA expression was high during fetal development and decreased rapidly after birth. Continuous i.v. infusion of ANG II (9.5 nM/h) for 24 h, which raised ANG II levels from 84+/-9 to 210+/-21 pg/mL had no effect on the expression of cardiac AT1 or AT2 mRNA, but increased adrenal and decreased liver AT1 mRNA levels. Administration of the AT1 receptor antagonist losartan (1.2 mg kg(-1) h(-1)) significantly decreased arterial blood pressure in fetuses at 110- and 135-d, but not 95-d gestation. Except for increased AT1 receptor gene expression in the right atrium at 95- and 135-d gestation, and left ventricle at 110-d gestation, cardiac AT1 and AT2 mRNA levels were unaltered by AT1 receptor blockade. In summary, this study demonstrates that cardiac AT2 but not AT1 receptor gene expression is regulated by the transition from fetal to newborn life. Neither ANG II nor blockade of AT1 receptors significantly alter the expression of AT1 or AT2 mRNA in the fetal heart. Endogenous ANG II also appears to significantly contribute to the maintenance of blood pressure homeostasis during the final third of gestation in fetal lambs.