Three-week neonatal hypoxia reduces blood CGRP and causes persistent pulmonary hypertension in rats

Abstract

To increase understanding of persistent pulmonary hypertension, we examined chronic pulmonary effects of hypoxia at birth and their relationships with immunoreactive levels of the potent vasodilator, calcitonin gene-related peptide (CGRP). Rats were born in 10% hypobaric hypoxia, where they remained for 1-2 days, or in 15% hypoxia, where they remained for 21 days. All were then reared in normoxia for 3 mo followed by reexposure to 10% hypoxia for 7 days (H-->H) or continued normoxia (H-->N); age-matched normoxic rats were hypoxic for the last 7 days (N-->H) or normoxic throughout (N-->N). Results are as follows. Pulmonary arterial pressure (P(PA)) in 10% H-->N rats was normal at the end of the experiment (13 wk), but in rats reexposed to hypoxia (H-->H), pressure rose to 19% above N-->H controls. In 15% H-->N rats, P(PA) remained high, similar to that of N-->H rats, and increased further by 40% on reexposure (H-->H). Medial thickness of small pulmonary arteries in 10% H-->H rats also increased by 40% over N-->H controls and was equally high in 15% H-->N and H-->H rats. In N-->H rats from both experiments, right ventricular hypertrophy index (RVH) was increased after hypoxia at 15-16 wk. Also, in the 15% study, RVH remained elevated in H-->N rats and increased in H-->H rats by 19% above N-->H controls. Blood CGRP was reduced by neonate and adult hypoxia, and hypoxic reexposure (H-->H) further lowered blood CGRP in the 15% but not 10% study. Declining left ventricular blood CGRP correlated highly with logarithmically increasing P(PA) in the 15% study (r = -0.81, P = 0.000). In conclusion, 1) short perinatal exposure to 10% O(2) exacerbated pulmonary hypertension with hypoxia later in life, 2) 15% O(2) at birth and for 21 days caused persistent pulmonary hypertension and exacerbation with reexposure, and 3) P(PA) correlated highly with declining blood CGRP levels in the 15% study.

Rescue treatment with a Rho-kinase inhibitor normalizes right ventricular function and reverses remodeling in juvenile rats with chronic pulmonary hypertension

“…Reversing effects on vascular remodeling of another ROCK inhibitor, fasudil, have been previously reported in adult rats with monocrotaline-induced chronic PHT (1,40). To our knowledge, this is the first study to examine the reversing effects of ROCK inhibition on vascular remodeling in the immature animal, which may be more resistant to reversal than adults (8,17,29,30,47,52,62) and the first to document normalized RV function as a consequence of sustained rescue treatment with a ROCK inhibitor. Our observation that sustained reduction of PVR and of RVSP were dependent upon ongoing inhibition of ROCK activity with Y-27632 are further in keeping with ROCK-mediated pulmonary vasoconstriction being the main determinant of raised pulmonary vascular pressure and resistance secondary to chronic hypoxia (38,58).…”

The Effects of Endogenous Sex Hormones and Acute Hypoxia on Vasoconstriction in Isolated Rat Pulmonary Artery Rings

“…Exposure to perinatal hypoxia and the development of pulmonary vasoconstriction and hypertension later in adulthood have been witnessed in many studies [41][42][43]. Hakim et al found that adult rats exposed to hypoxia in the perinatal period had increased reactivity to hypoxia and elevated pulmonary vascular resistance [41].…”

Targeted blocking of gene expression for CGRP receptors elevates pulmonary artery pressure in hypoxic rats

“…It has been localized with immunocytochemistry and in situ hybridization to airway epithelial neuroendocrine cells and interstitial ganglia (20) and also by immunocytochemistry to epithelial and vascular networks (17,36). We found early on that CGRP was significantly reduced in left ventricular blood of rats with HPH (18,34) and persistent PH (21), contributing to an imbalance between vasoconstrictors and vasodilators. We further found that exogenous CGRP prevents the development of HPH and reverses existing HPH via the CGRP type 1 receptor in rats (19,34).…”