Rho-associated serine/threonine kinase (Rho-kinase) is a downstream effector of small GTPase RhoA that has recently been shown to play an important role in regulating smooth muscle contraction. The present study investigated the role of Rho/ Rho-kinase in hypoxia-induced pulmonary vasoconstriction (HPV). Small pulmonary resistance vessels and cultured pulmonary arterial smooth muscle cells (PASMCs) from the rat were used. PASMCs exposed to hypoxia (PO(2) = 26 +/- 2 mm Hg) showed a significant increase in Rho-kinase activity. Exposure to hypoxia for 20, 40, 60, 90, and 120 min also resulted in a significant increase in myosin light chain (MLC) phosphorylation at all time points in PASMCs. Hypoxia-induced MLC phosphorylation was inhibited by Y-27632 (a Rho-kinase inhibitor), exoenzyme C3 (a specific Rho inhibitor), or toxin B (an inhibitor for Rho proteins). In addition, hypoxia-induced Rho-kinase activation was blocked by C3 and toxin B. Small rat intrapulmonary arterial rings, which were made hypoxic (PO(2) = 30 +/- 3 mm Hg), showed a slow sustained contraction, and Y-27632 caused a significant relaxation during the sustained phase of HPV in a concentration-dependent manner. In summary, the data show that Rho-kinase is activated by hypoxia in PASMCs, and Rho/Rho-kinase is functionally linked to hypoxia-induced MLC phosphorylation and plays a role in the sustained phase of HPV.
We investigated the development of insulin receptors in membranes of fetal rabbit lung during normal ontogeny and the effect of glucocorticoids and hypothyroidism. Specific binding of 125I-insulin to fetal lung membranes increased progressively to a peak at 29 days gestation, declining by 30 days. Scatchard plots were curvilinear and revealed a progressive increase in receptor numbers (X 10(10)/mg protein) from 129 +/- 7 (mean +/- SE) at 22-24 days to 575 +/- 16 at 29 days, declining to 467 +/- 12 at 30 days, term being approximately 31 days. Affinities did not change throughout gestation and were similar to those of adult lung; receptor numbers in adults were significantly lower than in fetuses at 26-30 days. Epinephrine and PGE1 could evoke a doubling of cAMP production in adult and fetal lung membranes until 29 days. Concomitantly with the fall in fetal insulin receptor number at 30 days, cAMP production in response to epinephrine or PGE1 increased fivefold. Induction of fetal hypothyroidism decreased insulin receptor numbers in the lung of the 28-day fetus by 70% from control (P less than 0.001) without a change in receptor affinity. In contrast, betamethasone administration increased fetal lung insulin receptor numbers by 250% (P less than 0.001) but did not alter their affinity; maternal lung insulin receptors were not altered. Thus, normal ontogeny of the fetal lung insulin receptor is characterized by a progressive increase in number followed by decline immediately before parturition associated with a sharp increase of cAMP responsiveness of the membranes. Hypothyroidism and glucocorticoid exposure can modulate the normal development of the fetal lung insulin receptor.
SummaryT o assess the functional maturity of adrenergic modulation of plasma concentration of glucose, a s well a s immunoreactive glucagon (IRC) and immunoreactive insulin (IRI) secretion in utero, adrenergic agonists with or without / 3 (propranolol) or a (phentolamine) antagonists were infused to the chronically catheterized sheep fetus (n = 35) late in the third trimester. Mean f S.E. days at study was 129.5 f 1.5; term is 150 days. In 9 separate studies at gestational age 129 f 1 days, the infusion of saline for 3 hr was not associated with significant changes in the basal levels of glucose, IRC, or IRI.With epinephrine, 6 pg/min (n = 6) glucose rose from 16.7 f 3.6 to 41.9 f 9.7 mg/dl, IRC rose from 75 f 8 to 219 f 45 pg/ml, and IRI fell from 22.6 + 1.7 t o 12.7 + 3.5 microunits/ml ( P < 0.05 for each). Propranolol alone (n = 4) did not alter basal glucose or IRC but significantly suppressed IRI. Propranolol did, however, markedly attentuate the rise in glucose and IRC while exaggerating the fall in IRI during epinephrine infusion. Qualitatively similar but smaller responses were obtained with epinephrine. 0.4 pg/min (n = 10). Similarly, elevation of glucose and suppression of IRI was obtained with norepinephrine, 2 gg/min (n = 5), but IRC levels did not rise significantly. a-Adrenergic blockade alone augmented IRI from 18 + 3 to 38 + 5 microunits/ml without affecting glucose or IRC concentrations; during a blockade, norepinephrine infusion failed to induce the rise in glucose, IRG remained unchanged, and IRI remained elevated (n = 5). 2-Deoxy-D-glucose, 200 mg IV over 30 min, did not affect glucose, IRG, or IRI (n = 5). Thus, appropriate adrenergic modulation of plasma concentrations of glucose, and of IRG and IR1 secretion is established in the third trimester.following placental separation and abrupt cessation of the transfer of nutrients from mother to fetus, thereby suggesting that hypoglycemia acts as the stimulus for the observed changes (15,-17). We have recently reported that in newborn lambs there is a similar 5-fold surge of IRG within minutes of delivery, whereas plasma IRI remains low and unchanged (17). In newborn lambs, however, there was no fall in plasma glucose concentration following delivery, so that unless curtailment of a different major nutrient for the lamb acts as the trigger for IRG secretion, hypoglycemia is not the stimulus for the observed surge in IRG. An abrupt increase in catecholamine secretion at birth could adequately explain the . .observed changes because catecholamines are-known to stimulate glucagon secretion, inhibit insulin secretion, and mobilize free fatty acids (9,12,19,23,26,29,32,38). A rise in circulating free fatty acid levels does occur shortly after delivery (1, 17). Moreover, catecholamines increase markedly and abruptly in the arterial plasma of newborns at delivery (10. 24), and urinary excretion of epinephrine increases in the initial hours of life (27). If this hypothesis regarding the role of catecholamines as the trigger for the observed neonatal cha...
Secretion of catecholamines may play an important role in several of the adaptations that characterize the transition from intra- to extrauterine life including cardiovascular, respiratory, and metabolic events, specifically the initiation of endogenous glucose production following curtailment of the transplancental maternal supply of glucose. Maturation of neural and enzymatic pathways involved in catecholamine secretion occurs late in gestation; fetal hypoxia can produce a 20- and 125-fold increase in plasma epinephrine (E) and norepinephrine (NE), respectively. Estimates of turnover (approximately 2,000 pg X kg-1 X min-1) and metabolic clearance rates (20-40 ml X kg-1 X min-1) indicate active secretion and metabolism of E from fetal sources with negligible transfer from the mother. Simultaneously, there is maturation of functional alpha- and beta-adrenergic receptors. At birth, plasma E and NE rise three- to tenfold; plasma levels are higher in hypoxic infants and lower in prematures. Concurrently, glucagon increases three- to fivefold; cortisol and growth hormone also are high, whereas insulin remains low and poorly responsive to stimuli; the number of glucagon receptors increases, whereas that of insulin decreases. Acting in concert these hormonal changes activate glycogenolysis, gluconeogenesis, lypolysis, and ketogenesis. Glucose production and gluconeogenesis, absent in utero, become evident within hours of birth in both humans and sheep. The spontaneous surge in catecholamine secretion at birth may be the key event because infusion of E or NE to fetal sheep in late gestation simulates the metabolic and hormonal profile of glucagon and insulin as well as glucose production that normally only occur with separation of the placenta.
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