Nitric oxide-mediated nonadrenergic noncholinergic relaxation of piglet pulmonary arteries decreases with postnatal age.

Nonadrenergic noncholinergic (NANC) vasodilator mechanisms may contribute to the maintenance of adult pulmonary and systemic vascular tone. However, their actions in the neonatal circulation have not been studied. We aimed to investigate NANC vasorelaxation in neonatal and 2-week-old piglet pulmonary and mesenteric arteries and to examine the potential role of nitric oxide (NO) in this phenomenon. Responses to electric field stimulation (EFS, 50V, 0.25-32 Hz) were investigated in pulmonary and mesenteric artery rings (external diameter 150-200 microm) precontracted with the thromboxane A2 mimetic U46619, in the presence of guanethidine (10 microM) and atropine (10 microM). Under these conditions, EFS resulted in a frequency dependent relaxation of newborn pulmonary (maximal relaxation of 53+/-9.1%), mesenteric (68.8.2+/-7.1%) and 2-wk-old mesenteric (46 6.3%) arteries but this relaxation was significantly reduced (4.5+/-2.2%) in 2-week-old pulmonary arteries. In neonatal pulmonary arteries, the neurotoxin tetrodotoxin (0.3 muM), the NO synthase inhibitor L-NAME (0.1 mM), and the guanylyl cyclase inhibitor ODQ (10 microM) abolished EFS-induced relaxations, suggesting that NANC relaxation of porcine neonatal pulmonary arteries is mediated by NO, which is probably neuronal in origin. However, The expression in pulmonary arteries of the neuronal NO synthase (nNOS), as determined by Western-blot analysis, increased with postnatal age whereas the expression of the endothelial NOS (eNOS) did not change. In conclusion, NANC relaxation is present in neonatal pulmonary and mesenteric arteries and it is, at least partially, mediated through NO. NANC relaxation of porcine pulmonary and mesenteric arteries decreases with postnatal maturation.

Adrenocortical responsiveness is blunted in twin relative to singleton ovine fetuses.

Twin fetuses experience much higher rates of perinatal mortality/morbidity than age- and weight-matched singletons. Across species, the prepartum increase in fetal plasma cortisol is responsible for maturing a number of systems in preparation for birth and the immediate postnatal period. In sheep, it is known that basal adrenocortical function is delayed in twins relative to singletons. Thus, it could be argued that relative immaturity in twins may explain their increased susceptibility to stress in the perinatal period and their relatively poor perinatal outcome. However, whether adrenocortical responsiveness to stress is also diminished in the twin fetus and whether the fetal cardiovascular, metabolic and endocrine defences to acute stress are comparatively weak in the twin fetus is unknown. This study investigated the effect of twinning on adrenocortical responsiveness to either the physiological stress of acute hypoxaemia or to an exogenous ACTH test, and on the fetal cardiovascular, metabolic and endocrine responses to acute hypoxaemic stress. Twenty Welsh Mountain sheep fetuses were chronically instrumented (1-2% halothane) at 121 +/- 3 days of gestation (term is ca 145 days) with amniotic and vascular catheters and with a transit-time flow probe around a femoral artery. The animals were divided into two groups based upon fetal number (singletons, n= 10; twins, n= 10), as determined at surgery. At 130 +/- 2 days, a 1 h episode of acute, isocapnic hypoxaemia (to reduce carotid P(O(2)) to 12 +/- 1 mmHg) was induced in all fetuses by reducing the maternal inspired O(2) fraction (F(IO(2)); 9% O(2) in N(2)). Fetal cardiovascular variables were recorded at 1 s intervals throughout the experimental protocol and arterial blood samples taken at appropriate intervals for biophysical (blood gases, glucose, lactate) and endocrine (catecholamines, vasopressin, cortisol, ACTH) measures. At 133 +/- 2 days a 2.5 microg bolus dose of synthetic ACTH (Synacthen; Ciba Pharmaceuticals, UK) was injected i.v. into eight of the singleton and six of the twin fetuses to determine adrenocortical steroidogenic sensitivity to exogenous ACTH. Under basal conditions, twins had lower plasma cortisol concentration, arterial blood pressure and femoral blood flow relative to singleton fetuses. Twins responded to acute hypoxaemia with similar pressor and vasopressor responses compared to singleton fetuses. However, the rate pressure product, an index of myocardial work, tended to decrease during hypoxaemia in twins, in contrast to the increase observed in singletons. Similar increases in the fetal plasma concentrations of ACTH, AVP, noradrenaline and adrenaline were observed during hypoxaemia in both groups; however, both the increments in fetal plasma concentration of cortisol in response to acute hypoxaemia and to exogenous ACTH were blunted in twins relative to singletons. This study shows that basal adrenocortical function as well as adrenocortical responsiveness is blunted in the twin relative to the singleton fetus. Further, the mechanism for adrenocortical blunting resides at the level of the adrenal cortex rather than higher up the axis. Relative adrenocortical immaturity in the twin fetus may reflect a specific endocrine adaptation to prolong gestation in multiple ovine pregnancies; however, such an adaptation does not affect the cardiovascular, metabolic or endocrine defence responses to acute hypoxaemia in the twin fetus.

Effects of prevailing hypoxaemia, acidaemia or hypoglycaemia upon the cardiovascular, endocrine and metabolic responses to acute hypoxaemia in the ovine fetus.

Although it is established that the fetus can successfully withstand a single, acute hypoxaemic challenge during gestation, little is known about what effects prevailing adverse intrauterine conditions might have on the fetal response to acute hypoxaemia. The aims of this study were therefore: (1) to characterise the effects of prevailing and sustained hypoxaemia, acidaemia or hypoglycaemia on the fetal cardiovascular responses to an episode of acute hypoxaemia; and (2) to determine the effects of these adverse intrauterine conditions on mechanisms mediating these cardiovascular responses. Thirty-three Welsh Mountain sheep fetuses were chronically instrumented (1-2 % halothane) between 117 and 125 days of gestation (term is ca 145 days) with amniotic and vascular catheters and with a transit-time flow probe around a femoral artery. The animals were divided retrospectively into four groups based upon post-surgical, sustained, basal blood oxygen (chronically hypoxaemic; P(a,O2), 17.3 +/- 0.5 mmHg; n = 8), glucose (chronically hypoglycaemic; blood glucose, 0.49 +/- 0.03 mmol l(-1); n = 6) and acid-base (chronically acidaemic; pH(a), 7.25 +/- 0.01; n = 5) status. Values for compromised fetuses were -2 S.D. from a group of control (n = 14) fetuses. At 130 +/- 4 days, a 1 h episode of acute, isocapnic hypoxaemia (9 % O(2) in N(2), to reduce carotid P(a,O2) to 12 +/- 1 mmHg) was induced in all fetuses by reducing the maternal inspired O(2) fraction (F(I,O2)). Fetal cardiovascular variables were recorded at 1 s intervals throughout the experimental protocol and arterial blood samples taken at appropriate intervals for biophysical (blood gases, glucose, lactate) and endocrine (catecholamines, vasopressin, cortisol, ACTH) measures. During acute hypoxaemia all fetuses elicited hypertension, bradycardia and femoral vasoconstriction. However, prevailing fetal compromise altered the cardiovascular and endocrine responses to a further episode of acute hypoxaemia, including: (1) enhanced pressor and femoral vasoconstriction; (2) greater increments in plasma noradrenaline and vasopressin during hypoxaemia; and (3) basal upward resetting of hypothalamic-pituitary-adrenal axis function. Only chronically hypoxaemic fetuses had significantly elevated basal concentrations of noradrenaline and enhanced chemoreflex function during acute hypoxaemia. These data show that prevailing adverse intrauterine conditions alter the capacity of the fetus to respond to a subsequent episode of acute hypoxaemia; however, the partial contributions of hypoxaemia, acidaemia or hypoglycaemia to mediating these responses can vary.