Upregulation of endothelial and neuronal constitutive nitric oxide synthase in pregnant rats

Abstract

Pregnancy is characterized by hemodynamic and body fluid alterations. Increased nitric oxide (NO) production has been suggested to play a role in the hemodynamic alterations of pregnancy and has also been reported to increase arginine vasopressin (AVP) release. We therefore hypothesized that gestation could increase both NO synthase (NOS) constitutive isoforms, neuronal NOS and endothelial NOS, and thereby contribute to the hyposmolality and peripheral arterial vasodilation of pregnancy, respectively. The present study was therefore undertaken to examine the constitutive NOS isoforms in aortas, mesenteric arteries, and hypothalami of pregnant rats on day 20 of gestation compared with age-matched nonpregnant rats. Plasma AVP was determined by radioimmunoassay and hypothalamic mRNA AVP by solution hybridization assay. Hypothalamic neuronal NOS was assessed by Northern blot and Western blot; endothelial NOS was assessed by Western blot in arteries and hypothalamus. The results demonstrated that 1) plasma AVP and hypothalamic AVP mRNA are increased in pregnant rats (n = 8), 2) neuronal NOS protein and mRNA are increased in hypothalamus of pregnant rats (n = 4), and 3) endothelial NOS expression, as assessed by Western blot analysis, is increased in both conductance (aorta) as well as resistance (mesenteric) arteries of pregnant rats (n = 4). We conclude that both of the constitutive NOS isoforms are increased in pregnant rats, suggesting that the peripheral arterial vasodilation and hyposmolality of pregnancy could be mediated by these isoforms.

Suppression of endotoxin-induced fever in near-term pregnant rats is mediated by brain nitric oxide

“…This is the first study to show that this febrile response can be restored and that brain NO plays a determining role in the mechanism of fever suppression. This NO-mediated mechanism is consistent with previous reports that the expression of NOS within the brain is increased during late pregnancy (38,47,48) and that central NO donors can inhibit LPS-induced fever (21). The dose of L-NMMA that we used did not cause significant hyperthermia by itself in either day 19 and 20 pregnant, day 15 pregnant, or virgin female rats, demonstrating that the febrile response in near-term dams was due to a restoration of the neuroimmune response to LPS and not a nonspecific response to L-NMMA.…”

“…However, these increases can be blocked by the nonspecific COX inhibitor indomethacin (31, 44), indicating interactions between COX and NO activity. Oestrogen and progesterone, secreted during pregnancy, increase expression of endothelial NOS within cerebral blood vessels (33), and the neuronal NOS isoform is also increased in the hypothalamus during the late stages of pregnancy (38,47,48).There is growing evidence that NO is involved in thermoregulation through neural signaling (31,42). Neurons containing NOS have been identified in the medial preoptic area (3), a key integrative site for thermoregulatory signals.…”

“…However, these increases can be blocked by the nonspecific COX inhibitor indomethacin (31, 44), indicating interactions between COX and NO activity. Oestrogen and progesterone, secreted during pregnancy, increase expression of endothelial NOS within cerebral blood vessels (33), and the neuronal NOS isoform is also increased in the hypothalamus during the late stages of pregnancy (38,47,48).…”

Systemic Arterial Vasodilation, Vasopressin, and Vasopressinase in Pregnancy

“…Estrogens are known to upregulate nitric oxide (NO) synthase, 2 and there is experimental evidence that NO contributes to this arterial vasodilation during pregnancy. 3,4 Moreover, an increase in circulating relaxin during early pregnancy is also known to increase NO-mediated arterial vasodilation. 5 Systemic arterial vasodilation in pregnancy is associated consequently with a secondary increase in cardiac output.…”

“…The hypotonicity seen in pregnant rats, which is similar to that observed in human pregnancy, is associated with increased plasma and hypothalamic vasopressin. 3 Because of the modest degree of hypotonicity during pregnancy, a large acute water load (20 ml/kg) may lower plasma osmolality substantially and override the nonosmotic release of AVP, thereby leading to urinary dilution.…”