Isoflurane increases the activity of the vascular matrix metalloproteinase-2 in non-pregnant rats and increases the nitric oxide metabolites in pregnancy

Abstract

Surgeries that require general anesthesia occur in 1.5-2% of gestations. Isoflurane is frequently used because of its lower possibility of affecting fetal growth. Therefore, we examined the isoflurane anesthesia-induced effects on maternal hemodynamic and vascular changes. We hypothesized that isoflurane would enhance endothelium-dependent vasodilation as a consequence of increased nitric oxide and decreased metalloproteinases (MMPs). Female rats (n=28) were randomized into 4 groups (7 rats/group): conscious (non-anesthetized) non-pregnant group, non-pregnant anesthetized group, conscious pregnant group, and pregnant anesthetized group. Anesthesia was performed on the 20th pregnancy day, and hemodynamic parameters were monitored. Nitric oxide metabolites, gelatinolytic activity of MMP-2 and MMP-9, and the vascular function were assessed. Isoflurane caused no significant hemodynamic changes in pregnant compared with non-pregnant anesthetized group. Impaired acetylcholine-induced relaxations were observed only in conscious non-pregnant group (by approximately 62%) versus 81% for other groups. Phenylephrine-induced contractions were greater in endothelium-removed aorta segments of both pregnant groups (with or without isoflurane) compared with non-pregnant groups. Higher nitric oxide metabolites were observed in anesthetized pregnant in comparison with the other groups. Reductions in the 75 kDa activity and concomitant increases in 64 kDa MMP-2 isoforms were observed in aortas of pregnant anesthetized (or not) groups compared with conscious non-pregnant group. Isoflurane anesthesia shows stable effects on hemodynamic parameters and normal MMP-2 activation in pregnancy. Furthermore, there were increases in nitric oxide bioavailability, suggesting that isoflurane provides protective actions to the endothelium in pregnancy.

Keywords: isoflurane; metalloproteinase; nitric oxide; non-pregnant rats; pregnancy.

Figure 1. Isometric contraction and relaxation of the abdominal aorta

(A) Acetylcholine (ACh)-induced vasodilation, (B) ACh-induced vasodilation in the presence of L-NAME, (C) Phenylephrine (Phe)-induced contraction in endothelium-intact aorta rings, (D) Phe-induced contraction in endothelium-denuded aorta rings, (E) KCl induced contraction in endothelium-intact aorta rings, (F) KCl induced contraction in endothelium-denuded aorta rings were evaluated in abdominal aorta rings of Non-Preg, Non-Preg+Iso, Preg, and Preg+Iso groups. Values represent mean ± SD. *P<0.05 versus Non-Preg, #P<0.05 versus Non-Preg+Iso.

Figure 2. Plasma levels of NOx were determined among the four groups

Values represent mean ± SD. *P<0.05 vs Non-Preg, #P < 0.05 vs Non-Preg+Iso.

Figure 3. Gelatinolytic activity of MMP-2 in aorta

(A) Representative zymography gel of aorta, (B) gelatinolytic activity of 75 KDa MMP-2, (C) 72 KDa MMP-2, and (D) 64 KDa MMP-2 examined in thoracic aorta of Non-Preg, Non-Preg+Iso, Preg, and Preg+Iso groups. Values represent mean ± SD. *P<0.05 vs Non-Preg group.

Figure 4. Gelatinolytic activity of MMP-9 and MMP-2 in plasma

Representative zymography gel of plasma (A), gelatinolytic activity of 92 kDa MMP-9 (B) and 72 kDa MMP-2 (C) examined in plasma of Non-Preg, Non-Preg+Iso, Preg, and Preg+Iso groups. Values represent mean ± SD. *P<0.05 versus Non-Preg and Non-Preg+Iso groups.