Increased Acetylcholine-Induced Vasodilation in Pregnant Rats

Abstract

Abstract-We have tested the hypothesis that increased gap junctional communication contributes to the augmented endothelium-dependent vasodilation in pregnancy. Contractile force and connexin43 expression were measured in aortic rings from nonpregnant and pregnant rats. Norepinephrine-constricted aortas from pregnant rats were more sensitive to acetylcholine, but not to sodium nitroprusside, compared with those from nonpregnant rats. Vessels from pregnant rats, constricted either with 45 mmol/L KCl or with norepinephrineϩ10 Ϫ4 mol/L N G -monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthase, also exhibited greater relaxation to acetylcholine. Heptanol, an uncoupler of gap junctional communication, inhibited acetylcholine responses in norepinephrine-constricted aortas from nonpregnant rats but greatly impaired acetylcholine relaxation in aortas from pregnant rats. Heptanol also inhibited in both groups acetylcholine responses in vessels constricted with KCl, only minimally affected acetylcholine relaxation in arteries constricted with norepinephrineϩL-NMMA, and did not change sodium nitroprusside-induced relaxation. Tetraethylammonium chloride induced greater contractions in control aortas compared with aortas from pregnant rats. Increased connexin43 mRNA levels were found in the uterus and in the mesenteric, uterine, and thoracic aortic arteries, but not in the heart and brain, from pregnant rats. These results suggest that increased gap junctional communication, possibly due to increased gap junction protein expression, may facilitate the effects of endothelium-derived relaxing factors, contributing to the augmented endothelium-dependent relaxation in arteries from pregnant rats. Key Words: preeclampsia Ⅲ rats Ⅲ gap junctions Ⅲ nitric oxide Ⅲ endothelium-derived factor P regnancy is associated with a decrease in systemic vascular resistance, which maintains or reduces maternal blood pressure despite the increase in plasma volume and cardiac output. 1 Pregnancy in women and in other mammals, such as the rat, is also characterized by a blunted pressor response 2,3 and decreased vascular reactivity 4,5 to a series of vasoconstrictors. The mechanism(s) responsible for these cardiovascular changes in pregnancy is not fully understood but has been under intense investigation, particularly because its malfunction may have a role in preeclampsia. 6 Because blunted constrictor responses in arteries from pregnant animals are observed in vitro 4,5 and no changes in receptor number or affinity seem to occur, 2,7 it has been suggested that a general mechanism, occurring within the blood vessel wall, is involved. Enhanced endothelium-dependent vasodilation, which may contribute to the attenuated vasoconstriction during pregnancy, has been systematically shown in vessels from pregnant animals, including the uterine, mesenteric, thoracic, and abdominal aortic arteries. 8 -11 Nitric oxide (NO), but not prostaglandins, is considered to contribute substantially to the increased endothelium-dependent relaxation in...

The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women

“…This indicates that gap junctions play a critical role in endotheliumdependent relaxation to BK in isolated subcutaneous resistance arteries from normal pregnant women. Our findings are in line with recent experimental evidence of gap junctions mediating EDHF-type responses in isolated arteries from both nonpregnant (6,17) and pregnant animals (11). In support of our findings, Kenny et al (23) demonstrated that several distinct agents that interfere with gap junctions inhibited non-NO, non-prostanoid-mediated responses to BK in isolated small myometrial arteries from normal pregnant women.…”

“…The NO dependence on gap junctions has been demonstrated in isolated arteries from nonpregnant animals (22). In contrast, other study has shown that inhibitors of gap junctions do not affect responses to sodium nitroprusside, an exogenous source of NO (11). Moreover, it is difficult to perceive that gap junctions could significantly increase the movement of NO toward smooth muscle cells, since NO itself is a highly diffusible molecule through cell membrane.…”

Connexin 43 mediates endothelium-derived hyperpolarizing factor-induced vasodilatation in subcutaneous resistance arteries from healthy pregnant women

“…Pregnant rats exhibit enhanced EDHF-mediated vasodilatation and upregulation of vascular Cx43 expression (8). These effects are markedly diminished in ovariectomized animals but can be restored by exogenous estrogen supplementation (16).…”

Vascular adaptations to pregnancy in mice: effects on myogenic tone

“…Connexin 43, in addition to connexin 40 and connexin 37, are predominantly located in the vascular system where they may play a role in vasomotor function (4,26). Connexin 43 mRNA levels were shown to be elevated in the uterus and uterine and mesenteric and thoracic arteries in pregnant rats (10). A recent study (20) showed that gap junctions are involved in the transfer of vasodilatory (hyperpolarizing) factors in human myometrial vessels in normal pregnancy.…”

“…Each channel consists of six connexin protein subunits arranged around a central pore. Increased gap junction communications were shown in the uterus and the uterine, mesenteric, thoracic aortic arterial segments of pregnant rats (10). Furthermore, involvement of gap junction communication in NO and prostanoid-independent vasodilation has been recently shown in human small myometrial arteries from normal pregnant women (20).…”