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Regulation of uteroplacental blood flow (UPBF) during pregnancy remains unclear. Large conductance, [Ca.sup.2+]-activated [K.sup.+] channels ([BK.sub.Ca]), consisting of [alpha]-and regulatory [beta]-subunits, are expressed in uterine vascular smooth muscle (UVSM) and contribute to the maintenance of UPBF in the last third of ovine pregnancy, but their expression pattern and activation pathways are unclear. We examined [BK.sub.Ca] subunit expression, the cGMP-dependent signaling pathway, and the functional role of [BK.sub.Ca] in uterine arteries (UA) from nonpregnant (n = 7), pregnant (n = 38; 56-145 days gestation; term, ~150 days), and postpartum (n = 15; 2-56 days) sheep. The a-subunit protein switched from 83-87 and 105 kDa forms in nonpregnant UVSM to 100 kDa throughout pregnancy, reversal occurring >30 days postpartum. The 39-kDa [[beta].sub.1]-subunit was the primary regulatory subunit. Levels of 100-kDa [alpha]-subunit rose ~70% during placentation (P < 0.05) and were unchanged in the last two-thirds of pregnancy; in contrast, [[beta].sub.1]-protein rose throughout pregnancy ([R.sup.2] = 0.996; P < 0.001; n = 13), increasing 50% during placentation and approximately twofold in the remainder of gestation. Although UVSM soluble guanylyl cyclase was unchanged, cGMP and protein kinase [G.sub.1[alpha]] increased (P < 0.02), paralleling the rise and fall in [[beta].sub.1]-protein during pregnancy and the puerperium. [BK.sub.Ca] inhibition not only decreased UA nitric oxide (NO)-induced relaxation but also enhanced [alpha]-agonist-induced vasoconstriction. UVSM [BK.sub.Ca] modify relaxation-contraction responses in the last two-thirds of ovine pregnancy, and this is associated with alterations in [alpha]-subunit composition, [alpha]:[[beta].sub.1]subunit stoichiometry, and upregulation of the cGMP-dependent pathway, suggesting that [BK.sub.Ca] activation via NO-cGMP and [[beta].sub.1] augmentation may contribute to the regulation of UPBF. uteroplacental blood flow; regulatory subunits; protein kinase G isoforms; cyclic guanosine 3',5'-monophosphate

Arginine vasopressin (AVP) is an important regulator of cardiovascular homeostasis in the fetus, but its role after birth is unclear. Although infused AVP increases mean arterial pressure (MAP) during the 1st mo after birth, pressor responses are unchanged, suggesting that vascular responsiveness is also unchanged. Alternatively, this could reflect increases in AVP metabolic clearance rate ([MCR.sub.AVP]). However, newborn AVP metabolism and synthesis are poorly studied. Therefore, we examined the pressor responses to infused AVP and the pattern of circulating AVP, AVP production rate ([PR.sub.AVP]), and [MCR.sub.AVP] in conscious newborn sheep (n = 5) at 9-38 days after birth. Basal MAP rose and heart rate (HR) fell during the study period (P [less than or equal to] 0.02), while circulating AVP was unchanged (P > 0.1), averaging 3.01 [+ or -] 0.86 pg/ml. Infused AVP elicited steady-state responses at 10-40 min, increasing plasma AVP and MAP and decreasing HR (P < 0.001). Although pressor responses were unchanged between 9 and 38 days, the rise in MAP correlated with increases in plasma AVP (R = 0.47, P = 0.02, n = 24). [MCR.sub.AVP] was unchanged throughout the 1st mo (P > 0.2), averaging 205 [+ or -] 17 ml x [kg.sup.-1] x [min.sup.-1], and was associated with an elevated [PR.sub.AVP], 973 [+ or -] 267 pg x [kg.sup.-1] x [min.sup.-1], which also was unchanged (P > 0.1). After birth, [MCR.sup.AVP] and [PR.sup.AVP] are elevated, probably accounting for the stable plasma AVP levels. The former is also likely to account for the stable pressor responses to infused AVP during the 1st too. The reason for the elevated [PR.sup.AVP] is unclear but may relate to increases in vascular volume associated with postnatal growth. metabolic clearance rate; neonatal blood pressure; arginine vasopressin production rate

Vascular smooth muscle (VSM) maturation is developmentally regulated and differs between vascular beds. The maturation and contribution of VSM function to tissue blood flow and blood pressure regulation during early gestation are unknown. The carotid artery (CA) contributes to fetal cerebral blood flow regulation and well being. We studied CA VSM contractility, protein contents, and phenotype beginning in the midthird of ovine development. CAs were collected from early (88-101 day of gestation) and late (138-150 day; term = day 150) fetal (n = 14), newborn (6-8 day old; n = 7), and adult (n = 5) sheep to measure forces in endothelium-denuded rings with KC1, phenylephrine, and ANG II; changes in cellular proteins, including total and soluble protein, actin and myosin, myosin heavy chain isoforms (MHC), filamin, and proliferating cell nuclear antigen; and vascular remodeling. KC1 and phenylephrine elicited age- and dose-dependent contraction responses (P < 0.001) at all ages except early fetal, which were unresponsive. In contrast, ANG II elicited dose responses only in adults, with contractility increasing greater than fivefold vs. that shown in fetal or neonatal animals (P < 0.001). Increased contractility paralleled age-dependent increases (P < 0.01) in soluble protein, actin and myosin, filamin, adult smooth muscle MHC-2 (SM2) and medial wall thickness and reciprocal decreases (P < 0.001) in nonmuscle MHC-B, proliferating cell nuclear antigen and medial cellular density. VSM nonreceptor- and receptor-mediated contractions are absent or markedly attenuated in midgestation and increase age dependently, paralleling the transition from synthetic to contractile VSM phenotype and, in the case of ANG II, paralleling the switch to the [AT.sub.1] receptor. The mechanisms regulating VSM maturation and thus blood pressure and tissue perfusion in early development remain to be determined. myosin heavy chain isoforms; nonmuscle myosin; fetal development; receptor and nonreceptor function; smooth muscle growth; angiotensin-II doi:10.1152/ajpregu.00851.2006

Rosenfeld CR, Liu X, DeSpain K. Pregnancy modifies the large conductance qa2±-activated K channel and cGMP-dependent signaling pathway in uterine vascular smooth muscle. Am J Physiol Heart Circ Physiol 296: H1878-H1887, 2009; doi:10.1152/ajpheart.01185.2008.Regulation of uteroplacental blood flow (UPBF) during pregnancy remains unclear. Large conductance, Ca[sup2+]-activated K[sup+] channels (BK[subCa]), consisting of aand regulatory 13-subunits, are expressed in uterine vascular smooth muscle (UVSM) and contribute to the maintenance of UPBF in the last third of ovine pregnancy, but their expression pattern and activation pathways are unclear. We examined BKca subunit expression, the cGMP-dependent signaling pathway, and the functional role of BKca in uterine arteries (UA) from nonpregnant (n 7), pregnant (n = 38; 56-145 days gestation; term, -150 days), and postpartum (n = 15; 2-56 days) sheep. The a-subunit protein switched from 83-87 and 105 kDa forms in nonpregnant UVSM to 190 kDa throughout pregnancy, reversal occurring >30 days postpartum. The 39-kDa 13,-subunit was the primary regulatory subunit. Levels of 100-kDa a-subunit rose -70% during placentation (P < 0.05) and were unchanged in the last two-thirds of pregnancy; in contrast, β[sub1]-protein rose throughout pregnancy (R[sub2] = 0.996; P < 0.001; n = 13), increasing 50% during placentation and approximately twofold in the remainder of gestation. Although UVSM soluble guanylyl cyclase was unchanged, cGMP and protein kinase G[sub1α] increasecd (P < 0.02), paralleling the rise and fall in β[sub1]-protein during pregnancy and the puerperium. BK[subca] inhibition not only decreased UA nitric oxide (NO)-induced relaxation but also enhanced a-agonist-induced vasoconstriction. UVSM BK[subCa] modify relaxationcontraction responses in the last two-thirds of ovine pregnancy, and this is associated with alterations in α-subunit composition, α:β,subunit stoichiometry, and upregulation of the cGMP-dependent pathway, suggesting that BK[subca] activation via NO-cGMP and β[sub1] augmentation may contribute to the regulation of UPBF. [ABSTRACT FROM AUTHOR]

Large conductance K+ channels (BKCa) are expressed in uterine artery (UA) smooth muscle from nonpregnant and pregnant sheep and contribute to the regulation of basal vascular tone and responses to estrogen and vasoconstrictors. To determine if BKCa are expressed in women and contribute to UA function, we collected UA from nonpregnant women (n =31) at elective hysterectomy and analyzed for subunit protein, localization with immunohistochemistry, and function using endothelium-denuded rings. UA expresses BKCa α-, β1- and β2-subunit protein. KCl and phenylephrine (PE, an α1-agonist) caused dose-dependent vasoconstriction (P <.001), and UA precontracted with PE dose-dependently relaxed with sodium nitroprusside (SNP; P <.001). Tetraethylammonium chloride (TEA, 0.2-1.0 mM), a BKCa inhibitor, dose-dependently increased resting tone (P =.004; 28% ±5.3% with 1.0 mM), enhanced PE-induced (10-6 M) vasoconstriction (P <.04), and attenuated SNP-induced relaxation at 1.0 mM (P =.02). BKCa are expressed in human UA and modulate vascular function by attenuating vasoconstrictor responses and contributing to nitric oxide-induced vasorelaxation. [ABSTRACT FROM AUTHOR]