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Biomedical subjects

Lubo Zhang

Publications and source records attributed to Lubo Zhang.

34 records · Page 2Linked to original sources
PubMed2004

Glucocorticoids and vascular reactivity.

Corticosteroid hormones play an important role in the control of vascular smooth muscle tone by their permissive effects in potentiating vasoactive responses to catecholamines through glucocorticoid receptors. Increased cortisol response has been associated with an increase in arterial contractile sensitivity to norepinephrine and vascular resistance. Glucocorticoids regulate vascular reactivity by acting on both endothelial and vascular smooth muscle cells. Both glucocorticoid receptor protein and mRNA have been identified in endothelial and vascular smooth muscle cells. In endothelial cells. glucocorticoids suppress the production of vasodilators. such as prostacyclin and nitric oxide. In vascular smooth muscle cells. glucocorticoids enhance agonist-mediated pharmacomechanical coupling at multiple levels. The effect of glucocorticoids on vascular reactivity is regulated by 11 beta-hydroxysteroid dehydrogenase (11beta-SD). The presence of 11beta-HSD in many tissues suggests that it modulates the access of corticosteroids to their receptors at both renal and extra-renal sites. The two 11beta-HSD isozymes catalyze the interconversion of cortisol and cortisone. Type 11beta-HSD has bidirectional activity, while the type 2 mainly converts cortisol into cortisone, the biologically inactive form. Both type 1 and type 2 11beta-HSD have been found in vascular endothelial and smooth muscle cells, suggesting that abnormal 11B-HSD expression may play a pathogenic role in the common forms of hypertension. In this article, we review possible mechanisms involved in the glucocorticoid-mediated potentiation of vascular reactivity, its regulation by 11beta-HSD, and their physiological and pathophysiological significance.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2003

Calcium homeostasis and contraction of the uterine artery: effect of pregnancy and chronic hypoxia.

The present study tested the hypothesis that chronic hypoxia alters pregnancy-mediated adaptation of Ca2+ homeostasis and contractility in the uterine artery. Uterine arteries were isolated from nonpregnant and near-term pregnant ewes of normoxic control or high-altitude (3820 m) hypoxic (oxygen pressure in the blood [PaO2], 60 mm Hg) treatment for 110 days. Contractions and intracellular-free Ca2+ concentration ([Ca2+]i) were measured simultaneously in the same tissue. In normoxic animals, pregnancy increased norepinephrine (NE), but not 5-hydroxy-thymide (5-HT) or KCl, contractile sensitivity in the uterine artery. Chronic hypoxia significantly attenuated NE-induced contractions in the pregnant, but not nonpregnant, uterine arteries. Similarly, 5-HT-mediated contractions of nonpregnant arteries were not changed. In the pregnant uterine artery, chronic hypoxia significantly increased NE-mediated Ca2+ mobilization, but decreased the Ca2+ sensitivity. In addition, hypoxia increased the calcium ionophore A23187-induced relaxation in pregnant, but not nonpregnant, uterine arteries. However, the A23187-mediated reduction of [Ca2+]i was significantly impaired in hypoxic arteries. In contrast, hypoxia significantly increased the slope of the [Ca2+]i-tension relationship of A23187-induced reductions in [Ca2+]i and tension in the pregnant uterine artery. The results suggest that the contractility of nonpregnant uterine artery is insensitive to moderate chronic hypoxia, but the adaptation of sympathetic tone that normally occurs in the uterine artery during pregnancy is inhibited by chronic hypoxia. In addition, changes in Ca2+ sensitivity of myofilaments play a predominant role in the adaptation of uterine artery contractility to pregnancy and chronic hypoxia.

Animals↗
PubMed2003

Cortisol-mediated regulation of uterine artery contractility: effect of chronic hypoxia.

We previously demonstrated that cortisol regulated alpha(1)-adrenoceptor-mediated contractions differentially in nonpregnant and pregnant uterine arteries. Given that chronic hypoxia during pregnancy has profound effects on maternal uterine artery reactivity, the present study investigated the effects of chronic hypoxia on cortisol-mediated regulation of uterine artery contractions. Pregnant (day 30) and nonpregnant ewes were divided between normoxic control and chronically hypoxic [maintained at high altitude (3,820 m), arterial Po(2): 60 mmHg for 110 days] groups. Uterine arteries were isolated and contractions measured. In hypoxic animals, cortisol (10 ng/ml for 24 h) increased norepinephrine-induced contractions in pregnant, but not in nonpregnant, uterine arteries. The 11beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone did not change cortisol effects in nonpregnant uterine arteries, but abolished it in pregnant uterine arteries by increasing norepinephrine pD(2) (-log EC(50)) in control tissues. The dissociation constant of norepinephrine-alpha(1)-adrenoceptors was not changed by cortisol in nonpregnant, but decreased in pregnant uterine arteries. There were no differences in the density of glucocorticoid receptors between normoxic and hypoxic tissues. Cortisol inhibited the norepinephrine-induced increase in Ca(2+) concentrations in nonpregnant arteries, but potentiated it in pregnant arteries. In addition, cortisol attenuated phorbol 12,13-dibutyrate-induced contractions in normoxic nonpregnant and pregnant uterine arteries, but had no effect on the contractions in hypoxic arteries. The results suggest that cortisol differentially regulates alpha(1)-adrenoceptor- and PKC-mediated contractions in uterine arteries. Chronic hypoxia suppresses uterine artery sensitivity to cortisol, which may play an important role in the adaptation of uterine vascular tone and blood flow in response to chronic stress of hypoxia during pregnancy.

Animals↗
PubMed2003

Extracellular signal-regulated kinases and contractile responses in ovine adult and fetal cerebral arteries.

Accumulating evidence suggests that extracellular signal-regulated kinases (ERK1/2) play a key role in regulating vascular tone. To test the hypotheses that ERK1/2 modulate cerebral artery agonist-induced contraction, and that this changes with developmental age, we measured both total and phosphorylated ERK1/2 in adult and fetal ovine cerebral arteries. In middle cerebral arteries (MCA) we also examined tension and [Ca2+]i responses to phenylephrine (PHE), in the absence and presence of the ERK1/2 inhibitor U-0126 and the mitogen-activated protein kinase kinase (MAPKK or MEK) inhibitor PD-98059. In the fetus, but not adult, U-0126 potentiated PHE-induced contraction. In both age groups, inhibition by U-0126, but not PD-98059, decreased the PHE-induced [Ca2+]i increase; in fact for adult, this eliminated any significant [Ca2+]i increase. In turn in the adult, but not fetus, protein kinase C (PKC) inhibition by staurosporine (3 x 10(-8) M) prior to ERK1/2 inhibition by U-0126 (10(-5) M) prevented this elimination of [Ca2+]i increase. In adult and fetal cerebral arteries basal total ERK1/2 levels were similar. However, in fetal arteries the basal phosphorylated ERK1/2 levels were significantly less than in adult. In fetal, but not adult, cerebral arteries, 10(-6)-10(-4) M PHE increased ERK1/2 phosphorylation in a concentration- and time-dependent manner. The ERK1/2 inhibitor U-0126, but not the MEK inhibitor PD-98059, lowered basal activated ERK1/2 levels in vessels of both age groups. These results suggest that basal levels of phosphorylated ERK1/2 play an important role in suppressing Ca2+ sensitivity, perhaps by PKC inhibition. The developmental increase in cerebral artery basal phosphorylated ERK levels from fetus to adult, suggests a transition in the regulation of contraction from Ca2+ sensitivity in the fetal arteries to Ca2+ concentration in the adult vessels.

Adrenergic alpha-Agonists↗
PubMed2003

Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart.

Chronic hypoxia during pregnancy is one of the most common insults to fetal development. We tested the hypothesis that maternal hypoxia induced apoptosis in the hearts of near-term fetal rats. Pregnant rats were divided into two groups, normoxic control and continuous hypoxic exposure (10.5% O2) from day 15 to 21 of gestation. Hearts were isolated from fetal rats of 21-day gestational age. Maternal hypoxia increased hypoxia-inducible factor-1alpha protein in fetal hearts. Chronic hypoxia significantly increased the percentage and size of binucleated myocytes and increased apoptotic cells from 1.4 +/- 0.14% to 2.7 +/- 0.3% in the fetal heart. In addition, the active cleaved form of caspase 3 was significantly increased in the hypoxic heart, which was associated with an increase in caspase 3 activity. There was a significant increase in Fas protein levels in the hypoxic heart. Chronic hypoxia did not change Bax protein levels but significantly decreased Bcl-2 proteins. In addition, chronic hypoxia significantly suppressed expression of heat shock protein 70. However, chronic hypoxia significantly increased expression of the anti-apoptotic protein 14-3-3, among other 14-3-3 isoforms. Chronic hypoxia differentially regulated beta-adrenoreceptor (beta-AR) subtypes with an increase in beta1-AR levels but no changes in beta2-AR. The results demonstrate that maternal hypoxia increases apoptosis in fetal rat heart, which may be mediated by an increase in Fas and a decrease in Bcl-2 proteins. Chronic hypoxia-mediated increase in beta1-AR and decrease in heat shock proteins may also play an important role in apoptosis in the fetal heart.

Animals↗
PubMed2003

Effect of fetal hypoxia on heart susceptibility to ischemia and reperfusion injury in the adult rat.

OBJECTIVE: Epidemiologic studies showed an association between adverse intrauterine environment and ischemic heart disease in the adult. We tested the hypothesis that prenatal hypoxia increased the susceptibility of adult heart to ischemia-reperfusion (I-R) injury. METHODS: Time-dated pregnant rats were divided between normoxic and hypoxic (10.5% oxygen from day 15 to 21) groups. Hearts of 6-month-old male progeny were studied using Langendorff preparation and were subjected to two protocols of I-R: 10 minutes of ischemia and 3 hours of reperfusion (I-R(10)) or 25 minutes of ischemia and 3 hours of reperfusion (I-R(25)). RESULTS: Prenatal hypoxia did not change basal left ventricular (LV) function. I-R(10) produced myocardial stunning and a transient decrease in LV function in control hearts but caused myocardial infarction and a persistent decrease in postischemic recovery of LV function in hypoxic hearts. I-R(25) caused myocardial infarction in both control and hypoxic hearts, which was significantly higher in hypoxic hearts. The postischemic recovery of LV function was significantly reduced in hypoxic hearts. I-R(25)-induced activation of caspase-3 and apoptosis in the left ventricle were significantly higher in hypoxic than control hearts. There was a significant decrease in LV heat shock protein 70 and endothelial nitric oxide synthase levels in hypoxic hearts. Prenatal hypoxia did not change beta(1)-adrenoreceptor levels but significantly increased beta(2)-adrenoreceptor in the left ventricle. In addition, it increased G(s)alpha but decreased G(i)alpha. CONCLUSIONS: Prenatal chronic hypoxia increases the susceptibility of adult heart to I-R injury. Several possible mechanisms may be involved, including an increase in beta(2)-adrenoreceptor and the G(s)alpha/G(i)alpha ratio, and a decrease in heat shock protein 70 and endothelial nitric oxide synthase in the left ventricle.

Animals↗
PubMed2003

Effects of chronic hypoxia on maternal vasodilation and vascular reactivity in guinea pig and ovine pregnancy.

During pregnancy, exposure to chronic hypoxia is thought to be associated with an increased risk of preeclampsia and fetal intrauterine growth restriction (IUGR). While some studies suggest that this process may be mediated through effects of chronic hypoxia on uterine artery vasodilation and growth, these observations are likely to be species specific and may represent genetic variability in maternal adaptation to hypoxia. This review is a comparative analysis of the effects of chronic hypoxia on vascular reactivity in pregnant and nonpregnant guinea pig and sheep. Data suggest that exposure to chronic hypoxia is associated with enhanced uterine artery blood flow in the sheep, whereas, in the guinea pig, blood flow is decreased.

Adaptation, Physiological↗
PubMed2003

Possible mechanisms underlying pregnancy-induced changes in uterine artery endothelial function.

The last 10 years has seen a dramatic increase in our understanding of the mechanisms underlying the pregnancy-specific adaptation in cardiovascular function in general and the dramatic changes that occur in uterine artery endothelium in particular to support the growing fetus. The importance of these changes is clear from a number of studies linking restriction of uterine blood flow (UBF) and/or endothelial dysfunction and clinical conditions such as intrauterine growth retardation (IUGR) and/or preeclampsia in both humans and animal models; these topics are covered only briefly here. The recent developments that prompts this review are twofold. The first is advances in an understanding of the cell signaling processes that regulate endothelial nitric oxide synthase (eNOS) in particular (Govers R and Rabelink TJ. Am J Physiol Renal Physiol 280: F193-F206, 2001). The second is the emerging picture that uterine artery (UA) endothelial cell production of nitric oxide (NO) as well as prostacyclin (PGI2) may be as much a consequence of cellular reprogramming at the level of cell signaling as due to tonic stimuli inducing changes in the level of expression of eNOS or the enzymes of the PGI2 biosynthetic pathway (cPLA2, COX-1, PGIS). In reviewing just how we came to this conclusion and outlining the implications of such a finding, we draw mostly on data from ovine or human studies, with reference to other species only where directly relevant.

Animals↗
PubMed2002

Effect of cortisol on norepinephrine-mediated contractions in ovine uterine arteries.

Cortisol potentiated norepinephrine (NE)-mediated contractions in ovine uterine arteries (UA). We tested the hypothesis that cortisol regulated alpha(1)-adrenoceptor-mediated pharmacomechanical coupling differentially in nonpregnant UA (NUA) and pregnant UA (PUA). Cortisol (10 ng/ml for 24 h) significantly increased contractile coupling efficiency of alpha(1)-adrenoceptors in NUA, but increased alpha(1)-adrenoceptor density in PUA. Cortisol potentiated NE-induced inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] synthesis in both NUA and PUA, but increased coupling efficiency of alpha(1)-adrenoceptors to Ins(1,4,5)P(3) synthesis only in NUA. Carbenoxolone alone did not affect NE-mediated Ins(1,4,5)P(3) production, but significantly enhanced cortisol-mediated potentiation of NE-stimulated Ins(1,4,5)P(3) synthesis in PUA. In addition, cortisol potentiated the NE-induced increase in Ca(2+) concentration in PUA, but increased NE-mediated contraction for a given amount of Ca(2+) concentration in NUA. Collectively, the results indicate that cortisol potentiates NE-mediated contractions differentially in NUA and PUA, i.e., by upregulating alpha(1)-adrenoceptor density leading to increased Ca(2+) mobilization in PUA while increasing alpha(1)-adrenoceptor coupling efficiency and myofilament Ca(2+) sensitivity in NUA. In addition, the results suggest that pregnancy increases type 2 11 beta-hydroxysteroid dehydrogenase activity in the UA.

Animals↗
PubMed2002

Chronic hypoxia alters the function of NOS nerves in cerebral arteries of near-term fetal and adult sheep.

In addition to adrenergic innervation, cerebral arteries also contain neuronal nitric oxide synthase (nNOS)-expressing nerves that augment adrenergic nerve function. We examined the impact of development and chronic high-altitude hypoxia (3,820 m) on nNOS nerve function in near-term fetal and adult sheep middle cerebral arteries (MCA). Electrical stimulation-evoked release of norepinephrine (NE) was measured with HPLC and electrochemical detection, whereas nitric oxide (NO) release was measured by chemiluminescence. An inhibitor of NO synthase, N(omega)-nitro-l-arginine methyl ester (l-NAME), significantly inhibited stimulation-evoked NE release in MCA from normoxic fetal and adult sheep with no effect in MCA from hypoxic animals. Addition of the NO donor S-nitroso-N-acetyl-dl-penicillamine fully reversed the effect of l-NAME in MCA from normoxic animals with no effect in MCA from hypoxic animals. Electrical stimulation caused a significant increase in NO release in MCA from normoxic animals, an effect that was blocked by the neurotoxin tetrodotoxin, whereas there was no increase in NO release in MCA from hypoxic animals. Relative abundance of nNOS as measured by Western blot analysis was similar in normoxic fetal and adult MCA. However, after hypoxic acclimitization, nNOS levels dramatically declined in both fetal and adult MCA. These data suggest that the function of nNOS nerves declines during chronic high-altitude hypoxia, a functional change that may be related to a decline in nNOS protein levels.

Aging↗
PubMed2002

Cortisol-mediated potentiation of uterine artery contractility: effect of pregnancy.

During pregnancy, maternal plasma cortisol concentrations approximately double. Given that cortisol plays an important role in the regulation of vascular reactivity, the present study investigated the potential role of cortisol in potentiation of uterine artery (UA) contractility and tested the hypothesis that pregnancy downregulated the cortisol-mediated potentiation. In vitro cortisol treatment (3, 10, or 30 ng/ml for 24 h) produced a dose-dependent increase in norepinephrine (NE)-induced contractions in both nonpregnant and pregnant (138-143 days gestation) sheep UA. However, this cortisol-mediated response was significantly attenuated by approximately 50% in pregnant UA. The 11 beta-hydroxysteroid dehydrogenase (11-beta HSD) inhibitor carbenoxolone did not change the effect of cortisol in nonpregnant UA but abolished its effect in pregnant UA by increasing the NE pD(2) in control tissues from 6.20 +/- 0.05 to 6.59 +/- 0.11. The apparent dissociation constant value of NE alpha(1)-adrenoceptors was not changed by cortisol in pregnant UA but was decreased in nonpregnant UA. There was no difference in glucocorticoid receptor density between nonpregnant and pregnant UA. Cortisol significantly decreased endothelial nitric oxide (NO) synthase protein levels and NO release in both nonpregnant and pregnant UA, but the effect of cortisol was attenuated in pregnant UA by approximately 50%. Carbenoxolone alone had no effects on NO release in nonpregnant UA but was decreased in pregnant UA. These results suggest that cortisol potentiates NE-mediated contractions by decreasing NO release and increasing NE-binding affinity to alpha(1)-adrenoceptors in nonpregnant UA. Pregnancy attenuates UA sensitivity to cortisol, which may be mediated by increasing type-2 11-beta HSD activity in UA.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2002

ERK MAP kinases regulate smooth muscle contraction in ovine uterine artery: effect of pregnancy.

The present study investigated the potential role of extracellular signal-regulated kinase (ERK) in uterine artery contraction and tested the hypothesis that pregnancy upregulated ERK-mediated function in the uterine artery. Isometric tension in response to phenylephrine (PE), serotonin (5-HT), phorbol 12,13-dibutyrate (PDBu), and KCl was measured in the ring preparation of uterine arteries obtained from nonpregnant and near-term (140 days gestation) pregnant sheep. Inhibiting ERK activation with PD-98059 did not change the KCl-evoked contraction but significantly inhibited the contraction to 5-HT in both nonpregnant and pregnant uterine arteries. PD-98059 did not affect PE-induced contraction in the uterine arteries of nonpregnant sheep but significantly decreased it in the uterine arteries of pregnant sheep. In accordance, PE stimulated activation of ERK in uterine arteries of pregnant sheep, which was blocked by PD-98059. PD-98059-mediated inhibition of the PE-induced contraction was associated with a decrease in both intracellular Ca(2+) concentration and Ca(2+) sensitivity of contractile proteins in the uterine arteries of pregnant sheep. PDBu-mediated contraction was significantly less in pregnant than in nonpregnant uterine arteries. PD-98059 had no effect on PDBu-induced contraction in nonpregnant but significantly increased it in pregnant uterine arteries. In addition, PD-98059 significantly enhanced PDBu-stimulated protein kinase C activity. The results indicate that ERK plays an important role in the regulation of uterine artery contractility, and its effect is agonist dependent. More importantly, pregnancy selectively enhances the role of ERK in alpha(1)-adrenoceptor-mediated contractions and its effect in suppressing protein kinase C-mediated contraction in the uterine artery.

Animals↗
PubMed2002

L-type Ca2+ channels in fetal and adult ovine cerebral arteries.

Recently, we reported that, whereas in cerebral arteries of the adult a majority of norepinephrine (NE)-induced increase in intracellular Ca2+ concentration ([Ca2+]i) comes from release of the sarcoplasmic reticulum (SR) Ca2+ stores, in the fetus the SR Ca2+ stores are relatively small, and NE-induced increase in [Ca2+]i results mainly from activation of plasma membrane L-type Ca2+ channels (20). In an effort to establish further the role of L-type Ca2+ channels in the developing cerebral arteries, we tested the hypothesis that, in the fetus, increased reliance on plasmalemmal L-type Ca2+ channels is mediated, in part, by increased L-type Ca2+ channel density. We used 3H-labeled (+)isopropyl-4-(2,1,3-benzoxadiazol-4-y1)-1,4-dihydro-(2,6-dimethyl-5-methoxycarbonyl)pyridine-3-carboxylate (PN200-110, isradipine) to measure L-type Ca2+ channel density (Bmax) in the cerebral arteries, common carotid artery (CCA), and descending aortae of fetal (approximately 140 gestation days), newborn (7-10 days), and adult sheep. In the cerebral and common carotid arteries, B(max) values (fmol/mg protein) of fetuses and newborns were significantly greater than those of adults. Western immunoblotting assay also revealed that the density of L-type Ca2+ channel protein in the cerebral arteries and CCA was about twofold greater in the fetus than the adult. Finally, compared with the adult, fetal cerebral arteries demonstrated a significantly greater maximum tension and [Ca2+]i in response to stimulation with the L-type Ca2+ channel agonist Bay K 8644. In addition, Bay K 8644-stimulated fetal vessels demonstrated a maximal tension and [Ca2+]i similar to that observed in response to stimulation with 10(-4) NE. These results support the idea that fetal cerebrovascular smooth muscle relies more on extracellular Ca2+ and L-type Ca2+ channels for contraction than does the adult and that this increased reliance is mediated, in part, by greater L-type Ca2+ channel density. This may have important implications in the regulation of cerebral blood flow in the developing organism.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2002

Pre- and postjunctional alpha(2)-adrenergic receptors in fetal and adult ovine cerebral arteries.

In ovine cerebral arteries, adrenergic-mediated vasoconstrictor responses differ significantly with developmental age. We tested the hypothesis that, in part, these differences are a consequence of altered alpha(2)-adrenergic receptor (alpha(2)-AR) density and/or affinity. In fetal (approximately 140 days) and adult sheep, we measured alpha(2)-AR density and affinity with the antagonist [(3)H]idazoxan in main branch cerebral arteries and other vessels. We also quantified contractile responses in middle cerebral artery (MCA) to norepinephrine (NE) or phenylephrine in the presence of the alpha(2)-AR antagonists yohimbine and idazoxan and contractile responses to the alpha(2)-AR agonists clonidine and UK-14304. In fetal and adult cerebral artery homogenates, alpha(2)-AR density was 201 +/- 18 and 52 +/- 6 fmol/mg protein, respectively (P < 0.01); however, antagonist affinity values did not differ. In fetal, but not adult, MCA, 10(-7) M yohimbine significantly decreased the pD(2) for NE-induced tension in the presence of 3 x 10(-5) M cocaine, 10(-5) M deoxycorticosterone, and 10(-6) M tetrodotoxin. In fetal, but not adult, MCA, UK-14304 induced a significant decrease in pD(2) for the phenylephrine dose-response relation. In addition, stimulation-evoked fractional NE release was significantly greater in fetal than in adult cerebral arteries. In the presence of 10(-6) M idazoxan to block alpha(2)-AR-mediated inhibition of prejunctional NE release, the fractional NE release was significantly increased in both age groups. We conclude that in fetal and adult ovine cerebral arteries, alpha(2)-AR appear to be chiefly prejunctional. Nonetheless, the fetal cerebral arteries appear to have a significant component of postjunctional alpha(2)-AR.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2002

Fetal and adult cerebral artery K(ATP) and K(Ca) channel responses to long-term hypoxia.

High-altitude long-term hypoxia (LTH) alters cerebral vascular contractile and relaxation responses in both fetus and adult. We tested the hypotheses that LTH-mediated vascular responses were secondary to altered K+ channel function and that in the fetus these responses differ from those of the adult. In middle cerebral arteries (MCA) from both nonpregnant adult and fetal (approximately 140 days gestation) sheep, which were either acclimatized to high altitude (3,820 m) or sea-level controls, we measured norepinephrine (NE)-induced contractions and intracellular Ca2+ concentration ([Ca2+]i) simultaneously, in the presence or absence of different K+ channel openers or blockers. In adult MCA, LTH was associated with approximately 20% decrease in NE-induced tension and [Ca2+]i, with a significant increase in Ca2+ sensitivity. In contrast, in fetal MCA, LTH failed to affect significantly NE-induced contraction or [Ca2+]i but significantly decreased the ATP-sensitive K+ (K(ATP)) channel and Ca2+-activated K+ (K(Ca)) channel-mediated relaxation. The significant effect of K(ATP) and K(Ca) channel activators on the relaxation responses and the fact that K+ channels play a key role in myogenic tone support the hypotheses that K+ channels play an important role in hypoxia-mediated responses. These results also support the hypothesis of significant developmental differences with maturation from fetus to adult.

Acclimatization↗