In vitro prostacyclin production by ovine uterine and systemic arteries. Effects of angiotensin II.

Magness, Ronald R.; Osei-Boaten, Kwabena; Mitchell, Murray D.; Rosenfeld, Charles R.

doi:10.1172/jci112229

Cited by 88 publications

(41 citation statements)

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“…At the end of the preincubation period the media was replaced with fresh oxygenated Krebs-Henseleit buffer and a 2-h incubation was performed, exchanging the buffer each hour to determine if substrate availability was rate limiting (21). As we have done previously in studies of other arteries (21), hyperoxic conditions were employed in vitro to maintain the degree of oxygenation at a level at which oxygen availability would not limit PG production (22,23). Selected segments were incubated in the presence of 100 MuM indomethacin to confirm that the PGs measured were newly synthesized.…”

Section: Methodsmentioning

confidence: 99%

“…Samples ofthe incubation media were assayed for the stable metabolite of prostacyclin, 6-keto-prostaglandin Fla, and for PGE2 by radioimmunoassay as previously described (21,24 and the tubes were incubated, bound and free ligand were separated, and bound ligand was quantified as in the 6-keto-PGFa assay. The unknown quantities of 6-keto-PGFia and PGE2 were determined from the standard curves generated.…”

Section: Methodsmentioning

confidence: 99%

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Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat.

et al. 1991

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IntroductionProstacyclin is a critical mediator of structure and function in the pulmonary circulation, causing both the inhibition of vascular smooth muscle growth and vasodilatation via the stimulation ofadenylate cyclase. To examine the potential role ofalterations in prostacyclin production or mechanism of action in chronic hypoxic pulmonary hypertension, we determined the effects of prolonged (7 d Hypoxic pulmonary hypertension is one of the critical mechanisms underlying persistent pulmonary hypertension ofthe neonate and the development of pulmonary hypertension in older children and adults with a variety of cardiac and respiratory illnesses (1, 2). This phenomenon has been well studied in the adult rat, yielding both physiologic and anatomic findings similar to those noted in the human (3-5). In the rat model, pulmonary hypertension is evident almost immediately after the onset of acute severe hypoxia, and it is also present with accompanying anatomic changes after more prolonged periods of hypoxia of milder degree. These events in the pulmonary circulation of the rat are contrasted by the maintenance of normal systemic blood pressure, mimicking the clinical experience with this problem (1, 4, 6, 7). Studies in the rat and other species indicate that locally-produced prostacyclin is important in the regulation ofvasomotor tone and vascular cell differentiation and growth in the pulmonary circulation (8, 9). These actions are mediated through the plasma membrane-bound enzyme adenylate cyclase, with prostacyclin stimulation of cyclic AMP (cAMP) production resulting in vasodilatation and the inhibition ofsmooth muscle cell growth (10, 1 1). In vivo experiments and in vitro studies with perfused isolated lung preparations have demonstrated that pulmonary production ofthis potent vasodilator increases with acute hypoxia, resulting in a degree of attenuation of the vasoconstrictor response (12,13). However, despite the initial increase in prostacyclin production, further hypoxia leads to the development of pulmonary hypertension with medial hypertrophy of muscular arteries and extension of vascular smooth muscle (VSM)' into peripheral, normally nonmuscular, arteries (3, 4). These alterations are prevented in the rat when angiotensin II is administered during the hypoxia period, most likely related to its ability to release prostaglandins (PG) (8). This suggests that changes in PG synthesis or PG-mediated mechanisms may be involved in the pathogenesis of chronic hypoxic pulmonary hypertension.To examine the potential role ofalterations in prostacyclin production or mechanism ofaction in chronic hypoxic pulmonary hypertension, we determined the effects ofprolonged (7 d) in vivo hypoxia on in vitro prostacyclin production and mediation of adenylate cyclase activity in rat main pulmonary arteries. PGE2 production and mediation ofadenylate cyclase activity were also investigated to determine if the results for prostacyclin are specific to that vasodilatory prostanoid. Based on the findings with acute hypox...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat.

et al. 1991

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“…Magness et al (30,31) suggested that increases in basal and ANG II-mediated synthesis of endothelium-derived prostacyclin (PGI 2 ) and/or nitric oxide (NO) contribute to the attenuated ANG II contractions in the pregnant ovine UVB. Alternatively, the pregnancy-related rise in plasma ANG II levels could decrease ANG II receptor (ATR) expression and/or binding and alter vascular responsiveness (29,32).…”

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confidence: 99%

Defining the differential sensitivity to norepinephrine and angiotensin II in the ovine uterine vasculature

Rosenfeld

DeSpain

Liu

2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Rosenfeld CR, DeSpain K, Liu X-t. Defining the differential sensitivity to norepinephrine and angiotensin II in the ovine uterine vasculature. Am J Physiol Regul Integr Comp Physiol 302: R59-R67, 2012. First published October 26, 2011 doi:10.1152/ajpregu.00424.2011The intact ovine uterine vascular bed (UVB) is sensitive to ␣-agonists and refractory to angiotensin II (ANG II) during pregnancy; the converse occurs in the systemic circulation. The mechanism(s) responsible for these differences in uterine sensitivity are unclear and may reflect predominance of nonconstricting AT2 receptors (AT2R) in uterine vascular smooth muscle (UVSM). The contribution of the placental vasculature also is unclear. Third generation and precaruncular/placental arteries from nonpregnant (n ϭ 16) and term pregnant (n ϭ 23) sheep were used to study contraction responses to KCl, norepinephrine (NE), and ANG II (with/without ATR specific inhibitors) and determine UVSM ATR subtype expression and contractile protein content. KCl and NE increased third generation and precaruncular/ placental UVSM contractions in a dose-and pregnancy-dependent manner (P Յ 0.001). ANG II only elicited modest contractions in third generation pregnant UVSM (P ϭ 0.04) and none in precaruncular/placental UVSM. Moreover, compared with KCl and NE, ANG II contractions were diminished Ն 5-fold. Whereas KCl and ANG II contracted third generationϾϾprecaruncular/placental UVSM, NEinduced contractions were similar throughout the UVB. However, each agonist increased third generation contractions Ն 2-fold at term, paralleling increased actin/myosin and cellular protein content (P Յ 0.01). UVSM AT 1R and AT2R expression was similar throughout the UVB and unchanged during pregnancy (P Ͼ 0.1). AT 1R inhibition blocked ANG II-mediated contractions; AT 2R blockade, however, did not enhance contractions. AT 2R predominate throughout the UVB of nonpregnant and pregnant sheep, contributing to an inherent refractoriness to ANG II. In contrast, NE elicits enhanced contractility throughout the ovine UVB that exceeds ANG II and increases further at term pregnancy. placental artery; systemic artery; actin/myosin; angiotensin II receptors; ␣-agonists OVINE PREGNANCY IS ASSOCIATED with numerous cardiovascular changes (43, 48), including a Ͼ30-fold rise in uterine blood flow (UBF) and Ͼ40% increase in cardiac output. Additionally, there is development of refractoriness to the pressor effects of infused norepinephrine (NE) and angiotensin II (ANG II) in women and sheep (44,49,53). Although the ovine uterine vascular bed (UVB) also develops refractoriness to these agonists during pregnancy (32, 49), Naden and Rosenfeld (36) reported that the intact pregnant ovine UVB was more refractory to the vasoconstricting effects of ANG II than the systemic vasculature. Thus, blood pressure increased in the absence of significant decreases in uteroplacental blood flow (UPBF). In contrast, the UVB was quite sensitive to ␣-agonists, which decreased ovine UPBF at nonpressor doses, demonstrating differenc...

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“…The incubation procedures employed were similar to those we have used in studies of uterine and systemic arteries from pregnant sheep (22). After collective equilibration, the segments were placed individually into sealed polypropylene chambers containing 2.0 ml of oxygenated (680 mmHg) KrebsHenseleit buffer at 37°C for 1 h. At the end of this preincubation period, the media was replaced with fresh Krebs-Henseleit buffer and a 5-20-min incubation was performed.…”

Section: Methodsmentioning

confidence: 99%

Oxygen modulates prostacyclin synthesis in ovine fetal pulmonary arteries by an effect on cyclooxygenase.

et al. 1992

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Prostacyclin (PGI2) plays an integral role in 02 mediation of pulmonary vasomotor tone in the fetus and newborn. We hypothesized that 02 modulates PG!2 synthesis in vitro in ovine fetal intrapulmonary arteries, with decreasing 02 causing attenuated synthesis. A decline in Po2 from 680 to 40 mmHg caused a 26% fall in basal PGI2 synthesis. PGI2 synthesis maximally stimulated by bradykinin, A23187, and arachidonic acid were also attenuated at low Po2, by 35%, 33%, and 35%, respectively. PGE2 synthesis was equally affected. In contrast, varying 02 did not alter PGI2 synthesis with exogenous PGH2, which is the product of cyclooxygenase and the substrate for prostacyclin synthetase. Prostaglandin-mediated effects of 02 on cAMP production were also examined. Decreasing Po2 to 40 mmHg caused complete inhibition of basal cAMP production, whereas cAMP production stimulated by exogenous PGI2 was not affected. In parallel studies of mesenteric arteries, PGI2 synthesis and cAMP production were enhanced at low 02. Thus, PGI2 synthesis in fetal intrapulmonary arteries is modulated by changes in 02, with decreasing 02 causing attenuated synthesis. This process is due to an effect on cyclooxygenase activity, it causes marked parallel alterations in cAMP production, and it is specific to the pulmonary circulation.

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In vitro prostacyclin production by ovine uterine and systemic arteries. Effects of angiotensin II.

Cited by 88 publications

References 38 publications

Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat.

Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat.

Defining the differential sensitivity to norepinephrine and angiotensin II in the ovine uterine vasculature

Oxygen modulates prostacyclin synthesis in ovine fetal pulmonary arteries by an effect on cyclooxygenase.

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