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C A Hubel

Publications and source records attributed to C A Hubel.

32 records · Page 2Linked to original sources
PubMed1996

Impairment of vascular function is associated with an age-related increase of lipid peroxidation in rats.

We tested the hypothesis that an increase in endogenous lipid peroxidation over time is associated with an impairment of endothelium-dependent vascular function in resistance-sized mesenteric arteries that is due in part to alterations of arachidonate metabolism. Susceptibility to red blood cell hemolysis and sera levels of malondialdehyde were increased (P < 0.05) from 20 wk (n = 12) to 40 wk (n = 12) in female Sprague-Dawley rats. Arteries were studied in a myograph by examining the endothelial modification of phenylephrine vasoconstriction and the relaxation responses of the mesenteric arteries to methacholine. We observed the following. 1) An increase in sensitivity to alpha 1-adrenergic stimulation occurred between 20 and 40 wk of age. Cyclooxygenase inhibition decreased the sensitivity to phenylephrine only in the arteries from the 40-wk-old rats, indicating that a cyclooxygenase-dependent vasoconstrictor was modifying the phenylephrine response. 2) Nitric oxide synthase inhibition caused a greater increase in phenylephrine sensitivity in the arteries from the 20-wk-old rats than those from the 40-wk-old rats, indicating that nitric oxide modification of phenylephrine sensitivity decreased with age. 3) Endothelium-independent relaxations were not affected between 20 and 40 wk of age. 4) At 40 wk, the sensitivity to the methacholine-mediated relaxation response decreased without impairing the maximal relaxation response. This reduced sensitivity was removed with cyclooxygenase inhibition or thromboxane A2/prostaglandin H2 (PGH2) receptor blockade. 5) Aortas from the 40-wk-old rats had an increased expression of PGH synthase. Collectively, these observations indicate that, in the female rat, an increase in lipid peroxidation over time is associated with changes in endothelium-dependent vascular function that were due in part to a cyclooxygenase-dependent vasoconstrictor.

Aging↗
PubMed1996

Distinct factors in plasma of preeclamptic women increase endothelial nitric oxide or prostacyclin.

The pathogenesis of preeclampsia is proposed to be due to uncharacterized circulating factors that activate endothelial cells. Support for this hypothesis is provided by in vitro activation of endothelial cells by plasma from preeclamptic women, eg, increased nitric oxide and prostacyclin generation. We performed molecular sizing, lipid extraction, and lipoprotein fractionation of plasma from normal pregnant and preeclamptic women and determined the ability of these plasma fractions to increase nitric oxide or prostacyclin generation by endothelial cells. Fractions from plasma of preeclamptic women were consistently more active than fractions from normal pregnant women, although characterization was qualitatively similar. The factors stimulating nitric oxide and prostacyclin were different. The factor (or factors) stimulating nitric oxide generation was extractable by charcoal and present in lipid extracts and lipoprotein isolates with a molecular weight greater that 1.5 million daltons, which is characteristic of a lipoprotein or lipoprotein aggregate. By contrast, activity to stimulate prostacyclin persisted after charcoal stripping or lipoprotein removal, partitioned to the aqueous fraction, and had a molecular weight of approximately 50,000 D. Two distinct factors in the blood of preeclamptic women alter endothelial function in vitro. This information should guide the search for circulating factors contributing to the pathophysiology of preeclampsia.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Endothelin-induced changes in intracellular pH and Ca2+ in coronary smooth muscle: role of Na(+)-H+ exchange.

The relationship between endothelin-1 (ET-1)-induced stimulation of Na(+)-H+ exchange and intracellular free Ca2+ ([Ca2+]i) was examined in primary cultures of porcine coronary artery smooth muscle cells. Intracellular pH (pHi) and [Ca2+]i were measured using 2,7-bis-carboxyethyl-5(6)-carboxyfluorescein and the acetoxymethyl ester of fura-2 respectively. In HCO3(-)-free buffer (pH = 7.4), ET-1 (0.1-50 nM) induced a sustained, dose-dependent increase in pHi. ET-1 (10 nM) increased pHi from 6.83 +/- 0.01 to 6.93 +/- 0.02 (P < 0.01). The alkalinization was blocked by the Na(+)-H+ exchange inhibitor, 5-(N-ethyl-N-isopropyl)amiloride (EIPA, 3 microM) or by substitution of Na+ with N-methylglucamine or choline chloride (P < 0.05). Recovery of pHi in response to acidification, induced by washout of a 20 mM NH4Cl prepulse, was > 90% inhibited by EIPA (3 microM), confirming the presence of an ET-1-responsive Na(+)-H+ exchanger. Coronary smooth muscle cells responded to ET-1 with a dose-dependent, biphasic increase in [Ca2+]i which was not inhibited by manipulations (EIPA pretreatment or Na(+)-free media) shown to block the Na(+)-H+ exchanger. The ET-1-mediated alkalinization was not inhibited by removal of extracellular Ca2+ ([Ca2+]o). However, complete blockade of the ET-1-mediated [Ca2+]i response using the intracellular Ca(2+)-chelator, [bis-(2-amino-5-methylphenoxy)ethane-NNN'N'-tetraacetic acid tetraacetoxymethyl ester] (MAPTAM), in [Ca2+]o-free media, demonstrated that an increment in [Ca2+]i is required for activation of the Na(+)-H+ exchanger by ET-1. The ET-1-induced rise in [Ca2+]i was not associated with a rise in pHi in the presence of CO2/HCO3-. We conclude that: (1) activation of Na(+)-H+ exchange by ET-1 requires an increment in [Ca2+]i; and (2) ET-1 stimulates EIPA-sensitive Na(+)-H+ exchange, but this stimulation does not modulate ET-1-induced changes in [Ca2+]i.

Amiloride↗
PubMed1994

Lipid peroxidation increases arterial cyclooxygenase activity during pregnancy.

OBJECTIVE: We tested the hypothesis that increased production of lipid peroxides (induced by a mild vitamin E deficiency) during pregnancy would alter the cyclooxygenase pathway of arachidonate metabolism, resulting in impaired endothelial-dependent vascular function. STUDY DESIGN: Mesenteric arteries from pregnant control (n = 12) and pregnant vitamin E-deprived (n = 12) Sprague-Dawley rats were studied in a myograph. RESULTS: Surprisingly, endothelial-dependent relaxations to methacholine were enhanced in arteries from the pregnant vitamin E-deprived rats compared with the pregnant control rats (mean effective concentration producing a 50% response = 0.034 vs 0.046 mumol/L, p < 0.05). In the arteries from the vitamin E-deprived rats this enhanced response was blunted and the group difference eliminated in the presence of a cyclooxygenase inhibitor (1 mumol/L meclofenamate, mean effective concentration producing a 50% response 0.057 vs 0.034 mumol/L, p < 0.05) but had no effect on the arteries from the control pregnant rats. The thromboxane A2-prostaglandin H2 receptor blocker (1 mumol/L SQ 29548) had no effect on the arteries from either group. Endothelial-independent relaxations to sodium nitroprusside were not affected by vitamin E deprivation. Arachidonic acid elicited less tension in the arteries from the vitamin E-deprived rats compared with the controls (at 10 mumol/L: 0.41 vs 0.90 mN/mm, p < 0.01). Cyclooxygenase inhibition potentiated the vasoconstrictor response only in the arteries from the vitamin E-deprived rats (at 10 mumol/L: 0.92 vs 0.41 mN/mm, p < 0.01) so that the group difference was eliminated. CONCLUSION: An elevation of lipid peroxides, mediated by a mild vitamin E deprivation, resulted in an increased cyclooxygenase-dependent vasorelaxation in the mesenteric arteries of the pregnant rat.

Animals↗
PubMed1993

Lipid hydroperoxides potentiate mesenteric artery vasoconstrictor responses.

The aim of this study was to investigate the effects of lipid and organic hydroperoxides on vasomotor activity of isolated rat superior mesenteric arteries. Hydroperoxides did not elicit measurable responses in unstimulated (quiescent) mesenteric arteries. Contractile responses to potassium, however, were significantly potentiated by 13-(s)-hydroperoxylinoleic acid (range 3-54 microM). Potentiation of potassium responses by linoleic acid (18:2) and linolenic acid (18:3) was increased by pretreatment of the fatty acids with lipoxygenase (p < .01). Lipoxygenase alone had no contractile effects. Lipoxygenase-treated 18:2, tert-butyl hydroperoxide, and hydrogen peroxide augmented contractile responses to phenylephrine, but to a lesser degree than corresponding augmentation of potassium responses. Contractile responses to lipoxygenase-treated 18:3 were blunted by vitamin E (p < .02) and by nitroblue tetrazolium (p < .02), whereas catalase and mannitol had no effects, implicating lipid free radicals in the contractile response. Responses to lipid hydroperoxides were not significantly altered by prostaglandin inhibitors. Endothelial cell denudation significantly enhanced the contractile responses elicited by 13-(s)-hydroperoxylinoleic acid (p < .05), indicating that lipid hydroperoxides enhance agonist-induced contractions by a direct effect on the smooth muscle. These results support a hypothesized link between lipid peroxidation and development of altered vascular function. They further suggest that the vascular endothelium may play an important role in regulation of vasomotor responses to lipid hydroperoxides.

Animals↗
PubMed1993

Cyclooxygenase-dependent vasoconstrictor alters vascular function in the vitamin E-deprived rat.

We tested the hypothesis that increased production of lipid peroxides, mediated by a dietary vitamin E deprivation, would alter the cyclooxygenase pathway of arachidonate metabolism, resulting in impaired endothelium-dependent vascular function. Mesenteric arteries from control (n = 12) and vitamin E-deprived (n = 12) Sprague-Dawley rats were studied in a myograph. Endothelium-dependent relaxations to methacholine were similar in the arteries from vitamin E-deprived rats compared with control arteries (EC50, 0.057 +/- 0.006 versus 0.065 +/- 0.009 microM). However, in the arteries from the vitamin E-deprived rats, this response was potentiated in the presence of a cyclooxygenase inhibitor (1 microM meclofenamate; EC50, 0.035 +/- 0.003 versus 0.057 +/- 0.006 microM; P < .05) or thromboxane A2/prostaglandin H2 receptor blocker (1 microM SQ 29548; EC50 0.029 +/- 0.002 versus 0.057 +/- 0.006 microM; P < .05) but had no effect on the arteries from the control rats. Endothelium-independent relaxations to sodium nitroprusside were not effected by vitamin E deprivation. Arachidonic acid increased tension twofold more in the arteries from the vitamin E-deprived rats compared with the control rats (at 1 microM; 0.43 +/- 0.05 versus 0.23 +/- 0.03 mN/mm; P < .05). The enhanced vasoconstriction was blunted, and the group difference was eliminated by a cyclooxygenase inhibitor (0.15 +/- 0.02 versus 0.43 +/- 0.05 mN/mm, P < .05) or a thromboxane A2/prostaglandin H2 receptor blocker (0.17 +/- 0.04 versus 0.43 +/- 0.05 mN/mm, P < .05). Prostaglandin endoperoxide synthase expression, determined by Western immunoblotting on aortas from the same rats, was increased in the vitamin E-deprived rats (3.14 +/- 0.8 versus 1.06 +/- 0.4 fmol/ng DNA, P < .05). In summary, mesenteric arteries from the vitamin E-deprived rats demonstrated altered endothelium-dependent responses that were in part due to a cyclooxygenase-dependent vasoconstrictor binding to the thromboxane A2/prostaglandin H2 receptor. In the aorta, there was an associative increase in the expression of prostaglandin endoperoxide synthase. We speculate that, in some vascular diseases, increased lipid peroxidation may influence endothelium-dependent vascular function by modulating the cyclooxygenase pathway of arachidonate metabolism.

Animals↗
PubMed1992

Sera antioxidant activity in uncomplicated and preeclamptic pregnancies.

Uncontrolled lipid peroxidation may play an important role in the pathophysiology of preeclampsia by causing vascular endothelial cell dysfunction. Sera contain antioxidant mechanisms that serve to control lipid peroxidation. We tested the hypothesis that the sera antioxidant protective mechanisms are diminished in women with preeclampsia. Blood samples were collected within 24 hours of delivery (pre-delivery) and by 24 hours postpartum (post-delivery) from women with preeclampsia (N = 8) and from matched controls with uncomplicated pregnancies (N = 8). Antioxidant activity was determined by the ability of sera to inhibit autoxidation of a standardized brain homogenate. Lipid peroxidation of both brain homogenate and sera was analyzed by high-pressure liquid chromatography using the amount of malondialdehyde present as an indicator of peroxidation. Pre-delivery sera from women with preeclamptic pregnancies had one-half the antioxidant activity of sera from women with uncomplicated pregnancies (42 versus 90%; P less than .01). Malondialdehyde values alone were not significantly different between the groups in either the pre-delivery or post-delivery samples. When using a ratio to evaluate the relative balance between lipid peroxidation and antioxidant activity, pre-delivery samples from women with preeclampsia had over a twofold increase in this ratio compared with samples from uncomplicated pregnancies. In conclusion, in contrast to women with uncomplicated pregnancies, women with preeclampsia have antioxidant activity that is markedly reduced by late gestation. For women with preeclampsia, this may result in a greater potential for endothelial oxidative damage.

Adolescent↗
PubMed1989

Preeclampsia: an endothelial cell disorder.

Despite intense study preeclampsia remains enigmatic and a major cause of maternal and fetal morbidity and mortality. Most investigative efforts have focused on the hypertensive component of this disorder with reduced attention given to other equally important characteristics. Increased sensitivity to pressor agents and activation of the coagulation cascade occur early in the course of preeclampsia, often antedating clinically recognizable disease. Inasmuch as endothelial cell injury reduces the synthesis of vasorelaxing agents, increases the production of vasoconstrictors, impairs synthesis of endogenous anticoagulants, and increases procoagulant production, these cells are likely to be implicated in the pathophysiology of preeclampsia. Indeed, evidence of endothelial cell injury is provided by the most characteristic morphologic lesion of preeclampsia, glomerular endotheliosis. Additional support for this hypothesis is derived from reports that indicate increased levels of circulating fibronectin (which can be released from injured endothelial cells) and increased factor VIII antigen present in the blood of preeclamptic women. More recently, direct evidence of activities that injure endothelial cells in vitro and increase the contractile sensitivity of isolated vessels has been presented. We propose that poorly perfused placental tissue releases a factor(s) into the systemic circulation that injuries endothelial cells. The changes initiated by endothelial cell injury set in motion a dysfunctional cascade of coagulation, vasoconstriction, and intravascular fluid redistribution that results in the clinical syndrome of preeclampsia.

Endothelium, Vascular↗
PubMed1989

Lipid peroxidation in pregnancy: new perspectives on preeclampsia.

Basic research during the past two decades has led to increased awareness of the role of lipid peroxidation in various physiologic and pathophysiologic processes. A number of reports indicate that preeclampsia is associated with elevated blood levels of lipid peroxidation products. In view of its potentially destructive character, uncontrolled lipid peroxidation has been suggested as an etiologic factor in preeclampsia. The present article summarizes current information regarding the occurrence of lipid peroxidation in normal and preeclamptic pregnancy. Recent progress concerning our understanding of the process of lipid peroxidation and its role in cardiovascular disease is also reviewed. This information is used to discuss potential mechanisms by which lipid peroxidation might contribute to the pathogenesis of preeclampsia.

Female↗
PubMed1989

Lipid peroxidation and altered vascular function in vitamin E-deficient rats.

Female rats deprived of dietary vitamin E for 35 wk postweaning were analyzed for changes in vascular function. A functional state of vitamin E deficiency was indicated by a marked increase in spontaneous hemolysis of washed red cells by 22 wk of feeding. Elevated thiobarbituric acid-reactive material in aorta, liver, and plasma samples from vitamin-E deficient rats indicated increased lipid hydroperoxide formation. Systolic blood pressures and heart rates measured biweekly were unaltered by diet. Before being killed, the rats were catheterized and allowed to recover from anesthesia (methohexital sodium ip). The pressor response to graded doses of angiotensin II was significantly increased in the vitamin E-deficient group relative to its control. Isolated superior mesenteric artery segments from vitamin E-deficient rats demonstrated significantly decreased relaxation responses to acetylcholine. In contrast, artery contractile responses to 50 mM potassium and to graded doses of extracellular calcium did not differ, indicating that contractile capability was maintained. Surface blebbing of the femoral artery endothelium was observed by scanning electron microscopy. These data support a proposed link between lipid peroxidation and development of altered vascular function.

Acetylcholine↗
PubMed1982

Ovine placental cortisol production.

Cortisol levels were determined by radioimmunoassay in samples simultaneously obtained from the four vessels serving the ovine placenta (uterine artery and vein, umbilical artery and vein). These samples were collected daily over a 20- to 30-day interval in three animals in the latter third of pregnancy. Cortisol levels in the uterine and umbilical veins were higher than those in the arteries in 67 of 73 sample sets. Net synthesis of 11-deoxycortisol and cortisol from 17 alpha-hydroxyprogesterone by dispersed placental cells was also demonstrated in vitro. These data provide strong evidence that the ovine placenta has the ability to synthesize 11-deoxycortisol and cortisol in vitro and normally does so in vivo.

Animals↗
PubMedDate not supplied

Low-density lipoprotein particle size decreases during normal pregnancy in association with triglyceride increases.

OBJECTIVE: To characterize the changes in low-density lipoprotein (LDL) peak particle diameter (diameter of the predominant LDL subclass) in relation to changes in serum triglyceride concentration during successive stages of normal gestation and postpartum. METHODS: Nonfasting venous blood was obtained longitudinally during and after uncomplicated primiparous pregnancy from 10 nonsmoking women with no history of metabolic disorders. Plasma LDL diameter was determined by nondenaturing polyacrylamide gel electrophoresis. Serum concentrations of total cholesterol, triglyceride, apolipoprotein B, apolipoprotein A-I, and LDL-cholesterol were measured. Gestational changes were analyzed by one-way repeated-measures analysis of variance and the paired multiple comparison Student-Newman-Keuls test. Pearson coefficients were computed for correlation of serum lipids and LDL diameter. RESULTS: Low-density lipoprotein diameter decreased progressively with advancing gestation, evident by 16-20 weeks relative to 5-12 weeks. Seven of 10 cases were subclass pattern B (diameter less than 255 A) by term, indicating that small, dense particles predominated. The average diameter decrease from early to late gestation was 13 A. All subjects reverted to subclass pattern A (diameter 255 A or more) by 6-12 weeks postpartum, indicating prevalence of large, buoyant LDL. Low-density lipoprotein diameter correlated inversely with concentrations of serum triglyceride (r = -.61, P < .0001), apo B (r = -.66, P < .0001), cholesterol (r = -.53, P < .001), LDL cholesterol (r = -.45, P < .005), and apo A-I (r = -.39, P < .02). CONCLUSION: Gestational triglyceride increases are accompanied by progressive decreases in LDL diameter in a majority of cases. These changes undergo reversal postpartum and therefore are transient. Small, dense LDL particles have a number of properties capable of altering vascular function. However, the consequences of the gestational LDL size decrease for maternal and fetal metabolism remain unknown.

Apolipoprotein A-I↗