Dual role of PKC in modulating pharmacomechanical coupling in fetal and adult cerebral arteries

2000 ◽  
Vol 279 (4) ◽  
pp. R1419-R1429 ◽  
Author(s):  
Lawrence D. Longo ◽  
Yu Zhao ◽  
Wen Long ◽  
Carolyn Miguel ◽  
Ryan S. Windemuth ◽  
...  
Keyword(s):  
Vascular Tone ◽  
Cerebral Arteries ◽  
Age Groups ◽  
Intracellular Ca ◽  
Membrane Bound ◽  
Near Term ◽  
Fetal Vessel ◽  
Pharmacomechanical Coupling ◽  
Induced Signal ◽  
Two Age Groups

This study tested the hypothesis that protein kinase C (PKC) has dual regulation on norepinephrine (NE)-mediated inositol 1,4,5-trisphosphate [Ins (1,4,5)P3] pathway and vasoconstriction in cerebral arteries from near-term fetal (∼140 gestational days) and adult sheep. Basal PKC activity values (%membrane bound) in fetal and adult cerebral arteries were 38 ± 4% and 32 ± 4%, respectively. In vessels of both age groups, the PKC isoforms α, βI, βII, and δ were relatively abundant. In contrast, compared with the adult, cerebral arteries of the fetus had low levels of PKC-ε. In response to 10−4 M phorbol 12,13-dibutyrate (PDBu; PKC agonist), PKC activity in both fetal and adult cerebral arteries increased 40–50%. After NE stimulation, PKC activation with PDBu exerted negative feedback on Ins(1,4,5)P3 and intracellular Ca2+ concentration ([Ca2+]i) in arteries of both age groups. In turn, PKC inhibition with staurosporine resulted in augmented NE-induced Ins(1,4,5)P3 and [Ca2+]i responses in adult, but not fetal, cerebral arteries. In adult tissues, PKC stimulation by PDBu increased vascular tone, but not [Ca2+]i. In contrast, in the fetal artery, PKC stimulation was associated with an increase in both tone and [Ca2+]i. In the presence of zero extracellular [Ca2+], these PDBu-induced responses were absent in the fetal vessel, whereas they remained unchanged in the adult. We conclude that, although basal PKC activity was similar in fetal and adult cerebral arteries, PKC's role in NE-mediated pharmacomechanical coupling differed significantly in the two age groups. In both fetal and adult cerebral arteries, PKC modulation of NE-induced signal transduction responses would appear to play a significant role in the regulation of vascular tone. The mechanisms differ in the two age groups, however, and this probably relates, in part, to the relative lack of PKC-ε in fetal vessels.

Cerebral artery KATP- and KCa-channel activity and contractility: changes with development

2000 ◽  
Vol 279 (6) ◽  
pp. R2004-R2014 ◽  
Author(s):  
Wen Long ◽  
Lubo Zhang ◽  
Lawrence D. Longo
Keyword(s):  
Channel Blocker ◽  
Cerebral Arteries ◽  
Dependent Manner ◽  
Channel Activity ◽  
Channel Opener ◽  
Channel Inhibition ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca ◽  
Near Term ◽  
Nonpregnant Adult

The present study was designed to test the hypothesis that in cerebral arteries of the fetus, ATP-sensitive (KATP) and Ca2+-activated K+channels (KCa) play an important role in the regulation of intracellular Ca2+ concentration ([Ca2+]i) and that this differs significantly from that of the adult. In main branch middle cerebral arteries (MCA) from near-term fetal (∼140 days) and nonpregnant adult sheep, simultaneously we measured norepinephrine (NE)-induced responses of vascular tension and [Ca2+]i in the absence and presence of selective K+-channel openers/blockers. In fetal MCA, in a dose-dependent manner, both the KATP-channel opener pinacidil and the KCa-channel opener NS 1619 significantly inhibited NE-induced tension [negative logarithm of the half-maximal inhibitory concentration (pIC50) = 5.0 ± 0.1 and 8.2 ± 0.1, respectively], with a modest decrease of [Ca2+]i. In the adult MCA, in contrast, both pinacidil and NS 1619 produced a significant tension decrease (pIC50 = 5.1 ± 0.1 and 7.6 ± 0.1, respectively) with no change in [Ca2+]i. In addition, the KCa-channel blocker iberiotoxin (10−7 to 10−6 M) resulted in increased tension and [Ca2+]i in both adult and fetal MCA, although the KATP-channel blocker glibenclamide (10−7 to 3 × 10−5 M) failed to do so. Of interest, administration of 10−7 M iberiotoxin totally eliminated vascular contraction and increase in [Ca2+]i seen in response to 10−5M ryanodine. In precontracted fetal cerebral arteries, activation of the KATP and KCa channels significantly decreased both tension and [Ca2+]i, suggesting that both K+ channels play an important role in regulating L-type channel Ca2+ flux and therefore vascular tone in these vessels. In the adult, KATP and the KCa channels also appear to play an important role in this regard; however, in the adult vessel, activation of these channels with resultant vasorelaxation can occur with no significant change in [Ca2+]i. These channels show differing responses to inhibition, e.g., KCa-channel inhibition, resulting in increased tension and [Ca2+]i, whereas KATP-channel inhibition showed no such effect. In addition, the KCa channel appears to be coupled to the sarcoplasmic reticulum ryanodine receptor. Thus differences in plasma membrane K+-channel activity may account, in part, for the differences in the regulation of contractility of fetal and adult cerebral arteries.

Effects of maturation on adrenergic neurotransmission in ovine cerebral arteries

1999 ◽  
Vol 277 (4) ◽  
pp. R931-R937 ◽  
Author(s):  
William J. Pearce ◽  
Sue P. Duckles ◽  
John Buchholz
Keyword(s):  
Cerebral Arteries ◽  
Age Groups ◽  
Peptidergic Neurons ◽  
Synaptic Density ◽  
Vasoactive Substances ◽  
Age Related ◽  
Middle Cerebral Arteries ◽  
Adrenergic Neurotransmission ◽  
Fractional Release ◽  
Two Age Groups

The present studies examine the hypothesis that multiple adrenergic neuroeffector mechanisms are not fully developed in fetal, compared with adult, ovine middle cerebral arteries. In arteries denuded of endothelium and pretreated with 1 μM atropine to block involvement of muscarinic receptors, 10 μM capsaicin to deplete sensory peptidergic neurons, and 10 μM nitro-l-arginine methyl ester (l-NAME) to block possible influences from nitric oxidergic innervation, transmural stimulation at 16 Hz increased contractile tensions to 9.5 ± 3.7% ( n = 6) of the potassium maximum in adult arteries. Corresponding values in fetal arteries, however, were significantly less and averaged only 1.1 ± 0.6% ( n =10). However, postsynaptic sensitivity to norepinephrine (NE) was similar in the two age groups; NE pD2 values (−log EC50) averaged 6.11 ± 0.12 ( n = 6) and 6.33 ± 0.09 M ( n = 9) in fetal and adult arteries, respectively. Similarly, NE content measured via HPLC was also similar in the two age groups and averaged 32.4 ± 5.0 ( n = 17) and 32.5 ± 3.9 ng/ng wet wt ( n = 13) in fetal and adult middle cerebral arteries, respectively. In contrast, stimulation-induced NE release was greater in fetal than in adult arteries, whether calculated as total mass released [883 ± 184 ( n = 17) vs. 416 ± 106 pg NE/mg wet wt ( n = 13)] or as fractional release [51.1 ± 5.3 ( n = 17) vs. 22.8 ± 3.8 pg/pg NE content per pulse × 10−6]. Measured as an index of synaptic density, neuronal cocaine-sensitive NE uptake was similar in fetal and adult arteries [1.55 ± 0.40 ( n = 10) and 1.84 ± 0.51 pmol/mg wet wt ( n = 7), respectively]. Overall, age-related differences in postsynaptic sensitivity to NE, NE release, and NE uptake capacity cannot explain the corresponding age-related differences in response to stimulation. The data thus suggest that total synaptic volume and cleft width, in particular, are probably greater and/or that adrenergic corelease of vasoactive substances other than NE is altered in fetal compared with adult middle cerebral arteries.

scholarly journals α1-Adrenergic receptor subtype function in fetal and adult cerebral arteries

2010 ◽  
Vol 298 (6) ◽  
pp. H1797-H1806 ◽  
Author(s):  
Ravi Goyal ◽  
Ashwani Mittal ◽  
Nina Chu ◽  
Lubo Zhang ◽  
Lawrence D. Longo
Keyword(s):  
Adrenergic Receptor ◽  
Cerebral Arteries ◽  
Age Groups ◽  
Critical Factor ◽  
Receptor Subtype ◽  
Erk Activation ◽  
Wb 4101 ◽  
Intracellular Ca ◽  
Nonpregnant Adult ◽  
And Function

In the developing fetus, cerebral artery (CA) contractility demonstrates significant functional differences from that of the adult. This may be a consequence of differential activities of α1-adrenergic receptor (α1-AR) subtypes. Thus we tested the hypothesis that maturational differences in adrenergic-mediated CA contractility are, in part, a consequence of differential expression and/or activities of α1-AR subtypes. In CA from fetal (∼140 days) and nonpregnant adult sheep, we used wire myography and imaging, with simultaneous measurement of tension and intracellular Ca2+ concentration ([Ca2+]i), radioimmunoassay, and Western immunoblots to examine phenylephrine (Phe)-induced contractile responses. The α1A-AR antagonists (5-MU and WB-4101) completely inhibited Phe-induced contraction in adult but not fetal CA; however, [Ca2+]i increase was reduced significantly in both age groups. The α1D-AR antagonist (BMY-7378) blocked both Phe-induced contractions and Ca2+ responses to a significantly greater extent in adult compared with fetal CA. In both age groups, inhibition of α1A-AR and α1B-AR, but not α1D-AR, significantly reduced inositol 1,4,5-trisphosphate responses to Phe. Western immunoblots demonstrated that the α1-AR subtype expression was only ∼20% in fetal CA compared with the adult. Moreover, in fetal CA, the α1D-AR was expressed significantly greater than the other two subtypes. Also, in fetal but not adult CA, Phe induced a significant increase in activated ERK1/2; this increase in phosphorylated ERK was blocked by α1B-AR (CEC) and α1D-AR (BMY-7378) inhibitors, but not by α1A-AR inhibitors (5-MU or WB-4101). In conclusion, in the fetal CA, α1B-AR and α1D-AR subtypes play a key role in contractile response as well as in ERK activation. We speculate that in fetal CA α1B-AR and α1D-AR subtypes may be a critical factor associated with cerebrovascular growth and function.

scholarly journals Pregnancy attenuates uterine artery pressure-dependent vascular tone: role of PKC/ERK pathway

2006 ◽  
Vol 290 (6) ◽  
pp. H2337-H2343 ◽  
Author(s):  
DaLiao Xiao ◽  
John N. Buchholz ◽  
Lubo Zhang
Keyword(s):  
Uterine Artery ◽  
Vascular Tone ◽  
Mek Inhibitor ◽  
Intraluminal Pressure ◽  
Myogenic Tone ◽  
Uterine Arteries ◽  
Intracellular Ca ◽  
Myogenic Responses ◽  
The Difference ◽  
Near Term

The mechanisms of adaptation of uterine artery vascular tone to pregnancy are not fully understood. The present study tested the hypothesis that pregnancy decreases the PKC-mediated Ca2+ sensitivity of the contractile process and attenuates myogenic tone in resistance-sized uterine arteries. In pressurized uterine arteries from nonpregnant (NPUA) and near-term pregnant (PUA) sheep, we measured, simultaneously in the same tissue, vascular diameter and vessel wall intracellular Ca2+ concentration ([Ca2+]i) as a function of intraluminal pressure. In both NPUA and PUA, membrane depolarization with KCl caused a rapid increase in [Ca2+]i and a decrease in diameter. A pressure increase from 20 to 100 mmHg resulted in a transient increase in diameter that was associated with an increase in [Ca2+]i, followed by myogenic contractions in the absence of further changes in [Ca2+]i. In addition, activation of PKC by phorbol 12,13-dibutyrate induced a decrease in diameter in the absence of changes in [Ca2+]i. Pressure-dependent myogenic responses were significantly decreased in PUA compared with NPUA. However, pressure-induced increases in [Ca2+]i were not significantly different between PUA and NPUA. The ratio of changes in diameter to changes in [Ca2+]i was significantly greater for pressure-induced contraction of NPUA than that of PUA. Inhibition of PKC by calphostin C significantly attenuated the pressure-induced vascular tone and eliminated the difference of myogenic responses between NPUA and PUA. In contrast, the MAPKK (MEK) inhibitor PD-098059 had no effect on NPUA but significantly enhanced myogenic responses of PUA. In the presence of PD-098059, there was no difference in pressure-induced myogenic responses between NPUA and PUA. The results suggest that pregnancy downregulates pressure-dependent myogenic tone of the uterine artery, which is partly due to increased MEK/ERK activity and decreased PKC signal pathway leading to a decrease in Ca2+ sensitivity of myogenic mechanism in the uterine artery during pregnancy.

Role of Ca2+ channels in NE-induced increase in [Ca2+]iand tension in fetal and adult cerebral arteries

1999 ◽  
Vol 277 (1) ◽  
pp. R286-R294 ◽  
Author(s):  
Wen Long ◽  
Yu Zhao ◽  
Lubo Zhang ◽  
Lawrence D. Longo
Keyword(s):  
Plasma Membrane ◽  
Cerebral Arteries ◽  
Channel Blockers ◽  
Developmental Age ◽  
Intracellular Ca ◽  
Lanthanum Ion ◽  
Near Term ◽  
Dose Dependent Decrease ◽  
Nonpregnant Adult

In vascular smooth muscle, elevation of agonist-induced intracellular Ca2+ concentration ([Ca2+]i) occurs via both Ca2+ release from intracellular stores and Ca2+influx across the plasma membrane. In the cerebral vasculature of the fetus and adult the relative roles of these mechanisms have not been defined. To test the hypothesis that plasma membrane L-type and receptor-operated Ca2+ channels play a key role in NE-induced vasoconstriction via alterations in plasma membrane Ca2+ flux and that this may change with developmental age, we performed the following study. In main branch middle cerebral arteries (MCA) from near-term fetal (∼140 days) and nonpregnant adult sheep, we quantified NE-induced responses of vascular tension and [Ca2+]i(by use of fura 2) under standard conditions in response to several Ca2+ channel blockers and in response to zero extracellular Ca2+. In fetal and adult MCA, maximal NE-induced tensions (g) were 0.91 ± 0.12 ( n = 10) and 1.61 ± 0.13 ( n = 12), respectively. The pD2 values for NE-induced tension were both 6.0 ± 0.1, whereas the fetal and adult maximum responses (%Kmax) were 107 ± 16 and 119 ± 7, respectively. The fetal and adult pD2 values for NE-induced increase of [Ca2+]iwere 6.2 ± 0.1 and 6.4 ± 0.1, respectively, whereas maximum [Ca2+]iresponses were 81 ± 9 and 103 ± 15% of Kmax, respectively. After 10−5 M NE-induced contraction, nifedipine resulted in dose-dependent decrease in vessel tone and [Ca2+]iwith pIC50 values for fetal and adult tensions of 7.3 ± 0.1 and 6.6 ± 0.1, respectively ( P < 0.01; n = 4 each), whereas pIC50 for [Ca2+]iresponses were 7.2 ± 0.1 and 6.9 ± 0.1, respectively. The pIC50 values for tension for diltiazem and verapamil were somewhat lower but showed a similar relationship. The receptor-operated Ca2+ channel blocker 2-nitro-4 carboxyphenyl- N,N-diphenyl carbamate showed little effect on NE-induced vessel contractility or [Ca2+]i. In the absence of extracellular Ca2+ for 2 min, 10−5 M NE resulted in markedly attenuated responses of adult MCA tension and [Ca2+]ito 39 ± 7 and 73 ± 8% of control values ( n = 4). For fetal MCA, exposure to extracellular Ca2+concentration resulted in essentially no contractile or [Ca2+]iresponse ( n = 4). Similar blunting of NE-induced tension and [Ca2+]iwas seen in response to 10−3M lanthanum ion. These findings provide evidence to suggest that especially in fetal, but also in adult, ovine MCA, Ca2+ flux via L-type calcium channels plays a key role in NE-induced contraction. In contrast, Ca2+ flux via receptor-operated Ca2+ channels is of less importance. This developmental difference in the role of cerebrovascular plasma membrane Ca2+ channels may be an important association with increased Ca2+sensitivity of the fetal vessels.

Cerebral artery sarcoplasmic reticulum Ca2+ stores and contractility: changes with development

2000 ◽  
Vol 279 (3) ◽  
pp. R860-R873 ◽  
Author(s):  
Wen Long ◽  
Lubo Zhang ◽  
Lawrence D. Longo
Keyword(s):  
Plasma Membrane ◽  
Sarcoplasmic Reticulum ◽  
Cerebral Artery ◽  
Cerebral Arteries ◽  
Induced Responses ◽  
Adult Sheep ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca ◽  
Near Term ◽  
Nonpregnant Adult

To test the hypothesis that sarcoplasmic reticulum (SR) Ca2+ stores play a key role in norepinephrine (NE)-induced contraction of fetal and adult cerebral arteries and that Ca2+ stores change with development, we performed the following study. In main branch middle cerebral arteries (MCA) from near-term fetal (∼140 days) and nonpregnant adult sheep, we measured NE-induced contraction and intracellular Ca2+ concentration ([Ca2+]i) in the absence and presence of different blockers. In adult MCA, after thapsigargin (10−6M), the NE-induced responses of tension and [Ca2+]i were 37 ± 5 and 47 ± 7%, respectively, of control values ( P < 0.01 for each). In the fetal artery, in contrast, this treatment resulted in no significant changes from control. When this was repeated in the absence of extracellular Ca2+, adult MCA increases in tension and [Ca2+]i were 32 ± 5 and 13 ± 3%, respectively, of control. Fetal cerebral arteries, however, showed essentially no response. Ryanodine (RYN, 3 × 10−6 to 10−5 M) resulted in increases in tension and [Ca2+]i in both fetal and adult MCA similar to that seen with NE. For both adult and fetal MCA, the increased tension and [Ca2+]i responses to RYN were essentially eliminated in the presence of zero extracellular Ca2+. These findings provide evidence that in fetal MCA, in contrast to those in the adult, SR Ca2+ stores are of less importance in NE-induced contraction, with such contraction being almost wholly dependent on Ca2+ flux via plasma membrane L-type Ca2+ channels. In addition, they suggest that in both adult and fetal MCA, the RYN receptor is coupled to the plasma membrane Ca2+-activated K+ channel and/or L-type Ca2+ channel.

Concordance of Glucose-Based and of HbA1c-Based Diagnoses of Diabetes in Patients with Peripheral Artery Disease—A Comparison between Two Age Groups

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1522-P
Author(s):  
CHRISTOPH H. SAELY ◽  
ALEXANDER VONBANK ◽  
CHRISTINE HEINZLE ◽  
DANIELA ZANOLIN ◽  
BARBARA LARCHER ◽  
...  
Keyword(s):  
Peripheral Artery Disease ◽  
Age Groups ◽  
Peripheral Artery ◽  
Artery Disease ◽  
Two Age Groups

Foundation for the Prevention and Pathological Aspects of Diseases of the Mucous Membranes of the Oral Cavity (Review)

2020 ◽  
Vol 3 (6) ◽  
pp. 8-11
Author(s):  
Bakaev Zh. N.
Keyword(s):  
Oral Cavity ◽  
Rural Women ◽  
Rural Areas ◽  
Southern China ◽  
Age Groups ◽  
Urban Residents ◽  
Volgograd Region ◽  
Mucous Membranes ◽  
The Russian Federation ◽  
Two Age Groups

According to the authors, the prevalence of SOPR diseases is from 3 to 20%.In a study of 1573 residents of southern China in two age groups who use tobacco and alcohol, the incidence of SOPR was higher among men living in rural areas compared to urban residents. Among women aged 35-44 years, the incidence was higher in urban women, and in the 65-77-year-old group in rural women. In the course of studies in Brazil, among 335 patients older than 60 years, 646 diseases of the SOPR were identified. Similar results were obtained in the analysis of SOPR diseases in the Volgograd region of the Russian Federation

Internet Sex discourse and porn viewing by Arab adolescents: The overt and the covert and its impact on their sexual education and behavior (Preprint)

2018 ◽  
Author(s):  
Anat Gesser-Edelsburg ◽  
Munawar Abed Elhadi
Keyword(s):  
Age Groups ◽  
Sexual Education ◽  
The Internet ◽  
Traditional Values ◽  
Sexual Discourse ◽  
Cultural Taboos ◽  
Internet Sex ◽  
And Behavior ◽  
Depth Interviews ◽  
Two Age Groups

BACKGROUND Due to the religious proscription, it was found that Arab youths acquire information and view pornography secretly. The internet exposes them to contents that contradict religious and cultural taboos. There are few studies about viewing habits of sexual contents among Arab adolescents and about the way they discuss sexuality. OBJECTIVE to characterize the barriers and difficulties that prevent sexual discourse in Arab society and enable pornography viewing, according to the perceptions of adolescents and mothers. METHODS phenomological qualitative research methods, in-depth interviews with 40 participants. 20 Arab adolescents, sampled by two age groups: 14-16 and 16-18. In addition, 20 mothers of adolescents from both sexes were interviewed. RESULTS The findings indicate that mothers “turn a blind eye” to porn viewing and sexual activity by boys, versus a sweeping prohibition and denial of such behavior by girls. The boys reported viewing porn routinely, whereas girls denied doing so, but admitted that their girlfriends watched porn. The study also found that the boys have guilt feelings during and after the viewing as a result of the clash between modernity and traditional values. CONCLUSIONS It is necessary to find a way to encourage a significant sexual discourse to prevent the violent consequences of its absence in Arab society. A controlled, transparent and critical sexual discourse could help youth make more informed decisions concerning the search for sexual contents, porn viewing and sexual behavior.

scholarly journals A Reduced Dose Whole Virion Aluminum Adjuvanted Seasonal Influenza Vaccine Is Immunogenic, Safe, and Well Tolerated in Pediatric Patients

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 500
Author(s):  
Zoltan Vajo ◽  
Gergely Balaton ◽  
Peter Vajo ◽  
Peter Torzsa
Keyword(s):  
Pediatric Patients ◽  
Geometric Mean ◽  
Age Groups ◽  
Aluminum Phosphate ◽  
Vaccine Virus ◽  
Serious Adverse Events ◽  
Reduced Dose ◽  
Viral Hemagglutinin ◽  
Virus Strains ◽  
Two Age Groups

Background: Data suggest that pediatric patients might react differently to influenza vaccination, both in terms of immunity and side effects. We have recently shown that using a whole virion vaccine with aluminum phosphate adjuvants, reduced dose vaccines containing 6 µg of viral hemagglutinin (HA) per strain are immunogenic, and well tolerated in adult and elderly patients. Here we show the results of a multicenter clinical trial of pediatric patients, using reduced doses of a new, whole virion, aluminum phosphate adjuvanted vaccine (FluArt, Budapest, Hungary). Methods: A total of 120 healthy volunteers were included in two age groups (3–11 years, receiving 3 µg of HA per strain, and 12–18 years, receiving 6 µg of HA per strain). We used hemagglutination inhibition testing to assess immunogenicity, based on EMA and FDA licensing criteria, including post/pre-vaccination geometric mean titer ratios, seroconversion and seropositivity rates. Safety and tolerability were assessed using CHMP guidelines. Results: All subjects entered the study and were vaccinated (ITT population). All 120 subjects attended the control visit on Day 21 (PP population). All immunogenicity licensing criteria were met in both age groups for all three vaccine virus strains. No serious adverse events were detected and the vaccine was well tolerated by both age groups. Discussion: Using a whole virion vaccine and aluminum phosphate adjuvants, a reduction in the amount of the viral hemmaglutinin is possible while maintaining immunogenicity, safety and tolerability in pediatric and adolescent patients.

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