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Cerebral artery alpha-1 AR subtypes: high altitude long-term acclimatization responses.

Goyal R, Goyal D, Chu N, Van Wickle J, Longo LD - PLoS ONE (2014)

Bottom Line: Following acclimatization to LTH, ovine MCA showed a 20% reduction (n = 5; P<0.05) in the maximum tension achieved by 10-5 M phenylephrine (PHE).Also, our results demonstrate that extracellular regulated kinase 1 and 2 (ERK1/2)-mediated negative feedback regulation of PHE-induced contractility is modulated by α1B-AR subtype.Overall, in ovine MCA, LTH produces profound effects on α1-AR subtype expression and function.

View Article: PubMed Central - PubMed

Affiliation: Center for Perinatal Biology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, California, United States of America; Epigenuity LLC, Loma Linda, California, United States of America.

ABSTRACT
In response to hypoxia and other stress, the sympathetic (adrenergic) nervous system regulates arterial contractility and blood flow, partly through differential activities of the alpha1 (α1) - adrenergic receptor (AR) subtypes (α1A-, α1B-, and α1D-AR). Thus, we tested the hypothesis that with acclimatization to long-term hypoxia (LTH), contractility of middle cerebral arteries (MCA) is regulated by changes in expression and activation of the specific α1-AR subtypes. We conducted experiments in MCA from adult normoxic sheep maintained near sea level (300 m) and those exposed to LTH (110 days at 3801 m). Following acclimatization to LTH, ovine MCA showed a 20% reduction (n = 5; P<0.05) in the maximum tension achieved by 10-5 M phenylephrine (PHE). LTH-acclimatized cerebral arteries also demonstrated a statistically significant (P<0.05) inhibition of PHE-induced contractility in the presence of specific α1-AR subtype antagonists. Importantly, compared to normoxic vessels, there was significantly greater (P<0.05) α1B-AR subtype mRNA and protein levels in LTH acclimatized MCA. Also, our results demonstrate that extracellular regulated kinase 1 and 2 (ERK1/2)-mediated negative feedback regulation of PHE-induced contractility is modulated by α1B-AR subtype. Overall, in ovine MCA, LTH produces profound effects on α1-AR subtype expression and function.

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PHE responses in presence and absence of α1A-AR subtype antagonist (10−7 M WB) in normoxic and LTH ovine MCA.(A) Dose-response curves in normoxic MCA. Vascular tensions (g) for MCA in response to PHE alone (•, solid line), and in the presence of 10−7 M WB (Δ, dashed line).(B) Dose-response curves in LTH MCA. (C) Tension (g) at EC50 in normoxic sheep MCA. (D) Tension (g) at EC50 in LTH sheep MCA. n = 5 sheep in each group. Values are means ± standard error of means. *Denotes P = <0.05.
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pone-0112784-g002: PHE responses in presence and absence of α1A-AR subtype antagonist (10−7 M WB) in normoxic and LTH ovine MCA.(A) Dose-response curves in normoxic MCA. Vascular tensions (g) for MCA in response to PHE alone (•, solid line), and in the presence of 10−7 M WB (Δ, dashed line).(B) Dose-response curves in LTH MCA. (C) Tension (g) at EC50 in normoxic sheep MCA. (D) Tension (g) at EC50 in LTH sheep MCA. n = 5 sheep in each group. Values are means ± standard error of means. *Denotes P = <0.05.

Mentions: In both normoxic and LTH ovine MCA (5 animals in each group), the α1A-AR subtype antagonist (WB) reduced the PHE-induced contractility (Figure 2A & B). In normoxic animals, in the presence of α1A-AR antagonist (WB4101, 10−7 M) the receptor sensitivity for PHE was reduced ∼20% (pD2 increased from –5.1±0.1 to –4.2±0.1). In LTH MCA, however, the α1A-AR antagonist reduced the receptor sensitivity for PHE only ∼15% (pD2 increased from –5.3±0.1 to –4.5±0.06). Importantly, in normoxic cerebral arteries 10−7 M WB reduced 10−5 M (EC50) PHE-induced contractile response ∼90% (Figure 2C). While, in LTH acclimatized arteries, the 10−7 M of WB only reduced the 10−5 M PHE-induced contractile responses ∼50% (Figure 2D). Thus, it appears that the role of α1A-AR subtype is reduced in PHE-induced contractility.


Cerebral artery alpha-1 AR subtypes: high altitude long-term acclimatization responses.

Goyal R, Goyal D, Chu N, Van Wickle J, Longo LD - PLoS ONE (2014)

PHE responses in presence and absence of α1A-AR subtype antagonist (10−7 M WB) in normoxic and LTH ovine MCA.(A) Dose-response curves in normoxic MCA. Vascular tensions (g) for MCA in response to PHE alone (•, solid line), and in the presence of 10−7 M WB (Δ, dashed line).(B) Dose-response curves in LTH MCA. (C) Tension (g) at EC50 in normoxic sheep MCA. (D) Tension (g) at EC50 in LTH sheep MCA. n = 5 sheep in each group. Values are means ± standard error of means. *Denotes P = <0.05.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4231100&req=5

pone-0112784-g002: PHE responses in presence and absence of α1A-AR subtype antagonist (10−7 M WB) in normoxic and LTH ovine MCA.(A) Dose-response curves in normoxic MCA. Vascular tensions (g) for MCA in response to PHE alone (•, solid line), and in the presence of 10−7 M WB (Δ, dashed line).(B) Dose-response curves in LTH MCA. (C) Tension (g) at EC50 in normoxic sheep MCA. (D) Tension (g) at EC50 in LTH sheep MCA. n = 5 sheep in each group. Values are means ± standard error of means. *Denotes P = <0.05.
Mentions: In both normoxic and LTH ovine MCA (5 animals in each group), the α1A-AR subtype antagonist (WB) reduced the PHE-induced contractility (Figure 2A & B). In normoxic animals, in the presence of α1A-AR antagonist (WB4101, 10−7 M) the receptor sensitivity for PHE was reduced ∼20% (pD2 increased from –5.1±0.1 to –4.2±0.1). In LTH MCA, however, the α1A-AR antagonist reduced the receptor sensitivity for PHE only ∼15% (pD2 increased from –5.3±0.1 to –4.5±0.06). Importantly, in normoxic cerebral arteries 10−7 M WB reduced 10−5 M (EC50) PHE-induced contractile response ∼90% (Figure 2C). While, in LTH acclimatized arteries, the 10−7 M of WB only reduced the 10−5 M PHE-induced contractile responses ∼50% (Figure 2D). Thus, it appears that the role of α1A-AR subtype is reduced in PHE-induced contractility.

Bottom Line: Following acclimatization to LTH, ovine MCA showed a 20% reduction (n = 5; P<0.05) in the maximum tension achieved by 10-5 M phenylephrine (PHE).Also, our results demonstrate that extracellular regulated kinase 1 and 2 (ERK1/2)-mediated negative feedback regulation of PHE-induced contractility is modulated by α1B-AR subtype.Overall, in ovine MCA, LTH produces profound effects on α1-AR subtype expression and function.

View Article: PubMed Central - PubMed

Affiliation: Center for Perinatal Biology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, California, United States of America; Epigenuity LLC, Loma Linda, California, United States of America.

ABSTRACT
In response to hypoxia and other stress, the sympathetic (adrenergic) nervous system regulates arterial contractility and blood flow, partly through differential activities of the alpha1 (α1) - adrenergic receptor (AR) subtypes (α1A-, α1B-, and α1D-AR). Thus, we tested the hypothesis that with acclimatization to long-term hypoxia (LTH), contractility of middle cerebral arteries (MCA) is regulated by changes in expression and activation of the specific α1-AR subtypes. We conducted experiments in MCA from adult normoxic sheep maintained near sea level (300 m) and those exposed to LTH (110 days at 3801 m). Following acclimatization to LTH, ovine MCA showed a 20% reduction (n = 5; P<0.05) in the maximum tension achieved by 10-5 M phenylephrine (PHE). LTH-acclimatized cerebral arteries also demonstrated a statistically significant (P<0.05) inhibition of PHE-induced contractility in the presence of specific α1-AR subtype antagonists. Importantly, compared to normoxic vessels, there was significantly greater (P<0.05) α1B-AR subtype mRNA and protein levels in LTH acclimatized MCA. Also, our results demonstrate that extracellular regulated kinase 1 and 2 (ERK1/2)-mediated negative feedback regulation of PHE-induced contractility is modulated by α1B-AR subtype. Overall, in ovine MCA, LTH produces profound effects on α1-AR subtype expression and function.

Show MeSH
Related in: MedlinePlus