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Absence of Calcium-Independent Release of Endothelial Nitric Oxide (NO) in Young Rats

Absence of Calcium-Independent Release of Endothelial Nitric Oxide (NO) in Young Rats. Timothy R. Nurkiewicz & Matthew A. Boegehold West Virginia University School of Medicine Department of Physiology & Pharmacology Morgantown, West Virginia.

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Absence of Calcium-Independent Release of Endothelial Nitric Oxide (NO) in Young Rats

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  1. Absence of Calcium-Independent Release of Endothelial Nitric Oxide (NO) in Young Rats Timothy R. Nurkiewicz & Matthew A. Boegehold West Virginia University School of Medicine Department of Physiology & Pharmacology Morgantown, West Virginia

  2. Weanling Arteriolar Responsiveness to ACh is Normal and Sensitive to NOS Inhibition * * * * * Juvenile Weanling +L-NMMA (10-4 M) Dilation (% of Maximum Response) * P<0.05 vs Normal * * * * * Current Dose of ACh (nAmp) 100 100 80 80 60 60 40 40 20 20 0 0 40 80 5 10 20

  3. Weanling Arteriolar Responsiveness to Shear Stress is Absent (Ca2+-Independent) Control Occlusion * Diameter (mm) Juvenile Weanling * P<0.05 vs Control Wall Shear Rate (s-1) 60 50 40 30 20 600 800 1000 1200 1400 1600

  4. Endothelium-derived NO Ca2+-independent and Ca2+–dependent transduction pathways EGF VEGF a  eNOS A23187 ACh Ca2+ [Ca2+] PI-3 Kinase Tyrosine Kinase Akt / PKB Tyr-P Ser-P + ERK ½ MAPK + Ser-P + +

  5. Methods • Weanling rats: 4 wks • Juvenile Rats: 8 wks • Intravital microscopy of the spinotrapezius muscle • Arcade bridge arterioles • Local, luminal perfusion: • A23187 • VEGF • Simvastatin

  6. Arteriolar A23187 (10-7 M) Infusion (Ca2+-Dependent) * P<0.05 vs Weanling † P<0.05 vs Vehicle Passive * † † Diameter (mm) † Juvenile Weanling Picospritzer Ejection Pressure (PSI) Vehicle-juvenile 120 100 80 60 40 40 0 10 20 30

  7. Weanling Arteriolar Responsiveness to A23187 is Normal and Sensitive to NOS Inhibition * * Juvenile * Weanling +L-NMMA (10-4 M) Dilation (% of Maximum Response) * P<0.05 vs Normal * * * Picospritzer Ejection Pressure (PSI) 100 80 60 40 20 0 100 80 60 40 20 0 5 10 20 40

  8. Arteriolar VEGF (5 mg/ml) Infusion (Ca2+-Independent) * P<0.05 vs Weanling † P<0.05 vs Vehicle Passive * † Diameter (mm) † * * * * Juvenile Weanling Picospritzer Ejection Pressure (PSI) Vehicle-juvenile 120 100 80 60 40 0 20 40 10 30

  9. Juvenile Weanling * * * * +L-NMMA (10-4 M) Dilation (% of Maximum Response) * P<0.05 vs Normal * Picospritzer Ejection Pressure (PSI) 100 100 80 80 Juvenile Arteriolar Responsiveness to VEGF is Sensitive to NOS Inhibition 60 60 40 40 20 20 0 0 5 10 20 40

  10. Endothelium-derived NO Ca2+-independent and Ca2+–dependent transduction pathways EGF VEGF a  eNOS A23187 ACh Ca2+ [Ca2+] PI-3 Kinase Tyrosine Kinase Akt / PKB Tyr-P Ser-P + ERK ½ MAPK + Ser-P + +

  11. Arteriolar Simvastatin (1 mM) Infusion (Ca2+-Independent) * P<0.05 vs Weanling Juvenile Weanling Vehicle-juvenile * * Diameter (mm) Picospritzer Ejection Pressure (PSI) 120 100 80 60 40 0 20 10 30 40 Passive

  12. Juvenile +L-NMMA (10-4 M) Dilation (% of Maximum Response) * P<0.05 vs Normal * * 20 40 Picospritzer Ejection Pressure (PSI) 100 80 Juvenile Arteriolar Responsiveness to Simvastatin is Sensitive to NOS Inhibition 60 40 20 0

  13. Conclusions • Endothelium-dependent arteriolar dilation in response to Ca2+-dependent, and -independent stimuli is present in juvenile rats, and is sensitive to NOS inhibition • Endothelial NO production in response to Ca2+-dependent stimuli (ACh & A23187) is present in weanling arterioles. • Endothelial NO production in response to Ca2+-independent stimuli (shear stress, VEGF, Simvastatin) is absent or not fully functional in weanling arterioles.

  14. Arteriolar Responsiveness to ACh is Identical (Ca2+-Dependent) Juvenile Weanling Dilation(% of Maximum Response) Current Dose of ACh (nAmp) 100 80 60 40 20 0 80 5 10 20 40

  15. Arteriolar Responsiveness to A23187 is Identical (Ca2+-Dependent) Juvenile Weanling 100 80 60 Dilation (% of Maximum Response) 40 20 0 5 10 20 40 Picospritzer Ejection Pressure (PSI)

  16. Weanling Arteriolar Responsiveness to VEGF is Attenuated (Ca2+-Independent) * P<0.05 vs Weanling Juvenile Weanling * Dilation (% of Maximum Response) * * * Picospritzer Ejection Pressure (PSI) 100 80 60 40 20 0 5 10 20 40

  17. Weanling Arteriolar Responsiveness to Simvastatin is Attenuated (Ca2+-Independent) * P<0.05 vs Weanling Juvenile Weanling * * Dilation (% of Maximum Response) Picospritzer Ejection Pressure (PSI) 100 80 60 20 40 40 20 0

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