1. Physiology of the Kidney 201
Nitric Oxide and Endothelin
Jeffrey J. Kaufhold, MD

2. Renal Physiology 201 Overview of Physiology 101
Nitric Oxide Physiology
Endothelin Physiology
Pathophysiology of the system
Volume regulation - the big picture.

3. Glomerular Physiology Blood flow determinants
Systemic
AT-II
ANS
Afferent
Efferent
PG's
Local
TGF
Filtration

4. Renal Physiology 201 Explosion of Research in NO and ET
In the last 4 years, over 3000 publications each.

5. Nitric Oxide Functions: Studies describe Pathophys. in: Regulate BP
Neurotransmitter
Suppress Pathogens
Studies describe Pathophys. in:
Pregnancy/Pre-ecclampsia
HTN
Hepatic Failure

6. Endothelin
Function:
Most potent vasoconstrictor
Studies describe broad range of Pathophysiologic conditions.

7. Why is this Important?
Inhibitors and Antagonists being developed which you will use soon
You already use some:
Nitroprusside
Isordil/NTG
Viagra

8. Nitric Oxide - NO Uncharged molecule - can go anywhere
Unpaired electron - highly reactive
Chemical generation:
Arginine + O2-----> NO + Citrulline
NOS

9. Enzyme Production Nitric Oxide Synthase (NOS) Two Types Constitutive
vasodilator
neurotransmitter
Inducible
Free radical scavenger
Pathogen killer

10. NITRIC OXIDE Constitutive

11. NITRIC OXIDE Inducible

12. Nitric Oxide Targets: Effects: Vascular Smooth Muscle Neurons
Pathogenic bacteria
Effects:
Vasodilator
Feedback for ET-1
Neurotransmitter
Free Radical/Killer

13. NonVascular Functions of NO
Modulates immune response
reduces toxicity of oxygen radicals
reduces adhesion of neutrophils, etc
inhibits mast cell degranulation

14. Clinical Aspects of N.O. Cirrhosis Pregnancy
decreased BP, low SVR, angiogenesis
NOS inhibitors work, sort of.
Pregnancy
reduced response to angiotensin
natural inhibitor found in pre-ecclampsia

15. ENDOTHELIN Three Types
Produced by endothelial cells, most renal cell types.
Two receptor types, A and B

16. ENDOTHELIN Stimulators: Vasoconstrictors Thrombin Hypoxia
Low shear stress
Cytokines

17. ENDOTHELIN Inhibitors of production Vasodilators Heparin
High shear stress

18. ENDOTHELIN Feedback inhibition by Nitric Oxide, PGI2
Also inhibited by activation of ET-B receptor on the endothelial cell

19. ENDOTHELIN

20. ENDOTHELIN Effect Target Vasoconstriction Vascular Smooth M.
Sodium excretion
Proliferation, accumulation of Matrix, and contraction.
Vascular Smooth M.
Renal Tubules
Mesangial cells

21. ENDOTHELIN Clinical Aspects
ATN
Contrast nephrotoxicity
Cyclosporine nephrotoxicity
Endotoxic shock
Hypertension
Chronic renal failure

22. WHY IS THE KIDNEY THE SMARTEST CORTEX IN THE BODY?

23. Volume regulation Active Sensors Passive system Renal Autonomic nerves
Like a system of lakes and spillways

24. Renal Structure C
Artery P
Vein M
Ureter

25. Renal Structure

26. Renal Structure U Cortex U osmotic Vascular 300 gradient bundle
Medulla
collecting tubule
Glomerulus
1200 U

27. Pathologic States
Hypertension
16 ml

28. Pathologic States
CHF
Renal Artery Stenosis
4 ml

29. Pathologic States Glomerular senescence Lower perfusion pressure
=low shear stress
-->stimulates ET

30. Glomerular Sclerosis

31. Summary Physiology and Pathophysiology of
Nitric Oxide
Endothelin
Physiology and structural aspects of volume regulation

32. Summary Keep learning Be the patients advocate
Be active in managing the system.