1. Control of the Circulation Control of the circulation depends on a variety of mechanisms that are directly related to the specific functions performed by the circulation.

2. Functions of the Circulation Function of the circulation Delivery of oxygen, glucose, amino acids, fatty acids. Removal of carbon dioxide and hydrogen ions. Maintenance of ion concentraions. Transport of hormones.

3. Variations in Blood Flow Large metabolic requirements:  Heart, brain, active muscle Need to process lots of blood  Kidney, liver, lungs Special cases:  Skin – for cooling in hot weather.

4. Methods of Regulation Vasodilator: Lack of oxygen produces lactic acid, adenosine (degradation of ATP) which directly affect vascular tone. Oxygen demand: Lack of oxygen prevents SMC from sustaining contraction. (But smc can remain contracted with extremely low oxygen). Need for other nutrients: e.g. vitamin B, as in beriberi.

5. Hyperemia Active Hyperemia: As a result of exercise.  Can increase blood up to 20-fold. Reactive Hyperemia: As a result of ischemia.  Used as a test for coronary stenosis.

6. Local Response to Pressure Metabolic: Increased pressure increases flow, leading to increased oxygen, tending to constrict the vessels. Mechanical: Stretch receptors in smooth muscle cause vascular constriction. Might lead to positive feedback.

7. Ability to compensate for pressure changes Arterial Pressure Blood Flow Chronic Acute 250 mm Hg 10 L

8. Special Mechanisms of Control Kidney (tubuloglomerular feedback): fluid composition in the distal tubule is detected by the macular densa. Excess fluid causes reduced flow rate. Brain: Oxygen, CO 2 and Hydrogen Ion play a dominant role.

9. Control of Large Vessel Tone EDRF (NO): Produced by endothelial cells. An EC response to shear stress. Also produced in response to acetylcholine, bradykinin, ATP. Potent vasodilator. Leads to post-stenotic dilitation. Has other purposes: Neurotransmitter, platelet inhibitor, inhibits cell proliferation

10. NO and Super Oxide NO is produced by NOS Requires L-arginine as substrate. Without L-arginine, NOS produces Super- Oxide, which can do major damage. It is thought that lack of L-arginine during reperfusion may be a major cause of reperfusion injury.

11. NO and Bacteria NO is a primitive immune response. Does not so much kill bacteria as maintain them in stasis so that they will not proliferate and grow. Produced during wound healing as a first line of defense.

12. NO and Viagra Viagra stimulates the production of NO.

13. Vasoconstrictors Angiotensin: 1 micro gram can cause 50 mm Hg increase in pressure. Acts on all arterioles Vasopression: Made in hypothalamus – released to pituitary from which it is distributed to the body. Highly potent. Controls flow in renal tubules

14. Vasoconstrictors (contd) Endothelin Effective in nanogram quantitites. Probably major mechanism for preventing bleeding from large arterioles (up to 0.5 mm). Constricts the umbilical artery of a neonate. Especially effective on coronary, renal, mesenteric and cerebral arteries.

15. Vasodilators Bradykinin: Causes arteriole dilation and increased capillary permeability. Kallerikin -> Kallikrein* (acts on) alpha 2 -globulin (releases) kallidin -> bradykinin (inactivated by) carboxypeptidase (or) converting enzyme Regulates flow to skin, salivary glands, gastrointestinal glands.

16. Vasodilators (continued) Serotonin (5-hydroxytryptamine or 5HT):  Found in platelets (potentiator of platelet activation).  Neurotransmitter.  May be vasoconstrictor or vasodilator.  Role in circulation control not fully understood.

17. Vasodilators (continued) Histamine:  Released by damaged tissue.  Vasodilator and increases capillary porosity.  May induce edema.  Major part of allergic reactions. Prostaglandins:  Most are vasodilators, some are vasoconstrictors.  Pattern of function not yet understood.

18. Other Ions Calcium: Vasoconstrictor (smc contraction) Potassium: Vasodilator (inhibit smc contraction) Magnesium: Vasodilator (inhibit smc contraction) Sodium: Mild dilatation caused by change in osmolality. Increased osmolality causes dilitation. Acetate and Citrate: Mild vasodilators. Increased CO 2 /pH: Vasodilation