Regulation of peripheral circulation: introduction

1. Regulation of peripheral circulation: introduction • Ion channels, membrane potential & vascular tone. • Intrinsic control of resistance vessels • Metabolic control • Autoregulation • Endothelial factors • Extrinsic control of resistance vessels RMP = resting membrane potential VSM = vascular smooth muscle

2. Extrinsic Central nervous system Intrinsic Autoregulation (myogenic, metabolic) Endothelial factors Cardiovascular reflexes Hormones metabolism Voltage gated Ca++ channels in VSM HR x SV Arteriolar tone F = DP/R CO = MAP/TPR MAP = CO x TPR MAP = CO x TPR Peripheral resistance vessels are regulated by intrinsic (local) mechanisms, and by extrinsic mechanisms (hormones & the autonomic NS). Distribution of blood flow among different organs is regulated by myogenic, metabolic, neural, & hormonal effects on arteriolar radius. Extrinsic actions are superimposed on intrinsic control.

3. Ca++ Na+ Extracellular Ca++ Sarcoplasmic recticulum Ryanodine receptor (SR Ca++ release channel) Ca++ SR Ca++ ATPase Ca++ stores Ca++ Ca++ Contractile mechanism L-type Ca++ channels (dihydropyridine receptors) are voltage gated, open with depolarization of cell membrane Excitation contraction coupling in vascular smooth muscle No T tubules and no fast Na+ channels. Ca++ enters cells via L-type Ca++ channels. SERCA = sarcoplasmic reticulum Ca++ ATPase

4. 0.4 0.3 Open probability of Ca++ channels L type voltage gated Ca++ channels are activated by depolarization. 0.2 0.1 -70 -50 -30 -10 +10 Resting Membrane Potential (RMP) Vascular smooth muscle (VSM) exhibits Intrinsic tone independent of nervous or hormonal input Sustained graded contraction without action potentials. Level of intrinsic tone is directly related to resting membrane potential (depolarization increases tone). Nervous & hormonal control is superimposed on intrinsic tone. Membrane potential of VSM controls cell [Ca++] via voltage gated Ca++ channels VSM RMP = - 40 to - 55 Mv RMP is a mostly a K+ diffusion potential.

5. - - - - Vascular smooth muscle cell - - - K+ Ca++ - - - - - Contraction of VSM depends on intracellular [Ca++] open K+ channels close K+ channels  K+ efflux  K+ efflux hyperpolarization depolarization inactivates voltage gated L type Ca++ channels activates voltage gated L type Ca++ channels  cell [Ca++]  cell [Ca++] K+ Ca++ EK+ = - 84 mV ECa++ = + 150 mV RMP = – 40 to – 55 mV vasodilation vasoconstriction Level of contraction of VSM is set by intracellular [Ca++] Ca++ enters VSM cells through voltage gated L type Ca++ channels

6. Vasoactive hormones & voltage gated L type Ca++ channels • Vasoconstrictors either • Open Ca++ channels directly or • Depolarize the cell membrane which opens Ca++ channels. • Vasodilators either • close Ca++ channels directly or • hyperpolarize the cell membrane which closes Ca++ channels.

7. K+ channels in vascular smooth muscle (VSM) • ATP sensitive channel (KATP channel) • ↓ [ATP] or ↑ [ADP] → ↑ open probability • Links metabolism to blood flow • Responds to vasoconstrictors and vasodilators • Contributes to resting membrane potential • (some KATP channels are open under resting conditions) • Voltage gated K+ channel (Kv) • Depolarization → ↑ open probability • May contribute to resting membrane potential • Inward rectifying K+ channel (Kir) • At ECF [K+] above normal, Kir channels open • Contribute to vasodilation in muscle during exercise • Despite their name, Kir channels allow outward diffusion of K+ under physiological conditions.

8. KATP channel can bind ATP or ADP  metabolism hypoxia KATP channel  ATP,  ADP ATP ADP K+ activates inactivates activates The SUR domain on the KATP channel is a sulfonylurea receptor or ABC cassette (adenosine binding cassette). KATP channel Activity of the KATP channels links metabolism to blood flow Hypoxia or increased metabolic rate activate the KATP channel.  K+ efflux hyperpolarizes the cell membrane. Voltage gated Ca++ channels are inactivated. VSM dilates.

9. Definition of metabolic control Local blood flow is regulated by the local metabolic level of the tissue. Increased metabolism produces vasodilators that cause an increase in flow. The increased flow increases delivery of O2 & nutrients and the removal of CO2 & waste products to match the new level of metabolism. Possible vasoactive metabolites include: carbon dioxide, H+, nitric oxide, adenosine, inorganic phosphate ions, interstitial osmolality.

10.  metabolism  tissue ADP, CO2, H+, lactate, adenosine, O2 open KATP channels Hyperpolarize cell membrane Close voltage gated Ca++ channels vasodilation  blood flow Local metabolic control of blood flow  Metabolism has the opposite effect Metabolism drives blood flow. Adenosine may be an important regulator of coronary flow

11.  skeletal muscle contraction ECF [K+] open Kir channels Hyperpolarize VSM cell membrane Close voltage gated Ca++ channels vasodilation  blood flow During heavy exercise ECF [K+] increases as K+ diffuses out of cells during repolarization. Kir channels: Despite their name, these channels allow outward diffusion of K+ under physiological conditions. Kir channels contribute to vasodilation during exercise

12. vasodilators Nitric oxide vasoconstrictors receptor receptor Vascular smooth muscle cell Gs cGMP PKC hypoxia cAMP  metabolism + + - K+  ATP,  ADP + KATP channel KATP channels are also affected by hormonal signals

13. Hormones that act via KATP channels Vasodilators Adenosine (coronary & renal circulation) Epinephrine Nitric oxide ANP (atrial natriuretic peptide) Vasoconstrictors Angiotensin II Vasopressin Endothelin

14. Passive system Rigid system Flow Flow Doesn’t occur in the circulation. Pressure Pressure Autoregulation Flow constriction dilation 0 100 200 Pressure Pressure-flow relationships Large veins exhibit a passive pressure flow relationship. Autoregulation: constancy of blood flow when arterial pressure changes.

15. Myogenic mechanism of autoregulation  pressure  Pressure has the opposite effect Stretches arterioles Autoregulation: constancy of blood flow when arterial pressure changes. Activates nonspecific cation channel in VSM cell An example of autoregulation in vivo: Standing up increases arterial pressure in the legs as a function of distance below the heart. Myogenic autoregulation constricts arterioles below the heart. Constriction maintains flow relatively constant Also, this myogenic response prevents an increase in capillary pressure & prevents pedal edema. Na+ enters cell cell depolarizes voltage gated Ca++ channels open constriction Myogenic autoregulation is especially effective in the kidney. constant flow

16. Metabolic mechanism of autoregulation Decreased blood pressure and flow have opposite effects.  Blood pressure  Blood flow   Tissue PO2  Tissue metabolic vasodilators Vasoconstriction Metabolic vasodilators include: low O2, high CO2, [H+], adenosine, PO4, interstitial osmolality. Autoregulation is a response to changes in blood pressure. Metabolic control is a response to changes in tissue metabolism.

17. Reactive hyperemia occlusion occlusion occlusion Pressure, mm Hg Flow, ml/min Occlusion of an artery is followed by an increase in blood flow above control level when the occlusion is released. The longer the occlusion, the greater the increase in flow. During occlusion hypoxia prevails and vasodilator metabolites accumulate. When flow resumes these metabolites produce vasodilation.

18. Catecholamines regulating the circulation: norepinephrine • NeuroeffectorReceptorAction • Norepinephrine Alpha Vasoconstriction • Norepinephrine Beta 1  Heart rate •  Contractility •  Cardiac output Skeletal muscle and coronary arterioles have beta receptors. They can be dilated by low dose epinephrine. Norepinephrine is a constrictor because it has a greater affinity for alpha receptors but it can react with beta receptors.

19. Catecholamines regulating the circulation: epinephrine • Secreted from the adrenal medulla. • Release controlled by sympathetic nerves • Cardiac actions • Heart rate • Contractility • Cardiac output • Vascular • Constricts • Kidney • Splanchnic bed • Skin • Dilates heart & skeletal muscle (low dose)

20. Angiotensin & vasopressin • Angiotensin II • Generated by angiotensin converting enzyme in blood in response to secretion of renin from kidneys. Renin secretion is stimulated by: •  Arterial pressure or blood volume • Low salt diet • Vasoconstrictor, increases TPR • Retains salt (kidneys) • Vasopressin • Secreted from posterior pituitary in response to •  Arterial pressure or blood volume • Dehydration • Pain • Fear • Vasoconstrictor • Retains water (kidneys) Vasoconstricting effects of sympathetic nerves, angiotensin and vasopressin are synergistic

21. Parasympathetic effects on blood flow NeuroeffectorReceptorAction Acetylcholine Muscarinic  Blood flow Salivary glands Gastrointestinal glands Erectile tissue Effects of acetylcholine on blood flow are indirect. Ach acts on the endothelium to release nitric oxide. NO diffuses to VSM & is a vasodilator.

22. Blood Flow Flow  Shear stress Ca++ Ca++ + Calmodulin Nitric oxide synthase endothelium L-arginine Nitric oxide (NO) Vascular smooth muscle relaxation NOS is a calmodulin -dependent enzyme Endothelium , shear stress & nitric oxide synthesis Nitric oxide is needed for maintenance of normal blood pressure. Pharmacological inhibition of nitric oxide synthase increases MAP into the hypertensive range.

23. Hypotension, hemorrhage, dehydration, pain, fear Baroreflex + +  Sympathetic nerve activity  secretion of epinephrine Constriction: skin, GI tract, kidney Dilation: skeletal muscle, heart Arteriolar constriction  total peripheral resistance  flow (GI tract, kidney, liver, resting muscle). Maintain systemic arterial pressure. Circulatory response to hypotension

24. Integration of sympathetic and metabolic control of circulation • In general: • At rest, blood flow is controlled primarily by a low level of sympathetic tone. • Increased work (muscle contraction, secretion, digestion, absorption etc) increases tissue metabolism. • Blood flow increases to match the new level of metabolism. • Blood flow decreases in inactive tissue due to increased sympathetic tone. • Effects of epinephrine on vascular smooth muscle are less important than sympathetic activity.

25. Femoral arterial & venous blood sampled Blood pressure cuff minimizes flow to lower leg Cycle ergometer sets work intensity Aim: to measure upper leg muscle work and metabolism during leg exercise.

26. Work drives oxygen consumption Upper Leg QO2 versus work intensity 0.8 0.6 Upper Leg QO2, L/min 0.4 0.2 0 20 40 60 Work Intensity, Watts

27. 6 4 2 0 20 40 60 Maximal cardiac output is the limiting factor in aerobic exercise. Graph shows leg blood flow as a function of work intensity VO2 = (F)(O2A- O2V) VO2 may be increased by increasing flow & increasing oxygen extraction Upper Leg Blood Flow, L/min Maximum flow = 2L/min per kilogram of muscle. If projected to the whole body, this flow would be equivalent to CO = 50 - 60 L/min. The capacity of skeletal muscle to receive blood is greater than the maximal cardiac output. Work Intensity, Watts

28. O2A- O2V VO2 = (F)(O2A- O2V) 16 12 • Exercising the other leg: • decreases flow • increases extraction • When both legs are exercised, flow is controlled by the balance of opposing sympathetic and metabolic effects 8 4 0 20 40 60 VO2 is increased by increasing oxygen extraction and blood flow Femoral A -V O2 Difference versus work intensity Femoral A-V difference, mlO2/100 ml blood Work Intensity

29. Summary Arteriolar resistance determines distribution of flow between organs. Vascular smooth muscle (VSM) has basal tone independent of nerves & hormones. Tone of VSM is regulated by gradual changes in RMP & cell [Ca++]. Stretch depolarizes VSM & increases tone (myogenic response). Increased local metabolism dilates VSM (metabolic regulation). Autoregulation maintains constant flow when pressure changes (brain, heart, kidney, skeletal muscle). Local metabolic control predominates in heart & brain. Muscle blood flow in active tissue is a balance between sympathetic (constrictor) & metabolic (dilator) effects. Neural control predominates in the splanchnic region and skin. Sympathetic nerves, angiotensin II and vasopressin potentiate each other’s effects.