W11 L1 Regulation of blood flow

Week 11 Lecture 1: Regulation of Tissue Blood Flow

Instructor: Emily Vyverberg, PharmD

Instructional Objectives

  • Explain variation in blood flow to different organs

  • Explain the importance of local blood flow control by tissues

  • Describe mechanisms of acute control of tissue blood flow

  • Describe mechanisms of long-term control of tissue blood flow

1. Explain Variation in Blood Flow to Different Organs

Variations in Blood Flow

  • Blood flow is not equally distributed among all organs at rest.

    • Kidneys:

      • Account for only ~0.5% of body mass.

      • Receive 22% of cardiac output (CO) → Approximately 1,110 mL/min.

      • High blood flow is necessary to supply adequate plasma for a high glomerular filtration rate (GFR).

    • Muscles:

      • Comprise approximately 40% of total body mass.

      • Receive only 15% of CO → Approximately 750 mL/min when inactive.

Blood Flow Distribution Variation

Figure 9.2 illustrates blood flow distribution to organs and tissues at rest and during heavy exercise:

  • Rest: 25 L/min total cardiac output

    • Significant flow to kidneys and liver.

  • Heavy Exercise:

    • Redistribution to muscles, with dramatic increases in blood flow.

    • Example:

    • Cardiac output goes from ~$5 L/min at rest to ~$20 L/min during heavy exercise.

Liver Blood Flow

  • Extremely large blood flow to the liver:

    • Receives 27% of CO → Approximately 1,350 mL/min.

    • Dual Blood Supply:

    • Approximately 75% from hepatic portal vein (drains GI organs).

    • Approximately 25% from hepatic artery.

    • Both sources empty into hepatic sinusoids (specialized sinusoidal capillaries).

2. Explain the Importance of Local Blood Flow Control by Tissues

Blood Flow Control

  • The heart acts only as a pump to provide the pressure for circulation.

  • Individual tissues regulate the amount of blood flow by adjusting the diameter of their arterioles.

  • Arterioles are rich in innervation and highly responsive to local chemical conditions, serving as "gatekeepers" for tissue perfusion.

Importance of Local Control

  • Ensures:

    • Homeostasis: Each tissue receives exactly the amount of O2 and nutrients it needs—no more, no less.

    • Efficiency: Cardiac output is distributed based on real-time metabolic demands (e.g., more to muscles during exercise).

    • Protection: Prevents both overperfusion and underperfusion, thus mitigating risk of tissue damage.

Special Requirements of Organs

  • Blood Conditioning Organs: Some organs, such as kidneys and skin, receive more blood than required for their metabolic needs to condition blood for body demands.

  • Conditioning in Skin: Blood flow varies with temperature and thermoregulatory needs:

    • Vasoconstriction minimizes heat loss.

    • Vasodilation increases heat loss.

  • Renal Circulation: Higher renal blood flow facilitates higher GFR despite lower metabolic O2 needs.

Summary of Local Control

  • Local control of blood flow is critical because it:

    • Matches perfusion to ongoing metabolic activity.

    • Maintains steady flow despite pressure changes.

    • Prevents ischemia or overperfusion.

    • Allows vital organs to prioritize needs during stress conditions.

3. Describe Mechanisms of Acute Control of Tissue Blood Flow

Mechanisms of Tissue Blood Flow Control

  1. Acute Control:

    • Facilitates rapid changes (seconds-minutes) in local perfusion to meet immediate metabolic needs.

    • Occurs primarily by altering the diameter of arterioles (VSM).

  2. Long-Term Control:

    • Involves structural changes (days-weeks) in blood vessels, ensuring supply meets chronic metabolic demands.

    • Associated with "vascular remodeling".

Acute Control Mechanisms

  • Vascular Smooth Muscle (VSM) Contraction:

    • Control changes by adjusting blood vessel diameter, which impacts blood flow and resistance (BP).

  • **Mechanism of VSM Contraction:

    • Increase in intracellular calcium concentration [Ca2+].

    • Ca2+ binds to calmodulin (CaM).

    • The Ca2+/CaM complex activates Myosin Light Chain Kinase (MLCK).

    • Phosphorylated myosin interacts with actin, resulting in VSM contraction.

Arterioles' Role

  • Arterioles:

    • Composed of 1-2 layers of vascular smooth muscle; allow diameter changes, thus controlling local blood flow.

    • Functions:

      • VSM contraction → Reduces blood flow.

      • VSM relaxation → Increases blood flow.

  • Regulated by local vasoactive and metabolic factors as well as SNS fibers.

Acute Control Mechanisms

  • Intrinsic Control Mechanisms:

    • Local metabolic mechanisms (Active Hyperemia).

    • Myogenic response (Autoregulation).

    • Endothelial-derived vasoactive substances.

    • Local autocoids.

  • Extrinsic Control Mechanisms:

    • Neural (Sympathetic Nervous System - SNS).

    • Hormonal control mechanisms.

Local Metabolic Mechanisms

  • Active Hyperemia:

    • Increased blood flow in a tissue corresponds with heightened metabolic activity.

    • Increased metabolism leads to augmented local O2 consumption and accumulation of vasodilators (K⁺, H⁺, CO₂, adenosine), causing arteriolar vasodilation and boosting blood flow to the tissue.

  • Example:

    • Exercising skeletal muscle requires increased blood flow (up to 20-fold) to restore O2 and remove waste.

Myogenic Response and Autoregulation

  • Myogenic Response:

    • Vascular smooth muscle in arterioles responds automatically by adjusting its tone based on pressure changes to maintain blood flow.

    • When arterial pressure increases, arteriolar walls stretch, leading to increased intracellular calcium, causing constriction (vasoconstriction) and increased resistance to maintain blood flow.

    • In contrast, decreased arterial pressure results in relaxation (vasodilation) to maintain perfusion despite lower pressure.

Autoregulation of Blood Flow

  • Various tissues regulate their blood flow to ensure relative constancy despite pressure fluctuations (70-175 mmHg).

  • Ohm's law: (F=rac△PR)(F = rac{△P}{R}) defines this relationship, where F = blood flow, △P = pressure difference, and R = resistance.

  • Autoregulation is crucial in vital organs (brain, heart, kidneys) to maintain blood supply under fluctuating systemic pressures.

Endothelial-Derived Vasoactive Substances

  • Endothelial cells synthesize/release substances affecting nearby VSM relaxation or contraction:

    • Vasodilators:

    • Nitric Oxide (NO): Produced in response to various stimuli, essential for normal blood flow during physiological conditions.

      • Mechanism:

      • Produced from l-arginine via endothelial nitric oxide synthase (eNOS).

      • NO diffuses into VSM, activates soluble guanylate cyclase (GC), resulting in increased cGMP → VSM relaxation.

      • Implications for endothelial dysfunction in DM, hypertension, and atherosclerosis.

      • Clinical Uses:

      • Nitrates like nitroglycerin for angina.

      • PDE-5 inhibitors (sildenafil) to prolong NO action for erectile dysfunction.

    • Prostacyclin (PGI2):

    • Vasodilator and inhibitor of platelet aggregation; its action involves increased cAMP leading to VSM relaxation.

    • Endothelin-1 (ET-1):

    • A potent vasoconstrictor released in response to endothelium damage and primarily functions in paracrine signaling to promote contraction to prevent hemorrhage.

Local Chemical Influences: Autocoids

  • Autocoids are locally produced mediators influencing vascular tone and local blood flow.

  • Examples include:

    • Prostaglandins.

    • Thromboxane A₂ (TXA₂): Acts as a potent vasoconstrictor and platelet aggregator, regulated via COX enzymes.

    • Histamine: Released from mast cells; induces vasodilation and increases capillary permeability.

    • Bradykinin: Involved in inflammation, induces vasodilation by activating eNOS to produce NO.

4. Describe Mechanisms of Long-Term Control of Tissue Blood Flow

Long-Term Control Mechanisms

  • Involves slow structural changes in blood vessels over days to months, allowing adaptation to metabolic needs and ensuring chronic blood supply.

  • Vascular Remodeling:

    • Changes in the size, number, and structure of blood vessels help meet chronic demands, particularly important for altering metabolic demands or dealing with pathological conditions.

Mechanisms of Long-Term Control include:

  • Angiogenesis: Formation of new vessels from existing ones, stimulated by factors such as:

    • Chronic hypoxia, increased tissue metabolism.

    • Key factors include Vascular Endothelial Growth Factor (VEGF) and other angiogenic factors.

    • Example: Aerobic exercise leads to increased capillary density.

  • Collateral Circulation: Development of new pathways for blood flow in response to blockage or narrowing, preserving perfusion in tissues.

  • Vascular Remodeling: Structural adaptations due to chronic blood flow or pressure changes.

    • Positive remodeling occurs in response to chronic exercise to accommodate higher flow.

    • Hypertrophic remodeling occurs when responding to hypertension to maintain structural integrity against elevated pressures.

Clinical Applications of Long-Term Control

  • Relevant in conditions such as:

    • Chronic ischemia, hypertension, and other metabolic demands.

    • Examples of clinical significance include CABG procedures and treatments for conditions such as age-related neovascularization in AMD involving VEGF inhibitors.