PHYS - Local and Systemic Control of Circulation

Question 1

PURPOSE OF BLOOD FLOW (Q) TO TISSUE

Answer 1

• Delivery of O2
• Delivery of nutrients (glu, AA, fatty acids, etc.)
• Removal of CO2
• Remove of H+
• Maintenance of proper ion concentrations
• Transport of hormones and substances

Question 2

RELATIONSHIPS OF BLOOD FLOW

Answer 2

• Q = (ΔP)/R = MAP/R
• Poiseuille’s Law: R = 8ηl/πr^4
• Ohm’s Law: Q = ΔPπr^4/8ηl
• Blood flow is:
  
  • Directly related to pressure and radius^4
  • Indirectly related to length of vessel segment and viscosity of blood

Question 3

PRINCIPLES OF CIRCULATORY FUNCTIONS

Answer 3

• Each tissue can control it’s local blood flow in response to metabolic needs
  
  • Increased metabolism in an organ = increased blood flow
  • Regulated to the minimal sufficient level
• Regulatory Mechanisms
  
  • Heart: adjustment of pump output
  • Resistance vessels: change diameter
  • Veins: change amount of blood pooled in capacitance vessels
  • Extracellular fluid volume: change in total volume and osmolality
• Regulatory Mechanisms
  
  • Local (intrinsic)
  • Systemic (extrinsic)

Question 4

LOCAL (INSTRINSIC) MECHANISMS OF CIRCULATORY REGULATION

Answer 4

• Metabolic (change length/diameter of vessels at tissue level)
  
  • Release of vasodilators
  • Nutrient deficiency for VSM (vascular SM)
• Myogenic (change in vascular SM tone)
  
  • Sudden stretch
  • Reduced stretch
• Pressure Flow Autoregulation
  
  • Maintenance of constant blood flow under changing pressures
  • By changing resistance (think Q = ΔP/R)
  • Safe flow range = 80%-125% of normal (60-160 mmHg)
    
    • Above 160 mmHg vascular resistance decreases, loss of autoregulation mechanism
• Hyperemia (“more blood”)
  
  • Active hyperemia
    
    • Increased blood flow caused by increased tissue activity
    • Ex: increased metabolism
  • Reactive hyperemia
    
    • Blood flow above control level upon release of an arterial occlusion
    • Ex: clamped/blocked vessel suddenly released → sudden increase in blood
  • Potential Metabolic Vasodilators to cause active/reactive hyperemia
    
    • O2/nutrient deficiency in VSM inhibits ability of muscle to contract
    • Link between metabolism and Q unknown, potential vasodilator metabolites:
      
      • Increased CO2
      • Decreased O2
      • K+
      • Adenosine
      • ATP
      • Pgl2 (prostaglandins)
      • Lactic acid
      • Decreased pH
      • PO4-
      • Increased osmolarity
  • Role of Vascular Endothelium
    
    • Interact with adjacent SM cells after activation from substances in blood by releasing
      
      • EDRF (endothelial derived relaxing factors) - ex: NO
      • PGl2
      • EDHF
    • Increased blood flow = released of EDRFs from endothelium = vessel dilation = decreased blood velocity through vessel

Question 5

SYSTEMIC (EXTRINSIC) MECHANISMS

Answer 5

• Humoral (Hormonal)
  
  • Adrenal medullary hormones
    
    • Stimulate nerves to adrenal glands → release of E (80%) and NE (20%) in systemic circulation
      
      • Epinephrine = poor NT
      • CS: pheochromocytoma
    • Adrenoreceptors
      
      • a1 = vasoconstriction, increased peripheral resistance, increased BP
      • b1 = tachycardia, increased myocardial contractility
      • a2 = inhibition of NE release, vasoconstriction (veins > arteries)
        
        • Negative feedback mechanism
      • b2 = vasodilation, slightly decreased peripheral resistance
        
        • Only slightly decreased, because not located everywhere
  • RAAS (renin-angiotensin-aldosterone system)
    
    • Renin secreted by kidneys
      
      • Stimulates angiotensinogen → angiotensin I –(ACE)→ angiotensin II
        
        • Stimulates renal gland to secrete aldosterone
          
          • Stimulates kidney to increase Na+/H2O reabsorption
        • Stimulates AT1/2 receptors → vasoconstriction
          
          • Increases BP
    • CS: renal hypertension; mitigated by ACE inhibitor drugs (antihypertensives)
  • Endothelins
    
    • Vasoconstriction (veins > arteries)
    • Initially depress BP (via Pgl2 release) then sustained increase in BP from vasoconstriction
    • Positive inotropic and chronotropic effects
    • Increase ANP, renin, aldosterone, catecholamines
    • Increased release of sympathetic NTs
    • Bronchoconstriction
    • Decreased glomerular filtration rate, renal Q
      
      • Increased Na+ reabsorption
  • Kinins
    
    • Bradykinin/lysylbradykinin
    • Vasodilatation
    • Degraded by kininase II (= ACE)
      
      • Degrades a vasodilator (kinins) and activates vasoconstrictor (aldo II)
      • Important clinical use for low BP
  • Natriuretic peptides
    
    • Counter-regulatory system to RAAS
      
      • Decreases: blood volume, arterial P, CVP, pulmonary wedge P, CO
    • ANP (heart, brain)
      
      • Released by atrial myocytes in response to atrial distension, ANG II stimulation, endothelium, and sympathetic stimulation
      • Cause SM relaxation and vasodilation
      • Also lead to natriuresis and diuresis via filtration of Na+
    • BNP (heart and blood, not in brain)
    • CNP (brain vascular endothelium)
• Neural
  
  • Sympathetic (heart & BVs)
    
    • Constrict(α)/dilate(β2) arteries
    • Constrict veins
  • Parasympathetic (heart >> BVs)
    
    • Dilates vessels, basal heart is parasympathetically stimulated

Question 6

NEURAL AND HUMORAL LOOPS IN SYSTEMIC REGULATION

Answer 6

• Autonomic Feedback Loop
  
  • MAP → Baroreceptors*
    
    • Parasympathetic*
      
      • Increased HR
    • Sympathetic^-X
      
      • Increased peripheral resistance
      • Increased venous tone
      • Increased contractility
• Humoral Feedback Loop
  
  • ANS input
    
    • Increased HR → increased CO → increased MAP
    • Increased contractility → increased SV → increased MAP
    • Increased venous tone → increased VR → increased MAP
    • Increased peripheral vascular resistance → increased MAP
  • Increased MAP
    
    • Increased renal Q/BP
      
      • Renin inhibited (if stimulated, these steps occur)
        
        • Angiotensin*
          
          • Aldosterone*
            
            • Increased blood vol → increased MAP

Question 7

VASCULAR SM EC-COUPLING

Answer 7

• Ca2+ → calmodulin → MLCK → myosin-P → cross-bridge cycling
• Vasoconstriction
  
  • Gq* → PLC* → IP3 + DAG → PKC → Ca2+ release → contraction
    
    • CS: a1, AT, ET, 5HT blockers = anti-HT drugs
  • Gi* → AC inhibited → decreased cAMP → decreased PKA → increase Ca2+ into cytoplasm
• Vasodilation
  
  • Gs* → AC* → increased cAMP → PKA* → K+ efflux inhibits Ca2+ influx → relaxation
    
    • CS: isoproterenol induced vasodilation
    • CS: in ischemia → adenosine → vasodilation
  • ANP→G*/NO → GC* → increased cGMP → PKG* → inhibits Ca2+ influx → relaxation
    
    • CS: induced by shear stress, ET, thrombin, atrial distension, ANP release

Question 8

ADRENAL HORMONES

Answer 8

• Hormones
  
  • These hormones are selective (effective at low concentrations)
  • Norepinephrine
    
    • α1: VSM cells, NMJs (constrict)
    • β1: Heart (vagal stimulation, decreased HR)
    • No change in CO, increased systemic vascular resistance, increased mean arterial BP (by increasing dias P)
  • Epinephrine
    
    • β1: Heart (increase HR)
    • β2: VSM cells (relaxation)
    • Increases CO, decreases systemic vascular resistance, no change in mean arterial BP (average of sys/dias)
  • Isoproterenol (clinical drug, not a hormone)
    
    • β1: Heart
    • β2: VSM cells