Cardiovascular Physiology V. 46. The regulation of local blood flow. 47. Factors determining cardiac output, the Guyton diagram. Ferenc Domoki, November 20 2017. Control of circulation Systemic control Major goal: to maintain constant pressure gradient ( P) chiefly by regulating mean arterial blood pressure (MABP) Local control Major goal: to maintain adequate blood flow to meet locally the metabolic and functional needs of the tissue. Hemostasis, and immune functions also affect local blood flow. 1
Common local blood flow regulation responses 1. Autoregulation (constant blood flow despite changing pressure gradient) 2. Active hyperemia (increased blood flow to meet metabolic/functional demands) 3. Reactive hyperemia (increased blood flow following an interruption of flow ischemia) 4. Decreased local blood flow when vessels are injured hemostasis 5. Increased local blood flow in inflamed tissues inflammatory hyperemia LOCAL CONTROL OF BLOOD FLOW 1. Autoregulation 2. Active hyperemia 3. Reactive hyperemia Kidney Flow Flow 60 180 mmhg Skeletal muscle 20 140 mmhg Flow is relatively constant in a pressure range. (Note that flow stops at pressures above 0 mmhg: Critical closing pressure). Increased tissue Hypoxia causes vasodilation. metabolism is associated with enhanced blood flow: the tissue is capable Hyperemia of adjusting its own Occlusion perfusion. Time Flow Occlusion is followed by increased flow. 2
Control of local blood flow Local blood flow will depend on the regional vascular resistance largely determined and exclusively regulated by the diameter of precapillary resistance vessels. All local regulation will thus converge on the contraction/relaxation of the vascular smooth muscle in these vessels. LOCALLY important components of arteriolar smooth muscle tone RESTING TONE = BASAL TONE + NEUROGENIC TONE Systemic hormones Myogenic tone Sympathetic vasoconstrictor tone Intrinsic vascular factors! Local vascular (endothelial) factors Local tissue humoral factors + PHASIC (not tonic) VASODILATORY INNERVATION CAN INCREASE BLOOD FLOW LOCALLY 3
Myogenic tone of arteriolar smooth muscle Arteriolar smooth muscles maintain spontaneous contraction myogenic tone Bayliss effect: some arteriolar smooth muscles are sensitive to mechanical stretching: they respond with contraction to stretch: blood pressure - wall stretch - vasoconstriction arteriolar resistance This simple response tends to stabilize flow when MABP changes Bayliss effect is the direct opposite of stressrelaxation observed in venous smooth muscle. Endothelial factors regulating arteriolar smooth muscle tone THE NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE, 1998 for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system Robert W. Furchgott Louis J. Ignarro Ferid Murad 4
Endothelial factors regulating arteriolar smooth muscle tone Dilators Nitric oxide Prostacyclin EDHF (endotheliumderived hyperpolarizing factor) Constrictor: endothelin Depending on the species, developmental stage, and organ, the presence and the contribution of these factors to the local regulation of arteriolar tone varies greatly The discovery of NO as ENDOTHELIUM-DERIVED RELAXING FACTOR (EDRF) Acetylcholine Acetylcholine Vascular smooth muscle (endothelial cells are removed) Endothelial lining is intact Contraction Relaxation 5
BIOSYNTHESIS AND ACTION OF NITRIC OXIDE Receptor G q α Calmodulin Arg NOS PLC IP3 Ca 2+ Citrulline + NO NO PKG Ca 2+ decrease Guanylylcyclase GTP cgmp Phosphodiesterase Inactivation Viagra RELAXATION Endothelial cell Smooth muscle NITRIC OXIDE SYNTHASE ISOFORMS NOS: NOS-1 (nnos): neural NOS-2 (inos): phagocytes (cytokine-induced NOS, NO is bactericide here) NOS-3 (enos): endothelial cells enos is stimulated by a number of mediators: acetylcholine histamine (H1) bradykinin VIP (vasoactive intestinal peptide) SP (substance P) NA (NO decreases NA-induced vasoconstriction) shear stress 6
EICOSANOIDS PLA2 Cortisol Membrane Phospholipids Arachidonic acid Cytochrome P450 products Lipoxins? EDHF? Cyclooxygenase COX-1, COX-2 Aspirin PGH2 Leukotrienes Inflammation, Allergic reaction Prostacyclin PGI2 Prostaglandins PGD2 PGE2 PGF2α Thromboxane A2 TXA2 vasodilation vasoconstriction EICOSANOIDS IN CIRCULATION Eicosanoids are general inter- and intracellular signal molecules that can be produced virtually by every cell. Circulation: 1. Endothelial PGI2: continuous vasodilator tone in arteries. It inhibits aggregation of platelets. (Receptor camp) 2. PGE2: putative mediator of metabolically induced vasodilation. (Receptor camp) 3. TXA2: vasoconstrictor released from platelets. (Receptor IP3/Ca) ASPIRIN can prevent coagulation/thrombosis: ASPIRIN COX COX cc. 4 hours COX COX TXA2 PGI2 PGI2 TXA2 PGI2 PGI2 7
EDHF: not yet identified There is an EDRF present in many vessels even when NO or prostacyclin is fully inhibited Its chemical identity is unknown, eicosanoids, reactive oxygen species, myoendothelial gap junctions are suspects It activates potassium channels on vascular smooth muscle, causing hyperpolarization and relaxation ENDOTHELIN Paracrine vasoconstrictor peptide produced by endothelial cells. ET1, ET2, ET3. Circulation: ET1. Az ET1 is the currently known, most potent vasoconstrictor. Receptor: ET-A (IP3/Ca). Stimulus: angiotensin, catecholamine, hypoxia, thrombin, shear stress Thus, the local regulators of blood flow can directly induce dilation or constriction of the arterioles by acting on the vascular smooth muscle, OR they can act indirectly by releasing vasodilator or vasoconstrictor substances from the vascular endothelium. Some mediators have both effects. 8
LOCALLY important components of arteriolar smooth muscle tone RESTING TONE = BASAL TONE Myogenic tone Local vascular (endothelial) factors Intrinsic vascular factors! Local tissue humoral factors + PHASIC (not tonic) VASODILATORY INNERVATION CAN INCREASE BLOOD FLOW LOCALLY Local vasodilator tissue metabolites Released from active cells or from cells of energy distress Hypoxia, carbon dioxide, lactic acid, acidosis, potassium ions NO PGE 2 adenosine 9
Adenosine Tissue cell ATP Na + A A A A Coffein Inosine S-adenozylhomocisteine A2 camp Smooth muscle cell Vasodilation LOCALLY important components of arteriolar smooth muscle tone RESTING TONE = BASAL TONE Myogenic tone Local vascular (endothelial) factors Intrinsic vascular factors! Local tissue humoral factors + PHASIC (not tonic) VASODILATORY INNERVATION CAN INCREASE BLOOD FLOW LOCALLY 10
LOCALLY important VASODILATORY autonomic innervation Parasympathethic innervation (Ach, VIP, NO) of salivary glands, external genitalia, pial vessels Sympathetic innervation of skeletal muscle arterioles (Ach, maybe not in humans) Enteral nervous system innervation of arterioles in GI tract glands (Ach, VIP, NO) Long-term changes in local blood flow: Angiogenesis Chronic elevation of metabolic activity, or hypoxia triggers angiogenesis HYPOXIA triggers humoral factors (vascular endothelial growth factor, fibroblast growth factor, angiopoietins) Steps: next slide Capillary density is determined by MAXIMUM flow need, not average flow need (muscle) Opposite phenomenon: arteriolar/ capillary rarefaction 11
The cellular steps involved in angiogenesis. Clapp C et al. Physiol Rev 2009;89:1177-1215 2009 by American Physiological Society Autoregulation Present in every organ (except pulmonary circulation), however, most pronounced in the cerebral, coronary and renal circulation. Based on the parallel increase or decrease of LOCAL vascular resistance with changes in arterial blood pressure Mechanisms of acute autoregulation: 1. myogenic (Bayliss effect) 2. metabolic (accumulation/washout of vasodilatory metabolites) 3. functional (in the kidney autoregulation of glomerular filtration produces the flow autoregulation) Long-term autoregulation (weeks to months): new vessel growth (angiogenesis) vessel degeneration arteriolar and capillary rarefaction 12
Active/Reactive hyperemia Long-term activation of the tissue leads to excess capillarization: angiogenesis! Hemostasis-induced vasoconstriction Loss of functional endothelium: decreased release of NO, prostacyclin and EDHF Vasodilator mediators acting via endothelium will be ineffective or their effect will reverse (for instance Ach) Thrombin induces release of constrictor endothelin Platelets release vasoconstrictors: serotonin, catecholamines, thromboxane 13
Inflammation-induced vasodilation 1. Histamine 2. Bradykinin and kallidine (Lys-bradykinin) 3. PGE 2 4. Neurogenic inflammation (Substance P, Neurokinin A, Calcitonin-gene related peptide) Tissue damage Immune reaction HISTAMINE Histamine HISTAMINE IS THE MOST IMPORTANT INFLAMMATORY MEDIATOR. H1-R (IP3/Ca) H2-R (camp) INFLAMMATION: Vasodilation Increased permeability Itching/pain 14
KININS XII XIIa Clotting Plasma kallikrein HMW kininogen LMW kininogen Prekallikrein Kininase I Bradykinin Lysil-Bradykinin Inactive peptides Tissue kallikrein Bradykinin and Lysil-bradykinin are both effective. Kininase II = ACE 15
NEUROGENIC INFLAMMATION TRIPLE RESPONSE: local erythema + local edema + flare TRAUMA FLARE LOCAL ERYTHEMA EDEMA FLARE vasodilation Chemosensitive Pain receptors (C-fibres) release neuropeptides: Calcitonin generelated peptide (CGRP) Substance P (SP) To spinal cord Mast cell: Histamin CGRP/SP PAIN Vasodilation + Local edema AXON-REFLEX Trauma Histamin Local Chemosensitiv Inflammation C-fibres Axon collaterals: FLARE vasodilation CNS: PAIN LOCALLY ACTING VASOACTIVE SUBSTANCES MUSCLE ENDOTHELIAL CELL ET-A IP3/Ca 2+ TP 5HT2a Endothelin-1 Contraction B1 TXA2 NK2 M1 Serotonin 5HT2a α1 Bradykinin B1 H1 Neurokinin A NK2 NK1 Contraction Acetylcholine M1 α2 Noradrenaline α1 camp A1 Histamine H1 Substance P NK1 H2 CGRP? Relaxation? VIP?? A2 Adenosine PGE2 camp EP1-4 IP PGI2 cgmp NO IP3/Ca 2+ NO 16
CARDIAC OUTPUT regulation Factors determining cardiac output: 1. The heart 2. Blood volume 3. Venous compliance 4. Total peripheral resistance Cardiac output does NOT have a homeostatic regulation as arterial blood pressure, rather the complex interactions of the above factors will determine the cardiac output. Guyton model: the graphic representation of factors determining Cardiac Output Cardiac function curve: effect of atrial pressure on cardiac output (Frank- Starling) Systemic vascular function curve: effect of atrial pressure on venous return (modified by blood volume, TPR, venous compliance) 17
Effect of atrial pressure on cardiac output (Frank-Starling mechanism) Systemic vascular function curve: effect of atrial pressure on venous return 18
Mean vascular filling pressure (MFP) Increasing cardiac output will decrease central venous pressure MFP 19
Exchanging the two axes will yield the vascular function curve MFP Merging the two curves will show the steady state equilibrium cardiac output of the system 20
Effect of sympathetic tone on the cardiac function curve Sympathetic stimulation Sympathetic inhibition Effect of venous compliance/blood volume on the vascular function curve Increased blood volume Decreased compliance (venoconstriction) Decreased blood volume Increased compliance (venodilation) 21
Effect of total peripheral resistance on the vascular function curve Decreased TPR Increased TPR MFP Guyton diagram at work: cardiac output change during exercise Sympathetic stimulation of the heart Decreased total peripheral resistance Sympathetic venoconstriction 22