L14 CVS Physiology 7 Intrinsic _ extrinsic control of circulation

Overview

This lecture explains how vascular tone, the tension in vascular smooth muscle, sets resistance-vessel calibre and therefore regional blood flow, arterial blood pressure and venous return. It divides control into intrinsic mechanisms (myogenic, metabolic/paracrine, physical) acting locally within an organ, and extrinsic mechanisms (sympathetic and parasympathetic nerves, circulating hormones) acting on the vasculature as a whole, closing with a summary diagram that integrates all these inputs onto vessel diameter.

Vessel types and vascular tone

• Aorta and large arteries: high-pressure reservoir/conduit, providing the pressure head that drives blood through the systemic circuit.
• Smaller arteries and arterioles: resistance vessels; controlling their tone determines the volume that flows through the circulation (“Do it by changing the vascular tone”).
• Vascular tone regulates vessel radius and hence flow: increased tone gives vasoconstriction and reduced local blood flow; decreased tone gives vasodilatation and increased local blood flow.
• Poiseuille relationship: $R=\frac{8\eta L}{\pi r^4}$, where $\eta$ is viscosity, $L$ is tube length and $r$ is tube radius. Because resistance depends on $r^4$, a small change in arteriolar radius produces a large change in resistance, letting a tissue adjust flow to its need.
• Distribution of cardiac output at rest versus moderately vigorous exercise (Table 14.1; cardiac output varies between individuals with age, fitness, nutritional status, training):
  • Cardiac output: 5.8 L/min (100%) rest, 20 L/min (100%) exercise
  • Brain: 0.75 L/min (13%), 0.75 L/min (4%)
  • Heart: 0.25 L/min (4%), 0.85 L/min (4%)
  • Gut: 1.5 L/min (26%), 0.6 L/min (3%)
  • Kidney: 1.0 L/min (17%), 0.5 L/min (3%)
  • Skeletal muscle: 1.2 L/min (21%), 15 L/min (75%)
  • Skin: 0.5 L/min (7%), 1.95 L/min (10%)
  • Other: 0.6 L/min (10%), 0.35 L/min (2%)
• Vascular tone also sets arterial blood pressure: $MABP=CO\times TPR$. Continuous adjustment of resistance-vessel tone helps control blood pressure while standing up and during hypovolaemic emergencies such as haemorrhage, and governs capillary recruitment, capillary pressure and central venous pressure.

Intrinsic and extrinsic control: overview and hierarchy

• Vascular tone is controlled by intrinsic mechanisms (myogenic response; paracrine factors such as metabolites, NO and autacoids; physical factors such as temperature and pressure) and extrinsic mechanisms (vasodilator nerves; sympathetic vasoconstrictor nerves; endocrine factors such as adrenaline, angiotensin and vasopressin). Both act on resistance vessels and on venules/veins (capacitance vessels); paracrine factors also affect pericytic venule permeability.
• Control hierarchy, broad to local: extrinsic factors, then endothelial secretions/vasoactive metabolites/autacoids, then local response.

Intrinsic control mechanisms

A. Myogenic response (flow autoregulation)

• When arterial pressure changes, blood flow in many vascular beds stays constant: autoregulation. Resistance vessels respond directly to a pressure change by constricting or dilating (myogenic response, Bayliss).
• Pathway when arterial pressure to an organ falls: decreased arterial pressure, decreased blood flow, decreased O2/increased metabolites/vessel-wall stretch, arteriolar dilation, blood flow restored toward normal.
• Mechanism involves activation of L-type Ca2+ channels; well developed in brain, myocardium and kidney, protecting organ perfusion against minute-to-minute blood pressure fluctuation.
• When the myogenic response narrows a vessel, the resulting increase in endothelial shear stress stimulates the endothelium to produce NO, which prevents excessive myogenic constriction.
• Experimentally, stepping arterial pressure up produces a transient overshoot in vessel radius that settles back near control level, with blood flow rising sharply then decaying back toward baseline over about a minute; releasing the step produces a mirror-image undershoot. Plotting muscle blood flow against perfusion pressure gives a relatively flat autoregulation curve (about 2 mL/min/100 g) across roughly 20 to 100 mmHg, rising toward about 4.5 mL/min/100 g by 180 mmHg, compared with a much steeper non-autoregulated relationship.

B. Metabolic regulation (active hyperaemia)

• Operates by release of local dilator substances (CO2, lactic acid, hydrogen ions, etc.), maintaining blood flow to organs such as brain, heart muscle and skeletal muscle in step with their metabolic activity.
• Pathway: increased metabolic activity of the organ, decreased O2/increased metabolites in interstitial fluid, arteriolar dilation, increased blood flow to the organ (active hyperaemia).
• Blood flow (relative to normal) rises steeply as the organ’s rate of metabolism increases from 1x up to about 7 to 8x normal, and also rises to about 3x normal as arterial oxygen saturation falls from 100% to 25%.

C. Reactive hyperaemia

• Occurs in response to complete obstruction of blood flow. Mechanism: obstruction leads to decreased O2/increased metabolites in the organ’s interstitial fluid, causing arteriolar dilation and markedly increased flow once the obstruction is released.
• Demonstrated with thermal/laser-Doppler imaging of the hand across baseline, occlusion, reactive hyperaemia and recovery: flow drops during occlusion, then peaks sharply above baseline at release before decaying back down.
• Clinical relevance: myocardial infarction; peripheral artery disease.

Endothelial-derived (paracrine) factors

• The endothelium produces both vasoconstrictors (endothelin, angiotensin II) and vasodilators (nitric oxide/NO, prostacyclin/PGI2, endothelial-derived hyperpolarizing factor/EDHF, adenosine, a potent vasodilator in the heart).
• Nitric oxide (NO):
  • Released following shear stress; 60 to 80% of NO production comes from shear stress. Circulating insulin and oestrogen activate NO production to a lesser extent. It is shear stress, not flow itself, that increases NO production. NO has a half-life of only 6 seconds.
  • Pathway: shear stress activates the PI3-kinase to PKB pathway (or receptor-dependent activation), which activates eNOS; eNOS converts O2 and L-arginine to NO and L-citrulline; NO diffuses to smooth muscle and activates soluble guanylate cyclase, producing cGTP then cGMP, causing smooth muscle relaxation.
  • Factors affecting NO production: shear stress (e.g. atherosclerosis, exercise); pregnancy, where high oestrogen levels lead to generalised vasodilatation, so that despite a 50% increase in cardiac output, total peripheral resistance falls and blood pressure decreases ($PAO=CO\times TPR$).
  • Drugs that mimic endothelial NO, glyceryl trinitrate, sodium nitroprusside and isosorbide dinitrate, are used as vasodilators to treat cardiac angina. They are effective venodilators and large-artery dilators; their therapeutic benefit comes from reducing central venous pressure and reducing systolic blood pressure.

Extrinsic control: purpose and overview

• Extrinsic controls exist to regulate overall TPR and hence control blood pressure, and to let the brain selectively alter blood flow to individual organs (e.g. vasodilatation of a secreting salivary gland).
• The extrinsic controls are vasomotor nerves (vasoconstrictor, vasodilator) and hormones (adrenaline, vasopressin, angiotensin II).
• Sympathetic vasoconstrictor fibres (noradrenergic) are by far the most widespread and important extrinsic control under normal conditions.

Sympathetic vasoconstrictor nerves

• Controlled by the brainstem (vasomotor centre); innervate most arterioles and veins of the body.
• Terminate at the edge of the tunica media in strings of synaptic varicosities, which release vesicles containing noradrenaline (NAd) and ATP.
• NAd activates adrenoceptors on the vascular myocyte that always cause vasoconstriction. The fibres are tonically active (about 1 impulse/sec); a fall in activity, or an adrenoceptor blocker such as phentolamine, causes vasodilatation.

Slides 27 to 28 name the adrenoceptor subtype and blocker type using a Greek-letter symbol that the pdftotext extraction did not capture. Context (noradrenaline, vasoconstriction, phentolamine) strongly suggests alpha, but this is not directly confirmed in the source text, so it is flagged rather than assumed.

• Reduced sympathetic activity leads to vasodilatation, for example: a rise in blood pressure activates the baroreflex, which inhibits sympathetic activity, lowering blood pressure; during exercise, increased body temperature reduces sympathetic nerve activity to the skin, causing vasodilatation, increased blood flow and heat loss (covered further in Lecture 10).
• Increased sympathetic activity produces vasoconstriction through three parallel effects, part of a “life-preserving package” response:
  1. Reduced tissue blood flow leads to contraction of local resistance vessels, arteriolar constriction, and increased TPR.
  2. Reduced tissue blood volume leads to contraction of local veins, increased venous return, and increased EDV.
  3. Reduced capillary pressure leads to contraction of local resistance vessels, interstitial fluid being absorbed into the plasma, and increased EDV.
     ($MABP=CO\times TPR$; $CO=HR\times SV$; $SV=EDV-ESV$.)

Vasodilator nerves

• Found in organs where the brain needs to command a profound increase in blood flow. Acetylcholine (ACh) and vasoactive intestinal peptide (VIP) are the common transmitters released by parasympathetic fibres.
• Parasympathetic vasodilator nerves: salivary glands (ACh and VIP); pancreas and intestinal mucosa (VIP); erectile tissues (NO and VIP).
• Sympathetic vasodilator nerves: skin, vasodilatation associated with sweating (ACh and VIP); in non-primates, muscle (ACh).
• Sensory (nociceptive C-fibre) vasodilator fibres: sensory fibres in the skin, activated in response to damage (substance P and CGRP).

Hormonal factors controlling circulation

• Adrenaline (epinephrine) is the main catecholamine secreted by the human adrenal medulla.
• Pathway from sympathetic postganglionic neurons to skeletal muscle arterioles: release of norepinephrine, increased norepinephrine in extracellular fluid, action via alpha receptor causing vasoconstriction, altered arteriolar radius.
• The adrenal medulla adds a parallel pathway: secretion of epinephrine into blood, increased plasma epinephrine, which acts via alpha receptor (vasoconstriction, as above) and via beta2 receptor (vasodilation); both converge on smooth muscle in skeletal muscle arterioles to alter arteriolar radius.
• Other circulating hormones: angiotensin II, important in the response to hypovolaemia (e.g. haemorrhage) and cardiac failure, and raised in some (not all) hypertensive patients; vasopressin (antidiuretic hormone, ADH), whose vascular action (vasoconstriction) is important in the response to hypovolaemia; atrial natriuretic peptide (ANP), which has moderate vasodilator and diuretic effects.

Summary: inputs onto vessel diameter

The lecture’s final diagram integrates all controls onto a single vessel-diameter node, with dilator and constrictor arrows from each source:

• Sympathetic activity: both dilator and constrictor input.
• Vasoactive metabolic factors: dilators, carbon dioxide, lactate, adenosine; constrictor, oxygen.
• Hormonal factors: constrictors, adrenaline via alpha receptors, angiotensin II, vasopressin (ADH); dilators, adrenaline via beta receptors, atrial natriuretic peptide (ANP).
• Endothelial secretions: constrictor, endothelin; dilators, nitric oxide, prostacyclins, adenosine.
• Myogenic regulation of blood pressure (autoregulation): both dilator and constrictor input.

Self-test

1. Define vascular tone and state how increases and decreases in tone affect local blood flow.
2. Using the Poiseuille relationship, explain why a small change in arteriolar radius has such a large effect on resistance.
3. Describe the pathway of the myogenic response when arterial pressure to an organ falls, and name three organs in which it is well developed.
4. Explain how endothelial shear stress limits excessive myogenic constriction.
5. Describe the pathway of metabolic regulation (active hyperaemia) from increased organ metabolic activity to increased blood flow.
6. Distinguish reactive hyperaemia from active hyperaemia in terms of what triggers each.
7. List the vasoconstrictor and vasodilator substances produced by the endothelium.
8. Describe the pathway from shear stress to smooth muscle relaxation via nitric oxide, and state NO’s half-life.
9. Explain why pregnancy causes blood pressure to fall despite a rise in cardiac output.
10. A patient is prescribed glyceryl trinitrate for angina. Explain how this drug relieves angina in terms of its vascular actions and the two mechanisms behind its therapeutic benefit.
11. Describe where sympathetic vasoconstrictor nerve varicosities terminate and what they release.
12. Predict the effect of an adrenoceptor blocker such as phentolamine on vascular tone, and explain why.
13. Describe the three parallel effects of increased sympathetic activity that combine to raise blood pressure and EDV.
14. Distinguish parasympathetic vasodilator nerves from sympathetic vasodilator nerves in terms of their target organs and transmitters.
15. List the hormones that act on the circulation, noting which are vasoconstrictors and which are vasodilators.
16. Distinguish the vascular action of adrenaline via alpha receptors from its action via beta2 receptors.
17. A patient presents in hypovolaemic shock following haemorrhage. Describe which extrinsic mechanisms would be activated and their combined effect on TPR, venous return and blood pressure.
18. Using the summary diagram, explain how vessel diameter integrates intrinsic and extrinsic inputs, distinguishing the two categories.

Answers

Reveal answers

1. Vascular tone is the tension exerted by vascular smooth muscle cells that sets resistance-vessel radius. Increased tone causes vasoconstriction and reduced local blood flow; decreased tone causes vasodilatation and increased local blood flow.
2. $R=8\eta L/(\pi r^4)$, so resistance is inversely proportional to the fourth power of radius; a small change in $r$ produces a disproportionately large change in $R$, letting a tissue markedly alter flow for a small change in radius.
3. Decreased arterial pressure to the organ leads to decreased blood flow, then decreased O2/increased metabolites/vessel-wall stretch, then arteriolar dilation, then blood flow restored toward normal. Well developed in brain, myocardium and kidney.
4. Myogenic constriction narrows the vessel, which increases endothelial shear stress; this stimulates the endothelium to produce NO, which prevents excessive myogenic constriction.
5. Increased metabolic activity leads to decreased O2/increased metabolites in interstitial fluid, causing arteriolar dilation and increased blood flow to the organ (active hyperaemia).
6. Active hyperaemia is driven by increased metabolic activity matching flow to demand; reactive hyperaemia follows complete obstruction of blood flow, with flow rising above baseline once the obstruction is released, driven by the O2 fall and metabolite build-up accumulated during occlusion.
7. Vasoconstrictors: endothelin, angiotensin II. Vasodilators: nitric oxide (NO), prostacyclin (PGI2), EDHF, adenosine.
8. Shear stress activates the PI3-kinase-PKB pathway (or receptor-dependent activation), activating eNOS, which converts O2 and L-arginine to NO and L-citrulline; NO diffuses to smooth muscle and activates soluble guanylate cyclase, producing cGTP then cGMP, causing relaxation. NO has a half-life of only 6 seconds.
9. High oestrogen in pregnancy increases NO production, causing generalised vasodilatation; despite a 50% rise in cardiac output, total peripheral resistance falls enough that blood pressure decreases overall.
10. Glyceryl trinitrate mimics endothelial NO, acting as a venodilator and large-artery dilator; its therapeutic benefit in angina comes from reducing central venous pressure and reducing systolic blood pressure.
11. They terminate at the edge of the tunica media in strings of synaptic varicosities, which release vesicles containing noradrenaline (NAd) and ATP.
12. Blocking the adrenoceptor removes the tonic vasoconstrictor drive normally provided by noradrenaline, so vascular tone falls and vasodilatation results, similar to the effect of a fall in sympathetic nerve activity.
13. (1) Arteriolar constriction increases TPR; (2) venous constriction increases venous return and EDV; (3) reduced capillary pressure allows interstitial fluid to be absorbed into plasma, also increasing EDV.
14. Parasympathetic vasodilator nerves supply salivary glands (ACh, VIP), pancreas/intestinal mucosa (VIP) and erectile tissue (NO, VIP); sympathetic vasodilator nerves supply skin (ACh, VIP, associated with sweating) and, in non-primates, muscle (ACh).
15. Adrenaline (vasoconstrictor via alpha receptors, vasodilator via beta2 receptors), angiotensin II (vasoconstrictor), vasopressin/ADH (vasoconstrictor), atrial natriuretic peptide (vasodilator).
16. Via alpha receptors, adrenaline causes vasoconstriction (like norepinephrine); via beta2 receptors, adrenaline causes vasodilation.
17. Hypovolaemia activates sympathetic vasoconstrictor nerves, raising TPR and venous return/EDV via the three parallel mechanisms, plus circulating angiotensin II and vasopressin, both vasoconstrictors; together these raise TPR and help restore blood pressure while preserving EDV.
18. Vessel diameter is set by the balance of intrinsic inputs (vasoactive metabolic factors, endothelial secretions, myogenic autoregulation) acting locally, and extrinsic inputs (sympathetic activity, hormonal factors) acting systemically; each source contributes both dilator and constrictor signals that sum to determine the final diameter.