Cardiovascular Control Mechanisms

CARDIOVASCULAR CONTROL MECHANISMS

PARASYMPATHETIC DILATORS:

They cause local vascular relaxation. Parasympathetics do not have an important effect on systemic blood pressure.

• Vasoactive Intestinal Peptide (VIP): This neurotransmitter is released directly onto the smooth muscle cells to cause relaxation.
• Nitric Oxide (NO):
  • The nerve terminals contain Nitric-Oxide Synthase.
  • NO, when released by nerve terminals, also acts directly on smooth muscle.

NOCICEPTORS: Sensory receptors to noxious chemicals or toxins. They also cause local vasodilation.

• Two peptides are released by Nociceptor Nerves:
  • Substance P
  • Calcitonin Gene-Related Peptide (CGRP)
• TRIPLE RESPONSE OF LEWIS: Wheal and flare response to a local irritant.
  • First, a small red area develops.
    • This is due to degranulation of mast cells ------> local vasodilation.
  • Second, a blanched raised area develops around the small red area.
  • Third, a reddened flare (vasodilation) radiates around the irritated region.
    • The flare is due to highly branched nociceptor nerves that are distributed through the skin.
    • The Nociceptors release SP and CGRP in the area to cause vasodilation.
• LOCAL NEURAL RESPONSE: The nociceptor reflex does not go through the CNS!
  • If you cut the Dorsal Root (proximal to the cell body), the neural response still occurs.
    • This shows that the reflex signal is independent of the CNS.
  • If you cut the peripheral nerve (distal to the Cell Body), then Wallerian Degeneration occurs and the reflex no longer happens.
• Capsaicin (red-pepper stuff) is an irritant that, if applied to the skin for a period of time, will overuse and numb the nociceptors. Thus it is a treatment that can prevent the irritant response.

SYMPATHETIC CONTROL OF VASCULAR MUSCLE: This is the primary short-term mediator of TPR and hence arterial blood pressure.

• Sympathetics are of course vasoconstrictive, with two possible exceptions:
  • beta2-Receptors are vasodilatory. They are most responsive to Epinephrine (which is not a neurotransmitter), but they are responsive to NorE at huge doses).
  • Dogs and cats have sympathetic cholinergic nerves (like eccrine sweat glands) that are vasodilatory.
• Norepinephrine: Released from small dense-core vesicles in the sympathetic varicosity.
  • Norepinephrine is released by any depolarization, of any impulse frequency.
  • NorE binds to alpha1-Receptors on smooth muscle to increase Ca⁺² concentration and effect smooth muscle contraction.
    • NorE has a very high affinity for alpha1-Receptors. Epinephrine does not.
• ATP: Released from small dense core vesicles in the sympathetic varicosity.
  • ATP is released by any depolarization. It works at impulse frequencies as low as 2Hz.
  • ATP binds to Purinoreceptors (P-Receptors) to cause depolarization of the smooth muscle membrane.
  • Each ATP dense-core vesicle yields +10mV of depolarization. Two simultaneous depolarizations (total of +20mV) are required to generate smooth muscle action potential.
• Neuropeptide-Y (NPY): Released from large dense-core vesicles in the sympathetic varicosity.
  • Neuropeptide-Y is only released by repeated depolarizations (i.e. strong sympathetic stimulation). It is only released if the impulse frequency is 8Hz or faster.
  • NPY binds to its own Y-Receptor.
• COTRANSMISSION: NorE, ATP, and NPY have additive effects.
  • At high impulse frequencies, NPY facilitates the release of additional NorE.
  • The summation of signals will lead to stronger contraction of vascular smooth muscle, up to a point.

MODULATION OF SYMPATHETIC NEUROTRANSMITTERS: Cotransmission principles are based on increased likelihood that a dense-core vesicle will fuse with the pre-synaptic membrane. The higher the impulse frequency, the more likely that is to occur.

• AUTORECEPTORS: Simple negative feedback. There are receptors for NorE, ATP, and NPY. When the respective hormones bind, they inhibit further release of the neurotransmitter (i.e. they decrease the likelihood of vesicle fusion).
• HETERORECEPTORS: These are pre-synaptic receptors that bind to other substances to inhibit or excite release of neurotransmitters.
  • Inhibitory Heteroreceptors:
    • Acetylcholine binds to muscarinic receptors on the sympathetic varicosity to inhibit the release of NorE.
    • Prostaglandins, Serotonin, and Histamine can all bind to inhibitory heteroreceptors as well.
  • Excitatory Heteroreceptors: ANGIOTENSIN II will bind to excitatory receptors to promote further release of NorE ------> vasoconstriction.

AUTONOMIC TONE: Heart rate and vascular tone is determined by the relative amounts of sympathetic and parasympathetic continual stimulation.

• PARASYMPATHETIC TONE: The Vagus Nerve (CN X).
  • Vagal tone for the heart and abdomen originates from:
    • Nucleus Ambiguus (NA)
    • Dorsal Motor Nerve of CN X (DMV)
  • Parasympathetics have the following general effects on CV-System:
    • They increase venous compliance ------> lower venous return.
    • They indirectly decrease systemic resistance by inhibiting sympathetics ------> lower blood pressure.
    • Vagal Tone on heart slows down the heart-rate at the SA-Node.
• SYMPATHETIC TONE:
  • In the brain, sympathetics originate from the C1 AREA, which is the Reticular Formation of the closed medulla.
    • From there, the pathway is Reticular Formation ------> Intermediolateral Column of Thoracic spinal cord.
  • Sympathetics have the following general effects on the CV-System:
    • They decrease venous compliance ------> higher venous return
    • They directly increase systemic resistance ------> higher blood pressure
    • They indirectly speed heart rate by inhibiting Vagal Tone on the SA-Node.
• Miscellaneous Drugs that Affect Heart Rate:
  • Chlorisondamine: Nicotinic blocker -- it blocks pre-ganglionics of both sympathetics and parasympathetics.
    • RESULT = a slight increase in HR.
  • Atropine: Blocks muscarinic receptors -- i.e. no parasympathetics.
    • RESULT = substantially increase HR.
  • Propanolol: It is a beta-Blocker -- it blocks beta1-Sympathetic receptors on the heart.
    • RESULT = Decreased HR.
• VAGAL TONE ON THE HEART:
  • Parasympathetics (CN X) decrease heart rate by slowing the rate of rise of autodepolarization on the SA-Node. That is, it directly decreases heart rate.
  • Sympathetics increase heart rate by inhibiting the release of parasympathetics, i.e. they increase heart rate indirectly.

VASCULAR BEDS: There are six main vascular beds in the body. Going from supine to upright lowers blood pressure, so blood is conserved for the organs that really need it.

BARORECEPTOR REFLEX: Short-term modulation of blood-pressure.

• MODE OF ACTION: Baroreceptor firing increases parasympathetic tone and inhibits sympathetic tone.
  • They decrease heart-rate via increase in vagal tone on the heart.
  • They decrease blood pressure via inhibition of sympathetic tone on the vessels.
• MODE OF STIMULATION: Baroreceptors are stretch receptors. They are stimulated by high volume and or pressure in the region.
• Three Baroreceptors:
  • Two Atrial Receptors -- detect "low" (venous) pressures
    • Locations:
      • At junction of SVC and RA.
      • At junction of pulmonary veins and LA.
    • It detects high venous return to the RA and goes off as a result ------> increase venous compliance ------> decrease venous return.
  • One Aortic Arch Receptor -- modulates "high" (arterial) pressures.
  • Carotid Sinus: Two high-pressure baroreceptors at the bifurcation of the Common Carotid Artery, bilaterally.
• BARORECEPTOR PATHWAY: The baroreceptor impulse is sent to the Nucleus of the Tractus Solitarius (NTS). It has two outputs in response to the impulse:
  • EXCITATORY IMPULSE is sent to the Vagal Nuclei (Dorsal Motor N and the N Ambiguus) ------> higher parasympathetic tone
  • INHIBITORY IMPULSE is sent to the C1-Area ------> lower sympathetic tone.
• Short-Term Modulation of Blood-Pressure:
  • STANDING UP: Blood pools to feet ------> much lower venous return to heart.
    • The drop in venous return can be as much as 500 mL. That's quite a bit.
    • Baroreceptors stop firing (i.e. are down-regulated) in response to standing up, so that sympathetics are dis-inhibited (turned on), and b.p. goes back up.
  • IF PRESSURE FALLS: Baroreceptors are turned off and sympathetics increase ------> faster heart rate and vasoconstriction.
  • IF PRESSURE RISES: Baroreceptors are turned on ------> higher activity on NTS ------> slower heart rate and vasodilation.
• Limitations: The Baroreflex is only short-term.
  • Autoregulatory Escape: Certain tissues can override the CNS baroreflex if they have been vasoconstricted for too long.
  • Baroreceptors do not determine blood pressure. They only modulate it.
  • They are a buffering system. They operate best between 180 mm Hg and 60 mm Hg.

Bainbridge Reflex: An exception to baroreceptor regulation, where increased stretching actually increases the inotropic state of the heart, i.e. turns on sympathetics.

• It occurs when the Left Atrium is stretched, indicating high preload on the heart.

CHEMORECEPTORS: They have the exact opposite effect as Baroreceptors.

• Two locations: One in the Aortic Region and one at the bifurcation of the Carotid, called the Carotid Body.
• Stagnant Hypoxia: Chemoreceptors respond to low O₂ levels. The cells have a higher metabolic rate, and when they run out of O₂ they fire.
• CHEMORECEPTOR REFLEX: It is the same pathway, but the exact opposite effect as the baroreceptors. They turn on sympathetics and turn off parasympathetics.
  • Reflex again goes back to the Nucleus of Tractus Solitarius (NTS)
  • Afferent signals stimulate the C1 Area (sympathetics) and inhibit the DMV of the Vagus.
• RESULTS: Typical sympathetic CV effects.
  • Arterial vasoconstriction in the splanchnic beds (alpha1) to divert blood to the brain and heart.
  • Venous vasoconstriction to increase venous return.
  • Faster heart-rate from inhibition of Vagus.
• CUSHING REACTION: Happens from high CSF pressure to the point that it occludes cerebral vessels.
  • This rather quickly causes massive sympathetic outflow and a huge increase in MABP.
  • Note that this can occur even when systemic b.p. was normal. All that is required is occlusion of cerebral blood flow due to CSF pressure.

THE SYMPATHO-ADRENAL SYSTEM: Intermediate and long-term modulation of blood pressure.

• Sympathetic Receptors:
  • alpha1-Receptor: Primary vasoconstrictor found in VASCULAR SMOOTH MUSCLE
  • alpha2-Receptor: Also found in vascular smooth muscle.
  • beta1-Receptor: Found in HEART AND KIDNEYS.
    • Increases heart rate via innervation of SA-Node.
    • Increases inotropic state via innervation of myocardial muscle.
    • Stimulates release of Renin from the kidneys.
  • beta2-Receptor: VASODILATOR found in VASCULAR SMOOTH MUSCLE
    • Epinephrine is the primary ligand to bind to these receptors ------> vasodilation ------> lower TPR.
• Sympathetic Neurotransmitters / Neurohormones:
  • Norepinephrine:
    • Binds to alpha1 and alpha2 Receptors (vasoconstriction)
    • Binds to beta1-Receptors (Positive inotropy and chronotropy)
  • Epinephrine:
    • Binds primarily to beta1 and beta2 receptors: positive inotropic / chronotropic on heart and VASODILATORY
    • Only at high doses, it also binds to alpha-receptors, which will tend to counteract or even override the vasodilatory effect of the beta2-Receptors.

ANTI-DIURETIC HORMONE (ADH): It increases Na⁺-retention in the kidney ------> more water retention ------> high blood volume. It is a "long-term," slow-responding effect.

• CAUSE of Release: ADH is stimulated to be released by lower baroreceptor firing. Not sure of the exact pathway -- but somehow that leads to posterior pituitary being stimulated to release ADH.
• EFFECTS:
  • Intermediate Effect: There are ADH receptors on arteries and veins. ADH causes vasoconstriction.
  • Long-Term Effect: ADH increases blood volume via increased Na⁺-Retention in the kidney.

RENIN-ANGIOTENSIN SYSTEM:

• Renin Release from Kidney:
  • The Juxtaglomerular Apparatus detects low renal blood flow. It will stimulate release of Renin from the kidney.
  • Sympathetic innervation of kidney will also stimulate release of Renin.
• Biosynthetic Pathway of Angiotensin II:
  • Renin, from the kidney, circulates in the blood stream.
  • Angiotensinogen ------> Angiotensin I.
    • This conversion occurs in the bloodstream.
    • This conversion is catalyzed by Renin from the kidney.
  • Angiotensin I ------> Angiotensin II (active form)
    • This conversion occurs in the lungs.
    • This conversion is catalyzed by Angiotensin Converting Enzyme (ACE).
    • ACE-INHIBITORS are common drugs to battle hypertension by preventing synthesis of Angiotensin II.
• EFFECTS OF ANGIOTENSIN II:
  • It binds heteroreceptors on sympathetic varicosities to cause increased release of NorE onto the vasculature ------> higher arterial resistance.
  • It stimulates the release of Aldosterone from adrenal medulla. Aldosterone goes to kidney where it causes Na⁺-retention and thus increased plasma volume.
  • It also directly affects the kidneys to decrease urine production and increase plasma volume.

ATRIAL NATRIURETIC PEPTIDE (ANP): It causes increased Na⁺-Excretion (opposite effect as ADH) in the kidney.

• It is found in granules in atrial muscle.
• RELEASE: Stretch of Atrial Muscle means there is high preload ------> mechanical release of ANP-granules from Atrium ------> to kidney to increase urine production and decrease plasma volume.

Carotid Sinus Syndrome: Hypersensitivity of the Carotid Sinus, in some old people. Turning their head to the right stimulates parasympathetics and makes them pass out.