CVPR 03-26-14 08-10am Regulation of the CV system - Proenza Flashcards
G Protein-Coupled Receptors (GPCRs) – defn.
7-transmembrane-spanning (7TM) integral membrane proteins that transduce ligand binding to intracellular signaling; some of the most prevalent drug targets (beta blockers, angiotensin II blockers)
Cardiovascular GPCRs include…
α & β adrenergic receptors, ACh receptors, endothelin receptors, adenosine receptors, angiotensin II receptors.
GPCR activation scheme
Agonist binds receptor –> GTP replaces GDP on α subunit of heterotrimeric G protein –> dissociation of α and βγ G protein subunits –> Both α and βγ can be active signals
GPCR deactivation:
Auto dephosphorylation of GTP to GDP by α subunit permits reassociation with βγ…..Rebinding of G protein to receptor causes inactivation.
Families of G proteins involved in cardiovascular function:
Gs and Gi/o proteins
Gs & Gi/o are stimulatory & inhibitory, respectively, for cAMP production by adenylate cyclase
Gq protein
Its activation increases intracellular Ca2+ via activation of phospholipase C (PLC) and Protein Kinase C (PKC)
α1 adrenergic receptor - G protein, signaling pathway, effects
Gq —- Pathway: PLC, PKC –> increases intracellular Ca2+ —> vasoconstriction
β adrenergic receptor - G protein, signaling pathway, effects
Gs (β1 and β2)— Pathway: Simulates adenylate cyclase, increases cAMP —> In heart, increases chronotropy, inotropy, lusitropy, dromotropy…..In skeletal muscle vascular beds, vasodilation.
Muscarinic receptor - G protein, signaling pathway, effects
Gi/o —- Pathway: Inhibits adenylate cyclase –> decreases cAMP; Releases βγ subunits….. Effect: Decreased chronotropy
Regulation of Inotropy
Autonomic; both sympathetic & parasympathetic
Sympathetic regulation of inotropy
cAMP signaling, Phospholamban (PLB), phosphorylation of L-type Ca2+ channels & RyRs by PKA, phosphorylation of TN-I
Process to Increase of cAMP
Sympathetic neurons innervate the heart, release norepinephrine –> binds β adrenergic receptors to increase cAMP
Phosphodiesterases - what it is & action
= counterpart to adenylate cyclase; Breakdown cAMP (and cGMP) —> help to establish intracellular signaling microdomains and specificity of signaling
Protein Kinase A (PKA) - what it is & action
cAMP-dependent protein kinase; Major effector for cAMP signaling in heart; Phosphorylates target proteins (its counterpart is phosphatases that dephosphorylate these targets) —> changes protein function by changing conformation & charge.
Phospholamban (PLB)
PLB is an inhibitor of SERCA (which removes Ca2+ from cytosol following contraction by pumping it back into the SR)
Un-inhibiting SERCA
Phosphorylation of PLB by PKA causes it to dissociate from SERCA, thereby relieving the inhibition and increasing Ca2+ reuptake rate.
Two effects of Faster Ca2+ reuptake has on cardiac performance:
1) directly increases “lusitropy” (relaxability) – and 2) increases inotropy by increasing SR Ca2+ load.
Lusitropy
the ability of the heart to relax
Inotropy
Alteration of the the force or energy of muscular contractions….Negatively inotropic agents weaken the force of muscular contractions, while Positively inotropic agents increase the strength of muscular contraction
L-type Ca2+ channels (LTCCs) - action
On the plasma membrane; Activated by depolarization —> influx of Ca2+ —> triggers larger Ca2+ release from SR via ryanodine receptors (Ca2+-induced Ca2+ release (CICR))
PKA & L-type Ca2+ channels
Phosphorylation of L-type Ca2+ channels
by PKA slows inactivation –> increases magnitude of L-type Ca2+ current —> this increase in “trigger Ca2+” elicits a larger release of Ca2+ from the SR, thereby increasing inotropy.
Troponin I (TnI) - action
The inhibitory unit of the troponin complex (TnC-TnI-TnT); Along w/tropomyosin, inhibits the interaction btwn actin & myosin in the absence of Ca2+.
Phosphorylation of Troponin I (TnI)
TnI is phosphorylated by multiple kinases, including PKA…..Phosphorylation of TnI decreases the Ca2+ sensitivity of TnC —> would expect to decrease inotropy (counter to the sympathetic effect), BUT it rather results in faster dissociation of Ca2+ from TnC, thereby increasing lusitropy, which allows the heart to fill more quickly (increases lusitropy; no effect on inotropy?). This is particularly important at higher heart rates.
Parasympathetic regulation of inotropy
Parasympathetic innervation of the ventricle is sparse, thus there is little parasympathetic control of inotropy.
Basal autonomic tone and “intrinsic” heart rate
Resting heart rate in humans is normally 60-80 bpm; However, both divisions of the autonomic nervous system have basal activity that influences the resting HR…..Normally the parasympathetic tone at rest is greater than the sympathetic tone (but there still is basal sympathetic activity at rest). Intrinsic heart rate is revealed by block of both sympathetic and parasympathetic tone (heart rate w/out nervous regulation).
Block of M2 muscarinic acetylcholine receptors with atropine - effect on HR
increases HR by inhibiting tonic parasympathetic activity
Block of β adrenergic receptors w/ propanolol - effect on HR
decreases HR by inhibiting tonic sympathetic activity
Molecular targets for sympathetic stimulation of chronotoropy
- Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs)…..2. L-type Ca2+ channels…..3. Ryanodine receptors and Sodium-Calcium exchanger
Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) - Action
HCN channels are highly expressed in SA node myocytes and produce the cardiac funny current (If), which is an inward (depolarizing) current at diastolic potentials —> promotes excitability & spontaneous APs
Sympathetic regulation of Hyperpolarization-activation cyclic nucleotide-gated channels (HCNs)
Sympathetic stimulation of SA cells causes an increase in activity of HCNs via cAMP binding (shifts voltage dependence of activation —> channels more likely to open —> more inward current to speed the rate of diastolic depolarization)
β adrenergic stimulation of L-type Ca2+ channels
β adrenergic stimulation increases L-type Ca2+ current —> net inward (depolarizing) current –> contributes to sympathetic increase in HR via increased excitability and all spontaneous APs, since nodal cells use “slow” Ca2+ APs….. Activity increased further by sympathetic stimulation (phosphorylation by PKA)
Sympathetic stimulation of Ryanodine receptors and Sodium-Calcium exchanger
Sympathetic stimulation increases SR Ca2+ load via PKA phosphorylation of L-type Ca2+ channels, RyRs, and phospholamban —-> increases spontaneous Ca2+ release rate & contributes to diastolic depolarization via the sodium-calcium exchanger, NCX (Ca2+ out, 3 Na+ in, generating a net inward current) –> removes Ca2+ from cytoplasm & promotes excitability / spontaneous APs
Parasympathetic regulation of pacemaking is mediated by…
…release of acetylcholine (ACh) from vagal nerve endings in the SA node; ACh activates M2 muscarinic ACh receptors coupled to Gi/o heterotrimeric G protein —> activation of Gi/o releases two signals: the Gαi/o subunit and the Gβγ subunit complex.
Molecular targets for parasympathetic inhibition of chronotropy
GIRKs, HCNs, L-type Ca2+ channels, and ryanodine receptors
GIRKs (G-protein coupled inwardly-rectifying K+) and Chronotropy
The Gβγ subunit complex binds directly to GIRK channels to activate the IKACh current - IKACh stabilizes the membrane potential near the K+ equilibrium potential, thereby dampening excitation & slowing spontaneous firing frequency = appears to be primary mechanism for parasympathetic slowing of HR
HCNs, L-type Ca2+ channels, and ryanodine receptors
The Gαi/o subunit inhibits adenylate cyclase, thus reducing intracellular cAMP levels —> opposite effect to sympathetic stimulation of pacemaking: reduction in inward current via HCN channels, L-type Ca2+ channels, and RyR-NCX = these mechanisms appear to play a secondary role in parasympathetic regulation of HR
Vascular smooth muscle cells (VSMCs) – characteristics
small mononucleate cells, electrically coupled via gap junctions.
Why smooth (vs. striated)?
Myofilaments are not arranged in sarcomeres in smooth muscle.
Ca2+ role in VSMCs (Vascular Smooth Muscle Cells)
Ca2+ release from SR not essential for contraction in VSMCs…..However, Ca2+ reuptake mechanisms are similar (SERCA and PLB are present) in VSMC & striated muscle.
Contraction in VSMCs vs. striated muscle
Rate of contraction is slower in VSMCs and contraction is sustained & tonic (vs. short duration in cardiac muscle).
Review of striated muscle contraction mechanism
At rest, troponin I is bound to actin. Troponin T recruits tropomyosin, which blocks myosin binding site on actin. An action potential (required) triggers Ca2+ release from SR via excitation-contraction coupling —> Ca2+ binds to troponin C —> rearrangement of troponin complex & tropomyosin that uncovers the myosin binding site on actin THIN filament —-> permits cross bridge cycling to occur……Contraction is halted by removal of Ca2+.
Smooth muscle contraction - ways to initiate
Can be initiated by mechanical (stretching, via myogenic response), electrical, or chemical stimuli [ rather than requiring AP]
Vascular Smooth muscle differences from Skeletal
Mononuclear; No sarcomeres; No troponin or tropomyosin; Different contraction mechanism (thick rather than thin filament regulation); APs not required
Electrical means to initiate smooth muscle contraction
Electrical depolarization can elicit contraction via activation of L-type Ca2+ channels…. Different from striated muscle in that APs are not required; graded potentials are sufficient, and strength of contraction is proportional to stimulus intensity
Chemical means to initiate smooth muscle contraction
Chemical stimulation by several neural & hormonal regulators (eg: norepi, angiotensin II, vasopressin, endothelin, and thromboxane A2) can directly activate contraction
Contraction of VSMCs depends on…
…phosphorylation of the myosin head as the essential step, rather than Ca2+ directly activating contraction (although it is indirectly Ca2+-dependent).
Ca2+ regulation of smooth vs. striated muscle contraction
Ca2+ regulation of SMOOTH muscle contraction is via myosin THICK filaments, whereas Ca2+ regulation of STRIATED muscle contraction is via actin thin THIN filaments. (Remember, smooth muscle does not have the Ca2+-sensitive troponin complex or tropomyosin).
How Calcium gets into the cytoplasm during VSMC activation
mainly from SR but also via voltage-gated Ca2+ channels on surface membrane
Calmodulin (CaM)
a ubiquitous intracellular Ca2+ binding protein
Steps in VSMC activation
Trigger (mechanical, chemical, electrical) –> Ca2+ enters cytoplasm —> Ca2+ binds Calmodulin (CaM) —> Ca2+-CaM binds to Myosin Light Chain Kinase (MLCK) to activate it. —> Activated MLCK phosphorylates the light chain of myosin (myosin head) —> cross bridge cycling.
cAMP’s effect on vascular smooth muscle cells
cAMP causes relaxation of VSMC (in contrast to its effect on cardiac myocytes, where it promotes contraction via PKA)…in VSMCs, PKA phosphorylates myosin light chain kinase to inhibit its activity, and thus reduce VSMC contraction
Type(s) of Autonomic Regulation of the Vasculature
Primarily sympathetic innervation of the vasculature (relatively little parasympathetic innervation)
Sympathetic stimulation in vasculature generally causes…
Vasoconstriction; Contraction of VSMCs, independent of membrane depolarization.
α1 adrenergic receptors
GPCRs coupled to the Gq heterotrimeric G protein
Phospholipase C (PLC) - what it is & what it produces
An enzyme activated by Gαq of the α1 adrenergic receptors, to produce diacylglycerol (DAG) and inositol trisphosphate (IP3).
Inositol trisphosphate (IP3) - action
Produced by PLC; Activates IP3 receptors on the SR of VSMCs (intracellular Ca2+ release channels, like RyRs) —> opens IP3Rs causing Ca2+ release from the SR into the cytoplasm —> VSMC contraction & thus vasoconstriction.
Protein kinase C (PKC)
Ca2+-dependent protein kinase; Phosphorylates many targets in VSMCs, including L-type Ca2+ channels (LTCC), which are activated —> Inward current through LTCCs in turn activates additional intracellular Ca2+ release (Ca2+-induced Ca2+ release)
Distribution of Sympathetic innervation of vascular beds throughout the body
Sympathetic innervation is not equal in all vascular beds: Abundant in skin & kidneys (so that sympathetic stimulation decreases blood flow)….Sparse in cerebral & coronary circulation; thus sympathetic activation reduces blood flow to skin w/out compromising blood flow to brain & heart.
Adrenergic receptors in vascular beds vs. striated muscle arteries
α1 adrenergic receptors are the predominant subtype in most vascular beds, BUT striated muscle arteries express both α1 and β2 adrenergic receptors
Norepinephrine & Epinephrine
Norepi released from sympathetic neurons acts on α1 receptors to cause vasoconstriction in all vascular bedsl However, circulating Epi causes a partially compensating vasodilation in striated muscle (so that flow in striated muscle may be somewhat higher than in other tissues). This is a relatively minor point, however, b/c vasodilation of striated muscle in response to activity is mediated primarily by local tissue metabolites.
α2 receptors on sympathetic fibers
Exert feedback inhibition of norepinephrine
Arterial baroreceptor reflex - action
Acute, Short-term, Fast (minute-to-minute) neural mechanism for control of blood pressure
Baroreceptors – purpose & what might change their sensitivity
Adapt to prolonged changes in blood pressure by simply resetting to the new level over a time course of minutes to hours; Useful b/c the feedback mechanism is preserved even in HTN; BUT, sensitivity of the baroreceptor reflex decreases in HTN & aging, so there is less feedback response to changes in blood pressure.
Arterial baroreceptors – what they are & their location
Pressure (stretch) -sensitive NEURONS (i.e., DON’T CONTRACT) in the aortic arch and carotid sinus
Arterial baroreceptors – respond to & how
Respond to stretch of arterial walls by increasing their firing rate; Stretch sensitivity conferred by epithelial Na+ channels (eNaC)
Epithelial Na+ Channels (eNaCs) – what & action
Mechanosensitive (NOT voltage-gated) channels that open in response to mechanical stimulation; The ensuing Na+ current depolarizes the baroreceptor neurons, causing them to fire action potentials.
Baroreceptor neurons – who they report to
Baroreceptor neurons project to the sensory area of the “cardiovascular control center” in the brainstem
Cardiovascular (CV) control center
In the brainstem; Integrates signals from baroreceptors as well as from other brain regions (eg: hypothalamus – CV response to emotion)…..Output areas of the CV center project sympathetic & parasympathetic fibers to the heart and sympathetic fibers to the vasculature.
Classic baroreceptor reflex:
Increase in BP —> increased firing rate of baroreceptors —> decreased sympathetic & increased parasympathetic output from CV center —–> decreased HR, inotropy, and vascular tone —> decrease BP (negative feedback to the increased BP the barorreceptors sensed)
Set point for baroreceptor reflex
~100 mmHg mean arterial pressure
Action of when mean arterial pressure is smaller or greater than the baroreceptor reflex set point
MAP increased HR, contractility, SV, & vasoconstriction)….. MAP>~100 causes the opposite.
Low Pressure Baroreceptors - location
In atria and vena cavae (NOT arteries)
Low Pressure Baroreceptors – respond to what & how
Respond to changes in venous pressure by changing firing rate (but the pressure sensitivity range is much lower for the venous system)
Low Pressure Baroreceptors project into (afferents & efferents)…
Afferents project via the vagus nerve; Efferents primarily innervate the SA node to control HR
Low pressure baroreceptors & the “Bainbridge reflex”
Low pressure baroreceptors mediate the “Bainbridge reflex,” whereby stretch of the atria causes an increase in HR.
Peripheral (arterial) chemoreceptors – location
Found in aortic & carotid bodies, which are near the aortic arch and carotid sinus baroreceptors.
Peripheral (arterial) chemoreceptors respond to…
…changes in arterial PO2 and PCO2
Peripheral (arterial) chemoreceptors regulate…
Primarily respiration, but also project to CV control center to regulate heart & vasculature, such that low PO2/high PCO2 results in increased sympathetic output (thus sparing O2 delivery to heart & brain).
Sensation of Angina
Other chemoreceptors in the heart respond to ischemia to transmit the sensation of angina.
Central chemoreceptors – location & action
Found in the medulla; Increase cerebral blood flow in response to ischemia.
Local control of the Vasculature - Mechanisms
- Control by vasocative metabolites…..2. Myogenic response (autoregulation)…..3. Endothelial-mediated regulation
Local control of vasculature by vasoactive metabolites - action
Primary mechanism by which flow in a capillary bed is matched to the metabolic demand of the tissue it perfuses.
Vasoactive substances are produced by…
… increased oxygen consumption, for example during skeletal muscle contraction; This is a direct, local response, independent of BP; Can have profound effects on blood flow (up to 50-fold increase in flow in active skeletal muscle).
Vasoactive metabolites - examples
Decreased PO2; Increased PCO2/ decreased pH (partly due to lactic acid); Increased K+; Increased adenosine
Production of Increased K+ as a vasoactive metabolite
In active skeletal muscle, Na+ enters cell and K+ leaves during action potentials; With a high level of activity, the Na+/K+-ATPase can’t keep up to pump K+ back in, so it accumulates in the interstitial space.
Production & Action of Adenosine as a vasoactive metabolite
Adenosine is produced by hydrolysis of ATP; In vascular smooth muscle cells, adenosine binds to A2 purinergic receptors (GPCRs coupled to Gs, the stimulatory G protein that activates adenylate cyclase) —> Thus, adenosine increases cAMP levels in VSMCs —> vasodilation via inhibition of myosin light chain kinase.
Adenosine action in other purinergic receptor subtypes (A1 and A3)
Other purinergic receptor subtypes (A1 and A3) are coupled to Gi (the inhibitory G protein), and thus adenosine REDUCES cAMP in cells expressing these receptor subtypes.
Adenosine as treatment
Used for emergency treatment of some re-entrant supraventricular tachycardias b/c it acts on A1 receptors to inhibit cAMP production in the AV node, thereby causing a transient conduction block.
Myogenic response (autoregulation) in local control of vasculature
Feedback mechanism to maintain constant flow through vasoconstriction? despite changes in pressure (independent of metabolic demand) [as in postural changes]
Postural change & Myogenic response (autoregulation of vasculature)
Stand up —> BP increases in legs (assume minimal change in metabolic demand)….The initial effect is an increase in blood flow due to the increased pressure (according to flow equation, Q = P/R)…..The myogenic response illustrates the steady state flow, after adaptation. The flow tends to return to the initial level, and is relatively constant across a range of pressures.
Mechanism of Myogenic response
Intrinsic to VSMCs (occurs in denervated vessels, and is independent of vascular endothelium); Stretch causes VMSC contraction by opening stretch-activated ion channels of the Trp family —> Inward Ca2+ current through Trp channels directly causes vasoconstriction, also depolarizes the VSMC, thereby further increasing intracellular Ca2+ via L-type Ca2+ channels.
Endothelial-mediated regulation
Many regulators of blood flow act via mechanisms involving the vascular endothelium, with two major mechanisms by which the endothelium controls vascular tone – nitric oxide (a vasodilator) and endothelin (a vasoconstrictor)
Nitric oxide (NO) – what it is, how produced
A gas& potent vasodilator produced in vascular endothelium by the enzyme nitric oxide synthase
Reactivity of NO
Free radical, highly reactive & labile, ½ life 10-60 s (short half-life = local response); Readily oxidized
Oxidizing agents & NO
Oxidizing agents reduce NO lifetime, & so reduce potency of vasodilatory response.
Basal release of NO
Helps set resting vascular tone (decrease NO = increase BP)
Agonist-stimulated release of NO
MAJOR physiological mechanism for vasodilation.
Effects of NO
- vasodilation…..2. decrease BP (resting vascular tone)…..3. anti-atherosclerotic
Anti-atherosclerotic effect of NO
NO inhibits many steps in development of plaques, and decreased NO is associated with greatly increased risk for atherosclerosis.
NO in hypertensive patients
NO is decreased in hypertensive patients; NOT an immediate cause of HTN, but makes the condition worse. (Also one mechanistic link for how HTN is a risk factor for atherosclerosis)
Nitric oxide synthase
Highly susceptible to CV disease risk factors (eg: oxidative stress, compounds in cigarette smoke –> less NO production –> increased HR)
Treatment strategies for CV disease using NO system
EX: L-arginine supplements (precursor to NO) and NO donors such as nitroglycerin
NO Pathways – Two cells involved
Vascular endothelial cells (produce NO) and vascular smooth muscle cells (site of NO action).
NO Pathways – type of signaling
“Paracrine” signaling.
NO production & entry into vasculature BY
Many humoral regulators (eg: ACh) activate GPCRs on endothelial membrane –> increase in intracellular Ca2+ —> stimulate Nitric Oxide Synthase (NOS) in vascular endothelial cells- produces NO from L-arginine & O2 —> Nitric oxide readily diffuses across the endothelial and vascular smooth muscle cell membranes.
Action of No once in vascular smooth muscle cells
NO activates the enzyme guanylate cyclase, which produces cGMP —> cGMP activates Protein Kinase G (PKG) —> PKG reduces intracellular Ca2+ via activation of SERCA & inhibition of L-type Ca2+ channels (among other targets) —> decreased [Ca2+]I causes relaxation of the VSMC (vasodilation)
Endothelin – what it is & where produced
A potent vasoconstrictor produced by vascular endothelium ; Natural counterpart to Nitric Oxide; 21 amino acid peptide, synthesized from precursors w/ Endothelin Converting Enzyme (ECE) being the rate-limiting step (ECE inhibitor being studied for treating HTN)
Endothelin mechanism of local vasculature control
Endothelin binds to ET receptors (GPCRs on VSMCs) —> ET receptors are primarily coupled to Gq & so increase intracellular Ca2+ levels —> vasoconstriction.
Endothelin vs. α adrenergic pathways/response
Pathways/responses are similar, but the time course is different – endothelin has both a transient (minutes) effect like α adrenergic system and a longer lasting (hours) effect.
NO vs. Endothelin
Both produced in vascular endothelium; NO is a vasoDILATOR; Endothelin is a vasoCONSTRICTOR
Mechanisms for Humoral Control of the Vascualture
- Renin-angiotensin-aldosterone system…..2. Atrial natriuretic peptide (ANP)…..3.
Renin-angiotensin-aldosterone system - purpose
Critical system for regulation of blood volume & long-term control of blood pressure (vs short term control by barorecptor reflex). Mediated by kidney
Renin - qu’est-ce que c’est?
A proteolytic enzyme that is released into circulation by juxtaglomerular (JG) cells (adjacent to renal glomerulus)
Renin relase is stimulated by:
1) sympathetic stimulation of JG cells, 2) decreased BP in the renal artery, and 3) decreased Na+ reabsorption in the kidney.
Renin-Angiotensin relationship
Renin cleaves circulating inactive precursor Angiotensinogen to another inactive precursor Angiotensin I (AI) —> Angiotensin I is cleaved by Angiotensin Converting Enzyme (ACE) to form the active peptide, Angiotensin II (AII), a potent systemic vasoCONSTRICTOR.
Drugs used to block the renin-angiotensin-aldosterone system
- ACE inhibitors (block Angiotensin Coverting Enzyme, ACE, for treatment of HTN & heart failure); 2. Angiotensin II receptor blockers
Direct effect of Angiotensin II (All)
Systemic vasoconstriction via binding to GPCRs on VSMCs.
Indirect effects of Angiotensin II (AII):
1) Stimulates sympathetic activity (thus more vasoconstriction), 2) stimulates Aldosterone release from adrenal cortex, 3) stimulates release of endothelin from vascular endothelium (= more vasoconstriction), and 4) stimulates release of ADH from the pituitary.
Aldosterone
A steroid hormone produced by the adrenal cortex, that acts on receptors in the kidney collecting ducts to promote reabsorption of Na+ and water —> increased blood volume & thus increased BP
Anti-Diuretic Hormone (ADH, Arginine Vasopressin) – production & release
Peptide hormone formed in hypothalamus, released by pituitary in response to hypovolemia, hypotension, high osomolarity, Angiotensin II, and sympathetic stimulation.
Major role of Anti-Diuretic Hormone:
Binds to receptors in kidney and increases water reabsorption.
Minor role of Anti-Diuretic Hormone:
Bind to receptors in vasculature to cause vasoconstriction.
Atrial natriuretic peptide (ANP) – what it is & function
Vasodilator peptide released by atria (more right than left) = endocrine function of heart; One of a family of natriuretic (i.e. sodium-excreting) peptides.
Atrial natriuretic peptide (ANP) - purpose
Involved in LONG-TERM regulation of Na+ & water balance, blood volume, and arterial pressure.
Atrial natriuretic peptide (ANP) - release
Secretion stimulated by mechanical stretch of atria.
Atrial natriuretic peptide (ANP) – site of action
ANP acts on Natriuretic Peptide Receptors found throughout the body; NPRs are receptor guanylate cyclases (not GPCRs) that produce cGMP —> activates SERCA to stimulate Ca2+ uptake, thereby reducing cytoplasmic Ca2+ levels.
Atrial natriuretic peptide (ANP) – actions in kidney
Increases glomerular filtration rate & increases secretion of Na+ and water (natriuresis and dieresis).
Atrial natriuretic peptide (ANP) – actions in vasculature
Vasodilator - mechanism similar to NO, but longer lasting.
Atrial natriuretic peptide (ANP) – actions in adrenal gland
Inhibits release of aldosterone and renin.
Gravity & the CV system - When a person stands up…
Blood pools in veins of legs (“venous pooling”) —> drop in upper body BP, increase in lower body BP —> increases lower body capillary hydrostatic pressure (Pc from Starling Law of Capillary) —> net capillary filtration & increase in interstitial fluid —> decreased venous return —> by the Frank-Starling mechanism, decreases stroke volume & cardiac output (by ~20%) —> reduced CO causes mean arterial pressure (MAP, Pa) to decrease —> in response, the baroreceptor reflex & myogenic response kick in
Compensatory reaction to standing - Baroreceptor reflex
Decreased arterial pressure —> Decreased firing of baroreceptors —> Increases sympathetic & decreases parasympathetic tone from the medullary CV centers —> increases HR & inotropy (increased contraction –> increased SV) to increase CO, and increases vasoconstriction to increase venous return and total peripheral resistance.
Compensatory reaction to standing - - Myogenic response
Increased pressure in vasculature in lower body stretches the vessels –> countered by myogenic response via vasoconstriction, which promotes venous return.
“Orthostatic Hypotension”
Fainting or lightheadedness upon standing can occur in patients with a compromised baroreceptor reflex, or those whose blood pressure is already low. This effect is more pronounced in warm weather, due to vasodilation in the skin.
Effects of Exercise on the Heart
Anticipation of exercise increases sympathetic & decreases parasympathetic activity to increase HR & inotropy, thereby increasing CO (“Central Command” mechanism)
Increased sympathetic activity – effect on non-exercising tissues
Increases arterial resistance (vasoconstriction) in non-exercising tissues, including skin, kidneys and inactive muscles (while in local, exercising muscles, there is vasodilation via vasoactive substances)
Activity of skeletal muscles – effect on venous return & stroke volume
Increases venous return, which increases stroke volume via the Frank-Starling mechanism.
Vasoactive metabolites action in exercising muscles
Vasoactive metabolites dilate arterioles to increase blood flow (as in Pouiseulle’s Law, r4).
Vasodilation in exercising muscle
Vasodilation in exercising muscles overcomes the vasoconstriction in other tissues to cause a net decrease in TPR (total peripheral resistance), which corresponds to an increase in CO (from Flow Equation, CO = Pa/TPR).
Hemorrhage – effect on CV system
(remember MAP ~ Pd + 1/3(Ps-Pd)) —> decreases CO (dramatically decreased venous return is more important than decreased afterload) —> baroreceptor reflex and the renin-angiotensin system kick in
Baroreceptor reflex in hemorrhage
As in postural change: decreased MAP –> decreased firing of baroreceptors increases sympathetic & decreases parasympathetic tone —> increases HR & inotropy; Vasoconstriction increases venous return.
Renin-angiotensin system in hemorrhage
Activated by decreased renal blood pressure. Angiotensin II increases vascular tone and promotes release of ADH, which increases blood volume.
Decreased capillary hydrostatic pressure, Pc, in hemorrhage
Promotes capillary reabsorption from the interstitial fluid, which increases blood volume.
Primary mechanism for parasympathetic control of HR
Activation of I-KAch current by Gβγ subunit binding to GIRK channel
Secondary mechanism for parasympathetic control of HR:
Decrease in intracellular cAMP by inhibition of adenylate cyclase by Gαi/o –> inward currents HCNs, L-type Ca2+ channels, RyR-NCX
