Regulation of vasculature Flashcards
Compare vascular smooth muscle cells (VSMC) to cardiac myocytes
VSMCs are mononuclear, not striated (no sarcomeres) cells connected by gap junctions. Ca release from SR is not required for contraction in VSMCs but Ca uptake is similar to cardiac myocytes. VSMCs have slower, sustained and tonic contraction
What causes contraction in vascular smooth muscle cells?
Mechanical stretching (myogenic response), activation of L-type Ca channels (via graded potentials, not necessarily Aps), or chemical stimulation (norepinephrine, angiotensin II, etc)
Strength of contraction in VSMCs are proportional to _______
Stimulus intensity
Thus Ca2+ regulation of smooth muscle contraction is via___________ , whereas Ca2+ regulation of striated muscle contraction is via ______________.
myosin thick filaments, actin thin filaments
Describe the steps in VSMC activation
- Ca2+ enters cytoplasm – from SR, also via voltage-gated Ca2+ Channels. 2. Ca2+ binds Calmodulin (CaM), a intracellular Ca2+ binding protein. 3. Ca2+-CaM binds to Myosin Light Chain Kinase (MLCK) to activate it. 4. Activated MLCK phosphorylates the light chain of myosin (myosin head), which permits cross bridge cycling to occur. 5. Contraction halted by dephosphorylation of myosin light chain by Myosin Light Chain Phosphatase (MLCP).
What effect does cAMP have on VSMc?
cAMP causes relaxation of vascular smooth muscle cells b/c PKA phosphorylates myosin light chainkinase to inhibit its activitycAMP causes relaxation of vascular smooth muscle cells b/c PKA phosphorylates myosin light chainkinase to inhibit its activitycAMP causes relaxation of vascular smooth muscle cells b/c PKA phosphorylates myosin light chainkinase to inhibit its activity
What effect does sympathetic stimulation usually have on vasculature? Describe the mechanisms by which sympathetic stimulation alters vascular tone.
Vasoconstriction - a) Sympathetic terminals release NE – activates alpha Adrenergic receptors on VSMCs (mainly a1 also some a2) b) aARs in VSMCs are coupled to Gq. c) Gq activation causes IP3 production. d) IP3 increases cytosolic Ca2+ by activating SR Ca2+ release via IP3 receptors (similar to ryanodine receptors). E) Protein Kinase C phosphorylates L-type Ca channels which are activated and inward current of Ca activates additional intracellular Ca release.
What is a fast and short term mechanism for control of blood pressure?
Baroreceptor reflex
What are arterial baroreceptors? Where are they found?
Pressure sensitive neurons found in aortic arch and carotid sinus
What type of channels are important for baroreceptor function?
epithelial Na+ channels (eNaC), which are mechanosensitive ion channels (NOT voltage-gated channels). Mechanical stimulation causes inward current of Na which fires an AP
Describe the arterial baroreceptor reflex arc
a) Increase in pressure increase firing rate of baroreceptors b) CV control centers decrease sympathetic and increase parasympathetic output.
c) In heart this causes decreases heart rate and inotropy.In vasculature, decreased sympathetic tone causes vasodilation
Where is the CV control center?
Brainstem- medulla
Where are low pressure baroreceptors found?
Atria and Vena cavae (NOT arteries)
What do low pressure baroreceptors do?
Mediate Bainbridge reflex (Increase HR in response to stretch of atria)
What do peripheral and central chemoreceptors do?
Peripheral chemoreceptors in arotic and carotid bodies respond to arterial O2 and CO2 levels. Central chemoreceptors are in the medulla and increase cerebral blood flow in response to ischemia
Name four tissue metabolites that control local flow to a capillary bed.
Decreased O2 pressure, increased CO2 pressure (decreased pH), increased K and increased Adenosine
Why is K 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.
Why is Adenosine a vasoactive metabolite?
Adenosine is produced by hydrolysis of ATP. In vascular smooth muscle cells, adenosine binds to A2 purinergic receptors, which are GPCRs that are coupled to Gs . Thus, adenosine increases cAMP levels in VSMCs causing vasodilation by inhibition of myosin light chain kinase.
What is the myogenic response.
Feedback mechanism to maintain constant flow despite changes in pressure (independent of metabolic demand). Increased pressure increases flow, but myogenic response produces vasoconstriction to reduce flow.
Describe mechanism of the myogenic response
Stretch causes VMSC contraction by opening stretch-activated ion channels of the Trp family. Inward Ca2+ current through Trp channels directly causes vasoconstriction
Where is NO made in vasculature?
Vascular endothelium by NO synthase
NO is anti-atherogenic. What does this mean?
decreased NO associated with greatly increased risk for atherosclerosis.
How is NO produced in vascular endothelial cells?
- Humoral agents (ACh, bradykinin, etc) activate GPCRs on endothelial membrane causing an increase in intracellular Ca2+ which activates nitric oxide synthase (NOS). NOS produces NO from L-arginine and O2
- Humoral agents (ACh, bradykinin, etc) activate GPCRs on endothelial membrane causing an increase in intracellular Ca2+ which activates nitric oxide synthase (NOS). NOS produces NO from L-arginine and O2
What is NO’s action in VSMCs?
- NO diffuses from endothelial cell to VSMC 2. NO activates guanylate cyclate > produce cGMP 3. cGMP activates PKG 4. PKG activates SERCA and inhibits L-type Ca channels 5. Decreased Ca causes reduced MLCK activity and vasodilation
What is the rate limiting step in endothelin production?
Endothelin Converting Enzyme (ECE)
Where is endothelin produced?
vascular endothelium
What is endothelins action in VSMCs?
o Endothelin binds to ET receptors, which are GPCRs on VSMCs. ET receptors are coupled to Gq and so increase intracellular Ca2+ levels, which results in vasoconstriction.
What stimulates endothelin? Inhibits?
stimulated by Angiotensin, ADH, thrombin. Inhibited by NO, ANP
What is the primary system for long term control of blood pressure?
Renin-Angiotensin-Aldosterone System
What is the general scheme for the renin-angitensin-aldosterone system?
Renin cleaves Angiotensinogen(inactive) to angiotensin I (AI)(inactive) > ACE cleaves AI into Angiotensin II (AII (active)) > AII causes direct and indirect effects (including release of aldosterone)
What is renin? Where is it released from and what causes its release?
oProteolytic enzyme released by renal juxtaglomerular cells oRelease stimulated by sympathetic stimulation, decreased blood pressure in renal artery, and decreased Na+ reabsorption
What are direct effects of Angiotensin II?
systemic vasoconstriction via binding to GPCRs on VSMCs
Indirect effects of Angiotensin II
Stimulates sympathetic activity and release of aldosterone, endothelin, and ADH
What is Aldosterone?
Steroid produced by adrenal cortex. Promotes reabsorption of Na+ and water in kidney collecting duct which increases blood volume and pressure.
What is Anti-diuretic hormone?
Aka vasopressin. Peptide hormone formed in hypothalamus, released by pituitary. Increases water reabsorption in kidney and causes vasoconstriction.
What stimulates release of ADH?
hypovolemia, hypotension, high osomolarity, Angiotensin II, and sympathetic stimulation
Where is atrial natriuretic peptide released from?
o Vasodilator peptide released by atria (more right than left) = endocrine function of heart.
What stimulates ANP release?
mechanical stretch of atria
What is the molecular function of ANP?
ANP acts on Natriuretic peptide receptors throughout body (guanylate cyclases that produce cGMP and reduce cytoplasmic Ca)
What are the physiological functions of ANP?
o In kidney, ANP increases glomerular filtration rate and increases secretion of Na+ and water, o In vasculature, ANP is a vasodilator, mechanism similar to NO, but longer lasting.
o In adrenal gland, ANP inhibits release of aldosterone and renin.
CV responses to standing up
Baroreceptor reflex causes increased HR, increased inotropy and increased CO, vasoconstriction, increased TPR, constriction of veins and increased venous return. Also a myogenic response
CV response to exercise
Central command causes increased HR, inotropy, CO, vasoconstriction, TPR, venous constriction and venous return. Local responses cause increase in vasoactive metabolites and vasodilation in exercising muscle.
CV response to hemorrhage
Baroreceptor reflex causes increased HR, increased inotropy and increased CO, vasoconstriction, increased TPR, constriction of veins and increased venous return. Also increased renin activates the angiotensin-aldosterone pathway which increases blood volume. Also, decreased capillary hydrostatic pressure increases capillary reabsorption.
