Cardiac Signaling Pathways and Vascular Signaling Pathways II

Question 1

Describe vascular smooth muscle cells (VSMCs)

Answer 1

o Small, mononucleated cells, which are electrically coupled via gap junctions.
o Not striated, myofilaments are not arranged in the sarcomere.
o Ca2+ release from the SR is not essential for contraction in VSMCs.
o Rate of contraction is slower and contractions are sustained and tonic in VSMCs.
o Contraction in VSMCs can be initiated by mechanical, electrical or chemical stimuli.
o VSMCs do not have troponin.

Question 2

Describe cardiac Myocytes (CMs)

Answer 2

o CMs are striated and arranged in sarcomeres.
o Ca2+ release from the SR is essential for contraction in CMs.
o Rate of contraction is faster and unsustained in CMs.

Question 3

Describe the molecular steps involved in Ca2+ regulation of vascular smooth muscle contraction

Answer 3

• Ca2+ regulation of VSM contraction
o Ca2+ enters the cytoplasm from the SR (mainly) and from voltage-gated Ca2+ channels on the surface membrane.
o Ca2+ binds to calmodulin (CaM), a ubiquitous intracellular Ca2+ binding protein.
o Ca2+-CAM binds to myosin light chain kinase (MLCK), activating it.
o Activated MLCK phosphorylates the light chain of myosin (the myosin head), which permits cross bridge cycling to occur.
o Contraction halted by dephosphorylation of myosin light chain by myosin light chain phosphatase (MLCP).
• cAMP causes relaxation of vascular smooth muscle cells, in contrast to its effect in cardiac myocytes, via PKA-mediated phosphorylation/inhibition of MLCK which reduces VSMC contraction.

Question 4

Describe the mechanisms by which sympathetic stimulation (via α1 adrenergic receptors) alters vascular tone

Answer 4

• a1 adrenergic receptors are GPCRs, which are coupled to the Gq G-protein.
o Gaq activates phospholipase C (PLC)→DAG and IP3.
o IP3 activates IP3Rs on SR of VSMCs.
o IP3Rs are intracellular Ca2+ release channels. Activation of IP3Rs ↑Ca2+ release from the SR.
o ↑Ca2+ →VSMC contraction and vasoconstriction.
o PKC (a Ca2+ -dependent protein kinase) phosphorylates many targets in VSMCs, including L-type Ca2+ channels, which in turn activates additional intracellular Ca2+ release (CICR)

Question 5

Arterial baroreceptors:

Answer 5

pressure-sensitive neurons in the aortic arch and carotid sinus.
o Mechanosensitive epithelial Na+ channels (eNaC) open in response to mechanical stimulation (stretching induced by high blood pressure) and the ensuing Na+ current depolarizes the baroreceptor neurons, causing them to fire action potentials.
o Baroreceptor neurons project to a sensory area of the “cardiovascular control center” in the brainstem. Distinct output areas of the CV center control sympathetic and parasympathetic output to the heart and vasculature.

Question 6

Arterial baroreceptor reflex arc

Answer 6

↑blood pressure→↑baroreceptor firing rate→↓sympathetic output and ↑parasympathetic output from the cardiovascular center→↓heart rate, ↓inotropy and ↓vascular tone (vasodilation)→↓blood pressure.
• The baroreceptor reflex is an acute short-term effect. Baroreceptors can adapt to prolonged changes in blood pressure by resetting to the new level over a time course of minutes to hours.
o Sensitivity of the baroreceptor reflex ↓ in hypertension and aging, so there is less feedback response to changes in blood pressure.

Question 7

Name four tissue metabolites that control local flow to a capillary bed

Answer 7

dec PO2

inc PCO2/pH, K+, Adenosine

Question 8

K+

Answer 8

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, so K+ accumulates in interstitial space

Question 9

Adenosine

Answer 9

Adenosine is used by hydrolysis of ATP. In VSMCs, adenosine binds to A2 purinergic receptors, which are GPCRs that are coupled to Gs. Thus, adenosine ↑cAMP levels in VSMCs causing vasodilation by inhibition of MLCK

Question 10

Describe the origin and effects of atrial natriuretic peptide on blood pressure

Answer 10

o Vasodilator peptide release by atria following mechanical stretch→endocrine function of the heart.
o Involved in long-term sodium regulation and water balance, blood volume, and arterial pressure.
o ANP acts on ANPRs throughout the body. ANPRs are receptor guanylate cyclases (NOT GPCRs_ that produce cGMP, which activates SERCA to stimulate Ca2+ uptake.
— Kidney: ↑glomerular filtration rate and ↑secretion of sodium and water.
— Vasculature: ↑ vasodilation
— Adrenal gland: inhibits release of aldosterone and renin release