At the neuromuscular junction, the Ach is released from the presynaptic cell via vesicles due to Ca influx. 2 Ach binds to the nicotinic receptor (cation-selective), causing it to open allowing all ions to pass through (although Na predominates). This causes an EPSP. Since the post-synaptic membrane is not excitable (to cause action potential), the EPSPs need to build up large enough to travel to the sides where voltage-gated sodium channels are awaiting to open. Once these open, then an action potential will occur.
Meanwhile, the Ach that is left in the synaptic cleft diffuse, get chewed up by acetylcholinesterases (and choline get reuptaken).
Meanwhile, the Lateral Sacs in the SR are storing Calcium bound to Calsequestrin. The calcium in the sarcomere keeps getting uptaken by the longitudinal portion of the SR and gets transported to the lateral sacs for storage. The lateral sacs are right adjacent to the T-tubules.
As the action potential reach the T-tubules, the depolarization triggers the L-type Ca channels in the T tubule to mechanically trigger the opening of the Ca-release channels in the Lateral sacs. Although Calcium may come into the cell, it is not the cause of the opening. The Ca-release channel in the lateral sacs open to release Ca, which binds to Troponin C on the tropomyosin to cause the muscle to contract.
As the Calcium is released from the lateral sacs, it also stimulates the longitudinal portion to uptake more Ca.
ATP attachment = crossbridge detachment
ATP Hydrolysis = crossbridge stroke and attachment
ADP falling off = POWER STROKE!!
Rigor mortis is due to lack of ATP. Ca cannot be pumped back into the lateral sacs, and so they accumulate, bind to the Ca and cause permanent contraction. There is no ATP to release the myosin heads either.
Resting force = preload = “stretched rubber band force,” so the more you stretch, the larger the resting force or preload. The more connective tissue a muscle has the more difficult it can stretch.
Q: What causes tetanus?
A: when you keep stimulating muscles to the point that more Ca is released than reabsorbed to the lateral sacs.
Q: What determines the maximum tetanus level?
A: the number of cross bridges available for contraction.
Q: Why can you not tetanize cardiac muscle?
A: Because you’ll die. Also because calcium takes longer to migrate through longitudinal SR to get to lateral sacs. The refractory period is also too long.
Q: Describe the load-velocity relationship.
A: Increase load, decrease velocity of shortening, and decrease shortening length. Vmax is the maximum velocity with no load. Isometric total force is heaviest load without velocity. Vmax reflects the intrinsic rate at which myosin ATPase can split ATP.
Cardiac Muscle actually has real calcium-stimulated calcium-release channels, as opposed to the mechanically linked channels in skeletal muscle. In cardiac muscle, L-type Ca channel is indirectly linked with Ryanodine receptor.
In addition to lateral sacs (which are not as regular as in skeletal muscle), cardiac muscle also has subsarcolemmal sacs to store Ca. They are NOT continuous with Sarcolemma.
As more calcium enter from extracellular spaces into the cardiac myocyte, the more calcium that can be reuptaken and stored in the lateral sacs → serve as an inotropic reserve for the heart.
Ca2+ leaves a cardiac myocyte through sarcolemmal channels by several mechanisms. A Na+-Ca2+ exchange is one mechanism. Dijoxin (drug that makes heart beat harder) – blocks sodium/potassium pump → sodium gradient not maintained → calcium cannot be pumped out → more calcium stay bound to TnC → heart beats harder.
Mitochondria play a role in buffering cyoplasmic Ca2+. Since Mitochondria can also reuptake Calcium, it acts as a buffer for calcium levels in the cardiac muscle cell. It also has a Na/Ca exchanger, with Ca coming into the mitochondria. The intracellular sodium concentration gradient needs to be maintained via a Na/H+ exchanger. Of course, all this H+ outside the mitochondria also helps it produce ATP.
Catecholamines → faster reuptake of calcium by longitudinal bands → faster relaxation of heart → faster beating.
Changes in force or shortening due to more available internal Ca2+ are termed an increase in inotropism or contractility.
One definition of inotropism or contractility is a change in active force development in the absence of a change in preload or resting muscle length.
Q: Why does increasing number of action potentials increase force development in cardiac muscle?
A: Because when you increase number of Na coming in, you reduce the Ca/Na exchange (Na in, Ca out). More calcium will stay in cell, and cause more inotropy and more force per beat.
Preload does not affect Vmax in Cardiac Muscle. Catecholamines do (but does not change resting force-length relationship)
Smooth Muscle = same force, but more shortening, less energy consumed, less velocity of shortening than skeletal or cardiac muscle.
Visceral Smooth Muscle – Stretch Activated → Ca channels open → myosin regulatory light chain phosphorylation
Multiunit Smooth Muscle – Graded Voltage (Local Depolarization) Activated (caused by neurotransmitters) → Ca channels open → myosin regulatory light chain phosphorylation
Smooth muscle does not require extracellular Calcium. Either by neurotransmitter (Ach,Norepi) or hormone (endothelin)-induced production of IP3 in multiunit smooth muscle or stretch-activation in visceral smooth muscle, Ca channels in SR can open, causing calcium to influx in, binding to Calmodulin, which phosphorylates myosin kinase, which phosphorylates calponin (inhibitory) to fall of regulatory light chain on myosin. Myosin can then bind actin and cause contraction. Myosin phosphatase is needed to dephosphorylate the light chain myosin, and so this is why Smooth muscle contracts slower.
Nicotinic = ionotropic, blocked by curare
Muscarinic = metabotropic, blocked by atropine
AUTONOMIC NERVOUS SYSTEM
Hypertension – Propranalol, Phentolamine (side effects – shunt to cardiac), Calcium Channel Blocker
Hypotension — Epinephrine
Angina Pectoris – Propranalol, Nitroglycerine (produces NO)
Raynaud’s Disease — Phentolamine
Anaesthesia Adjunct– alpha-adrenergic agent (AAA for AA), cocaine
Diarrhea – muscarinic receptor blocker (atropine) (stops parasympathetic/bowel movement), opioids
Irritable Bowel Sydrome – Serotonin antagonist or Serotonin reuptake blockers
Glaucoma: 2 Causes:
Closed Angle = aqueous humor can’t drain → drill hole in iris or use cholinergic agent (parasympathetic,
to constrict pupils)
Open Angle = canal of schlemm blocked → aqueous humor can’t drain → treat with beta-receptor
blocker (sympathetic blocker, since sympathetic secretes aqueous humor). But since
sympathetic also contracts levator palpebrae and orbicularis oculi (so you look “shocked”), you’ll have ptosis and sunken eyeballs with this treatment.
Parasympathetic: Cilliary contraction (rounder lens, see near)
Sympathetic: Dilates pupil, Secrete Aqueous Humor (so you look “shocked”)
Basically, you should encourage parasympathetic or stop sympathetic with Glaucoma patients.
Parasympathetic: watery salivary secretion
Sympathetic: thick salivary secretion, sweating (only palms and soles are adrenergic, all others ACh), goose bumps
Remember Hands and Soles are adrenergic. Rest of body is Cholinergic for sweating.
Sweaty palms patients need beta-adrenergic blocker. A cholinergic would have elevated body temperature to a lethal degree!!
Remember: Beta-Adrenergic blocker NOT Cholinergic blocker!!!
HORNER’S SYNDROME – When sympathetic nerve is blocked
S = stellate ganglion
S = superior cervical ganglion
S = sunken eyeball
P = Ptosis
A = Anhydrosis
M = Miosis
And other sympathetic-block symptoms.
Allergy → histamine released → Laryngeal muscle swell → so you also sound very high-pitched with an allergic reaction! → treat with beta-adrenergic drug or epinephrine → increase sympathetic (remember bronchiole constriction is parasympathetic)
ASTHMA – use parasympathetic blocker or beta-adrenergic agent (NOT blocker)
URINARY INCONTINENCE — That’s why you want to pee (relaxed detrusor) when you are startled, but you can’t (closing of internal sphincter). Treat with sympathetic blocker.
ERECTILE DYSFUNCTION — Viagra –> inhibits Nitric Oxide destruction (released by ACh)
Increase preload, increase velocity of shortening, increase force, same time, same Vmax
Increase afterload, decrease velocity of shortening
Increase inotropy, increase velocity of shortening, increase force, shorten time, increased Vmax