Autonomic nervous system- Neuroanatomy Flashcards

1
Q

Sym preganglionic neurons synapse on ———– cells of adrenal medulla and secrete ———-as NT that binds to N<strong>2</strong> R’s.

A

Chromaffin cells of adrenal medulla

Secrete ACh binds to N2 Receptors.

N2’s are a type of Cholinergic receptors( Cholinergic- nicotinic).

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2
Q

wide spread action of SNS via

causes globalization of sympathetic reaction

A

Adrenal medulla

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3
Q

3 general locations of nicotinic receptors

A

1- N2 -Nn- Autonomic ganglia

2- Nn-Adrenal medula

3- Nm- Neuromuscular Junction

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4
Q

The absence of this enzyme leads to the production of NE only in sympathetic postganglionic neurons (sym. post.gng nn’s):

A

PNMT- phenylethanolamine

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5
Q

ß1 produces/causes:

A

Excitation

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6
Q

Activation of nicotinic receptors cause:

A

Excitation

Ion- channels for Na+/K+

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7
Q

all neurons that conduct SENSORY information from viscera are located in

A

peripheral ganglia- either dorsal root or cranial nerve ganglia

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8
Q

The effect of SNS on the skin’s arrector muscle, peripheral bv, and sweat glands:

A

Hairs stand out

Blood vessels constrict- vasoconstriction

Sweat glands secret (sweating)

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9
Q

Autonomic center(s) of pons

A

pneumotaxic center

Part of respiratory center, the other two parts are located in medulla.

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10
Q

à1 adrenergic receptor Location:

G-protein:

Mechanism of action:

A

smooth muscles

Gq

Inc. IP3/[Ca2+]

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11
Q

ß2 produces

A

Relaxation-Dilation

  • Relaxation of vascular smooth muscles
  • Dilation of bronchioles
  • Relaxation of bladder wall
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12
Q

The effect(s) of sysm. tone on the:

1- SNA node and HR

2- AV nodal conduction

3- contractility

A

Increase for all three under sympathetic tone.

Inc. HR

Inc. AV nodal conduction

Inc. contractility

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13
Q

The only division that exerts control over the vasomotor functioning of the vessels of the body wall

A

Sympathetic division

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14
Q

Autonomic center(s) of midbrain:

  • Name an example
A

Micturition center

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15
Q

(Beta-2) ß<strong>2</strong> adrenergic receptor Location:

G-protein:

Mechanismof action:

A
  • smooth muscles
  • Gs
  • Inc. [cAMP]
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16
Q

vasodilation is typically elicited by this division of ANS

A

Parasympathetic

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17
Q

à-Receptor affinity fo NE and EPI

A

Greater affinity for norepinephrine

N.E. > EPI

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18
Q

Activation of B2 receptors of skeletal muscles’ b.v.:

A

Sympathetic tone →

Stimulates B2vasodialation in skeletal muscle

(blood vessels of the skeletal muscles).

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19
Q

Contractility of the heart under parasym. influce:

A

The receptor for the parasym division is M- muscarininc

Reduction of contractility- ATRIA

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20
Q

Innervation of the chemoreceptors and baroreceptors of the aortic arch:

A

GVA

Parasympathetic/ CN X

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21
Q

CNIII

A

parasym. Preg. neuron

oculomotor

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22
Q

Symp. action in the kidney and fat cells

(B1 adrenergic receptors)

A
  1. Kidney- inc. renin secretion
  2. Fat cells- inc. lipolysis
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23
Q

Parasym. tone causes the ———– of detrusor muscle and ———- of the internal sphincter of the bladder.

A

Contraction of the detrusor muscle

Relaxation of the internal sphincter.

“full” state

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24
Q

Parasympathetic function of CN X

A

visceromotor

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25
Result of the binding ATP to its receptors (P2x)
Rapid contraction of smooth muscle Tension of vascular smooth muscle ***Ionotropic***- _inflow_ of Ca2+ and Na+
26
Stimulation of **M3 R's** of the smooth muscles of GI tract leads to:
**M3 stimulation** (for **both** glands and smooth muscles) has **_excitatory_** effects **M3 activation ⇒ Increased GI motility**
27
Stimulation of M3 R's leads to --------- of glands.
M3 stimulation of **both** _glands_ and _smooth muscles of GI_ has excitatory effects. ## Footnote **M3 activation ⇒ increased secretion**
28
Ganglion associated with **glossopharyngeal nerve**
**otic ganglion**
29
The center for **conscious perception**
**cerebral cortex** ## Footnote -Regulates *hypothalamus*, which **in turn** regulates _cranial nerve_ and _spinal cord_ mediated ***autonomic*** activities.
30
Mechanism of action of B2 and B1
both via GPCR- Gs proptein --\>stimulation of adenylate cyclase (AC) --\> Inc. cAMP
31
Parasympathetic Efferent cranial nerves
CN IX and X carry significant amt of parasym afferent
32
The postgnanglionic n. branching from submandibular ganglion innervates
innervates submandibular and sublingual glands
33
Degrades **cGMP**
cGMP **phosphodiasterase**
34
Primary NT of preg. neurons of _SNS and PNS_
**ACh- Acetylcholine**
35
The _dominant_ ANS division during _"filling"_ state of bladder: \* status of the detrusor muscle and the internal sphincter
**sympathetic** is dominant detrusor muscle- relaxed (B2 R) internal sphincter- constricted (a1 R).
36
2 compounds that _activate_ nicotinic receptors
ACh and nicotine
37
SNS effects on the heart HR, contraction strength and coronary vessels
* Inc. HR * Inc. contraction strength * _In **coronary vesse**l_ - SNS i**nhibits** PNS * PNS inhibition ► Allows dilation (**exception**)
38
**carotid** sinus and body impulses are carried to medulla via:
**Sinus- glossopharyngeal nerve** **Body- vagus nerve** Sinus- localized dilation of internal carotid artery at its origin(resp to inc.dec BP). Carotic body- chemoreceptor- mainly responds to changes in arterial o2 and co2. impulses are carried by vagus nerve.
39
**Sympathetic** effect on the **radial muscles** of the *iris*
SNS causes **pupil dilation**
40
Stimulation/activation of **a1 receptors** in blood vessels of _skin and splanchnic:_
Sympathetic → **a1** stimulation → bv **constriction** in skin and splanchnic.
41
M3 R's (cholinergic\_muscarinic receptors) of the smooth muscles and the GI glands are activated by
**ACh and muscarine**
42
Mechanism when B1 produces excitation in the heart ## Footnote Examples of B1 excitation: inc. HR, inc. conduction velocity, and inc. contractility
**GPCR- Gs protein** → adenylate cyclase (AC) → Inc. [cAMP] ► inc. ( HR, conduction velocity, and contractility)
43
The effect of nicotine on N2 and N1 R's:
Nicotine is **agonist** to both (N2 receptor is different from neuromuscular N1).
44
Location of **muscarinic** receptors: - PNS division
* heart **(M2)** * smooth muscles **(M3)** * glands **(M3)** The **sysmpathetic post-ganglionic** receptors of the **_sweat glands_** are also **muscarinic** (exception).
45
Mechanism of action of **sweat gland's muscarinic** R's (SNS):
**Inhibition** of adenylyl cyclase ⇒ dec. [cAMP]
46
The type of **vascular smooth muscles** _regulated_ during secretion
**Unitary**
47
The effect of PNS on the Heart: HR, Contraction strength and coronary vessel
1. Reduced HR- 2. Reduced Contractile strength 3. _Coronary artery_ **constricts** In general, reduced demand for the heart
48
Muscarinic receptors are _generally_ found in:
Effector organs of PNS
49
B1 response and mechanism of action
GPCR-Gs sensitive to both epi and norepi
50
a2 mechanism of action
**Gi-GPCR** ## Footnote inhibition of adenylate cyclase (AC)- dec. cAMP
51
a1 mechanism of action
**Gq-GPCR** → stimulation of **PLC** → Inc **IP3 /Ca2+**
52
Nicotinic (_cholinoreceptor_) mechanism of action:
Via **depolarization** opening of Na+/K+ channel
53
parasympathetic visceral sensory pathway
from **pelvic viscera** travel in spinal n. through **ventral root**
54
symp. action in bladder via B2 and a1 R's
B2-relaxes the wall a1- const. sphincter
55
Ganglion associated with occulomotor
ciliary ganglion
56
The effect of PNS on the M3 R's ofGI tract
M3- increased motility M3- sphincter relaxation
57
Beta-1 (B1) adrenergic receptor Location: Gprotein: Mechanism:
heart Gs IInc. cAMP
58
epinephrine synthesis in adrenal medulla
Tyrosine --\> L-dopa --\> Dopamine --\> Norepinephrine --\> epinephrine
59
Visceromotor function of CN X influences
thoracic and abdominal viscera up to the first 2/3 of the colon
60
autonomic center(s) of hypothalamus
temp reg center thirst-food intake regulation center.
61
Viagra mode of action
prolongs cGMP action by inhibiting the cGMP phosphodiasterase
62
autonomic centers of medulla
vasomotor center respiratory center swallowing, coughing and vomiting center
63
Primary NT of postgang. neurons SNS
NorEpi, neurons to sweat glands- Ach
64
parasym. action in bladder via M3 receptors
M3- contraction of the wall M3- relaxn of the internal sphincter
65
SNS impact in glands other than sweat
indirect- vasoconstriction
66
pupil- PNS
pupil constriction - retina protection
67
Cholinergic receptor-Nicotinic-N2 (Nn) Location: Gprotein: Mechanism:
Autonomic ganglia (NEJ- Neuro effector juction) - opening of Na+/K+ channel
68
a2 receptors- adrenergic- location and impact
located on sym postgang nerve terminal, platelets, fat cells and the walls of GI tract Gi- Inhibition
69
binding of ------ to Guanylyl cyclase (GC) activates this E in smooth muscle and leads to
NO + GC --\> Active GC ---\> first phase of muscle relaxation
70
Nociceptor info carried exclusively by --------- while info from physiological receptor travel; primarily in ------
symp- parasym
71
B2 receptor location
1- vascular smooth muscles of skeletal muscles 2- bronchial smooth muscles 3- walls of the GI tract and bladder
72
peripheral visceral nociceptor pathway
symp sympathetic n. ---\> sympathetic trunk ---\> White Ramus ---\> Dorsal root ---\> spinal chord ---------\> used locally for Autonomic reflexes
73
NE r synt. from dopamine in ---------- and stored in -------- vesicles
varicosities and strored in small-dense core vesicles.
74
SNS effect on B1 R's of fat cells
inc. lipolysis
75
atropine inhibits the ------ receptors.
muscarinic receptors (M2 and M3)
76
Preganglionic neuron of parasympathetic system (the origin):
Cranial nerves: III, VII, IX, X Sacral spinal segments- S2-S4
77
list the three compns. f t heart with B1 and M R's (und. contl of sym. and psrasym,)
SA node & HR AV node conduction contractility
78
Target tissues with muscarininc receptors:
All **effector organs** under **parasympathetic** effect Plus, **sweat glands** innervated by the **sympathetic**.
79
**a1- adrenergic receptors** are found in this tissue and functian via this mechanism
* cause _contraction_ and _constriction_ (**excitation in general**) in **smooth muscle.** * Function by inc IP3 /Ca2+
80
**vasoconstriction** is *sympathetically* stimulated with the exception of ..................... in whch results in vasodilation. Hint: cardiac muscles and blood vessels
SNS ► vasodilation of **coronary artries**
81
ACh-R channel type of NMJ
**Na+/K+ ion channel** ## Footnote Binding of ACh to the **alpha subunit** → opens the channel
82
Referred pain
**visceral pain** that is _diffused and poorly_ localize. It signifies the **incorrect perception** of the the origin of pain detected by the stimulation of **_visceral nociceptor,_** as a result of release of endogenous compounds due to tissue breakdown.
83
**M1 muscarinic** receptor location (subtype of cholinergic receptors) G-protein: Mechanism of action:
M1 receptors are located in **CNS** ## Footnote **Gq -GPCR** **Inc. IP3/Ca2+**
84
Cholinoreceptors include:
**nicotinic** and **muscarinic** receptors
85
2 ganglions associated with the **facial nerve**
1. **Pterygopalatine** 2. **Submandibular**
86
Adrenoreceptors include (subtypes):
1. **à1** 2. **à2** 3. **ß1** 4. **ß2**
87
*Ganglionic blockers* **inhibit** majority of the nicotinic receptors **_except_**:
**Nm** ## Footnote **N2 (Nn)** are blocked by ganglionic blockers. **However**, nicotinic receptors of **NMJ (Nm)** are **_not affected_** by it.
88
**VIP**
Vasoactive Intestinal Peptide
89
ACh binds to this receptor on _endothelial cells_ and results in the _release_ of **NO**
**ACh + muscarinic R** **(M3)** → Inc. IP3 → Inc Ca2+ ► **NO _formation_ and _release_** ⇒ NO diffuse into smooth muscle
90
Gland secretion is generally under the control of --------- except sweat glands
PNS
91
**Rapid** relaxation of smooth muscle achieved via these 2 NT's:
**ACh and NO**
92
Preganglionic NT and assciciated R of SNS and PNS
ACh- Nicotinic R
93
**Specialized** ganglion of SNS, capable of secreting **both** NE and EPI
adrenal medulla Secrete both NE and EPI into the general circulation
94
Examples of organs with _excitatory_ **M** receptors
M3 of **smooth muscle** and **glands**
95
B1 mch. of action
stimulation of adenyl cyclase ► inc. [cAMP]
96
B2 mch act
Stimulation of adenyl cyclase. ► inc. [cAMP]
97
Adrenergic receptors release ------------- with the *exception* of _sweat glands_ and _vascular smooth muscle in deep skeletal muscle_.
**Norepinephrine (NE)**
98
Relative affinity of B receptors for NE and EPI
**Higher** affinity for **EPI** **EPI\>NE**
99
_Activation_ of **M3** receptors leads to: Hint: smooth muscles and glands
**Excitation via Gq** Stimulation of PLC ► **Inc. IP3/[Ca2+]i *** \* Increase in the **_intracellular_** conc. of Ca2+
100
Vasoactive Intestinal Peptide (VIP) are _stored_ in ------------ vesicles.
**Large-dense core vesicles**
101
**Lacrimal** and **salivary** glands' secretion under the influence of SNS and PNS
**Sympathetic** tone **reduces** the secretion of **both** lacrimal and salivary glands. **Parasympathetic increases** the secretion of **both** glands.
102
Sympathetic pegang neurons **directly** synapse on thie cells of this organ
**Chromaffin** cells of **adrenal medulla**
103
Delayed relaxation of smooth muscle
Relaxation caused by VIP
104
Parasympathetic efferent neurons
CN III, VII, IX and X carry visceromotor
105
The **finial 1/3** of the **colon,** the **pelvic viscera**, and **genitalia** receive _parasympathetic motor_ functions through
The **sacral** parasympathetic neurons
106
Location of B1 R's of the heart:
SA node, AV node and ventricular
107
Explain the mechanism of inhibition is producedby the stimulation of adrenergic a2 R's
Stimulation of a2 → inhibition via **Gs-GPCR →** inhibits adenylate cyclase → Red. [cAMP] Examples of **inhibition** via a2 includes **dilation and relaxation** in the following targets: 1. sym. pst. gng nerve terminals, 2. platelets, 3. walls of GI tract 4. fat cells
108
SNS effect on the **pupil**
**Dilation** to: 1- **increase** light and 2- **reduce** _depth of focus_
109
CN VII
facial The facial nerve is the seventh cranial nerve, or simply cranial nerve VII. It emerges from the pons of the brainstem, controls the muscles of facial expression, and functions in the conveyance of taste sensations from the anterior two-thirds of the tongue.
110
ANS and alteration of glandular secretion + SNS
**Bood flow restriction ► Reduced section** ## Footnote With the help of **vascular smooth muscles**( ***unitary unit type*** )
111
parasym. **postgang**. cells are --------------- operating via -------- receptors.
**Cholinergic** that operate via **muscarinic** receptor
112
**eNOS**
**Endothelial nitric oxide synthase**
113
Sensitivity of **adrenergic B2-R's**
More sensitive to EP thanNE ( EP\> NE ) ## Footnote **B2-EP \> a1-EP (B2 receptors are more sensitive to EP than a1)**
114
Sym. tone causes the ------------ of detrusor muscle and --------- of the ibladder's nternal sphincter.
relaxatio, constriction
115
**alpha-2 (a2) adrenergic** receptor location: G-protein: Mechanism:
1. **GI tract** 2. **Gi-GCPR** 3. **Red. cAMP**
116
**CN III** **Oculomotor parasympathetic effect on the pupil**
Pupil **constriction**
117
_Submandibular_ ganglion and _pterygopalatine_ ganglion are innervated by this CN
**CN VII**
118
The receptors of v_ascular smooth muscles **deep** in skeletal muscle_ and _sweat glands_
Muscarinic receptors that receive cholinergic input
119
Ganglionic blockers **only** block the ------------ receptors.
Autonomic ganglion
120
2 types of cholinergic receptors
**Nn and Nm**
121
Presence of **PNMT** in chromaffin cells lead to the production of
**Both NE and Epi** ## Footnote PNMT catalyzes the synt, of EPI from NE. sym. pst.gng. nn lack PNMT ► **only** secret NE (Thus the name *adrenergic neurons*)
122
Sym classical NT's in effector organs
NE except sweat glands (ACh)
123
**SAC** mechanism
Conformational channel results in release of Na+/ Ca2+ **into** the cell.
124
Two examples of reciprocal innervation of organs by SNS and PNS
1- SA node and HR elevation when BP dec. 2- urinary bladder: both detrusor and internal sphincters are innervated by both SNS and PNS
125
M3 R's (cholinergic/muscarinic) of the smooth muscles and the glands are **inhibited** by
Atropine
126
End result of VIP binding to its receptor (VIP-R)
Inc. [Ca]2+ ► smooth muscle r**elaxation**
127
Once stimulated, a2 receptors produce:
**Inhibition** (dilation/relaxation) via **Gs-GCPR**
128
Activates muscarinic receptors
ACh and muscarine
129
Once stimulated (by binding to NE), **a1 receptors** produce:
**excitation/contraction** Gq-GPCR's → stimulating PLC→ inc IP3, inc [Ca2+] *_intracellular_*
130
occulomotor nerve
CN III
131
**CN IX**
glossopharyngeal nerve
132
PNS and the **circular muscles** of the *iris*
Constriction of the pupil
133
a1 receptor locations:
Vascular smooth muscles of _skin_ and _splanchnic region_ Sphincters of _GI_ and _bladder_
134
GVA- visceral sensory Afferent
Sym splanchnic nerve sym cardiac nerve parasym division of vagus nerve and the pelvic nerves
135
B2 receptors
**same as B1- Gs** **But** produce relaxation and dialation * dilation of vascular smooth muscle * dilation of bronchioles * relaxation of bladder wall * Relaxation of GI tract
136
**CN VII** (parasympathetic) effect on: * Tears * Mucus secretion * Salivation
1. Inc. tears 2. Inc. mucous secretion: nasal Palatine and pharangeal 3. Inc. salivation
137
**Non-classical** NT's of parasym. pst.gng nn
VIP and NO ## Footnote VIP-Vasoactive Intestinal Peptide
138
Autonomic sensory information is gathered by these 2 receptors
* Nociceptive (painful) * Specialized physiological receptors for stretch and touch *
139
The effect of SNS and PNS on the **ciliary body**
SNS has no effect **Only** under PNS ► **_ciliary contraction_** ► thickening of the lense.
140
The *drop in BP* is detected and later processed by the -------------center of **brain stem**. As a result, the parasympathtic activity is ------- and sym. activity is ------. This result in an *increase* in HR which ultimately raises and adjusts the BP.
Initial signal \< drop HR \> is detected by the **vasomotor center (**brain stem ). **Reduction** of the **parasympathatic** tone, and *_simoultaneous_* **increase** in **sympathetic** tone ⇒ increased HR ⇒ increased BP
141
The effect(s) of **SNS** on **GI** tract via **a2/B2** receptors
Decreased motility
142
Exceptions in which SNS induces **vasodilation**
**Coronary Arteries** and **Deep muscles**
143
SNS is both ----------- and -----------. But, PNS is only --------- . Hint: pattern of distribution
SNS: global and local PNS: only local
144
VIP Mode of operation
GPCR
145
Locations of nicotinic receptors **(N1 and N2)**
**N1 (Nm)** - Skeletal muscle, motor end plate - **NMJ**. **N**2 - Postganglionic neurons, **SNS** and **PNS** **N2** - Adrenal medulla
146
Large-dense core vesicles contain (located in the vasicosities of nerve terminals):
**Neuropeptide Y** & **VIP**
147
Initiates the *activation* of **_ionotropic_** receptors and an *increase* in Na+/K+**conduction**
Binding of 2 ACh's to a-domains of the receptor.
148
**Binding of ACh** to this receptor on *endothelial cell* results in its activation and the **release of NO**.
M3- muscarinic receptors on endothelial cells
149
The effect of *glossopharyngeal* impulses on **parotid gland**
**Increased** secretion
150
Outline the process once the **M2 R's** of the **heart** are activated:
M2 stimulation is **inhibitory**. 1. **Activation Gi-GPCR** of the heart's **SA node** 2. **Inhibition** of the adenylate cyclase enzyme 3. **Opening** of the **K+ channels** 4. **Slowing** *spontaneous* depolarization of *phase 4*
151
M2 (cholinergic/muscarinic) Location: G-protein: Mechanism:
* **Heart** * **Gi-GPCR** * **dec. cAMP**
152
PNS receptors on the effector organs
Muscarinic
153
Multitransmission release from postganglionic symp cells Receptors: Hint- two different Ca2+ surges and 3 distinct phases
1. P2XR- binds to ATP ► Na+-Ca2+ entry ► depolarization ♦ phase I- fast. 2. Opens **Ca2+-sensitive gated** channels ► **_1st Ca2+ surge_ ♦** phase II- slower. 3. NE binds to a1- adrenergic R's (smooth muscles) ► Gq Activation (Inc IP3 ) ► Release of Ca2+ from ER _ **_2nd Ca2+ surge_** 4. Polypeptide Y binds to Y1 ♦ Phase III- slowest.
154
**Adrenergic receptors** of **1**- s_ympathetic pstganglionic nerve terminals_ and **2**- _walls of the GI tract_ are:
**a1-R's** (excitation/contraction via Gq CPCR's -PLC)
155
These receptors are located in the _autonomic ganglia of the SNS_, _PNS_, and in _adrenal medulla_
N2- nicotinic receptor
156
The effects of SNS on the **a1 R's** of **GI tract:**
Constriction of sphincters
157
SNS effect on **B1 R's** of the *kidneys*
Inc. renin secretion
158
The effect of **PNS** on the **skin's** **arrector muscle**, **peripheral bv**, and s**weat glands**:
Parasympathetic has **No** effect
159
Stimulated sym. postganglionic neurons secret these two NT's
ATP and NE- both act as NTs. ## Footnote 1st- ATP binds to purinergic receptor and then, NE follows the action of ATP (similar but stronger physiological response).
160
Secretion of chromaffin cells into the circulation is composed of:
**80% EPI & 20% NE**
161
Primary NT of postgang. PNS
ACh
162
SNS non-classic NT's
**Neuropeptide Y & ATP** ## Footnote \* most of the time ATP is cosecreted with NE (colocalized with NE)
163
**Metabotropic** receptors
**Muscarinic receptors** of parasympathetic postganglionic nerves
164
**SAC** Is an example of SAC
**Stretch Gated Channel** Heart- mechanoreceptor
165
small-dense core vesicles contain
Dopamine-B-hydroxylase, NE, and ATP- Which is colocalized with NE.
166
1. **Nicotinic-N1 (Nm)** Location: 2. G-protein: 3. Mechanism:
1. Skeletal muscle (NMJ) 2. No G-protein involved 3. Opening of Na+/K+ channel
167
Stimulation with ***high intensity*** or ***highfrequency*** leads to the **co-secretion** of ------- _in addition_ to ACh to augment its effectd.
**VIP**
168
Muscarinic receptors can be found in:
1- Heart 2- Smooth muscle 3- Glands
169
**vago- vegal**
CN X- Parasym- GVA- sensation of fullness
170
Block nicotinic receptors
ganglionic blockers
171
Carotid sinus baroreceptor and body chemoreceptor are
parasym Afferent- GVA - CN IX
172
Nicotine effect on autonomic nervous system: both PNS and SNS Which one dose last longer?
SNS: **hypertension** via cardiac stimulation PNS: **hypotension** via cardiac relaxation Sympathetic effects lasts longer.
173
The **micturition** (emptying the bladder) is under the ---------- control. _However_, the **micturition reflex** is controlled by ANS and regulated by the -------.
The micturition (emptying the bladder) is under the **voluntary** control. However, the **micturition reflex** is controlled by ANS and regulated by the **mid-brain**.
174
M2 receptors have ---------- effects on the heart.
**Inhibitory**