Cardiovascular Lecture 7

Front 1

Arterioles have a _____ wall made of _____ ______.

Back 1

Arterioles have a thick wall made of smooth muscle.

Front 2

Two Roles of Arteries/ Arterioles

Back 2

1: Regulators of Upstream Pressure (MAP)

2: Gatekeepers of Flow to the Vascular Beds

Front 3

Precapillary Sphincters

Back 3

A single layer of smooth muscle
--> Under intrinsic control: are not innervated.
-->Influence the distribution of flow within a capillary bed by restricting flow to certain areas.
--> Regulate Flow: Impact the overall distribution within the capillary system

Front 4

Precapillary Sphincters are under ______ control.

Back 4

Intrinsic Control (are not innervated by nerves.).

Front 5

True Capillaries

Back 5

Have a single layer of endothelium (no smooth muscle).

They create a resistance that does not change (their diameter does not change).

DO NOT regulate flow.

Myosin/ Actin proteins in capillary endothelial only serve to increase or decrease the size of the leaky pore b/n the cells. This does not change the vessel diameter and therefore, does not affect blood flow. Only filtration.

Front 6

Reservoir of blood is the

Back 6

veins.

Front 7

The active tension of vascular smooth muscle is referred to as

Back 7

tone.

Front 8

True or false

Basal tone of vascular smooth muscle is at zero.

Back 8

FALSE

Basal tone of vascular smooth muscle is slightly contracted. This allows for vasodilation or vasoconstriction.

Front 9

Arteries and Arterioles intrinsically regulate the blood flow to vascular beds. This serves which of their two roles?

Back 9

Gatekeeper of Flow

They regulate the amount of BF to different vascular beds.--->INTRINSICALLY

Via LOCAL FACTORS:
1 - Myogenic Changes
2 - Metabolic Changes
3 - Physical (local) Changes
4 - Autacoids

VIA CIRCULATORY ADJUSMENTS:
1 - Autoregulation
2 - Active Hyperemia
3 - Reactive Hyperemia

Front 10

Arteries and Arterioles Extrinsically regulate the blood flow to vascular beds.

This serves which of their two roles?

Back 10

Regulators of Upstream Pressure.

Regulate BF to organ systems in order to maintain MAP.

Via:
1 - NEURAL CONTROL: of Sympathetic Fibers:
------>Adrenergic fibers (a - mediated VASOCONSTRICTION, increased resistance)
------> VASODILATION via inihibition of SNS
------>SNS Venoconstriction - Decreased Compliance
------->Cholinergic fibers (VASODILATION OF SKIN)
--------> Vasodilation of skeletal muscle via Beta2 and low doses of epi

2 - HORMONAL CONTROL
----->Adrenal Medulla release of EPI
-----> ANGIOTENSIN
----->ARGININE VASOPRESSIN (AVP)/ANTIDIURETIC HORMONE (ADH)
-----> NATRIURETIC PEPTIDES (Arial Natriuretic Peptide, ANP and Brain Natriuretic Peptide, BNP)

3 - DOPAMINE (given clinically)
------> Low Dose, Med Dose, High Dose

Front 11

Myogenic Mechanism

Back 11

PART OF THE GATEKEEPER ROLE
LOCAL FACTOR

Intrinsic (nerve free) Regulation of vascular tone by vascular smooth muscle in response to changes in intravascular pressure.

The arteriole will VC or VD to change the radius and keep Wall Tension constant.
(Law of Leplace: T = Pr/t)

* Increased intravascular pressure--> Vasoconstriction

* Decreased intravascular pressure--> Vasodilation

Front 12

Metabolic Regulations of Arterioles

Back 12

PART OF THE GATEKEEPER ROLE
LOCAL FACTOR

Products of tissue metabolism cause
vasodilation.

VASODILATORS: CO2, K+, H+, Adenosine(from ATP breakdown)
-->These attempt to get more BF to get them out.

A DECREASE in O2 will also vasodilate. (need more groceries)

This only happens in SYSTEMIC vasculature (not pulmonry).

Front 13

Physical (local) arterial changes that affect vascular tone:

Back 13

PART OF THE GATEKEEPER ROLE
LOCAL FACTOR

* TEMPERATURE (a direct, reflex effect)
-->Heat - Dilates
-->Cold - Constricts

* TISSUE PRESSURE(outside pressure from transmural pressure gradient).
-->Increase tissue pressure, Transmural pressure DECREASES (VC). (Can happen with skeletal muscle contraction).
-->Decrease tissue pressure, Transmural pressure INCREASES (VD).
-This is why DBP drives the coronary blood supply.

Front 14

In what vascular beds are local changes in tissue pressure most important?

Back 14

Skeletal Muscle vascular beds.

Contraction increases tissues pressure, lowers transmural pressure....long periods of contraction could cause ischemia to tissues.

Front 15

Autacoids

Back 15

PART OF THE GATEKEEPER ROLE
LOCAL FACTOR

Vasoactive substances (impact smooth muscle tone) that are produced, released, and act locally.

TYPES OF AUTOCOIDS:
1 - ENDOTHELIUM DERIVED AGENTS: Nitric Oxide, Endothelins, Prostacyclin (PGI2)

2 - THOSE THAT VASODILATE BY INCREASING NO: Bradykinin, ACh, Neuropeptides: Substance P (SP) and Vasoactive intestinal peptide (VIP) (These bind to receptors on endothelial cells to cause release of NO)

3 - OTHERS: Histamine, Leukotrienes,

Front 16

Nitric Oxide

Back 16

AUTACOID - Part of Local Factors of Intrinsic Vasoregulation of BF. (GATEKEEPER ROLE)

An ENDOTHELIUM DERIVED Autacoid.

*ACTIVATED BY: 1)Shear Stress, 2)Other vasoactive agents (Bradykinin, ACh, SP, VIP), and 3) Shock.

*Produced which L-argenine splits into NO and L-Citrulene.
*This reaction is catalyzed by the enzyme NO SYNTHETASE (NOS).

Here is the process
1) Shear stress on blood vessels opens Ca ion channels. Ca enters the endothelial cell and binds with Calmodulin.
2) Ca-Calmodulin complex activates NO synthetase.
3) NO synthetase catalyzes the rxn of L-arginine to produce NO and L-Citruline.
4) NO diffuses to Smooth Muscle.

*POTENT VASODILATOR: Acts on Smooth Muscle to increase cGMP. Increased cGMP causes dephosphoryltation of myosin and SM relaxation.

TONIC REGULATOR OF TONE! (Basal vascular tone is caused by NO. Shear stress is always occuring, always producing NO. If yo block NO, or stop shear stress, you will get vasoconstiction throughout.)

Front 17

Endothelins

Back 17

AUTACOID - Part of Local Factors of Intrinsic Vasoregulation of BF. (GATEKEEPER ROLE).

An ENDOTHELIUM DERIVED Autacoid.

Come from endothelial cells of blood vessel, go to smooth muscle and cause VASOCONSTRICTION.

These are important in PATHOLOGIES: Primary Pulmonary HTN. We use drugs to block endothelins in this condition.

Front 18

Prostacyclin (PGI2)

Back 18

AUTACOID - Part of Local Factors of Intrinsic Vasoregulation of BF. (GATEKEEPER ROLE)


One of the ENDOTHELIUM DERIVED Autacoids.

This is a PROSTAGLANDIN and is POTENT VASODILATOR made in endothelial cells.

*Membrane Phospholipids in the endothelial cell are converted to Arachidonic Acid by Phospholipase A2
*Arachidonic Acid is converted to Prostaglandins by Cyclooxygenase, and to Leukotrienes by Lipoxygenase.

Aspirin blocks cyclooxygenase, prevent Prostacyclin synthesis and decreasing inflammation.

Front 19

What causes the basal tone of vascular smooth muscle?

(Tonic regulator of overall tone?)

Back 19

SNS provides basal tone of the vascular smooth muscle. Nitric Oxide is the tonic regulator of overall tone. Regulates SNS tone.

(From shear stress on the blood moving through arteries. ).

Front 20

What autacoid is the main molecule causing primary pulmonary HTN?

Back 20

Endothelins

Front 21

Aspirin blocks the enzyme

Back 21

Cyclooxygenase

Prevents Prostaglandin synthesis from Arachidonic Acid.

This prevents inflammation associated with the vasodilation.

Front 22

Kinens

Back 22

AUTACOID - Part of Local Factors of Intrinsic Vasoregulation of BF. (GATEKEEPER ROLE).

Cause VASODILATION by INCREASING NITRIC OXIDE.

*Bind to receptors on endothelial cells, causing increased intracellular Ca.
*Ca-calmudulin complex then activates NO Synthetase to make NO from L-arginine.
*NO then diffuses to smooth muscle, where it causes increased cGMP, MLC Phosphatase activation, and SM relaxation.

Bradykinin (Made only from high MW Kinogens)

Kalligen (Made from both Hi and Low MW Kinogens).

Front 23

High molecular weight Kinogens Synthesize ________.

Low molecular weight Kinogens synthesize __________.

Back 23

High molecular weight Kinogens Synthesize Bradykinen and Kalligen.

Low molecular weight Kinogens synthesize only Kalligen.

Front 24

ACh's role in vasoregulation

Back 24

AUTACOID - Part of Local Factors of Intrinsic Vasoregulation of BF. (GATEKEEPER ROLE).

Cause VASODILATION by INCREASING NITRIC OXIDE.

*Bind to receptors on endothelial cells, causing increased intracellular Ca.
*Ca-calmudulin complex then activates NO Synthetase to make NO from L-arginine.
*NO then diffuses to smooth muscle, where it causes increased cGMP, MLC Phosphatase activation, and SM relaxation.

Front 25

Substance P (SP)

Back 25

A neuropeptide.

AUTACOID - Part of Local Factors of Intrinsic Vasoregulation of BF. (GATEKEEPER ROLE).

Cause VASODILATION by INCREASING NITRIC OXIDE.

*Bind to receptors on endothelial cells, causing increased intracellular Ca.
*Ca-calmudulin complex then activates NO Synthetase to make NO from L-arginine.
*NO then diffuses to smooth muscle, where it causes increased cGMP, MLC Phosphatase activation, and SM relaxation.

Front 26

Vasoactive Intestinal Peptide (VIP)

Back 26

Neuropeptide

AUTACOID - Part of Local Factors of Intrinsic Vasoregulation of BF. (GATEKEEPER ROLE).

Cause VASODILATION by INCREASING NITRIC OXIDE.

*Bind to receptors on endothelial cells, causing increased intracellular Ca.
*Ca-calmudulin complex then activates NO Synthetase to make NO from L-arginine.
*NO then diffuses to smooth muscle, where it causes increased cGMP, MLC Phosphatase activation, and SM relaxation.

Front 27

Histamine's role in vasoregulation

Back 27

AUTACOID - Part of Local Factors of Intrinsic Vasoregulation of BF. (GATEKEEPER ROLE).

Secreted by MAST cells and BASOPHILS

**Action depends on receptor subtype but usually they VASODILATE VERY SMALL vessels (usually).

This causes INCREASED CAPILLARY PERMEABILITY as well. (EDEMA). (by contracting the fenestrae of the capillaries).

Front 28

Histamine increases _______ ________.

Back 28

Histamine Increases capillary permeability.

Front 29

Leukotrienes

Back 29

AUTACOID - Part of Local Factors of Intrinsic Vasoregulation of BF. (GATEKEEPER ROLE).

Cause VASODILATION.

Sister to Prostaglandins - daddy is arachynoi..acid and granddaddy is Phospholipids

Very important in ANAPHYLAXIS

Inhibited by glucocorticoids.

Front 30

Leukotrienes are important in _________.

Back 30

Leukotrienes are important in anaphylaxis.

Front 31

Autoregulation

Back 31

CIRCULATORY ADJUSTMENT
PART OF THE GATEKEEPER OF FLOW

Maintenance of a relatively constant flow in the face of changes in pressure via vasoconstriction.

Normally, increases in pressure increase flow (Q = Chg P/ R.). In the AUTOREGULATORY RANGE, the resistance increases via Vasoconstriction. This keeps flow constant for increased pressure. (takes a while to kick in.).

If pressure goes down, resistance (VC) will decrease. VD. This will increase flow back to normal.

This correlates to the myogenic change (increased pressure causes VC.)

HTN will shift the autoregulatory curve to the right. This means that your autoregulatory range is now higher....your body adjusts to the chronic HTN. If you have a normal BP in these people...they will lose perfusion to the brain and other tissues due to the adaptative changes of HTN. Must maintain their baseline High BP.

Front 32

Active Hyperemia

Back 32

CIRCULATORY ADJUSTMENT
PART OF THE GATEKEEPER OF FLOW

An increase in metabolism increases blood flow.

Metabolism produces vasodilatory compounds as byproducts. (autacoids). These cause vasodilation.

Front 33

Reactive Hyperemia

Back 33

CIRCULATORY ADJUSTMENT
PART OF THE GATEKEEPER OF FLOW

An increase in blood flow after a temporary stoppage or reduction in blood flow (occlusion of the vessel).

The LONGER you occlude the vessel, the LARGER the resultant increase in flow. The area under the curves of both will be the same, like the rebound is paying back the O2 debt that was created.

Mechanism:
1 - MYOGENIC: (T - Pr/t )Occlusion decreases the pressure downstream. When pressure drops, vessel vasodilates to maintain wall tension. When you unocclude the vessel, blood is flowing into a dilated vein (increased flow).

2 - METABOLIC - When vessel is occluded, blood downstream fills up with vasoactive metabolites due to lack of flow. This cause vasodilation. When you unocclude, the blood is going into a dilated vessel - increased flow.

Front 34

How does a blood vessel maintain the rate of flow to the organs within a safe range?

Back 34

Autoregulation via vasoconstriction (highpressure) and vasodilation (low pressure).

Q = Chg P/ R

Front 35

The autoregulatory curve is shifted to the right in

Back 35

Chronic HTN.

BP now need to be maintained at their new autoregulatory range. .

Front 36

Nervous System Control of Vasoregulation

Back 36

EXTRINSIC CONTROL, which serves to REGULATE UPSTREAM PRESSURE.

The SYMPATHETIC NERVOUS SYSTEM controls vasoregulation. (Parasympathetic has no receptors on BV's).

1 - ADRENERGIC FIBERS:
----->NE binds to alpha-1 receptors causing VASOCONSTRICTION.
----->NPY (Neuropeptide Y) - Causes direct vasoconstriction and Facillitates the actions of NE on alpha-1.

2 - VENOCONSTRICTION (alpha receptors). DECREASES COMPLIANCE, Decreases venous volume, increases venous return to the heart.

3 - CHOLINERGIC FIBERS (ACh) - sympathetic cholinergics - ACh to a M receptor. Cause VASODILATION. Only important in SKIN vascular beds.

Front 37

What will alpha mediated vasoconstriction with NE what will happen to TPR, BP, MAP?

Back 37

It will go UP.

This is UPSTREAM PRESSURE

(What extrinsic regulation controls).

Front 38

Does alpha mediated venoconstriction increase resistance?

Back 38

No.

(Alpha mediated arterial vasoconstriction increases resistance.) (It doesn't increase resistance because the arterioles have already decreased the pressure so it's moot.)

Alpha mediated venoconstriction REDUCES COMPLIANCE and increases venous return.

Front 39

In what vascular bed are sympathetic cholinergic fibers important in vasodilation?

Back 39

SKIN!! :)

Also present in skeletal muscle but not important.

ACh to a Muscarinic Receptor.

Front 40

Where is the only place in the body where you can find Parasympathetic NS stimulated vasodiation?

Back 40

The penis. For erection.

PNS nerve releases ACh.

*ACh acts by increasing NO. See below if you want the whole process:

ACh binds to endothelial cell receptors and cause Ca influx.
*Ca binds to Calmodulin
*Ca-calmodulin complex activates NO Synthetase
*NO Synthetase forms NO and L-Citrulline from L-Argenine.
*NO diffuses to SM where it increases cGMP.
*cGMP activates MLC Phosphatase
* Myosin light chain is dephosphorylated causing SM relaxation and vasodilation.

This is how viagra works. (increases cGMP).

Front 41

How does viagra work???

Back 41

Increases cGMP by inhibiting the enzyme that degrades cGMP in the penis.

Allowing cGMP to stay around longer will allow the smooth muscles to be relaxed longer, VD longer....longer erection.

This is why it's so dangerous to give Nitric oxide drugs with viagra...can cause HOTN.

Front 42

Hormonal Vasoregulation

Back 42

EXTRINSIC CONTROL, which serves to REGULATE UPSTREAM PRESSURE.

1) EPI from the ADRENAL MEDULLA (considered a hormone bc in the bloodstream)
------>Alpha-1 mediated Vasoconstriction
------>Beta-2 mediated Vasodilation
------>Varies depending on tissue receptor density and Epi dose

2) ANGIOTENSIN
------>Angiotensin II(1-8) will activate AT1 receptors to cause VASOCONSTRICTION, Aldosterone production, Renal Na reabsorption, and cell proliferation. (increased BP).
------>Angiotension (1-9) will activate mas and AT (1-7) receptors to cause VASODILATION, Decr. cell proliferation, and decr. Renal Na reabsorption. (ie, Decr. BP).
------> (Check out the pathway).

3) ARGINE VASOPRESSIN (AVP) AKA Anti-Diuretic Hormone (ADH)
-----> Potent Vasoconstrictor (V1 - Gp)
-----> Made from posterior hypothalamus
-----> Released from posterior pituitary
------> Hypothalamus inhibits it's release when stimulated by NTS.
-----> Causes water reabsorption in principal cells of teh collecting duct of the kidney (V2 - Gp)

4) NATRIURETIC PEPTIDES (ANP & BNP) - vasodialators via GUANYLYL CYCLASE activation.

------>ATRIAL NATRIURETIC PEPTIDES (ANP)
------> Made in the atrium
------> Released in response to atrial stretch (volume overload), causing a "naturesis" - which is SODIUM LOSS. Will also cause water loss. and VASODILATION via activation of GUANYLYL CYCLASE.
------> In essence, ANP works act to COUNTER the actions of ALDOSTERONE and the renal effects of AVP, causing a natriuresis and diuresis.

------> BRAIN NATRIURETIC PEPTIDE (BNP):
-------->Minimal amount produced in the heart under normal conditions, but markedly elevated in DILATED HEARTS. Plasma levels "roughly" CORRELATE with degree of ventricular dilation.

Front 43

Epi, in contrast to NE, stimulates _______ receptors causing _______.

Back 43

Beta 2

Causing vasodilation (in the lungs and skeletal muscle).

Front 44

Decribe the Angiotensin Pathway

Back 44

*Angiotensinogen (synthesized in the liver) is converted to Angiotensin I by Renin (which is released by the kidney).
*Angiotensin I is converted to Angiotensin II by ACE and CHYMASE.
*Angiotensin II bind to AT1 receptors, causing vasoconstriction, Increased aldosterone, Increased Na reabsorption, and cell proliferation.
*Angiotension II binds to AT2 receptors causing vasodilation.

*Angiotensin I is also converted to Angiotensin 1-9 by ACE2 and Angiotensin 1-7 by E (endopeptidase).
*Angiotensin II is also converted to Angiotensin 1-7 by ACE2.
* Angiotensin 1-9 is converted to Angiotensin 1-7 by ACE.
* Angiotensin 1-7 binds to mas and AT1-7 receptors causing vasodilation, decreased cell proliferation, and decreased Na reabsorption.

Front 45

Angiotensin converting enzyme is found in _____ _____.

Back 45

Capillary endothelium (and in the lungs).

Front 46

The pathophysiological effect of angiotensin II (HTN) acts on what receptor?

Back 46

AT-1 receptors

Causing vasoconstriction, increased aldosterone, increased Na reabsorption, and cell proliferation.

Front 47

What types of drugs are given for HTN that work on angiotensin?

Back 47

ACE Inhibitors - prevent the formation of AT-II

AT1 Receptor Blockers: the new frontier.

New drugs to stimulate ACE II - to form AT 1-7 (via ACE2) instead of 1-8 (AT II). Causing vasodilation instead of vasoconstriction.

Chymase blocking drugs - to help reduce the production of Angiotensin II (1-8).

Front 48

Giving ACE inhibitors with ______ inhibitors will ensure no production of AT II (1-8) and no vasoconstriction.

Back 48

Giving ACE inhibitors with chymase inhibitors will ensure no production of AT II (1-8) and no vasoconstriction.

Front 49

Explain the cough that is a side effect of ACE inhibitors.

Back 49

ACE breaks down Bradykinin.

ACE inhibitors lead to an increase in bradykinin and a cough due to bradykinin's in the lung.

Front 50

ANP works by counteracting the effects of __________ and __________.

Back 50

ANP works by counteracting the effects of Aldosterone and AVP/ ADH causing natriuresis and diuresis, decreasing BP in order to REGULATE UPSTREAM PRESSURE.

Front 51

ANP is released in response to ________.

Back 51

ANP is released in response to stretch in the atrium. Means volume overload.

Will cause natriuresis and diuresis. AND vasodilation.

Front 52

Plasma levels of BNP correllate with....

Back 52

the level of ventricular dilation.

Front 53

HIgh plasma levels of BNP indicate.....

Back 53

A DILATED HEART

Front 54

Natriuretic peptides activate what enzyme

Back 54

Guanylyl Cyclase.