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Changes in heart rate via an increase or decrease of the SA node. Primarily influenced by rate of phase 4 in pacemaker cells (inward Na+ current); also rate of phase 0 in AV node of pacemaker cells (inward Ca2+ current).
Changes in conduction velocity primarily at the AV node and influences the PR interval on EKG. Negative dromotropic effect slows conduction from atrium thru the AV node, prolonging the PR interval. Primarily influenced rate of phase 0 in AV node of pacemaker cells (inward Ca2+ current).
Force of contraction. Influenced by preload or EDV, the free cytosolic Ca2+ concentrations, sarcomere length.
ALL muscles requires ___________ to induce the process of contraction.
Why do drugs we use to impact blood pressure not have a significant or noticeable effect on skeletal muscle?
Skeletal muscle predominantly utilizes pools of calcium stored in the SR rather than calcium moving thru VG calcium channels to induce contraction. SR is MUCH larger in skeletal muscle as compared to smooth muscle.
What is "preload"?
The EDV more specifically related to the right atrial pressure.
What happens to preload when venous return is increased?
Preload will increase which will stretch the sarcomere further and increasing the contractility (forward flow).
What happens when there is a sudden drop in preload?
Baroreceptor reflex is activated resulting in reflex tachycardia and angina.
What is "afterload"?
The reflected aortic pressures that must be overcome by the left ventricle or pulmonary artery pressures that must be overcome by the right ventricle. Afterload increases work load and can worsen angina (if ischemic heart disease is present).
What are the 2 functions of the arterial system?
- Provide sufficient blood to body tissues
- Convery a highly pulsatile flow into a more continuous flow at the level of smaller arteries
How and where is pulsatile blood flow dampened as to not destroy smaller arteries in the periphery?
- It is dampened by elastin-containing central arteries (thoracic aorta and proximal branches).
- 1. Expansion during systole to store some of each stroke volume.
- 2. Recoil during diastole.
Define mathematically "pulse pressure".
PP = SBP-DBP; assumes a constant CO and HR
What does a wide pulse pressure indicate?
Decreased elasticity or increased arterial stiffness
Mean Arterial Pressure (MAP)
Average blood pressure over time; 100 mmHg
What are the 3 endogenous catecholamines?
- Norepinephrine (NE)
- Epinephrine (Epi)
- Dopamine (DA)
What 2 factors potently stimulate adrenomedullary release of NE?
What type of receptors are found on postsynaptic cells in smooth muscle and the heart that regulate smooth muscle contraction and myocardial inotropy?
Alpha 1 adrenoreceptors
What type of receptor is found presynaptically, autoregulates NE release, and inhibits subsequent NE release when activated?
Alpha 2 adrenoreceptors
Phenylephrine [stimulates/inhibits] alpha-1 adrenoreceptors.
Doxazosin [stimulates/inhibits] alpha-1 adrenoreceptors.
Clonidine [stimulates/inhibits] alpha-2 adrenoreceptors.
Yohimbine [stimulates/inhibits] alpha-2 adrenoreceptors.
What type of receptors are found in the heart, kidney, and adipose tissue that increases the rate and force of cardiac contraction, stimulates lipolysis in fat cells, and stimulates renin release from the kidneys when activated?
Beta 1 adrenoreceptors
Dobutamine [stimulates/inhibits] beta-1 adrenoreceptors.
Metoprolol [stimulates/inhibits] beta-1 adrenoreceptors.
Propranolol [stimulates/inhibits] beta-1 adrenoreceptors.
Where are alpha-1 adrenoreceptors found? What is the cardiovascular response when NE binds to the receptor?
- Found in vascular smooth muscle and heart.
- Response is constriction (+ inotropic effect)
Where are alpha-2 adrenoreceptors found? What is the cardiovascular response when NE binds to the receptor?
- Found in brain, sympathetic nerve endings, and kidneys.
- Response is inhibition of NE release and renin release.
Where are beta-1 adrenoreceptors found? What is the cardiovascular response when NE binds to the receptor?
- Found in heart and kidneys.
- Response is (+) inotropic and chronotropic effect, cell growth, hypertrophy, and renin is released.
Where are beta-2 adrenoreceptors found? What is the cardiovascular response when NE binds to the receptor?
- Found in bronchial smooth muscle of the lungs.
- Response is relaxation.
Alpha-2 receptors are [pre-/post-] synaptic.
Alpha-1 receptors are [pre-/post-] synaptic.
Beta-1 receptors are [pre-/post-] synaptic.
What 4 regulatory mechanisms cause active renin to be secreted, thereby raising BP?
- 1. Renal baroreceptor - respond to volume
- 2. Macula densa - distal tubular salt sensor
- 3. Renal nerves - sympathetic outflow
- 4. Humoral factors - angiontensin, endothelin, ANP
What is the rate-limiting step in angiotensin II production?
What are 3 effects of the AT1 receptor in response to Angiotensin II?
- 1. Stimultes vascular smooth muscle contraction and aldosterone synthesis.
- 2. Stimulates formation of superoxide which deactivates NO (vasodilator).
- 3. Stimulates the activation, release, and synthesis of several growth factors.
What is the general effect expected when AT2 receptor is bound?
Antagonism of all the effects of binding to AT1. Major rationale for propsed superiority of ARBs.
What is the cardiovascular effect of Angiontensin II on smooth muscle in the vasculature?
What is the cardiovascular effect of Angiontensin II on endothelium of the vasculature?
Prostaglandin, NO, and endothelin production
What is the cardiovascular effect of Angiontensin II on connective tissue of the vasculature?
Extracellular matrix synthesis
What is the cardiovascular effect of Angiontensin II on the myocardium
- Strength of contraction
What is the cardiovascular effect of Angiontensin II on platelets
Aggregation by catecholamines
What is the cardiovascular effect of Angiontensin II on monocytes?
Adhesion to vessel wall
What is the cardiovascular effect of Angiontensin II on the adrenal glomerulosa?
What is the cardiovascular effect of Angiontensin II on the adrenal medulla?
What is the cardiovascular effect of Angiontensin II on the adrenal fasciculata?
What is the cardiovascular effect of Angiontensin II on the posterior pituitary gland?
What is the cardiovascular effect of Angiontensin II on the juxtaglomerular cells of the kidney?
Inhibits renin release
What is the cardiovascular effect of Angiontensin II on the proximal tubule of the kidneys?
What is the cardiovascular effect of Angiontensin II on sympathetic neurons?
What is the cardiovascular effect of Angiontensin II on the brain?
- Pressor center activation
- Baroreceptor blunting
- ADH synthesis
- Promotes thirst
- Prostaglandin release
What is the cardiovascular effect of Angiontensin II on the intestines?
Salt and water absorption
What is the cardiovascular effect of Angiontensin II on the liver?
- Angiotensinogen synthesis
What 4 factors is tissue angiotensin II a significant contributor?
- Changes in:
- 1. blood pressure
- 2. local inflammation
- 3. fibrosis
- 4. remodeling
Vasoregulation in the CNS continuously regulates constriction of [peripheral/central] veins and arterioles to control __________, __________, and ___________.
- peripheral veins and arterioles;
- HR, blood flow, and BP
How is the medulla of the CNS involved in vasoregulation?
Maintains SNS activity based on sensory information received from baroreceptors and chemoreceptors.
How is the hypothalamus involved in vasoregulation?
Coordinates BP thru alterations in neurohormonal release.
How are the cortical/subcortical areas of the CNS involved in vasoregulation?
Alter CV function based on emotion and stress. So basically, it wigs the hell out when the ex-wife calls.
Describe the baroreceptor reflex at carotid sinus in vasoregulation when there is a drop in arterial pressure?
Drop in arterial pressure --> drop in the stretch on walls of carotid sinus --> decrease in firing of the carotid sinus nerve to the nucleus regions in the medulla oblongata --> decreaced outflow of the PNS to the heart via efferent vagus nerve and increase in SNS outflow down descending tract of intermediolateral column of gray matter in spinal cord --> some preganglionic nerve fibers synapse eventually to heart and blood vessels where post-ganglionic sympathetic nerve fibers release NE and other preganglionic sympathetic nerves synapse on adrenal glands releasing both NE and Epi into circulation
Arterial barorelexes are known as [high/low] pressure baroreceptors.
Where are arterial baroreflexes found?
- Aortic arch and carotid bifurcations
Cardiopulmonary baroreflexes are known as [high/low] pressure baroreceptors.
Where are cardiopulmonary baroreflexes found?
- Cardiac atria and ventricles
Can you draw the "Effects of RAAS & SNS on MAP" diagram?
Hell no! Are you crazy?
Best get on that with the quickness.
What type of hypertension do adolescents and young adults predominantly suffer from? What are they sensitive to?
- Isolated Systolic Hypertension (ISH)
- These patients are salt sensitive.
List 3 lifestyle factors that affect the pathophysiology of hypertension.
- 1. Aging
- 2. Obesity
- 3. Sleep Apnea
What type of hypertension is characterized in 20-50 years old? What is this type of HTN associated with?
Diastolic hypertension. Associated with increased vascular resistance and MAP.
What type of HTN is found in patients greater than 50 years of age? Why is this significant?
- Resurgence of ISH due to central artery stiffness.
- Significance: DBP is highly dependent on the stiffness of central arteries. Elasticity in these is lost as we age, manifesting as a rise in SBP, a decrease in DBP, and thus a rise in pulse pressure.
True or False: The majority of men and women with HTN are not overweight or obese.
False. 78% of men and 65% of women with HTN are overweight or obese. Get off the couch fatty and run a lap around the house!
What 6 potential effects on BP can obesity have?
- 1. Insulin resistance
- 2. Fluid volume
- 3. SNS
- 4. Leptin resistance/hyperleptinemia
- 5. RAAS
- 6. Inflammation
Why is insulin important to BP when considering insulin resistance and obesity?
- 1. Insulin increases absorption of Na+ in the distal nephron resulting in water retention (increased volume).
- 2. Insulin increases adrenergic activity.
- 3. Insulin causes vascular smooth muscle hypertrophy.
- 4. Insulin resistance/hyperinsulinemia impairs insulin-mediated vascular signaling pathways associated with vasorelaxation.
How are obese patients with HTN affected by fluid volume?
They have a higher total body volume which largely distributes centrally and leads to augmented venous return, ventricular filling, and cardiac output.
How is the SNS affected by HTN in obese patients?
- 1. Peripheral catecholamine levels/sympathetic activity is not always increased in obese patients.
- 2. Organ-specific sympathetic activity in muscle and kidneys is elevated.
- 3. Increased activity in the kidneys is likely related to elevated leptin levels.
What is leptin and how is it affected in HTN?
- Hormone produced by adipose tissue that is responsible fore regulating food intake.
- Contributes to HTN due to increasing sympathetic activity.
- Acute infusion leads to natriuresis and NO production.
- Chronic infusion decreases natriuresis and NO production and increases renal sympathetic activity and BP.
- Correlation between leptin levels, adipose tissue mass, and HTN suggests a leptin resistance mechanism, however this concept is still being researched and not sure at this time.
How is the RAAS system affected by HTN in obese patients?
BMI is positively correlated with plasma angiotensinogen, plasma renin activity, plasma ACE concentration, and plasma aldosterone.
How is inflammation involved in hypertension in obese patients?
Inflammatory cytokines are released from adipose tissue that initiate and/or sustain the low-grade inflammatory state characteristic of the progression of HTN.
True or False: Sleep apnea is a common cause of drug-resistant hypertension.
How does sleep apnea affect the SNS in hypertensive patients?
- Apnea and hypopnea produce transient hyposemia, hypercapnia, and respiratory acidosis, and each event triggers activation of SNS. Enhanced sympathetic activity is present during sleep and wake times.
- Alteration of peripheral (carotid) and central regulation of sympathetic outflow contribute to elevated arterial pressure.
True or False: Patients with sleep apnea (OSA) have depressed angiotensin II and aldosterone levels.
False. These patients have ELEVATED angiotensin II and aldosterone levels.
How does sleep apnea lead to vascular dysfunction?
Hypoxia leads to endothelial dysfunction - endothelin increase, NO decrease
How is vascular remodeling affected by sleep apnea (OSA)?
- Leads to increased carotid intima-media thickness and arterial stiffness.
- 1. Hypoxia stimulates PDGF, endothelin-1, VEGF; 2. alters balance between extracellurlar matrix metalloproteinases/their inhibitors; 3. stimulates vascular RAS via cyclical stretch of vascular smooth muscle; and 4. causes hypertrophy secondary to chronic sympathetic activation.
What organs can become damaged due to hypertension?
- 1. Heart
- 2. Brain
- 3. Kidney
- 4. Eye
List several risks for hypertension.
- 1. White coat HTN - lame crutch to use
- 2. Masked HTN - not as in Freddy Kruger or Jason
- 3. Anxiety and Stress - avoid the ex
- 4. Obesity, fat distribution, & insulin resistance - avoid McD's
- 5. Physical activity - turn off Jersey Shore and The Real Housewives of BFE
- 6. Diet & alcohol - moderation is the key
- 7. Sodium and Potassium - put down the salt and pick up a banana (just don't eat the whole banana tree)
- 8. Calcium and Magnesium
Prehypertension is defined as BP of ___/___ mmHg.
Stage I hypertension is defined as BP of ___/___ mmHg.
Stage II hypertension is defined as BP of ___/___ mmHg.
What is the mechanism of action (MOA) of beta blockers in reducing BP?
- Blockade of beta-1 receptors in kidney decreases renin release.
- The decreased NE binding results in lower HR and lower CO.
- Na+ current slows down --> HR slows down --> slower firing of action potentials
What 3 clinical reasons should beta blockers be avoided or used with caution?
- 1. Initiate/adjust with caution in patients with HF (no crackles!)
- 2. Avoid in asthma/COPD patients unless benefit > potential risks
- 3. Avoid abrupt discontinuation - relfex tachycardia
What vasoactive substance are we most concerned with in HTN?
What effect does agonism of alpha-2 receptors by NE have? Give an example of an alpha-2 agonist.
- Agonism of alpha-2 receptors turns of NE release.
- Example: clonidine
Name 3 selective beta blockers, which receptor they bind to, and common adverse effects.
- Atenolol, metoprolol, and bisoprolol
- beta-1 receptors
- bradycardia, ED, insomnia, heart palpitations, dizziness
Name 2 non-selective beta blockers, which receptors they bind to, and a common adverse effect?
- Propranolol and nadolol
- beta-1 and beta-2 receptors
Name 2 mixed-selective beta blockers.
Carvedilol and labetalol
What is the overall long-term effect of using diruetics in hypertension?
Reduction in SVR
True or False: Alpha-1 blockers, like terazosin and doxazosin, are used primarily for hypertension.
False. They are not used primarily for HTN but are used if patient has BPH.
True or False: The African American special population responds well to thiazides.
True or False: The African American special population responds well to ACE-inhibitors when used as monotherapy.
False. They do NOT respond well to ACEi monotherapy.
What is the maximum effective dose of clonidine tablets?
0.8mg/day; usually divided BID
What is the maximum effective dose of clonidine patches?
0.6mg/24 hrs; patches changed once weekly. Don't have a "senior moment" and forget to remove old patch before applying a new patch.
What frequent problems are caused by clonidine?
What is the mechanism of action (MOA) of thiazide diuretics?
- Bind to receptors on the luminal side of the DCT
- Compete for the Cl- binding site, thus inhibiting the Na+/Cl- symporter causing increased excretion of Na+, Cl-, H20, and K+
What is the short-term effect of using diruetics in HTN?
Reduced extracellular and plasma fluid volume (Na+ and H2O
What is the starting and maximum effective dose range per day for Thiazide diruetics?
What special populations must be considered when using Thiazide diruetics?
- African Americans (+)
- Elderly (-) --> hyponatremia, hypokalemia
What is the Mechanism of Action (MOA) of Loop diruetics?
- Binds receptors on the luminal side of the thick ascending limb of the loop of Henle.
- Compete for the Cl- binding site of the Na+, K+, 2Cl- symporter causing increased excretion of Na+, Cl-, H2O, K+, Mg2+, Ca2+
True or False: Loop diuretics are generally not used for hypertension monotherapy.
What is the Mechanism of Action (MOA) of potassium-sparing sodium-channel blockers, like amiloride or triamterene?
Block Na+ channels in the laste distal tubule and collecting duct.
What is the Mechanism of Action (MOA) of potassium-sparing aldosterone inhibitors, like spironolactone?
- Bind the mineralocorticoid receptor in the late distal tubule and collecting duct.
- Net result is blockade of sodium movement from luminal to interstitial space through dosium channels and pumps.
What part of the nephron do Carbonic anhydrase inhibitors work?
In the early proximal convoluted tubule (PCT)
What part of the nephron do Thiazide diuretics work?
In the distal convoluted tubule (DCT)
What part of the nephron do loop diuretics work?
In the thick ascending loop of Henle
What part of the nephron do sodium-channel blockers work?
In the late DCT and collecting duct
What part of the nephron do Aldosterone inhibitors work?
In the late DCT and collecting duct
What is the MOA of ACE inhibitors?
- Inhibits the conversion of Angiotensin I to Angiotensin II which causes a drop in SVR due to vasoconstriction and a rise in Na+ and H2O excretion due to a drop in aldosterone.
- Inhibits conversion of active bradykinin to inactive bradykinin.