Lecture 9 Hypertension and Diabetes
From Iusmphysiology
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- continued here from Lecture 8 Shock on 01/28/11 at 9:20 AM.
Hypertension and Diabetes
Objectives
- What are the systolic and diastolic arterial pressures usually used as indicators of hypertension?
- What is the labile stage of essential hypertension? What is the primary mechanical cause of increased arterial pressure?
- How does the sustained phase of essential hypertension differ from the labile phase in terms of mechanical cause of increased arterial pressure?
- What are the general characteristics of essential hypertension in terms of the following items:
- Resistance of the majority of vascular beds
- Constrictor response to norepinephrine
- Cardiac work load
- Long term changes in arteriolar wall distensibility and smooth muscle development
- Understand how each of the following treatments of hypertension can be effective to lower the arterial blood pressure
- Sodium restriction or diuretic loss of sodium
- Beta blockers for the heart and alpha blockers for the vessels
- Central nervous system suppression of sympathetic nervous system activity
- Peripheral acting drugs which cause vasodilation
- Angiotensin converting enzyme inhibitors and blockade of angiotensin II receptors
- Correction of insulin resistance
What is hypertension
- Smoking was exchanged for eating.
- If bp gets above 140/90, we say pt is hypertensive.
- Age doesn't matter.
- 90-95% of all cases of hypertension are caused by abnormal hyper-reactivity to noreepi and angiotensin II
- Risk factors:
- Agiing
- This is probably because kidney function decreases so we can't handle NaCl imbalances.
- Obesity and sedentary accelerates this process.
- 80% of people over 60 are obese
- Race
- African Americans: genetics and obesity affect this
- Mexican-Americans, too.
- Menopause
- Estrogen replacement used to be the go-to therapy, but now we don't do this because estrogen increased obesity and hypertension
- Diabetes mellitus, type 1
- Insulin resistance
- Sodium intake
- BP goes down if sodium intake goes down
- Could be a problem with the H/Na pump in the kidney.
- Family history
- Stressful life
- Has lots to do with being able to handle personal and professional relationships
- Low arobic condition
- Agiing
Na and hypertension
- Impairment of sodium handling in contractile cells leading to vasoconstriction
- Na/H antiport is excessive, bringing too much Na into cell
- Low function of Na/K pump due to endogenous ouabain or similar compounds
- Both possibilities depolarize the muscle cell, increase calcium intake for removing sodium ions, and likely open voltage dependent calcium channels - the cell is hyperactive
- Ouabain blocks the Na / K pump
- Lots of hand waving in hypertension! One of these is broken, but this is multifactoral.
Various Mechanisms of Hypertension
- Less than 5% of hypertension is due to these things.
- Renal tissue or vascular disease to increase renin-angiotensin-aldosterone production
- Water is retained
- Obesity (covered latter)
- Pheochromocytoma
- tumor that increases epi and ne
B Essential Hypertension: What Is Wrong With the Cardiovascular System
- There is evidence that people with essential hypertension have too much cardiac output as youth.
- By the tyme they are fully int ohypertension, they have normal output witha hypertropied heart.
- Over time the primary reason for hypersention is ?
- In the early phase is called the "early" or "labile" stage.
- They are hypertenstive when stressed.
- "White coat hypertension"
- Hence we have them follow bp at home.
- Possible outcomes
- CV system resets the setpiont pressure and regulates to maintain it.
- barroreceptros and sympahtetics must reset to meet this new point.
- Problem:
- Heart hypertrophies
- Smooth muscle cells of vessels hypertrophy
Established phase of hypertension
- Most who get hypertension are in the 30s / 40s.
- Unless they see a physician regularly, they may not get caught early.
- Pharma can stop it, but it will often come back worse if they stop the pharma.
- Losing weight is good because pressure will come down and will rise at a lower rate.
- Remember that all the vascular beds are involved in this disease.
- The microvasculature is in great shape in hypertension
- they heal, they vasodialte / constrict.
- Just set at a higher setpoint pressure.
- Cardiac output is ok
- Blood volume is a little higher in bp
- But this is hard to measure, really so data is a little unreliable.
d. Neural and Hormonal Issues
- Sympahteics are running high to support blood flow
- Kidneys and heart are the primary targets
- Kidney
- Might cut sympathetic innvervation to help with tx.
- Heart:
- Innervation increases contractility
- Rate is fine
- Obesity:
- In general, it accentuates the sympathetic activity
- More leptin is released.
- So decreasing weight decreases leptin decreases sympathteic which is good
- Renin, angiotensin II, and aldosterone
- Blocking renin-angiotensin is very effect
- Captopril, was first, based on venom; seen from snake that bites and cuases fainting
- Acutely blocks ACE, bp drops fast
- Increased constrictor response to norepi
- Heart forced to work harder and msucle enlarges
- Arterial baroreceptors reset to high pressure range
- Kidney absorbs more sodium from filtered fluid than in normotensive people
- If you give salt to a hypertensive person, they get rid of it faster than a healthy person.
- But na retention have to be off by much to change physiology.
- Arterioles forced to survive at high pressure
- SHR = spontaneously hypertensive rat
- Note that the high pressure of SHR is most apparent at the large arteries.
- The smooth muscles of the large arteries and arterioles hypertrophy in order to handle blood presure.
- Compromised NO? Probably, over time.
- Less distensible vessels – mechanically help cause constriction??
- Nitric oxide generation is compromised
- Vascular muscle may have a Na+- H+ antiport malfunction
Image
- ABout half of hypertenstives have a proportionally higher increase in bp b/c of dietary Na.
- Salt-sensitive
- If you take lots out of their diet, their bp starts heading for normal.
- BP won't improve much for non-salt-senstive
III. Effective medical interventions for Essential Hypertension
- Diet restriction
- Increased Na excretion at kidney via diuretics
- Are we trading hypovolemia for hypertension?
- May not be dood?
- Are we trading hypovolemia for hypertension?
- Decrease sympathetics
- Number of drugs do this, but it leads to exercise intolerance.
- Beta blockers
- Reduce contractility, just makes the person weak, really.
- Resistance isn't lowered.
- Alpha blockers
- Makes more physiological sense
- Decreases arterial resistance
- Decreases areterial response to norepi.
- stopped here on 01/28/2011 at 10AM.
- started here on 01/28/2011 at 11AM.
Early essential hypertension treatment
- Life style is so hard to change.
- Exercise and lower sodium
- Give diuretic
- Reduce vasoconstriction
- Reduce aldosterone (hence diuretic)
- Not many side effects
- ACe inhibitors:
- Causes lower resistance
- Causes lower total Na content in the body
Late essential hypertension treatment
- Diet and exercise
- Diuretics
- Ca cahnnel blockers
- Lower vasc resistance
- Lower contractility
- Exercise tolerability goes down
- This affects the pt's life
- Beat blockers
- Slower heart
- less contractility
- Decreased exercise toler
- Definitatley affecting their life
- Move on to Alpha-blockers
- Very compromising to pts
- Vasodilators
- Chemically relaxes vessels direclty
- Little too much and they faint
- Can really affec thte life of the pt.
- Can cause impotence, too.
- these were listed in order of application
Side effects of hyptertensive therapy
- Orthostatic hypotenstion
- Can't exercise / work as hard
- Get tired
- Can cause loss of job in construction, etc.
- Can't stand heat
- Because blood flow increase to skin will require more blood flow and they will get less elsewhere and get tired
- patient feels...
Diabetes
- Type I:
- More children have some sort of cardiac proceedures than get type I diabetes.
- So not many kids get diabetes.
- If all goes well, give insulin and the pt lives just fine.
- Oftne there are problems, though.
- More children have some sort of cardiac proceedures than get type I diabetes.
- Type II:
- Probably underdiagnosed
- Cause: insulin resistant
- Can have 5-10 times as much insulin
- Use "lean" not "thin"
- Treatment:
- Improve insulin secretion but that will make them more resistant; lots of pharma does this.
- Improve insulin receptor activity.
- Eventually we have to give them recombinant insulin
- Ab will be generated, unfortunately.
- Lose weight, exercise
- Prognosis:
- Good if hyperglycemia is controlled
- Obesity with insulin resistance:
- BMI > 25.
- 30% of population has BMI > 30
- Causes same probs as type 2 dm but slower
- BP goes up
- atherosclerosis
- Treatment:
- diet and exercise
- emotional support; many improve with anti-depressant
- Pharma intervention: some drugs can help lose weight
- Prognosis:
- Good if weight loss occurs
- Patient compliance is a significant problem
213 POUNDS VS 178 POUNDS
- One gallon of fat = 7.3 pounds.
What we used to look like
- Cro-Magnon man by Zdenek Burian
- Little bit of a pounch.
- They ate grasses, leaves, seeds, roots, birds, small animals, fish, and some large animals.
- Roots are lousy sources of nutrition, actually.
% men and women with hypertension vs BMI
- As BMI increases, both men and women have significant increase in blood pressure.
- T2DM is rare in low BMIs.
- If BMI is above 30 and you're not yet T2DM, you will be in 10 years.
FACTORS IN OBESITY HEREDITARY
- Since obesity is one of the strongest correlations with disease.
- Exactly what is worng in obesity is hard to say
- many theories, many genes.
- Heredity
- Some say biochem abnormalities that are genetically linked along with psychological issues that are genetically based.
- Exercise
- Exercising increases insulin sensitivity of skeletal muscle.
- Routine exercise decreases emotional stress.
- Glucose uptake is increased in the short term
- Lipids are burned when exercising.
- Food intake
- Obesity doesn't occur on healthy food.
- High in carbohydrates, usually
- Fatty foods
- Snacking is high
- Food as an emotional issue
What does Insulin do for the vasculature?
EM of microvessel
- Microvessels get torn up and are all ratty.
=Endothelial cells
- Insulin takes about an hour to take effect beucase they have to get into the cells via vesicle, etc.
- High insulin is a good way to turn on NO.
- This hapens by activating the PKA (AKT) system which increases eNOS.
- This is good because it increases blood flow to the skeletal muscle so the muscle can take up the glucose for use later.
- This is happening all over the body, actually (brain included).
Vascular smooth muscle cells
- Probably don't need insuoin for glucose transport
- Use glut2 not glut4
- We don't really know what insulin does for them.
- Could be that insulin makes them healthy or helps transport aas.
- They don't need it to haveneough glucose, though.
Graphs
Hyperinsulinemia
- What happens?
- it isn't doing much good because you're resistant.
- The more resistant, the more bp goes up?
- Lack of NO? not sure
- Something about hyperinsulinemia increases sympahtetics.
- Insulin goes trhough BBB endothelial cells
- Talks to many systems in brain cells.
- Na is retained
- Probably because symp is increased and renin / aldosterone increases
- Leptin is also elvated and icnreases bp.
Flow chart
- The pt gets to choose what percent of the background is expressed.
- As insluin resistance goes up, Na and Ca go up, contract too much, increased vascular resistance
- In the kidney, Na is retained, volume goes up, sympathetics go up, arterial pressure goes up.
Atherosclerosis and insulin
- Lots of epidemiological studys look at diabetes and BMI > 30.
- Obesity increases risk of atherosclerosis 2-3 times.
- T2DB increases risk 3-4 fold.
- Biggest problem for obese is coronary problems, strokes, peripheral vascular problems, etc.
- Have high LLDL, low HDL, and high TAGs.
- Have lots of hypertorphy, less hyperplasia, less NO.
- eNOS is expressed but signaling to use it is fubarred.
Microvascular disease in obesity
- Microvascular disease is rare in obesity unless you have T2DM.
Flow chart
- When hyperglycemic, you lose glucose and make lots of DAG.
- DAG turns on PKC:
- Phospholipases are turned on which increase DAG and IP3 such that Ca goes up, contraction of muscle goes up. DAG also suppresses eNOS so NO is low.
- Lipid breakdown increases AA, and then prostaglandins (more constrictors like thromboxanes than dilators). Then oxygen radicals are made and endothelial cells are damaged.
- Too many oxygen radicals destroy NO and could make peroxate nitride that permanently nitrides proteins such that they stop working.
Glycation of enzymes
- Some is good, some is purposeful.
- But high glucose can increase glycation and cause enzymes not to function.
- Glycated sites can also help make oxygen radicals.
- Glycation of Hb, causes Hb to not release oxygen as well in tissue.
Image of ankle
- Microvessels usually repair very rapidly: one day.
- In a wound they grow into it to provide blood.
- In diabetes, they don't heal or grow into wounds.
- Hence amputation is so bad in diabetes
Outcomes of diabetes without traatment
- REgression of microvessels, poor wound healing, amputations.
- No hair on legs as diabetics
- Accelerated atherosclerosis
- Kidney microvascular damage:
- Leaking fluid into microtubules can cause damage and decrease renal damage
- Vasospastic stroke
- When the artery spasms and stops blood to the brain.
- Ca channel blocker can help stop the spasm.
- Occlusive strokes
- Clot formationat, no blood, bad for brain
- Peripheral and sympathetic nervous sytem deteriorate
- Lots of arguments why this occurs
- Could be because nerves have limited microvascular supply so when microvascular are damaged the nerve is damaged
- Brain has better supply and they are fine in diabetes
- Peripheral Nerves, smooth muscle cells, and endothelial cells could be damaged by too much glucose (because they didn't need glucose int he first place to have neough glucose)
- Blindness
- Loss of mmicrovessels, especially caps
- Capillary overgrowth causes blindness
- Endothelial cells
- In a mess
Clinical example
- Injuries
- Short of breath
- Good pedal pulses (not much atherosclerosis)
- BP = 175/110
- HR = 75 / min
- Renal failure b/c of poor perfusion of the kidney
- Probably from an injury to a renal vessel.
- A. could be
- B. no because bp would have been elevated sooner in life
- C. could be but not likely
- D. no because he has good pressure in legs (coarctaction (partially occluded)
- E. he's the right age, but his bp is fine and pulmonary vascular disease usually doesn't raise his bp.
- continued on to Lecture 10 Coronary Artery Disease on 01/28/2011 at 11:50AM.