Lecture 9 Hypertension and Diabetes

From Iusmphysiology

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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

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?
  • 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.
  • 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.


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