Physiological Bases of

Stress and Adaptation

Dr. Paola S. Timiras

Origin and Evolution of Stress• Claude Bernard (1813-1878)

– Leçons sur les phénomènes de la vie communs aux animaux et aux végétaux

– Constancy of the internal environment• Walter Cannon (1871-1945)

– The Wisdom of the Body– Homeostasis, stress, autonomic (sympathetic)

nervous system• Hans Selye (1907-1982)

– The Physiology and Pathology of Stress; a Treatise Based on the Concepts of the General-Adaptation-Syndrome and the Diseases of Adaptation

– Alarm reaction, adaptation, exhaustion– Hypothalamo-pituitary-adrenocortical axis (HPA)

Origin and Evolution of Stress

• Robert Sapolsky– Stress, the Aging Brain, and the Mechanisms of

Neuron Death – Why Zebras Don’t Get Ulcers: an Updated guide

to Stress, Stress-Related Diseases, and Coping– Role of limbic system (hippocampus) in regulation

of HPA• Bruce McEwen & Theresa E. Seaman

– The End of Stress as We Know It– Allostasis, homeodynamics

• Gordon Lithgow and others– Hormesis, endocrine regulation of longevity in

flies, worms and mice

Hypothalamo-pituitary-adrenocortical axis (HPA)

Section of the adrenal illustrating the various zones & hormones

Cortisol: Principal glucocorticoids in humans

NE and E: Principal catecholamines in humans

Corticosterone levels in young (3-5 mo.) & aged (24-28 mo.) rats during one hour of immobilization stress

followed by 4 hours of post stress recovery

Generic neuroendocrine axis

Hypothalamo-pituitary-adrenal-cortical axis (HPA)

Anterior pituitary & its major hormones; target endocrines & their hormones

Exposure to Stress Generates:

• Specific responses: vary with the stimulus and generate different responses with each stimulus.

• Nonspecific responses: (also called non- specialized) are always the same

– regardless of the stimulus

– mediated through stimulation of neural, endocrine, and immune axis

“Fright, Flight, or Fight” Responses to Stress

• Increased blood pr essure• Increased heart r at e• Increased force of heart cont ract ion• Increased heart c onduc t ion velocity• Shif t of blood f low dist ribut ion

away fr om th e skin and splachnic regionsand m ore t o heart, skele t al muscle, and brain

• Cont ract ion of s pleen capsule(Increased hemato crit* )

• Increased dept h and r at e of r espirat ion• Mobilizat ion of liver glycogen t o glucose ( glycogenolysis)• Mobilizat ion of f ree fa tty acids f rom adipose t issue

( lipolysis)• Mydriasis (widening of pup il)• Accommodat ion for f ar v ision

(relaxat ion of ciliary muscle)• Widening of pa lpebral f issure

(eyelids wide open)• Piloerect ion• Inhibit ion of g astro int est inal m ot ilit y and secret ion,

contr act ion of sph inct ers• Sweat ing

( cold sweats as skin blood vessels are constr ict ed)

Pathophysiologic Responses During StressDuring Stress

Energy storage ceases because:↑ sympathetic activity

( i.e. increased vigilanc /e arousal)↓ parasympathetic activity↓ insulin secretion

Access to energy storag e is facilitateda nd energy storage steps are reversed becaus e of:

↑ glucocorticoid secretion↑ epinephrine/ norepinephrin e secretion

↑ glucag on secretion glucagon secretion

Pathophysiologic Responses After StressIf physiologic responses are insufficient and adaptation is incomplete,

symptoms of poor health are registered (e.g. loss of energy whenfreeing energy from storage and returning to storage)

Examples of consequences:Muscle wastingDiabetes (Type 2)Ulcers, colitis, diarrheaInhibition of growth (in childhood)Osteoporosis (in old age)↓ LHR , H ↓ testosterone

The hypothalamic pituitary connections

with major hypophysiotropic

hormones

Hypothalamus, limbic nuclei, cerebral connections

Some physiologic and

pathologic responses to

stress in selected organs

Functions Stimulated or Inhibited by Physical/Psychological Stress

Functions Stimulated by Stress:

Cardiovascular• Increased cardiac r at e• Elevat ed blood pr essure• Increased blood c oagulat ion• Redist ribut ion of b lood f rom

peripheral ( skin) and int ernalsyste ms (gast ro-int est inal) toheart, skeleta l m uscles, brain

Respirat ory• Increased respirator y vent ilat ion

Met abolic• Increased glycogen mobilizat ion• Increased glycemia• Increased lipolysis

Hormonal• Increased CRH, ACT H,

Glucocort icoids• Increased vasopr essin, NGF• Increased cat echolamines (E & NE)

Functi ons Inhibit ed by St ress:

All funct ions not immediat elynecessary for defense andsurvival are decreased:

• Decreased growth• Decreased appeti t e ( anorexia)• Decreased reproduct ive funct ion

and sex dr ive• Decreased circulat ion in t issues not

invo lved in st ress response• Decreased response to p ain• Decreased immune funct ion• Decreased th ym us size• Decreased th ym ic hormones and

cyto kines

Selected Parameters of Allostasis

1, 2. Systolic and diastolic blood pressure(Indices of cardiovascular activity)

3. Waist-hip ratio (index of long-termmetabolic/l ipid deposition)

4, 5. Serum High Density Lipoprotein (HDL)and total cholesterol levels

(Indices of atherosclerotic risk)

6. Blood plasma levels of total glycosylated hemoglobin (Index of glucose metabolism)

7. Serum dehydroepiandrosterone (DHEA)sulfate levels (Index ofhypothalamo-pituitary-adrenal (HPA)inhibitor/ antagonist)

8. 12-hour urinary cortisol excretion(index of 12 hour integrated HPA activity)

9, 10. 12-hour urinary norepinephrine and epinephrine excretion levels

(Index of 12 hour integrated sympathetic activity) sympathetic activity)

Risk Factors (Allostatic Load)Endangering Health and Shortening Life Span

Elevated Physiologic Indices (at risk)• Syst olic b lood pr essure: ≥ 148 m m Hg

• Diasto lic blood pressure: ≥ 83 mm Hg

• Waist -hip rat ion: ≥ 0.9 4

• Tot al cholest erol-High Densit y Lipopr ot ein r at io: ≥ 5.9

• Tot al glycosylat ed hemoglobin level: ≥ 7.1 %

• Urinary co rt isol level: ≥ 25. 7 mg/ g creat inine

• Urinary epinephrine level: ≥ 5 m g/ g creat inine

• Urinary no repinephrine level: ≥ 48 mg/g creat inine

Lowered Physiologic Indices (at r isk)• HDL cholest erol level: ≤ 1.4 5 mmol/ L

• DHEA ( Dehydroepiandrost erone) level: ≤ 2.5 μmol/ L

Additional NotesMutant flies & worms obtained by knocking out

the receptor for GH & IGF-1Prolongation of life span is less efficient in

mammals than in worm/flies because

greater difficulty in mammals to switch from a preponderant aerobic source of energy to an

anaerobic one(Shane & Johnson, 2003, Developmental Cell, 5, 197)