Neuroendocrine function and Hypothalamic control

Neuronal regulation (e.g., of the cardiovascular system);

what is the point?

• CV system regulates quite well with no neuronal input. Heart beat regulated by intrinsic pacemakers and arteriolar constriction regulated by local agents and circulating hormones.

• At rest that is fine, but when the organism is challenged, then there is a need to alter overall CV output and local circulation.

Parallel pathways regulate arterial pressure, but their time constants are very different.

Blood volume

• Intake – output.

• Regulated by Aldosterone, Angiotensin, Atrial Natriuretic Peptide, Vasopressin, etc.

• Kidney main organ regulating volume homeostasis.

It’s the flow that is important

Regional blood flow is important and acute changes in it are largely regulated by the nervous system.

What are the ultimate neuronal controls of blood flow

• Sympathetic nervous system (NE+)

• Parasympathetic nervous system (Ach+)

• Circulating hormones

• Locally released hormones

• Local neuronal and glial regulation in the brain

Feedback control of nervous system regulation of CV system

• Baroreflexes• Chemoreceptors• O2/CO2 receptors• Pain• exercise• Stretch• Heat• Nutrition

Baroreflexes

High pressure receptors in the aorta and carotid artery

Low pressure (cardiopulmonary receptors) atria

Both the IX and X nerves carry baroreceptor information to the brain. Other baroreceptors located throughout the body organs, but their influence is less global.

Variability of AP control without baroreceptor feedback.

Chemoreceptors

• Especially sensitive to O2 and CO2

CNS regulated neurohormones in CV control

SNS activates renin release in the kidney

• Renin in the circulation converts anagiotensinogen to A I and ACE converts AI to vasoactive AII.

• Also regulated by plasma ions (esp. NaCl)

• Local AII system in brain and kidney and heart.

Renin-Angoiotensin/nervous system interplay

promotes vasoconstriction via

• Directly acting through AT1 receptors on arterioles

• Increasing presynaptic release of NE from sympathetic nerves

• Blunting baroreflex restraint

• Activating circumventricular organs, esp. SFO and AP to increase SNS activity and drinking and regulates vasopressin

Vasopressin(AntiDiuretic Hormone; ADH)

• Released into the circulation by neurons in the hypothalamus

• Circulating AVP elicits vasoconstriction via V1 receptors and induces antidiuresis via v2 receptors in the kidney

• Also alters baroreflex and tonic control of SNS activity by direct release from neurons and circulating AVP diffusing to neurons

CNS controls Norepinephrine (NE) & Epinephrine (Epi) release, but these

catecholamines have different actions

• Beta-adrenergic receptors have much higher affinity for Epi << NE, while alpha-AR have the opposite affinity.

• Beta-AR (vasodilatory) numerous on heart and arterioles in heart and skeletal muscle

• Alpha-AR much more prominent on peripheral arterioles and vasoconstrict.

• Stimulation of adrenal medulla increases heart and skeletal muscle related vasodilation and HR.

Unlike an injection of NE which raises BP and HR via alpha1-AR equally, epinephrine injections act primarily on beta-AR increasing HR/contractility and thereby increasing CO. BF is increased to the skeletal muscle heart and brain but decreased to the kidney and skin. TPR is reduced as reflected in decrease in diastolic pressure. Increase in CO reflected in increased systolic arterial pressure.

VII. Autonomic Nervous System

Integrated Neurendocrine regulation of the CV system

Brain areas involved in neuroendocrine and autonomic regulation

Rostral Ventral Lateral Medulla (RVLM)

• RVLM generates sympathetic tone.

• Appears that the RVLM vasomotor neurons are final integrators of a large amount of information relative to CV control.

Sensory regulation of RVLM via nucleus of the solitary tract (NTS)

• Both high and low pressure baroreceptor feedback to the brain synapses in the NTS

• Gustatory and other inputs also reach NTS in discrete regions

• The NTS has widespread projections to forebrain and medulla

APAPNTSNTS

Brainstem BP Brainstem BP control control pathwaypathway

ANGIOTENSIN

Higher control

I. Hypothalamus (Head autonomic ganglion)

Fig. 1.3

Optic chiasm

Hypothalamus

Hypothalamus as Homeostatic Regulator

Parent, 17.1

A. Vegetative function of hypothalamus;regulation of eating, drinking and digestion

Parent, Fig. 17.1

Areas that receive information about warmthPreoptic areaAnterior hypothalamic area

Parent, 17.1

Sympathoinhibitory nuclei

• Warm receptors– Activation leads to inhibition of SNS

• Sweating• Vasodilaiton• Pyrogens bind here and allow fever to continue

by changing setpoint• Renal excretion

• Drinking regulation (defending against dehydration and overheating)

Circadian rhythm

• Suprachiasmatic nucleus– Sets rhythm of AP/HR– Daily blood pressure rhythm can be over

30 mmHg and reduction in nighttime dip is sign if potential organ damage

– Normal rhythm is slightly over 24 hours, but this is entrained by light to the eye

– Interesting regulation via sympathetic innervation of pineal gland, thereby releasing melatonin

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Circadian rhythm

Circadian output of SCN via sympathetic nervous system

Regulates melatonin release from the pineal

Which modulates sleep and sex

B. Activating nuclei to respond to cold or stressShut down eating/peristalsisShiverRenal inhibitionVasoconstrict non-required vascular beds

Increase blood flow to skeletal muscle

Parent, 17.1

Sympathoexcitatory nucleiPHA

• Direct projection to the spinal cord

• May provide direct hypothalamic modulation of CV system

• Cold sensors (defense of body heat)– Vasodilation– Shivering

Sympathoexcitatory nucleiVMH

• Important in the defense/escape reaction and also in eating and sexual activity

Sympathoexcitatory nucleiLHA

• Homeostatic regulator– Leptin, glucose and insulin receptors

Monitoring inner world Circumventricular organs

• Organum vasculosum of the lamina terminalis (OVLT)– sodium and osmotic sensitivity

• Subfornical organ (SFO)– Angiotensin II

• Area postrema (AP) – Toxin monitoring

D. Endocrine control

Parent, Fig. 17.20

Circulating Neuroendocrine Elements

Parent, 17.1

Paraventricular (PVN) and supraoptic nucleus

Fig. 11.16

Vasopressin Oxytocin

Hormone regulators

Circulating hormones

E. Anterior lobe controled by arcuate nuclei, e.g., sexual function, etc.

Parent, 17.20, 17.1

Interactions of neuropeptides and other transmitters in autonomic control

Natriuretic peptide family

• ANP causes inhibition of NE release in CNS and PNS (i.e. it acts opposite of AII).

• In PNS cause reduction in AP and increased diuresis/natriuresis

• In hypothalamus it causes the opposite effects.

• Regional distribution of ANP and receptors underlie this effect. ANP inhibition of NE throughout the hypothalamus causes differential effects.

Sex steroids and Vasopressin/Oxytocin

• SON/PVN

• Increases dendritic activation (electrical and chemical) by juxtaposing the dendrites.

• Regulation of fluid volume, memory, sex, etc.

Beer Stories

• Drink beer; lots of beer fast

• About 30 minutes later need to urinate badly

• Why??

• What happens if you keep drinking?

Beer Potomania

• Potomania: An intense and persistent desire to drink alcohol to excess.

• Dilutional hyponatraemia

• Pass out/death

Why?

• Decrease ADH (vasopressin) as much as possible in first hour

• Continue ingestion of fluid low in solutes and lack of protein intake

• Decrease in plasma Na and osmolality

• Kidneys can only excrete limited load

Young individual can excrete up to 25 L/day about 1.2 L/hour, but when intake is increased above that level dilution will occur first in vascular space and then in

extracellular and intracellular space.

Result:

• intracellular dilution and dysfunction of neurons and muscle.

VIII. Enteric Nervous System

Approximately 108 neurons = all spinal cord neurons

Regulate peristalsis in gut

While parasympathetic input accelerates parastalsis, sympathetic input inhibits it

The system is truly peripheral with only CNS regulation of speed

Summary Points• The hypothalamus regulates the autonomic

nervous system and neuroendocrine system• The anterior parts of the hypothalamus increase

parasypathetic responses while the posterior areas tend to activate sympathetic responses.

• The paraventricular nucleus directly releases neurohormones into the blood

• Other hypothalamic sites release hormone releasing/inhibiting substances that circulate to the anterior lobe of the pituitary and other sites to release/inhibit the active circulating hormone.

• Autonomic control is regulated by the joint actions of the nervous system and circulating hormones