Regulation II

Humoral Regulation of MAP

• Intermediate regulation of cardiovascular functions involves humoral factors.
• This regulation adapts over minutes to tens of minutes.
• Key substances involved:
• Circulating catecholamines
• Renin-angiotensin-aldosterone system
• Antidiuretic hormone
• Atrial natriuretic peptide (ANP)

Effects and Receptors

• Circulating catecholamines cause:
• Vasoconstriction via α1-G protein, increasing PLC, IP3, Ca2+ release from SR, and intracellular Ca2+ concentration.
• Vasodilation via β2-G protein, increasing AC, cAMP, stimulating the SR Ca2+ pump, and decreasing intracellular Ca2+ concentration.
• Renin-angiotensin-aldosterone system leads to:
• Vasoconstriction through AT1-G protein, increasing PLC, IP3, Ca2+ release from SR, and intracellular Ca2+ concentration.
• Increased Na+ reabsorption in the distal nephron via aldosterone.
• Antidiuretic hormone results in:
• Vasoconstriction via V1-G protein, increasing PLC, IP3, Ca2+ release from SR, and intracellular Ca2+ concentration.
• Increased water reabsorption in the distal nephron via V2-G protein, increasing AC, cAMP, and aquaporine channel incorporation into membranes.
• Atrial natriuretic peptide (ANP) causes:
• Vasodilation through catalytic receptor GC-A, guanylate cyclase, and increased cGMP.
• Decreased Na+ resorption in the distal nephron (GC-A).

Circulating Catecholamines Details

• Adrenaline (epinephrine; from adrenal medulla):
• Increases heart rate.
• Decreases total peripheral resistance (β1, β2).
• Noradrenaline (norepinephrine; from sympathetic postganglionic neurons):
• Increases total peripheral resistance (α1).
• Increases MAP.
• Decreases heart rate due to baroreflex.
• α1 receptor affinity: Noradrenaline > Adrenaline
• β2 receptor affinity: Adrenaline >> Noradrenaline

NORADRENALINE and ADRENALINE Effects

• Noradrenaline:
• Causes overall vasoconstriction (α1).
• Leads to a transient increase in cardiac output (β1).
• Increases MAP.
• Activates the baroreceptor reflex, resulting in bradycardia.
• Adrenaline:
• Causes vasoconstriction (α1) in splanchnic region, skin, and kidneys.
• Causes vasodilation (β2) in skeletal muscles.
• Increases cardiac output (β1).
• Results in systolic pressure increase.
• Diastolic pressure may decrease or not change.

Catecholamines Release

• Catecholamines are released due to stress (e.g., hypoglycemia, pain, emotions, muscle activity).
• This triggers general activation of the SNS via the CNS.
• Activation of sympathetic fibers leads to vasoconstriction and heart stimulation.
• The adrenal medulla releases adrenaline which leads to:
• Alertness.
• Hyperglycemic effect.
• Increased metabolic rate.
• Cardiovascular effects.

Renin-Angiotensin-Aldosterone System

• The juxtaglomerular apparatus consists of:
• Tubular epithelial cells (macula densa) sensitive to Cl- concentration.
• Granular juxtaglomerular cells secrete renin when BP in the afferent arteriole decreases, NaCl flow to the macula densa decreases, or renal SNS is stimulated.
• Extraglomerular mesangial cells transmit signals from the macula densa to the afferent arteriole.
• Decreased MAP, decreased NaCl in the tubular fluid, and increased SNS activity lead to Renin release.
• Renin converts angiotensinogen (plasma) into angiotensin I (10 AA).
• Angiotensin-converting enzyme (ACE; in pulmonary endothelial cells) converts angiotensin I into angiotensin II (8 AA).
• Angiotensin II causes:
• Vasoconstriction via AT1 receptors.
• Increased renal Na+ (and water) resorption.
• Aldosterone (from the adrenal cortex) increases due to Angiotensin II.

Antidiuretic Hormone (ADH) / Vasopressin

• Produced in the hypothalamus (ncl. supraopticus) and secreted by the posterior pituitary.
• Secretion is in response to:
• Increased osmolality of ECF.
• Decreased ECF volume.
• Decreased blood pressure.
• Pain, nausea, emotions, nicotine, morphine, ANG II, decreased alcohol.
• Results in decreased water excretion by kidneys (antidiuresis).
• Higher ADH concentrations cause vasoconstriction.
• Decreased MAP stimulates the hypothalamus to increase ADH secretion.
• Increased ADH secretion leads to:
• Vasoconstrictor area stimulation.
• Direct vasoconstriction via V1 receptors.
• Increased ECF volume.
• Increased venous return.
• Increased CO.

ADH - Antidiuretic Effect

• Stimulates water reabsorption in the distal nephron.
• V2 receptors increase cAMP in tubular cells, causing protein water channels to connect with the luminal membrane.
• Increases the number of water channels and the permeability of the luminal membrane for water.

Atrial Natriuretic Peptide (ANP)

• ANP (1984) is a 28 AA peptide released from atrial cardiomyocytes due to distension.
• Causes vasodilation and natriuresis, leading to a decrease in MAP.
• Actions include:
• Increased sodium excretion in kidneys.
• Direct vasodilatory effect by inhibiting RAAS.
• Receptor GC-A directly catalyzes conversion of GTP to cGMP.

ANP Effects on ECF Volume

• Dilates afferent arteriole and constricts efferent arteriole to increase glomerular filtration and sodium tubular load (increased sodium excretion).
• Decreases sodium reabsorption in the distal nephron.
• Inhibits renin secretion.
• Decreases aldosterone secretion.