Angiotensin II (Ang II) - Actions

1. Cardiovascular Actions (Blood Pressure)

• Direct vasoconstriction: Ang II binds AT1 receptors on vascular (especially arteriolar) smooth muscle, activating an IP3/Ca²+ second messenger system, causing potent vasoconstriction and increasing total peripheral resistance (TPR), raising blood pressure.
• Rapid onset: The pressor response to IV Ang II begins within 10-15 seconds and is sustained during long-term infusion.
• Baroreceptor resetting: Ang II acts on the brain to reset the baroreceptor reflex to a higher pressure set-point, reducing efferent vagal tone - so the pressor response is NOT accompanied by reflex bradycardia.
• Autonomic stimulation: Stimulates sympathetic ganglia, increases epinephrine/norepinephrine release from the adrenal medulla, and facilitates sympathetic transmission (increased NE release + reduced NE reuptake).
• Cardiac: Minor positive inotropic effect; physiologic significance is unclear. (Katzung's Basic and Clinical Pharmacology, 16th Edition)

2. Adrenal Cortex

• Stimulates aldosterone synthesis and release from the zona glomerulosa - the most important indirect mechanism for sodium and water retention.
• At higher concentrations, also stimulates glucocorticoid synthesis.
• Aldosterone acts on principal cells of the distal tubule and collecting duct to increase Na+ reabsorption - this process requires gene transcription/new protein synthesis, accounting for the slow (hours to days) response time of RAAS. (Costanzo Physiology, 7th Edition)

3. Renal Actions

• At low doses: Increases renal vascular resistance (RVR) and lowers renal blood flow (RBF) without affecting GFR - filtration fraction increases.
• At higher doses: Further increases RVR with reduction in both RBF and GFR; filtration fraction still elevated.
• Afferent and efferent arteriolar constriction: Ang II constricts both arterioles, but preferentially raises efferent arteriolar resistance - maintaining GFR despite reduced RBF.
• Proximal tubule Na+ reabsorption (direct effect): Stimulates the luminal Na+/H+ exchanger and basolateral Na+/HCO3- cotransporter and Na+-K+ ATPase at picomolar concentrations - enhances Na+ and HCO3- reabsorption independently of aldosterone. (At concentrations >10⁻⁹ M, these same transporters are inhibited - biphasic effect.)
• Distal tubule: Stimulates apical Na+/H+ exchange (early distal tubule) and amiloride-sensitive Na+ channels (late distal tubule).
• Acid-base regulation: In collecting duct, stimulates vacuolar H+-ATPase in intercalated A-cells via AT1R, promoting H+ secretion.
• Intraglomerular pressure: Raises intraglomerular capillary pressure (Pgc) and reduces the ultrafiltration coefficient (Kf). Chronic infusion can lead to glomerular capillary damage and proteinuria. (Brenner and Rector's The Kidney)

4. Brain Actions

• Thirst: Acts on the hypothalamus to stimulate thirst and increase water intake.
• ADH secretion: Stimulates antidiuretic hormone (ADH/vasopressin) release from the posterior pituitary, increasing water reabsorption in collecting ducts.
• Salt craving: Directly promotes salt appetite.
• Baroreceptor resetting (as noted above). (Costanzo Physiology, 7th Edition)

5. AT2 Receptor Actions (opposing AT1)

• Vasodilation (via increased NO synthesis and cGMP - bradykinin-dependent and independent mechanisms)
• Natriuresis (AT2R is abundant on proximal tubule epithelium)
• AT2 effects appear to be counter-regulatory against the pressor/volume-retaining actions of AT1 (Brenner and Rector's The Kidney)

Summary Table