4 NO, ET and AII

Objectives and Aims

• Understanding of:

  • Nitric Oxide (NO)

  • Angiotensin receptor system

  • Endothelin receptor system

Lecture Outline

1. Nitric Oxide (NO)

2. Angiotensin (AT) receptor system

3. Endothelin (ET) receptor system

Control of Vascular Smooth Muscle Tone

• Vascular smooth muscle tone controlled by mediators:

  • ↑ or ↓ tone by substances secreted from:

    • Sympathetic nerves (e.g., noradrenaline)

    • Vascular endothelium (e.g., nitric oxide, prostanoids, endothelin)

    • Circulating hormones (e.g., adrenaline, Angiotensin II)

Nitric Oxide (NO)

• Considered the "Molecule of the Year" in 1992.

• Acts as a biological messenger in mammals affecting:

  • Neuroscience

  • Physiology

  • Immunology

Discovery of NO

• Loss of relaxing response in rabbit aorta preparations indicates the role of NO.

• Nobel Prize in Physiology 1998 awarded for discoveries concerning NO as a signaling molecule.

Synthesis of NO

• Synthesized from l-arginine by nitric oxide synthase (NOS).

• Three isoforms of NOS:

  • Neuronal (nNOS)

  • Endothelial (eNOS)

  • Inducible (iNOS)

Effects of Nitric Oxide

• Involved in relaxation of smooth muscle by activating cyclic GMP pathway.

• Changes in intracellular calcium levels lead to relaxation.

Therapeutic Approaches

• NO administered as a gas for:

  • Dilating blood vessels in ventilated alveoli

  • Treating pulmonary hypertension

• NO donors like Glyceryl Trinitrate and Isosorbide Mononitrate are powerful vasodilators used for angina.

Renin-Angiotensin System

• Regulates:

  • Arterial blood pressure

  • Renal function

• Plays a critical role in conditions like hypertension and heart failure.

Pathway Overview

• Circulating angiotensinogen cleaved by renin to produce angiotensin I.

• Angiotensin I converted to active angiotensin II by ACE.

• Angiotensin II binds to AT1 and AT2 receptors affecting vascular tone and blood pressure.

Receptor Effects

• AT1 Receptors:

  • Found in multiple tissues (vascular smooth muscle, liver, heart).

• AT2 Receptors:

  • Fetal tissue abundance, counter-regulates AT1 activities.

Therapeutic Targets

• Angiotensin converting enzyme inhibitors (ACEIs) and AT1 receptor blockers as treatment for hypertension and heart failure.

Endothelin (ET)

• Identified in 1988 as a potent vasoconstrictor.

• Ends with three isoforms: ET-1, ET-2, ET-3, mediated by ETA and ETB receptors.

Receptor Functions

• ETA is primarily for vasoconstriction.

• ETB receptors release NO and PGI2, facilitating smooth muscle relaxation.

Pharmacological Management of Pulmonary Arterial Hypertension

• Bosentan improves exercise endurance and survival in pulmonary arterial hypertension patients by blocking ET receptors.