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Cardiovascular Pharmacology 1 Review

PMCOL 343: Cardiovascular Pharmacology 1 (2025)

Introduction

  • Instructor: Ramana Vaka, PhD

  • Position: Assistant Lecturer, Department of Pharmacology

  • Contact: vaka@ualberta.ca

  • Drug Effects on Contraction and Excitation in Skeletal, Cardiac, and Smooth Muscle.

  • Copyright Notice: Images reproduced under ss 29-29.4 of the Copyright Act. Slides are available for personal use only; further distribution may infringe copyright.

Learning Objectives

  1. Understanding the key role of calcium in the regulation of tissue excitability and contractility.

  2. Grasping the contractile mechanisms of skeletal, cardiac, and smooth muscle.

  3. Comprehending drug effects and their pharmacological relevance.

Muscles Overview

  • Smooth Muscle

  • Cardiac Muscle

  • Skeletal Muscle

  • Reference Credit: Creative Commons, http://www.scientificanimations.com/wiki-images/, CC BY-SA 4.0

Regulation of Cytoplasmic Ca²⁺ Levels

  • Importance of Ca²⁺

    • Ca²⁺ is essential for contraction, excitation, and secretion.

    • [Ca²⁺]i (intracellular calcium concentration) is meticulously regulated.

    • Typical free [Ca²⁺]i is approximately 10^{-7} ext{ M} (100 nM).

    • Extracellular [Ca²⁺] concentration, [Ca²⁺]o, is approximately 2.5 imes 10^{-3} ext{ M} (1:25,000 gradient across the plasma membrane).

    • High intracellular Ca²⁺ concentrations can be cytotoxic.

    • Ca²⁺ is stored in intracellular organelles, notably the endoplasmic/sarcoplasmic reticulum and mitochondria.

Control of Cytoplasmic Ca²⁺ Levels

  • Mechanisms Control Ca²⁺ Levels:
    a) Calcium Entry Mechanisms
    b) Calcium Extrusion Mechanisms
    c) Calcium Exchange between Endoplasmic Reticulum (ER)/Sarcoplasmic Reticulum (SR) and Cytosol.

a) Calcium Entry Mechanisms

  • Store Operated Calcium Channels:

    • These channels open in response to the depletion of Ca²⁺ in the ER.

  • Various Agonists and GPCRs:

    • Ligand-gated calcium channels (LGC) activated by neurotransmitters or other agonists permit Ca²⁺ influx.

  • Voltage-Gated Calcium Channels (VGCC):

    • Types include L-type, N-type, P/Q-type, R-type, and T-type.

    • L-type VGCC: present in skeletal, cardiac, and smooth muscle.

    • N-type and P/Q-type: located in neuronal CNS/PNS facilitating neurotransmitter release (presynaptic).

    • T-type VGCC: found in rapidly firing cells such as the SA node in the heart and thalamic neurons, linked to arrhythmias and epilepsy.

b) Calcium Extrusion Mechanisms

  • Plasma Membrane Calcium ATPase (PMCA):

    • An active transport mechanism extruding Ca²⁺ out of the cell.

  • Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA):

    • Moves Ca²⁺ into the SR.

  • Na⁺-Ca²⁺ Exchanger (NCX):

    • Typically operates to extrude Ca²⁺ but can reverse to allow Ca²⁺ entry.

    • Exchanges 3Na⁺ for 1Ca²⁺, causing depolarization due to net inward movement of positive charge (action potential in heart regions).

c) Calcium Exchange Between ER and Cytosol

  • Inositol Tris-Phosphate Receptor (IP3R):

    • Ligand-gated ion channel in the SR/ER activated by IP3.

  • Ryanodine Receptor (RyR):

    • Responds to Ca²⁺, involved in Ca²⁺-induced Ca²⁺ release (CICR).

    • Ryanodine affects RyR by opening at nanomolar levels and closing at millimolar levels.

Molecular Targets for the Action of Ca²⁺

  • Enzymes, kinases, and phosphatases.

  • Ca²⁺-sensitive ion channels (e.g., K⁺ channels).

  • Transcription factors.

  • Proteins necessary for neurotransmitter release (synaptic vesicle proteins).

  • Contractile proteins, with calmodulin often serving as an intermediate binding to Ca²⁺.

The Resting Cell

  • Ion Concentrations:

    • High Na⁺ outside (~150 mM) versus low Na⁺ inside (~10 mM).

    • Low K⁺ outside (~5 mM) versus high K⁺ inside (~140 mM).

    • Very low Ca²⁺ inside (100 nM) contrasting with higher extracellular Ca²⁺ (2.5 mM).

  • Distribution of Cl⁻ varies by cell type.

  • Potassium channel activity determining resting potential, around -50 mV to -80 mV.

Drug Effects on Muscle Contraction

  • A classical pharmacological methodology is applied to study contractions within vascular, intestinal, uterine, and other smooth muscle contexts.

  • Muscle is incubated in an organ bath, with contractions monitored via a transducer.

1. Skeletal Muscle Contraction

  • Binding Pathway:

    • Acetylcholine (ACh) binds to nicotinic ACh receptors (nAChR) ⇒ depolarization ⇒ threshold reached ⇒ opens voltage-sensitive Na⁺ channels ⇒ action potential activation ⇒ DHP receptor at L-type Ca²⁺ channel opens RyR ⇒ Ca²⁺ release from SR ⇒ Ca²⁺ binds to Troponin, facilitating actin-myosin binding, initiating contraction.

  • Each fiber has a distinct neuromuscular junction (NMJ) - no gap junctions, unlike cardiac and smooth muscle. No extracellular Ca²⁺ is necessary.

Drug Examples in Skeletal Muscle Contraction

  • Caffeine:

    • A methylxanthine that sensitizes RyR leading to Ca²⁺ release from ER/SR at physiological Ca²⁺ concentrations.

  • Dantrolene:

    • Similar action to ryanodine, blocks RyR; used to treat malignant hyperthermia from RyR genetic abnormalities.

2. Cardiac Muscle Contraction

  • Similar Pathway as Skeletal Muscle:

    • Sequence follows: depolarization ⇒ threshold reached ⇒ opens voltage-sensitive Na⁺ channels ⇒ activates L-type Ca²⁺ channels (T-tubule) ⇒ Ca²⁺ induces RyR activation ⇒ SR Ca²⁺ release (CICR) ⇒ Ca²⁺ binds to Troponin, allowing contraction.

  • Key differences include absolute dependence on L-type Ca²⁺ channels and requirement for extracellular Ca²⁺.

  • Drug Examples:

    • Digoxin: for heart failure with reduced ejection fraction (HFrEF) and arrhythmias.

    • Diltiazem & Verapamil: for angina and arrhythmias.

    • Gap Junctions: Present in cardiac muscle.

3. Smooth Muscle Contraction

  • Process:

    • Similar activation as in skeletal muscle; however, instead of Troponin, uses myosin light chain kinase (MLCK).

  • Drug Examples:

    • Nifedipine (DHP):

    • Diltiazem (non-DHP): for hypertension.

    • Albuterol & Salmeterol: utilized in asthma management.

    • Prazosin & Terazosin: for hypertension or benign prostatic hyperplasia (BPH).

  • Gap Junctions: Present in single-unit smooth muscle.

Conclusion/Review

  • Students should now:
    1) Recognize the crucial role of calcium in regulating tissue excitability and contractility.
    2) Comprehend how excitable cells regulate intracellular calcium levels.
    3) Understand the contractile mechanisms of skeletal, cardiac, and smooth muscle and their pharmacological interactions.

  • Reference: Rang and Dale, Chapter 4.