PHCL 554 Cardiovascular Pharmacology Douglas Larson, Ph.D

Course Format Mondays – basic concepts Wednesdays – applied concepts Fridays – problem based learning Exams – 50% multiple choice and 50% essay Final – NIH grant take-home grant

Cardiovascular Physiology Introduction: The Heart Anatomy Cardiac output Effectors of cardiac output

Cardiovascular Physiology No understanding of the circulatory reactions of the body is possible unless we start first with the fundamental properties of the heart muscle itself, and then find out how these are modified, protected, and controlled under the influence of the mechanisms - nervous, chemical, and mechanical - which under normal conditions play on the heart and blood vessels. E.H. Starling, 1920

Cardiovascular Physiology The heart pumps blood through two vascular systems - the low pressure pulmonary circulation in which gas exchange occurs, and then the systemic circulation, which delivers blood to individual organs, matching supply to metabolic demand. Blood pressure and flow is largely controlled by the autonomic nervous system.

Cardiovascular Physiology The heart comprises four chambers, and is divided into a right and left side, each with an atrium and a ventricle. The chambers are separated by four valves.

Cardiovascular Physiology What is the physiologic function of the atria? What is the physiologic function of the valves?

Cardiovascular Physiology Answers What is the physiologic function of the atria? Continuous inflow What is the physiologic function of the valves? Provides direction to blood flow

Coronary Arteries

Myocardium transverse section

Intercalated Disks (ID)

Functionally the ID acts as a communication site and a point of adherence between two myocytes. The ID is a site of lowered electrical resistance. Gap junctions running between the two myocytes take care of the communication. The passage of ions through the gap junctions into the intercellular space keeps adjacent cells "informed" about what's happening.

Intercalated Disks The coordination of the heartbeat and the transmission of the contraction signal from one cell to the next is dependent on the integrity and proper functioning of the ID's gap junctions. Cell-to-cell adherence is maintained here (as at other sites) by numerous desmosomes. These are scattered along the length of the ID.

Gap Junction

Cardiac Myocyte

Two myocytes connected by ID

Myofibrils A band (anisotropic) myosin – actin filament overlap I band (Isotropic) contain only actin filaments H band (helle) only myosin M band are cross filaments that hold myosin Z line (Z disk) is junction of sarcomere

A M & H Z I

Cardiac Myocyte

Autonomic nerves and the heart

Autonomic nerves & heart Sympathetic – These nerves arise mainly from the stellate ganglion below the head of the first rib – Innervates both atria and ventricles and release norepinephrine – Change heart rate, systolic and diastolic function Parasympathetic – Cardiac branches of the vagus nerve – Innervate mainly atria and release ACH – Confined to changes in heart rate

Question Parasympathetic stimulation of the heart a. Increases heart rate b.Decreases heart rate c. Increases contractility d. Uses norepinephrine as a neurotransmitter

ELECTROPHYSIOLOGY OF THE HEART Myocardial contraction results from a change in voltage across the cell membrane (depolarisation), which leads to an action potential. Although contraction may happen spontaneously, it is normally in response to an electrical impulse. This impulse starts in the sinoatrial (SA) node, a collection of pacemaker cells located at the junction of the right atrium and superior vena cava.

ELECTROPHYSIOLOGY OF THE HEART These specialised cells depolarise spontaneously, and cause a wave of contraction to pass across the atria. Following atrial contraction, the impulse is delayed at the atrioventricular (AV) node, located in the septal wall of the right atrium. From here His-Purkinje fibres allow rapid conduction of the electrical impulse via right and left branches, causing almost simultaneous depolarisation of both ventricles.

ELECTROPHYSIOLOGY OF THE HEART

Action Potential

Question The ion responsible for the rapid depolarization of the cardiac myocyte is: a. Norepinephrine b. Ca ++ c. Na + d. K +

3Na + Calcium Cycling Proteins

Cardiac Cycle

Factors influencing cardiac performance Resting muscle fiber length (preload or end- diastolic pressure/volume) Starling's Law. Degree of after loading (pulmonary artery pressure, mean arterial pressure) Inotropic state (contractility): drugs and hormones can profoundly affect cardiac performance through this mechanism. Frequency of contraction (increased heart rate is a postive inotropic stimulus).

Starling’s Law Starling's law of the heart, which states that the energy of contraction of the muscle is related/proportional to the initial length of the muscle fiber.

Preload

Afterload

Definitions Inotropic = increased force and rate of contraction Lustitropic = increased rate of relaxation Chronotropic = increased heart rate

Questions?

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