- determined by several processes that lead to the movement of actin and myosin filaments in the cardiac sarcomere.

contraction results from interaction of calcium with actin - troponin-tropomyosin system.

- calcium released from SR 

1.  sensitivity of contractile proteins to calcium.

2.  amount of calcium released from SR.

3.  amount of trigger calcium.  e.g. availability of membrane calcium channels (primarily the L type) and duration of opening.

4.  sympathomimetics - lead to increased calciuminflux.

5.  activity of na/cal. exchanger:  

1.  removal of soidum and water (diuresis)

2.  decrease of afterload and wter and salt (ACEI).

3.  decrease excessive sympathetic stimuli (beta blockers)

4.  decrease of preload and afterload (vasodilation).

5.  augmenting of cardiac contractility (positive inotropes and digitalis).

other:  angiogentsin antagonists and aldosterone antagonists.

4 major mechanisms:

1.  tachycardia.

2.  increased PVR

3.  retention of sodium and water leading to increased blood volume -> oedema and pulmonary congestion -> increased end diastolic length.

4.  cardiomegaly

- there is an initial increase of CO but in the long term - increased load leads to further decline.  Myocytes undergo apoptosis -> fibrous connective tissue.

donnan gibbs showed that the presence of a nondiffusible ion, the diffusible ions ditribute themselves to that at equilibrium their concentration ratios are equal.

3 effects in the body:  1) because of charged proteins in cells there are more osmotically active particles in cells than in ISF, and because animals have flexible walls, osmosis would make them swell and eventually rupture if it were not for Na/K+ ATPase pumping ions back out.

2) because at equilibrium the distribution of permeant ions across the membrane is asymmetric, an electrical difference exists across the membrane.

3) because there are more proteins in plasma than in ISF, there is a donnan effect on ion movement across the capillary wall.

osmosis - the diffusion of solvent molecules into a region which there is a higher concentration of solute to which the membrane is impermeable.

This can be prevented by applying pressure to the more concentrated solution.  The pressure necessary to prevent solvent migration is the osmotic pressure of the solution.  

process by which a gas or subsantance in a solution expands, because of the motion of its particles, to fill all available volume.  

there is a net flux of solute particules from areas of high concentration to areas of low concentration.  The magnitude of the diffusing tendency from one region to another is directly proportionate to the cross sectional area across which diffusion is taking place and the concentration gradient (ficks law)

in order for a potential difference to be present across a membrane lipid bilayer, two conditions must be met.

1.  an unequal distribuation of ions of one or more species across the membrane.

2.  the membrane must be permeable to one or more of these ion species.

the resting membrane potential represents an equibilibrium situation at which the driving force for the membrane-permeant ions down their concentration gradients across the membrane is equal and opposite to the driving force for these ions down their electrical gradient.

oxidation is the combination of a substance with oxygen or loss of hydrogen or loss of electrons.

cofactors (simple ions) or coenzymes (organic, nonprotein substances) are substances that usually act as carriers for products of the reaction.

reduction - opposite.

protein synthesis translation - it the conversion of information encoded in mRNA to a protein. (in ribosomes)

after polypeptide chain is formed it "folds" into its biological form and can be further modified by to the final protein by hydroxylation, carboxylation, glycosylation or phosphorylation.

- made up of individual fibres.

- most begin and end in tendons, with the fibres arranged in parallel.

each muscle fibre in a single cell that is multinucleated, long, cylindrical, surrounded by cell membrane (sarcolemma).

- no syncytial bridges between the cells.

muscle fibres made up of myofibirils which are divisible into individual filaments.

- filaments are made up of contractile proteins.

conjugation of proteins to ubiquitin marks proteins for degradation (ubiquitination). 

degraded via proteasomes and lysosomes.

CAMs - fasten cells to their neighbours, transmit signals into and out of the cell.

4 broad families:  1.  integrins, heterodimers that bind to various receptors

2. adhesion molecules of the IgG superfamily of immunoglobulins

3.  Cadherins, calcium dependent molecules that mediate cell-cell adhesions by homophilic reactions and

4.  selectins which have lectin-like domains that bind carbodhydrates.

dcell mediated immunity initiated by specifically sensitised T-lymphocytes, includes:

- delayed type hypersensitivity.

- T cell mediated cytotoxicity.

delayed hypersensitivity:  principal manner of response to TB, fungi and protozoa and parasites; also contact skin sensitivity and allograft rejection.

- largely mediated by CD4+ -> secrete cytokines -> recruitment and activation of monocytes and macrophages.

- T cell mediated cytotoxicity:

- generation of CD8+ (cytotoxic T cells) in response to viral infections and tumour cells.

- damage is from apoptosis mediated by perforin granzyme and fas-FasL pathways.

localised tissue vasculitis and necrosis:

- formation or deposition of immune complexes is extremely localised (eg: s/c injection site).

- relevant antigen id planted only within particular tissue (e.g. glomerulus) -> in situ immune complex formation.

type III - immune complex mediated hypersensitivy mediated by antigen-antibody complexes forming in the circulation or at the site of the antigen.

pathogenesis:

- pathogen is either endogenous or exogenous.

immune complex mediated disease can either be systemic or localised.

- systemic:  circulating immune complexes that are systemically deposited.

acute serum sickness it eh prototype disease -> complexes in circulation as well as deposits in capillary walls -> vasculitis.

IC deposition enhanced by increased vascular permeability caused from inflammation cell activation by IC binding to Fc or C3b receptors.

deposition of IC -> activates complement cascade -> tissue damage.

clinical examples:  SLE, acute GN, serum sickness.

- mediated by antibodies directed towards intrinsic and extrinsic antigens present on the cell surface or extracellular matrix.

- damage occurs secondary to 3 major pathways:

1.  opsonisation and complement and Fc receptor mediated phagocytosis:

cells lysed directly via the C5-C9 complement MAC; or 

opsonised as a result from fixation of Ab or C3b fragments.

antibody dependent cell mediated cytotoxicity (ADCC):  bound IgG or IgE on cells -> phagocytosis by non specific cells with Fc receptors (e.g. NKC).

2.  complement and Fc receptor - mediated inflammation:

- deposition of autoantibodies in extracellular matrix: 

- complement activation.

- recruitment and activation of non specific inflammatory cells (neutrophils and macrophages) cause release of injurious proteases and reactive oxygen species -> tissue damage.

3)  antibody mediated cellular dysfunction.

- no tissue damage per se.

antibodies can either block or stimulate normal cellular or hormonal function.

primary:  biogenic amines - most important is histamine.  Causes intense smooth muscle contraction, increased vascular permeability and increased secretion by nasal, bronchial and gastric glands.

enzymes - contained in granule matrix and include neutral proteases and acid hydrolases.

proteoglycans - include heparin.

secondary mediators:  2 classes of compounds.

1)  lipid mediators - generated by sequential reactions in the mast cell membranes that lead to activation of phospholipase A2 (membrane phospholipids to arachidonic acid).  

leukotrienes, prostaglandin D2, platelet activating 

2) cytokines.

MOA:  presentation of antigen to naive CD4+ helper cells by dendritic cells -> T cells differentiate into Th2 cells -> produce cytokines upon subsequent encounter with the antigen.

1L-4 - turning on the IgE producing B cells.

IL-5 - activates eosinophils.

IL 13 - promotes IgE production and acts on epithelial cells to stimulate mucus secretion.

Mast cells and basophils bind IgE antibodies upon subsequent exposure:  mast cell degranulation and de novo synthesis and release of secondary mediators.

role of susceptibility genes:  

-mutations and polymorphisms in the Fas, AIRE, CTLA -4 and Foxp3 genes.  Although most autoimmune disorders have complex, multigenic patterns of susceptibility and are not attributable to single gene mutations.

Role of infections:  infections may upregulate the co-stimulatory molecules which may help bypass the peripheral tolerance.  Also molecular mimicry.

epitope spreading.

fundamental defect in SLE is a failure of the mechanisms that maintain self tolerance.

antibodies against an array of nuclear and cytoplasmic compenents of the cell and another grouop of antibodies against cell-surface antigens of blood cells.

ANAs are directed against nuclear antigens and can be grouped into four categories:  1)  antibodies to DNA 2) antibodies to histones, 3) antibodies to non histone proteins bound to RNA and 4) antibodies to nucleolar antigens.

- acute or insidious in onset.

- chronic, remitting and relapsing disease.

- causes injury to skin, kidneys, joint and serosal membranes.

high prevalence (up to 1/2500).

- female: male = 9:1.

- anti-DNA and anti-smith Ab are diagnostic.

- lupus anticoagulant -> procoagulant in vivo.

genetics:  - 20% concordance with identical twins.  MHC and non-MHC genes identified.

environmental factors:  - exacerbated by some drugs (procainamide, hydralazine);

- UV light

- female sex hormones.

Immunological factors:  both immune complex deposition (typeIII) as well as a component of antibody dependent damage to RBCs.

What is the sequence of events of an AP?

- Beginning of depolarization of the membrane

After an initial 15mV of depolarization rate becomes more rapid at the firing

point Overshoot of the spike to about 35mV above isopotential line (zero)

Rapid reversal and fall below isopotential line during repolarization

At about 70% repolarization, slowing of rate (after-depolarization)

Slight dipping of the tracing below previous resting level (after-

hyperpolarization).

- the period during the rising and much of the falling where the neuron is refractory to stimulation.

- absolute refractory period:  the period from the firing level until repolarization is about 1/3rd complete.

- relative refractory:  from absolute refractory period to the start of after polarisation.

- Tyrosine is transported in and converted to dopa by tyrosine hydroxylase (rate limiting step) in presence of tetrahydrobiopterin

Dopa converted to dopamine by dopa decarboxylase

Dopamine enters granulated vesicles and converted to NA by dopamine beta

hydroxylase

NA inhibits tyrosine hydroxylase in a negative feedback fashion

- sliding of thin filaments over thick.

- sliding during contraction occurs when myosin heads bind firmly at the junction of the head and the neck --> detach = power stroke.

- power stroke depend on the simltaneous hydrolysis of ATP.

- this cycle repeatedly (5sec) --> gross muscle contration

- each power stroke shortens sarcomere about 10mm.

- contractile mechanism has no refractory period, therefore:

- repeated stimulation before relaxation has occurred = summation of contractions.

- fast repeated stimulation causes a fused continuous tetanic contraction.

- can be complete or incomplete.

- chemical synapse - a synaptic cleft separates the terminal of the presynaptic cell from the post synaptic cell.  An impulse from the presynaptic axon causes secretion of a chemical that diffuses across the synaptic cleft and binds to receptors on the surface of the post synaptic cell.

electrical synapses - the membranes of the presynaptic and post synaptic neurons come close together and gap junctions form between the cells.  These become low resistance bridges through which ions can pass with relative ease.

a few are conjoint synapses.

temporal summation - occurs if repeated afferent stimuli cause new EPSPs before previous EPSPs have decayed.

spatial summation - when activity is present in more than one synaptic knob summates with activity in another to approach the firing level.

- binds to post synaptic receptors.

- binds to presynaptic receptors.

- reuptake into presynaptic neurons.

-catabolism by monoamine, oxidase and COMT.

- no acetylecholine uptake.

- catabolsim by acetylcholinesterase.

- reuptake of choline.

-catabolism of pseudocholinesterase.