TIME CONSTRAINED ESSAY Flashcards
Paragraph 1
Sympathetic nervous system plays a huge role cardiac physiology during fight or flight response.
Causes an increase in heart rate, contractility and atrioventricular function.
Vital for maintaining peripheral resistance and cardiac output to meet changes to metabolic demand.
Paragraph 2
Heart failure - unable to provide body with required amount of oxygen due to insufficient cardiac output.
Disease that has progressive reduction in cardiac performance
Systolic failure: reduced ejection fraction and reduced contractility
Diastolic failure: stroke volume significantly reduced because of ventricular chamber stiffening and loss of relaxation
Sympotoms are shortness of breath, fatigue, oedema and crackles being heard
paragraph 3
Excitation coupling process by which action potential in cardiomyocytes leads to contraction.
Process is augmented by SNS acting at beta adrenergic receptors in cardiac cells.
Beta-adrenoceptors in the hearts which are GPCR which increase cAMP and PKA which phosphorylates L-type calcium channels allowing the entry of more trigger calcium. Has many functions in the heart:
1. Enhanced release of calcium from SR increasing contractility
2. Ions linked to pacemaker channels open in SAN - increased heart rate
3. Enhanced release of calcium from ryanodine receptors allowing more binding to troponin C - increasing contractility
4. Phosphorylates MLCK contributing to enhancements in contractility
paragraph 4
Function of beta-adrenoceptors is to increase heart rate and contractility. Increase in relaxation rate and conduction velocity. Four subtypes.
Heart contains predominantly beta-1 and 2 subtypes.
bet-1 in heart predominates in function as there are more receptors.
Paragraph 5
Receptor gets desensitised by uncoupling receptor from G Protein
Phosphorylated by PKA or GRK.
Negative feedback mechanism - prevents over stimulation
PKA induced phosphorylation causes Gs to be converted to Gi for beta-1
Alters receptors role
Extended stimulation causes downregulation and reduction in receptor number
This decrease b-adrenergic signalling worsening heart failure
paragraph 6
Hypertrophy occurs due to the binding of Angiotensin II to the receptors - in particular AT1 which initiates a signalling cascade involving DAG and PKC. This causes inhanced protein synthesis and cell growth or hypertrophy. Ventricular remodelling takes place which is where the shape of the heart changes.
Process aims to improve ventricular functionality but overtime reduces cardiac efficiency.
The SNS is activated to preserve cardiac output and systemic bp.
Hypertrophy is linked with reduced contratility and contributes to hf.
paragraph 7
Constant stimulation of catecholamine causes further negative feedback of GPCR activity.
G Protein binds to B-ARK which phosphorylates the b-adrenoceptor.
Allows b-arrestin to bind to occupied receptor and uncouples it.
Receptor is transported to endosome where it gets degraded and this lowers the number of receptors,
paragraph 8
A decrease in number of receptors makes cardiomyocytes less sensitive to neurotransmitters and neurohormones.
Stimulation of b-adrenoceptors causes apoptosis of cardiomyocytes.
Fas receptor and TNF-1 are expressed in cardiomyocytes which initiate a signalling cascade.
Activation of Gq protein, for example by ang II, activates mitochondrial death pathway leading to apoptosis.
MAP Kinases may also activate mitochondrial death pathway directly
paragraph 9
b-4 is considered a low affinity state of b-1 which requires pharmacological and genetic characterisation.
B-3 adrenoceptors are less expressed in the heart.
They regulate metabolism, vasodilation, relaxation and cardiac contractility.
It is a GPCR which may couple with Gs increasing cAMP and PKA or may couple with Gi which prevents overactivation of beta-1 and beta-2.
It also increases the levels of endothelial NO which mediates many biological effects.
B-3 are more resistant to desensitisation
Conclusion
Heart consists of b-adrenoceptorw
Expression of b-1 altered
Unable to perform its functionmleading to hypertrophy as well as reduced contractility, reduced cardiac output and in general reduced performance. This is one of the main contributing factors of heart failure
