Nitric Oxide Muscle and Nerve 2024 PDF

Nitric oxide signalling Stuart Cruickshank 5 December 1 2024  Nitric oxide is a free radical gas (NO). Formed in atmosphere during electrical storms. ALSO formed in an enzyme catalysed reaction between m...

Nitric oxide signalling Stuart Cruickshank 5 December 1 2024  Nitric oxide is a free radical gas (NO). Formed in atmosphere during electrical storms. ALSO formed in an enzyme catalysed reaction between molecular oxygen and L-arginine. NO is a key signalling molecule in cardiovascular and nervous systems. 5 December 2 2024  L-arginine is a protein amino acid. Present in the proteins of all life forms. Classified as a semi-essential or conditionally essential amino acid. Means: that under normal circumstances the body can synthesize sufficient L-arginine to meet physiological demands. Dietary sources include animal and plant proteins. 5 December 2 3 024  Biosynthesis of NO under control of NO synthase. 3 forms. 1) Inducible NOS (iNOS) (present in vascular smooth muscle, endothelial cells, neutrophils fibroblasts) 2) Two remaining forms: eNOS in the endothelium and nNOS present in neurons. eNOS also found in cardiac myocytes, platelets, osteoclasts. iNOS produces ~ 1000 X more NO than eNOS/nNOS. 5 December 2 4 024 Control of Vascular Tone by the Endothelium Blood flow Platelets ET cells EDR F’s EDCF’s Contraction Relaxation VSM cells Relaxation  Endothelium-derived Vasoactive Substances EDR F’s EDCF’s – Nitric Oxide (NO) Endothelin (ET-1) Thromboxane A2 (TxA2) – Prostacyclin (PGI2) 5 December 2 6 024  Synthesis and Release of NO from the Endothelium L-arginine + O2 NOSNO + L-citrulline NOS activity is controlled by intracellular calcium/calmodulin Important stimuli for NO synthesis likely to be mechanical (shear stress, pulsatile flow) Agonist-induced (e.g. Ach, BK, ADP) NO release mediated by [Ca2+]i NO diffuses out of the cell and onto smooth muscle cells to exert its effects 5 December 2 7 024 Ach bradykinin Shear stress [Ca2+] calmodulin Ca-calmodulin active inactive NOS NOS L-citrulline L-arginine + NO  NO guanylate guanylate cyclase - cyclase - basal activated cGMP GTP Protein kinase G smooth muscle relaxation  Mechanism of Action of NO NO exerts its effects by activating guanylate cyclase GC GTP cGMP  [Ca2+]i Relaxation 5 December 2 10 024  NO not only affect blood vessels. NO modulates: 1) Skeletal muscle 2) Myocardial contractility 3) Metabolism 4) Intimately linked with insulin signalling. 5) Neuronal function Acts as 6) Anti-oxidant 7) Anti-thrombotic 8) Anti-inflammatory 5 December 2 11 024 PL1003 Muscle  Tissues Different types of cells must coordinate their efforts in order to work efficiently. Cells working together form “tissues” i.e., collections of specialised cells and cell products that perform a limited number of functions (common structure & function). 5 December 13 2024  4 Tissue Types Connective: Fills internal spaces; Provides structural support for other tissues; Transports materials within the body; Stores energy reserves as fats. Epithelial: Cover exposed surfaces [eg. skin]; Line internal passageways and chambers; Form glands. Muscle: Skeletal; heart; walls of hollow organs Nervous: Carries information in form of electrical impulses. 5 December 14 2024 Characteristics of muscular tissue Highly abundant tissue in most animals Constructed to generate force Muscle contraction accounts for much of the energy- consuming cellular work in an active animal 5 December 15 2024 How do muscles contract? Within the cytoplasm of muscle cells are many myofibrils arranged in parallel. These consist of contractile proteins myosin and actin. So what regulates this myosin/actin interaction? 5 December 16 2024 Sliding filament theory Myosin filaments use energy from ATP to “walk” along the actin filaments with their cross bridges, thereby pulling the actin filaments closer together 5 December 17 2024  Muscle fibres composed of long cells (up to 30 cm). capable of contracting when stimulated by nerve impulses. In vertebrates there are three different muscle types: 5 December 18 2024  Three types of muscle. 1) Smooth muscle 2) Cardiac muscle 3) Skeletal muscle. All rely on an interaction by actin and myosin fillaments. Fuelled by ATP and initiated by increasing [Ca2+]i. The effects of drugs on muscle contraction is the basis of many therapeutic applications. 5 December 19 2024  1. Skeletal muscle Named for its location, is attached to bones of the skeleton. Is striated, with fibres containing alternating light & dark bands (striations), parallel to each other, and perpendicular to the long axis of fibre. Stained histological Are voluntary i.e., made to contract or relax by section of muscle tissue conscious control. (pink) with Many nuclei. dark purple nuclei. 5 December 20 2024  Skeletal Muscle 1) Possesses array of transverse T-Tubules 2) T-tubule possesses proteins (dihydropyridine receptors (DHPR )) 3) DHPR NOT a channel but connected to the SR. 4) Depolarization activates ryanodine receptors in the SR 5) Releases Ca2+ into sarcoplasm. 6) Ca2+ bind to protein TROPONIN 7) Troponin hold tropomyosin in place. 8) Tropomyosin normally blocks actin/myosin interaction 9) Ca2+/troponin complex displaced and actin and myosin interact. 10) Muscle responds with rapid twitch. 5 December 21 2024  Skeletal Muscle Fast twitch: Rapid contraction, function anaerobically, relies on more rapid glycolytic pathways for ATP production Slow twitch: Slowly produces contraction, utilizes a slower aerobic mechanisms for ATP production. Necessary fibre in endurance exercise! 5 December 22 2024 2. Smooth muscle Located in walls of hollow Usually, involuntary. internal structures, such as blood Non-striated (hence the term ‘smooth’) vessels; airways to lungs; Small, spindle-shaped stomach; intestines; gall bladder; Single, centrally located nucleus urinary bladder 5 December 23 2024  Many smooth muscles, such as those in the gut, are connected by “gap junctions”, so they contract in synchrony. 5 December 24 2024  Others, such as those controlling the iris of the eye, have no gap junctions and act individually: 5 December 25 2024  Smooth muscle 1) Ca2+ increases in cytosol. (entry either by GPCR, or LGCC or VGCC) 2) Ca2+ binds to protein CALMODULIN. 3) Ca2+-calmodulin complex activates Myosin Light Chain Kinase (MLCK) 4) MLCK phosphorylates MLC. 5) Allows actin/myosin interaction (contraction) 6) Myosin phosphatase (MP) reverses the phosphorylation and causes relaxation. 7) cAMP and cGMP regulate MLCK and MP activity. 5 December 26 2024  3. Cardiac muscle Forms bulk of heart wall and like skeletal muscle, is also striated. Like smooth muscle is involuntary i.e., contractions are not consciously controlled. Fibres are attached end to end by intercalated discs i.e., thickened plasma membrane, unique to cardiac muscle, containing gap junctions. 5 December 27 2024 5 December 28 2024  Cardiac Muscle 1) Possesses large transverse T-Tubules 2) T-tubule L-Type Ca2+ channels 3) L-Type is a channel but is NOT connected to the SR. 4) Depolarization activates Ca2+ influx. 5) Ryanodine receptors in the SR release Ca 2+ in Ca2+-induced Ca2r release. 6) Releases Ca2+ into sarcoplasm. 7) Ca2+ bind to protein TROPONIN 8) Troponin/tropomyosin normally blocks actin/myosin interaction 9) Ca2+/troponin complex displaced and actin and myosin interact. 10) Muscle responds with rapid twitch. 5 December 29 2024 PL1003 Nerves  Nervous system Senses stimuli & transmits signals from one part of body to another. Functional unit = neuron = nerve cell Uniquely specialised to transmit signals = nerve impulses. 98% concentrated in brain & spinal cord. 5 December 31 2024 5 December 32 2024  Neurons Longest cell in body, Can be up to 1 metre long, Most cannot divide under normal circumstances, Very limited ability to repair themselves after injury, Surrounded by the myelin sheath, an insulating layer made of Myelin sheath protein and lipids. Allows electric impulses to transmit efficiently. If damaged, the impulses slow down. 5 December 33 2024  Neuron Consist of: Cell body (Nucleus and organelles), with extensions - Dendrites transmit pulses from tip in to neuron. Short, highly branched Axons transmit pulses towards other neurons or effector (eg. muscle cell) to carry out a response [output]. Thin, can be long. 5 December 34 2024 5 December 35 2024 5 December 36 2024  Neuroglia (Glia) Are various cells not involved in electrical impulses. Make up more than half the neural tissue in the human body. Surround, protect and maintain neurons e.g., cleaning up debris and forming myelin. Thought to also be involved in e.g., facilitating neuron-to-neuron communication and immune regulation. 5 December 37 2024