Browsing Pathways

This pathway illustrates the tocainide targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cellsŠ—È extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Tocainide, the alpha-methyl analogue of lidocaine, is a Class 1B antiarrhythmic drug. It has similar electrophysiological effects as lidocaine and may be used to treat ventricular arrhythmias. Unlike lidocaine, tocainide may be administered orally and has a long plasma half-life of 12 hours (plasma t1/2 of lidocaine = 15 Š—– 30 minutes). Like other Class 1B antiarrhythmic agents, tocainide preferentially blocks sodium channels in their inactivated state. Voltage-gated sodium channels (I-Na) are responsible for the rapid depolarization phase of cardiac myocyte action potentials. Inhibition of I-Na results in an increased threshold of excitability and decreased automaticity. The membrane stabilizing effects of tocainide also cause a slight decrease in action potential duration. Tocainide is administered as a racemic mixture. The R-isomer is four times more potent than the S-isomer and is cleared faster in anephric patients.

Carvedilol, trade name Coreg, is a nonselective beta-blocker that blocks both alpha and beta receptors of the heart and blood vessels. It is prescribed to treat hypertension, stable angina pectoris and congestive heart failure. Carvedilol also blocks calcium channels. Its activity decreases heart rate, myocardial contractility and oxygen demand and decreases vascular resistance. It also posses a unique feature for a beta-blocker, it has an anti-free-radical effect. This effect may prevent free radical damage to treat chronic heart failure.

The Krebs cycle, also known as the citric acid cycle (CAC) or tricarboxylic acid cycle (TCA cycle) occurs in the mitochondria, and it involves the oxidation of acetyl-CoA from glycolysis to form molecules of ATP, as well as NADH, which will later be used to form more ATP. Intermediates from the Krebs cycle can be used as inflammatory signals in the body, specifically in immune cells such as macrophages. Succinic acid, or its anion succinate, can leave the mitochondria and can directly inhibit the prolyl 4-hydroxylase subunit alpha-3 protein, which then allows for additional activation of the hypoxia-inducible factor 1-alpha (HF-1α). The higher levels of HF-1α enhance the expression of genes, including those for interleukin-1 beta (IL-1β). Succinic acid is also necessary for the succinylation of proteins, leading to changes in their structure and function. Another intermediate of the Krebs cycle, NAD, activates the NAD-dependent protein deacetylase sirtuin-3, which is involved in the deacetylase of proteins in the cell, regulating ATP levels and promoting mtDNA transcription when needed. Activated sirtuin-3 inhibits NACHT, LRR and PYD domains-containing protein 3, which works to activate the inflammasome, and thus the increase in NAD+ leads to anti-inflammatory actions in the body. Citric acid is another intermediate of the Krebs cycle, and it activates the production of reactive oxygen species, nitric oxide, which is the precursor for reactive nitrogen species, and prostaglandins. Prostaglandins can act as vasodilators, and as such are involved in the inflammation response. Finally, glutamine is important for immune cells to carry out their functions, and when LPS binds to the Toll-like receptor 4 (TLR4) on the cell surface, activating this response, extra L-glutamine can be transported into the cell to fill this need. The L-glutamine can then be converted to oxoglutaric acid, which is important in the Krebs cycle, leading to the effects from its intermediates on the rest of the inflammatory response.

Cilazapril (trade name: Dynorm, Inhibace, Vascace) belongs to the class of drugs known as angiotensin-converting enzyme (ACE) inhibitors and is used primarily to lower high blood pressure (hypertension). This drug can also be used in the treatment of congestive heart failure and type II diabetes. Cilazapril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form cilazaprilat via cleavage of its ester group by the liver. Angiotensin-converting enzyme (ACE) is a component of the body's renin–angiotensin–aldosterone system (RAAS) and cleaves inactive angiotensin I into the active vasoconstrictor angiotensin II. ACE (or kininase II) also degrades the potent vasodilator bradykinin. Consequently, ACE inhibitors decrease angiotensin II concentrations and increase bradykinin concentrations resulting in blood vessel dilation and thereby lowering blood pressure.

Adenosine is thought to play a role in the pathophysiology of asthma. Stimulation of A2B can induce production of interleukin-8 mast cells. The adenosine receptor A2b activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates down stream effectors that lead to a specific cellular response. This occurs though activation of the MAPK/ERK signaling cascade.

Timolol is a beta blocker medication, making it part of the antihypertensive drug class. It relieves symptoms such as tachycardia, vascular headaches, hypertension, angina and tremors. Timolol, much like propranolol or oxprenolol, begins its journey by inhibiting the beta-1 adrenergic receptors in the heart. Entering the myocyte, this activates a G-protein signalling cascade, which activates cAMP -dependent protein kinase type 1-alpha regulatory subunit. From there, cAMP-dependent protein kinase catalytic subunit alpha activates outage-dependent L-type calcium channel subunit alpha 1C and 2 other transports which bring calcium into the myocyte from outside of the cell. cAMP-dependent protein kinase catalytic subunit alpha is activated through ryanodine receptor 2, which is also transporting calcium into the myocyte from the the sarcoplasmic reticulum. The calcium and calmodulin then activate myosin light chain kinase, which is located in the smooth vascular muscle. This, paired with the calcium activating a series of troponin enzymes that activate tropomyosin enzymes in the striated muscle, results in a muscle contraction. Then in the cell membrane we have PIP2(16:0/20:3(8Z,11Z,14Z)) catalyzing into DG(14:0/14:1(9Z)/0:0) and inositol 1,4,5-triphosphate with the help of the enzyme 1-phosphatidylinositol 4,5-biphosphate phosphodiesterase beta-1. This enzyme is activated through the G-protein signalling cascade, which stems from the type-1 angiotensin II receptor. Around the cell there are many transports happening through many different transporters, leading in and out of the cell Some of the transports into the cell include sodium and calcium, while transports are also working hard to constantly export potassium from the cell. Returning to the sarcoplasmic reticulum, cardiac phospholamban inhibits the transporter sarcoplasmic/endoplasmic reticulum calcium ATPase 2, which sees water and ATP catalyzed through it to become phosphorus and ADP, while transporting calcium into the sarcoplasmic reticulum.

Nimodipine (also known as Nimotop or Periplum) is a dihydropyridine calcium channel blocker that may not be used for treatment of hypertension. Compared to other DHP CCBs, nimodipine is more active in the cerebral vasculature than in the periphery. This may be due to its high lipophilicity and ability to penetrate the blood brain barrier. This unique property of nimodipine led to clinical studies for its use to improve neurological outcomes in patients following subarachnoid hemorrhage from ruptured intracranial aneurysms. While it has been approved as adjunct treatment for this indication, the exact mechanism by which it exerts these effects is unclear. Nimodipine has little effect on cardiac myocytes and conduction cells at therapeutic sub-toxic concentrations. Nimodipine binds the major channel in muscle cells: L-type calcium channels. Binding of Nimodipine on L-type calcium channels can change channels' confirmation to its inactive form, so that the channel couldn't faciltate the influx of calcium ions, which leads to decreased arterial smooth muscle contractility and subsequent vasoconstriction. Activated mysoin light chain kinase (MLCK) is required for muscle contraction since it can catalyze the phosphorylation of the regulatory light chain subunit of myosin. Without calcium ions in muscle cell, calmodulin couldn't form the calcium-bound calmodulin, which is required for binding and activating MLCK. Lack of initial influx of calcium can also reduce the level of contractile activity of muscle cells and results in vasodilation, which ultimately lead to overall decresing in blood pressure.

Levobunolol (also known as Betagan) is an ophthalmic beta blocker (non-selective) that can produce cardiovascular effects and systemic pulmonary effects. Levobunolol bind to beta1-adrenergic and beta2-adrenergic receptors in heart and vascular smooth muscle to block the binding of other adrenergic neurotransmitters such as norepinephrine, which lead to decreased blood pressure, heart rate and cardiac output.

The 5-HT4 receptor is primarily found in the CNS, GI tract, and PNS. Peripheral receptors have important roles in the function of many organ responses (alimentary tract, urinary bladder, heart, and adrenal gland). Alimentary tract receptors have a role in smooth muscle tone, mucosal electrolyte secretion, and the peristaltic reflex. Urinary bladder receptors control cholinergic/purinergic transmission. Atrial heart receptors produce positive inotropy and tachycardia that can precipitate arrhythmias. This receptor is also thought to have roles in anxiety, appetite, GI motility, learning, memory, mood, and respiration. The 5-HT4 receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.

cAMP dependent protein kinase is a signalling molecule, found in the nucleus and cytoplasm of cells. Cellular regulation and signal transduction in eukaryotic cells is driven by the phosphorylation of proteins. cAMP dependent protein kinase is created as an active enzyme, which is made possible by a fully phosphorylated activation loop.