How Adrenaline Nifedipine Alter Vascular Muscle Tone Cells Biology Essay

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Include precise details of cellular mechanisms of action and therapeutic indications for these agents. The vascular system consists of blood vessels which have a significant function in carrying blood around the body, from the aorta to smaller arterioles which branches into capillaries. The capillaries converges into venules and then into veins (J.R Levick, 2003 p8).

The blood vessels consist of three layers in which vascular smooth muscles (VSM) are found in the middle layer called the tunica media. Vascular smooth muscles cells are "spindle-shaped cells" helically arranged around the axis of artery, arterioles, and venules and vein and have an essential role in sustaining the structure and function of blood vessels. VSM tone i.e. the contractile state can regulate the diameter of the blood vessels associated with peripheral resistance, arterial pressure and central venous blood pressure which are important factors in controlling and determining blood flow (J.R Levick, 2003 p198,104-105).

The vascular tone is controlled and regulated by vasoactive drugs i.e. vasoconstrictor and vasodilator agents. Vasoconstrictor agent can increase the vascular tone i.e. contraction by causing a rise in the intracellular calcium concentration [Ca2+]i resulting in contraction of the VSM. Vasodilator agents can decrease the vascular tone by lowering the [Ca2+]i resulting in the relaxation of the VSM. It is the vasoconstrictor and vasodilator agent that determines how VSM functions and how they affect factors relating to blood flow. (J.R Levick, 2003).

In this essay I will be describing as well as explaining the mechanism of action of the drugs adrenaline and nifedipine, and how they regulate and maintain the vascular smooth muscle tone and their beneficial indications.

Adrenaline is administered as a potent vasoconstrictor agent, it is a sympathomimetic drug which mimics the sympathetic effects. Adrenaline is a short acting as well as "direct-acting agonist" that binds to both alpha (α1) and beta (β2) adrenoreceptor on VSM (Lippincotts's et al, 1997 p61). The extent to which adrenaline acts on alpha (α1) or beta (β2) adrenoreceptor depends on its dose. Adrenaline at a higher dose binds to alpha-1 adrenoreceptor causes constriction of VSM. Adrenaline at low doses binds selectively to β2 adrenoreceptor commonly in arterioles and also in the veins causing relaxation of VSM. However, in the majority of vascular beds the β2 adrenoreceptor is not very significant as there are few of these receptors and a larger number of α-adrenoreceptor hence α -adrenoreceptor predominates. (Lippincotts's et al, 1997; Eric P.Widmair et al, 2008; Bennett and Brown, 2003).

α1 Receptor

Endogenous adrenaline (at high dose) binds to alpha-1 adrenoreceptor on the vascular smooth muscle of arterioles and veins this activates G-protein coupled receptor Gq/11 at the C-terminal which activates phospholipase C (PLC) which is an enzyme that hydrolyse phosphatidylinositol bisphosphate (PIP2) into two second messengers inositol triphosphate (IP3) and diacylglycerol (DAG) . IP3 acts on the IP3 receptor on the sacroplasmic reticulum (SER) causing the calcium ions to be release from the SER by activating the opening of calcium channel on the SER, hence calcium moves out of the SR down its electrochemical gradient and into the cytosol. Therefore increasing [Ca2+]i in the cytosol (Ziolkowski and Grover, 2010; Zhong and Minneman,1999).

DAG (diacylglycerol) activates protein kinase C which phosphorylates protein ion channels, causing them to open resulting in the depolarisation of membrane potential. It is the depolarisation which causes the voltage-gated Ca2+ion channel (VGCC) to open resulting in Ca2+ ions uptake into the VSM thus increasing the [Ca2+]i (Ziolkowski and Grover, 2010). Therefore an increase in [Ca2+]i, causes calcium to bind to calmodulin (a protein) to form calcium-calmodulin complex this activates the myosin light chain kinase (MLCK) which utilises ATP to phosphorylates the myosin head (myosin light chain), resulting in the formation of cross-bridges between phosphorylated myosin cross-bridges binding to actin filaments. Thus, causes shortening and an increase in tension resulting in contraction of the VSM, promoting vasoconstriction of arterioles in the skin, a reduction in the diameter of the blood vessels, an increase in peripheral resistance and blood pressure (increases systolic and diastolic pressure).In addition, there is an increase in the central venous pressure and a decrease in vascular compliance. (Ziolkowski and Grover, 2010; R. Clinton Webb, 2003 ; HIDEAKI KARAKI,2009).

β2 Receptor

Adrenaline at low doses binds to β2 adrenoreceptor on VSM of arterioles linked to the Gs stimulatory protein which activates adenylyl cyclase (AC) to covert ATP to cyclic AMP (cAMP). Therefore a rise in cAMP activates the enzyme protein kinase A (PKA) which phosphorylates proteins in three different pathways. Firstly, PKA phosphorylates myosin light chain kinase (MLCK) inactivating it resulting in the reducing the cross-bridge formation of actin-myosin due to a reduction in [Ca2+]i. In the second pathway, PKA phosphorylates potassium channels causing hyperpolarisation inhibiting voltage dependent L-type calcium channels therefore a decrease in the calcium ion entry to VSM. In the third pathways PKA phosphorylates the protein calcium ATPase pumps in the SER this causes both expulsion and sequestration of Ca2+ therefore decreasing cytosolic [Ca2+]. All pathways cause a reduction in the cytosolic [Ca2+], thus inducing relaxation of vascular smooth muscles. (Dale and haylett, 2009; J.R Levick, 2003 p213-214)

Therapeutic indication for adrenaline

Adrenaline is used in life-saving emergency situation as a first-line treatment for acute anaphylaxis. Anaphylaxis is a hypersensitive allergic reaction caused by allergens. Anaphylactic shock occurs as a result of allergens triggering the release of chemicals such as serotonin, histamine and bradykinin. The release of these chemicals gives symptoms e.g. redness of the skin, itching, rashes and oedema. These symptoms are experienced by suffers as chemicals e.g. histamine causes vasodilatation, a drop in blood pressure, spasm of the smooth muscles and a higher capillary permeability. Histamine also causes bronchospasm a condition whereby the sufferers have difficulties in breathing due to obstructive airways. Adrenaline given as a 1:10000 intravenous injection is used to treat hyposensitivity reaction (type 1 reaction) by binding to both α and β adrenoreceptor. Adrenaline binds to β2 in the bronchiolesresulting in smooth muscles relaxation thus opening up the airways. Symptoms e.g., oedema can be reduced by adrenaline causing vasoconstriction of arterioles. Adrenaline in arterioles binds to the α-1 adrenoreceptor enhances vasoconstriction effect resulting in an increase peripheral resistance and an increase blood pressure.

Adrenaline is used in local anaesthetics at a low concentration of 1 in 100 000. Local anaesthetics are vasodilators to stop pain these are vasodilators injected locally in tissue. Adrenaline is used to prolong the effects and time duration of local anaesthetics in tissues. Adrenaline causes vasoconstriction to occur at the injection site, to allow the local anaesthetics to remain at the site prior to its absorption into the circulation and is metabolised. (Lippincotts's et al, 1997 p63)

Other treatment of adrenaline is that it is used to treat cardiac arrest by restoring the heart rhythm adrenaline does this by peripheral vasoconstriction therefore increasing the blood supply to the heart hence causing the contraction of the heart muscle. Adrenaline also used to treat glaucoma by decreasing the production of the aqueous humour hence reducing the intraocular pressure via constricting the blood vessels in the capillary body.



Nifedipine belongs to a class of calcium channel blocker called 1, 4-dihydropyridine these are short acting Ca2+ channel blockers (David J. Triggle, 2007). Nifedipine has a higher affinity to block calcium channels on the VSM in comparison to cardiac muscles found in the heart. (Rang et el, 2003). Nifedipine is a vasodilator agent which reduces the vascular tone, and functions mainly as an arteriolar vasodilator.

Mechanism of action

Nifedipine directly blocks or antagonises the opening of the induced L-type voltage gated calcium channels (VGCC) i.e. a CaV1 class, long opening slow type Ca2+ channel, in response to depolarisation, by binding to the VGCC in the VSM in both peripheral and coronary arteries, however most abundant in arterioles ( Mycek et al., 1997; David J. Triggle, 2007).

Nifedipine when bounded to VGCCs on the N binding site, reduces the uptake of influx calcium ion into VSM therefore decreasing the cystolic [Ca2+]. This results in a decrease in calcium binding to calmodulin thus hindering the formation of calcium-calmodulin complex. Thus deactivating the activity of MLCK resulting in the activation of the myosin light chain (MLC) phosphatase causing a dephosphorylation of the myosin head hence inhibiting the formation of cross-bridges causing relaxation of the arteriolar VSM cells. Therefore causing vasodilatation of coronary and peripheral arteries (J.R Levick, 2003 p206-210). The arterioles dilate thus increasing the diameter this occurs more commonly than veins leading to an high levels of oxygen supply by the blood to myocardial tissues, reducing the peripheral vascular resistance, capacitance, afterload and blood pressure (Bennett and Brown, 2003; M.J Neal, 2002, pg36-38; Rang et al, 2003 p298)). On the whole, a reduction in the [Ca2+]i causes a decrease in the vascular tone (vasodilatation) which is regulated and maintained by Nifedipine, a vasodilator agent.

Therapeutic indication for Nifedipine

Nifedipine is therapeutically used as an anti-hypertensive for prophylaxis of hypertension. Hypertension is a condition of high blood pressure, 140/90mmHg. Nifedipine reduces blood pressure to a normal blood pressure level by inhibiting the depolarisation induced L-voltage gated calcium channels hence causing VSM relaxation, a decrease in peripheral resistance and a decrease in the arterial blood pressure. (Rang, et al, 2003)

Nifedipine is used to treat angina (chest pain) symptom such as variant angina. Variant angina occurs due to the spasm of the coronary arteries. Nifedipine acts by dilating the vascular blood vessels hence preventing condition e.g. Ischemic heart disease. Prevention of such disease is by improving the coronary perfusion to allow sufficient blood supply to heart via coronary arteries. (Rang, et al, 2003)

Nifedipine is used to treat Reynaud's phenomenon, a vasospasm condition that results from poor blood circulation due to vasoconstriction of arterioles therefore reducing the blood flow to the hands and feet (skin), this occurs in cold weather. Symptoms include hand and toes getting white and cold, "numbness" leading to the skin turning red and painful. Nifedipine works by relaxing and dilating the blood vessels hence improving blood circulation via vasodilatation to the skin (Nhs choice

On the whole, both Adrenaline and Nifedipine acts through different cellular mechanisms to alter