1. Give an account of the roles of calcium in the cardiovascular system. Using named examples, explain how drugs perturb the cellular functions of calcium (directly or indirectly) in order to exert their physiological effects?
2. (a) Give an account of the pharmacology of catecholamines and their actions in the cardiovascular system?
(b) With reference to appropriate guidelines, explain how antagonists which perturb the cellular functions of catecholamines are used in the treatment of cardiovascular disease?
3. (a) With reference to appropriate clinical guidelines, describe the rationale for the use of drugs acting on the renin-angiotensin-aldosterone system in the management of hypertension.
(b) “The primary concern of the physician, when presented with a newly-diagnosed hypertensive patient, should be rapidly to reduce their blood pressure to within normal levels” To what extent could this statement be said to be true?
1: In the cardiovascular system the calcium is known as second messanger. It is worked as intracellular messenger. Through the calcium-sensing receptor (CaR) it is act as extracellular first messanger. In G-protein-coupled receptor of family C the calcium sensing receptor is found. Transmembrane domain receptors are also called as calcium-sensing receptor(CaR). Calcium acts as first messanger. Vrious cellular functions are regulated by calcium-sensing receptor (CaR). In blood vessels the calcium–sensing receptors (CaR) have physiological roles. For maintaining and regulating mineral ion homeostasis calcium-sensing receptor (CaR) plays an important role. To maintain the potential differences through out the extra cellular cell membranes and proper bone formation extra cellular calcium plays an important role. In signal transduction calcium ions (Ca2+) are played an important role. The neurotransmitters are released from neuron and for this functions the calcium ions (Ca2+) are played a vital role as second messanger.
In the physiology and biochemistry and the cell calcium ions (Ca+) play an important role. Ca2+ act as a second messanger. And also in transduction pathways they play a major role. In case of neurotransmitter release from neurons the calcium ion (Ca2+) acts as a second messenger. (SMAJILOVIC and TFELTHANSEN, 2007). Cytoplasmic Ca(2+) concentration is kept low level of about 10(-7)M. When Ca(2+) concentration increases by specific stimuli via opening of channel proteins, Ca(2+) binds to Ca(2+)-binding proteins, activating specific proteins, results in responding the stimuli.
2. (a): By the conversion of tyrosine to 3,4-dihydroxyphenylalamine (DOPA) catecholamines (epinephrine, norepinephrine and dopamine) are biosynthesized. From tyrosine to 3,4- dihydroxyphenylalamine by the enzyme tyrosine hydroxylase is the rate limiting step. Catecholamine consists of two groups : catechol and an amine group. By activating G-protein coupled receptor catecholamines are acted exclusively.
Circulating catecholamines are epinephrine and norepinephrine.
Circulating Epinephrine Causes:
- The heart rate and inotrophy (β-adrenoceptor mediated)is increased.
- Vasoconstriction is the major effect in most systemic arteries and veins.
- The cardiac output is increased because of the overall cardiovascular response. It happens for the response of cardiovascular system which shows low to moderate contractions. And the response of the cardiac output is redistributed to muscular. When the cardiac output is increased it is natural that the arterial pressure is also changed. But here arterial pressure is not changed becaused the activation of β2 receptor is helped to fall the systemic vascular resistance (Kalbunde, 2012). Arterial pressure is increased by epinephrine at high plasma concentrations because the α2 adrenoceptors are bound on blood vessels and for this reason β2 adrenoceptor mediated vasodialation is seen.
Circulating Norepinephrine Causes:
- The heart rate and inotrophy (β1 adrenoceptor mediated) are increased. And for this reason the nrepinephrine is effected directly on the heart.
- Vasoconstriction is the major effect in most systemic arteries and veins (post junctional α1 and α2 adrenoceptors).
- The cardiac output is increased because of the overall cardiovascular response and the systemic vascular resistance is also increased. As a reult the arterial blood pressure is raised. When the baro receptors are activated the heart rate is stimulated by norepinephrines.
(b) : β-blocker drug blocks the receptors to inhibit the functions of catecholamines. And as a result the heart rate and blood pressure are reduced. β blockers are given to patient through a vein or by mouth. (Brindis and Walsh, 2010). When receptor numbers and catecholamine levels are increase, the effects of β-blockers are greatest. The heart’s ability to respond to stress is not completely diminished by β-blockers. β-blockers modify the response of heart to stress. Ability of heart for the responding to stress is not completely diminished by β blockers.
Fig: β- adrenergic blocking drug’s physiological effect in the presence of circulating catecholamines ; Source: (Brindis and Walsh, 2010)
3. (a) : Blood pressure and water (fluid) balance is regulated by rennin-angiotensinsystem (RAS) or the rennin-angiotensin-aldosterone system (RAAS). It is a hormone system.
Fig: Reninangiotensin aldosteron system; Source: (Paiardi et al., 2007)
If there is loss of blood volume then the system is activated. An angiotensin-converting-enzyme inhibitor (ACE inhibitor) is a type of drug which are used primarily for the treatment of hypertension and congestive heart failure.
Examples of ACE inhibitor includes:
Capoten(captopril), Vssotec(enarapril), Monopril (fosinopril).
Guidelines for ACE Inhibitors:
- According to guidelines on an empty stomach one hour before meal the drug should be taken. The patient should follow the directions to use the drug and how to take it. As per the condition of the patient the medication is decided and also followed some mojor factors. The factors which are to be followed are : the number of doses of drug should take each day, the time intervals between doses and the medication period. The medication period is very important for a patient and it is decided considering the condition of the patient. The prescribed order should be followed by a patient.
- Salt substitutes should not be taken by the patient who are suffering from hypertension. Because it contains potassium. The potassium is stored on the body by ACE inhibitors. It is necessary for a patient to choose a food chart which is not contained the sodium and the potassium levels. In this matter he dietitian chart should be followed by a patient.
(b): “The primary concern of the physician, when presented with a newly-diagnosed hypertensive patient, should be rapidly to reduce their blood pressure to within normal levels”
The statement is true. And the patients should follow the following advices:
- Preventing or treating obesity: NICE recommends starchs (potatoes, rice, bread and pasta), wholegrain, brown rice, bread. And very importantly snacks are not allowed for hypertension patients. The patient with hypertension should change his/her life style behavior. By changing the life style behavior the person can improve his/her health condition. Proper medication and the instructions (made by general physician) should be followed by the patients.
- Stopping smoking: Patients should stop smoking.
- Encouraging exercise: Physical activities (eg, walk or cycling, use the stairs instead of the lift if possible, walk at lunch time) are very useful to prevent hypertension.
- Salt reduction.
- Starting treatment.
Brindis, R. and Walsh, M. (2010). President's Page: Patient-Centered Cardiovascular Care: An ACC Initiative. Journal of the American College of Cardiology, 56(2), pp.155-157.
Klabunde, R. (2012). Cardiovascular physiology concepts. Philadelphia, PA: Lippincott Williams & Wilkins/Wolters Kluwer.
Paiardi, S., Porteri, E., Rodella, L., De Ciuceis, C., Boari, G., Rezzani, R., Ricci, F., Bianchi, R., Rizzoni, D. and Agabiti Rosei, E. (2007). Angiotensin Receptor Blockers and Ace Inhibitors Prevent Microvascular Rarefaction in the Skeletal Muscle of Spontaneously Hypertensive Rats.High Blood Pressure & Cardiovascular Prevention, 14(3), pp.145-196.
SMAJILOVIC, S. and TFELTHANSEN, J. (2007). Calcium acts as a first messenger through the calcium-sensing receptor in the cardiovascular system. Cardiovascular Research, 75(3), pp.457-467.