Article:

Article

Mechanisms of regulating blood pressure to within normal limits, and pharmacological agents

Abstract

This article outlines the mechanisms regulating blood pressure, keeping it within normal limits, and discusses the pharmacological interventions used to correct abnormalities in these mechanisms. Perfusion and blood pressure are introduced, and the relation of the latter to cardiac output and total peripheral resistance is outlined. Common mechanisms in the pathophysiology of hypertension are briefly covered followed by descriptions of the mechanisms involved in regulating blood pressure to within normal limits. Antihypertensive drugs are examined in detail; those acting on the sympathetic arm of the autonomic system, those acting on the vascular system, and finally those potentiating renal control of plasma volume and blood pressure. The use of a selection algorithm is described and the pharmacological treatment of hypertensive crises is also outlined.

Introduction

“Hypertension affects around 10 million in the UK” according to Dr. Neal Uren, consultant cardiologist at Edinburgh Royal Infirmary, that is approximately 1 in 5 (NetDoctor). These general figures translate into large numbers of sufferers in the UK, who in turn will inevitably come to rely on pharmacological intervention, especially given that hypertension is a predisposing factor to cardiovascular disease. Hypertension is an interesting physiological state as there are various different systems involved in the control of blood pressure, and as a result, various specific mechanisms which may be targeted pharmacologically. (Al-Nasir). In addition, there is likely a genetic predisposition to hypertension in black Africans (ABC of Hypertension, p65), which may also affect choice of drug, although detailed discussion of the factors implicated is beyond the scope of this paper.

Blood Pressure and perfusion

The cardiovascular system is essentially a transport system delivering oxygen and nutrients to tissue and removing carbon dioxide and waste from this tissue with the blood functioning as the carrier. Thus adequate blood flow, termed perfusion, to organs and tissues is crucial. The relationship between pressure, flow and resistance is analogous to Ohm’s law, and is given by Darcy’s law. (Levick) In essence Darcy’s law is the fluid equivalent of Ohm’s law relating electrical current, voltage and resistance, where the corresponding variables in Darcy’s Law would be blood pressure, pressure gradient between two ends of a blood vessel and total peripheral resistance, respectively. Blood pressure is a product of cardiac output and total peripheral resistance, TPR (BP=CO x TPR). Additionally, TPR is dependent on the action of vasoconstrictors and vasodilators. High blood pressure (³140mm Hg systolic b.p. in person ³18 yrs), is termed hypertension. Another methodological definition that is widely accepted is “The level of blood pressure above which the benefits of investigation and treatment outweigh the risk s”. (Khong). Hypertension can lead to proteinuria, and cardio-vascular disorders such as left ventricular hypertrophy, vascular damage (i.e. stroke or vasculitis) and potentially fatal cardiac incidents such as aortic aneurysm. Conversely, low blood pressure, termed hypotension, can lead to renal failure and seizure.

(Figure 1.0, left) - This graph illustrates that cardiac risk is a continuous variable linked with an increase in b.p. (ABC of Hypertension, p6)

Autoregulation of blood pressure therefore is critical to normal functioning, and thus a variety of mechanisms are employed by the body to serve this function, which will be discussed below. It is noteworthy that there is no determined set-point for optimal blood pressure as there are many factors which makes impractical a one value for all approach. “...within a given population there is a continuous distribution of BP about a single modal value, although this value varies with age, genetic group etc...” (Greene & Harris, p93). In addition, hypertension is often idiopathic, that is, having no identifiable origin.

Pathophysiology of Hypertension

According to Goljan, the development of hypertension may be dependent on one or more of the following: (i) An increase in ECF (Extra-Cellular-Fluid) volume due to high salt intake. (ii) Vasoconstriction, increased TPR (Total Peripheral Resistance) and thus increased cardiac output and (iii) Salt retention, an increase in ECF volume, leading to an increase in cardiac output due to increased stroke volume and increased TPR. (Goljan, pp197-201). Secondary causes may be endocrine (Cushing’s syndrome, Conn’s disease, adrenal hyperplasia etc), renal (renovascular disease/renal artery stenosis, glomerulonephritis etc...) or a side-effect of drug therapy (oral contraceptives, steroids, carbenoxolone). (Khong)

Mechanisms that regulate blood pressure

As mentioned from the outset, various mechanisms act to regulate blood pressure, and these may grossly be divided into short term and long-term homeostatic systems. Examples of the former are the baroreceptor reflex, atrial stretch receptors, and vaso-dilation/-constriction whilst renal control is an example of the latter, that is, a longer-term physiological solution. It is important to note that the effectors of such systems often overlap, for instance in the RAA system, some of the anti-hypertensive effects ultimately culminate in vasodilation. The baroreceptor reflex control of bp The baroreceptor reflex serves to rapidly counter the physical effect on blood pressure of changes in posture. The reflex is somewhat more sensitive to decreases in pressure than to increases, and is more sensitive to sudden changes in pressure than to more gradual changes (e.g. when a patient stands up after lying down). (Van De Graaff and Fox, p677).

Control of bp via sensory systems in the heart

Atrial stretch receptors in the heart relay back to cardiovascular centres via a vagus afferent. Interestingly, these receptors are located in the left-atrium, and act to pre-empt the development of LVH, Left-ventricular hypertrophy. LVH develops due to prolonged increase in preload (i.e. blood supplied by atrium), which, in time, thickens the left ventricular walls and impairs the hearts ability to supply blood to the systemic circuit. In response to stretch, the atrium produce the hormone ANP (Anti-Natriuretic-Peptide). ANP is an arteriolar vasodilator, increases GFR, decreases tubular re-absorption of Na+, and decreases effect of ADH, and the Renin Angiotensin Aldosterone system (discussed below). It can decrease circulating plasma volume in a matter for minutes, hence decreasing TPR and CO, lowering BP. (Lecture notes in Physiology, p382)

Osmotic and Vascular control of bp

The relationship between changes in pressure and volume is given by Boyle’s law, (P1V1 = P2V2), and it can be deduced that pressure is inversely proportional to volume such that if the volume of arteries is decreased due to vascular constriction then the pressure of the blood in those arteries will increase. Conversely, vascular dilation increases the volume of arteries and hence reduces blood pressure within them. Consequently, endogenous chemical agents that mediate in the alteration of vascular tone are extremely important as those that act as vaso-contrictors may be targeted by means of blockade and those that have a vasodilatory effect may be subject to induction in order to reduce vascular tone and reduce TPR, and hence B.P. Examples of endogenous vasodilators are Nitric oxide released by vascular endothelium, Bradykinin, Histamine, Substance P and Acetylcholine. (Large) Blood pressure is also dependent on blood plasma volume and in turn osmolarity, and therefore hypertension may be regulated by the renal system. According to Rang & Dale, hypertension 'goes with' the kidney, that is, transplantation from normotensive donor to hypertensive donor results in a decrease in blood pressure (Rang & Dale, p311). In the Renin-Angiotensin Aldosterone (RAA) system the macula densa area of the glomerulus detects the ionic content in the fluid of the DCT (Distal Collecting Duct), and in turn stimulates granule cells of the Juxtaglomerular-apparatus to secrete Renin. This initiates the RAA system, whereby Renin converts Angiotensinogen to Angiotensin I. This is converted to Angiotensin II (a potent vasoconstrictor) in the lungs. Angiotensin II stimulates the release of Aldosterone from the adrenal cortex to effect the increase in tubular re-absorption of Na+/K+, resulting in increased blood volume and pressure.

Anti-Hypertensives and their mechanism of action

Sympathetic autonomic nervous system

b-adreno-receptors and their antagonists

Beta adreno-receptor antagonists (Beta-Blockers) act to inhibit the sub-systems of the sympathetic arm of the autonomic nervous system. As their name suggests, they act on b-adreno-receptors, un-selectively (Sub-type I & II) or selectively (Sub-type I only). Their mode of action is to decrease cardiac output via negative chronotropic and negative inotropic effect, which therefore lowers Mean Arterial Pressure, MAP. The older, unselective Beta blockers such as propranolol are contra-indicated in asthma sufferers, as blockade of Sub-type II b-adreno-receptors can lead to potentially fatal bronchospasm. According to the NICE guidelines of June 2006, they are also associated with an increased risk of developing type II diabetes. Looking more closely at the intracellular mechanism involved in the increase in blood pressure, we find that the positive inotropic effects on the heart are brought about by Adrenaline acting on b1-adreno-receptors within the heart. These beta-receptors are G-Protein coupled (GPCR) to Adenylyl cyclase (Gs coupling). Adenylyl cyclase converts ATP into cAMP, which in turn activates Protein Kinase A PA) that induces the release of intracellular calcium, leading to increased contractibility of the cardiac myocytes. The positive chronotropy (rate) effects are brought about by b1-adreno-receptor activation on the pacemaker current (if). All of which act to increase cardiac output. It follows that blockade of b1-adreno-receptors reduces cardiac output and hence mean arterial pressure.

a-adreno-receptors and their antagonists

Alpha adreno-receptor antagonists (Alpha-Blockers) also act on sub-systems of the sympathetic nervous system. They function through the blockade of α1-adreno-receptors which are responsible for vaso-constriction, and hence useful in treating vascular disease such as Reynauds syndrome. Increased vascular tone occurs as a result of adrenaline acting on a1-adreno-receptors leading to (vasoconstriction). These receptors are G-Protein coupled (GPCR) to Phospholipase C (Gs, i.e. stimulatory coupling). Phospholipase C (PLC) cleaves PIP2 (phosphatidyl-Inositol Biphosphate) into IP3 (Inositol Triphosphate) and DAG (Diacylglycerol). DAG serves to activate Protein Kinases and facilitate calcium release. IP3 acts on receptors on IP3 receptors of the Sarcoplasmic reticulum to cause the release of Intracellular Ca2+, this in turn increases contraction and vascular tone. It can be seen that again, blockade of receptors may be used to facilitate a reduction in vascular tone (i.e. vaso-dilatory effect). Alpha adreno-receptor antagonists are also useful for older male patients who in addition to suffering from hypertension suffer from benign prostatic hyperplasia, and in prescribing an alpha blocker, a reduction in prostatic symptoms together with amelioration of hypertension may be achieved. (Rang & Dale, p.311) Vascular system Alternatively, the modus operandi of calcium channel antagonists and nitrates such as Amlodipine and glycerol trinitrate, respectively, differs completely from that of the diuretics mentioned above. Instead of acting on the renal system, these drugs exert their anti-hypertensive effects via the vasodilation of vascular smooth muscle.

Calcium channels and their antagonists

In the case of calcium channel antagonists, this is achieved by the blockade of L-Type calcium ion channels in the smooth muscle, which reduce the concentration of intracellular Ca2+ ions causing it to relax and vasodilate. The physiological effect is that of decreased peripheral vascular resistance and thus lowered blood pressure.

Nitrates

Nitrates operate on the same principle though are short acting, stimulating the release of a local vasodilator (nitric oxide) from the endothelial lining of arterioles. Nitrates are susceptible to substantial first pass metabolism and are usually administered sublingually; this in itself is not a major problem as their effects are generally required immediately. However, patients often suffer from painful vascular headaches, which is detrimental to patient compliance. Renin-Angiotensin-Aldosterone and Renal systems As discussed earlier, the Renin-Angiotensin-Aldosterone (RAA) system has a crucial role in long-term management of blood pressure via regulation of blood osmolarity. Three classes of drugs exert their effects on this system, namely ACE inhibitors, Angiotensin receptor antagonists, also known as ARBs (Angiotensin Receptor Blockers), and finally diuretics.

ACE Inhibitors

ACE Inhibitors act by inhibiting Angiotensin Converting Enzyme (ACE) which catalyses the conversion of Angiotensin I (AngI) to Angiotensin II (AngII); a process occurring in the lungs. The ACE enzyme is structurally very similar to that of the digestive enzyme Carboxypeptidase A, CPA which cleaves amino acid residues from a polypeptide, except ACE differs in that the cleavage is of a di-peptide as opposed to a single amino acid. It is this action that converts AngI to AngII. Additionally the ACE enzyme possess a positively charged binding site at a corresponding location in place of the hydrophobic one in CPA. The similar Structure Activity Relationship between CPA and ACE led to the development of the first synthetic ACE inhibitor drugs such as Captopril and Enalapril (the non-synthetic ones having been obtained from snake venom). (Christie) ACE inhibitors, whilst effective anti-hypertensives, are associated with unpleasant side effects, most notably dry cough and rash. The side-effect of dry cough is a result of the ACE enzyme also catalysing bradykinin; Prostaglandins, and substance P are also implicated. The onset of the cough may be weeks or even months, and is not dose related. Studies have shown that the sensitivity of the cough reflex is elevated in both healthy and hypertensive patients receiving captopril and this is also the case with other ACE inhibitors as well.(Martindale) Notably ACE inhibitors are less efficacious in Afro-carribeans, and such genetic variations in response will determine selection of hypertensive (ABC of hypertension, p.65).

ARBs – Angiotensin Receptor Blockers

Another class of drugs exist also potentiate the effects of Angiotensin II, known as Angiotensin Receptor Blockers, ARBs which are void of the side-effects related to ACE inhibition. Instead of inhibiting ACE to reduce AngII production, ARBs act to antagonise AngII on the AT-1 subtype type receptor, thereby blocking the vasodilatory effect of AngII. In doing so, they also block the release of Aldosterone from the Adrenal cortex. The overall anti-hypertensive effect then, is a result of both decreased vasoconstriction, and a reduction of aldosterone induced tubular re-absorption, thereby decreasing plasma volume and BP. (Lullmann et al, p.124) Aldosterone Antagonists such as Spironolactone, which also functions as an anti-androgen may be used, especially in Conn’s syndrome, however generally they are only tolerated in low doses and are associated with oestrogenic effects such as gynaecomastia (breast development in males).

Diuretics

Diuretics promote diuresis, that is, the loss of water via the renal system, which ultimately reduces plasma volume, TPR and in turn bp. Loop diuretics exert their effects on the ascending loop of Henle (Thick ascending limb), whereas the thiazide diuretics act on the Distal convoluted tubule. Thiazides dilate arterioles and affect the early segment of the distal tubule acting on the luminal membrane where they inhibit re-absorption of sodium and chloride. (Pharmacy review, p308). A potential side-effect of thiazide diuretics is hypokalaemia (depletion of potassium), especially at high doses. For this reason it is often necessary to monitor Potassium levels and provide the patient with supplements, alternatively potassium sparing diuretics may be used. Navispare is a combined diuretic with potassium sparing diuretic (containing Cyclopenthiazide and amiloride hydrochloride respectively). The Cyclopenthiazide component is a Thiazide diuretic used to treat hypertension, oedema and chronic heart failure (BNF, p77). Amiloride hydrochloride, in addition to functioning as a diuretic, acts to conserve potassium and is a useful adjunct when hypokalaemia results and where patient compliance in taking supplements is an issue (i.e. both drugs combined in a single tablet).

In hypertensive crisis (emergency)

In the cases of emergency where hypertension required rapid treatment, many of the already discussed drugs can be used parentally for immediate action. The direct acting vasodilator Nitroprusside may also be used, it increases GMP concentration in vascular smooth muscle, reducing intracellular ca2+ concentration, hence reducing vasoconstriction and bp. Short acting ganglion blockers such as Trimethaphan (an irreversible nicotinic receptor antagonist) may also be used for hypertensive emergencies. Additionally, Hydralazine, another vasodilator that modulates GMP, is useful for hypertension during pregnancy. It is noteworthy that some vasodilators have varying specificity to veins or arterioles, whilst Nitroprusside and alpha blockers show no such specificity. Nitroprusside is therefore is a useful treatment in hypertensive crises.

(Figure 6.0, left) – Diagram depicting vasodilatory venous/arteriolar specificity

Conclusion

Asymptomatic hypotension often requires no treatment, and more salt may be added to the patients’ diet, this however is not the case for hypertension, which is a more serious condition associated with increased risk of morbidity. Hypertension therefore requires intervention regardless of whether or not the patient is asymptomatic. This intervention may be in terms of lifestyle changes (diet, smoking cessation), or pharmacological.

There is a wide choice of anti-hypertensive drugs, selection of which is based on specific criteria and pre-existing conditions. As we have seen there are also genetic variations in the response to different classes of anti-hypertensives, and therefore varying efficacy. This requires a selection approach based on clinical findings and studies, and for that a suitable protocol or algorithm is used to select the most appropriate drug therapy. The ABC algorithm devised by the British Hypertension Society & Royal College of Physicians, is one such protocol and is widely used in the UK.

The future looks promising for treatment of hypertension with new, exploratory studies on an anti-hypertensive vaccination, namely Cyt006-AngAb. The process involves passive injection of antibodies that target Angiotensin II. The main advantage would be in patient compliance as injections need only be administered a few times a year (Miller et al). This new technology, however, is only in its early stages and more trials and studies are necessary to judge both its efficacy and safety.

References

NetDoctor.co.uk - Public health website [online]: http://www.netdoctor.co.uk
Al-Nasir, J. (2008) The Molecular targets of the ten best-selling drugs, paper for module PY2010 (Introductory Pharmacology), Kingston university. {Unpublished}
Levick, J.R. () An Introduction to Cardiovascular Physiology, St. Georges Hospital Medical School, University of London, UK
Khong, T. (2006) Systems Pharmacology: Management of Hypertension module guide for PY2050, St. Georges Hospital Medical School, University of London, UK
Goljan, E.F. (1998) Pathology, Philadelphia, Pensylvania: W.B. Saunders
Van De Graaff, K. M. & Fox, S.I. Concepts of Human Anatomy and Physiology, 5th Edition, Boston: WCB McGraw-Hill
BNF.org (2007) BNF British National Formulary, 53rd Edition. London: BMJ (British Medical Journal) and RPS (Royal Pharmaceutical Society) publishing.
Rang, H.P. & Dale, M.M. et al (2007), Rang and Dale’s Pharmacology, 6th Edition: London, Elsevier
Shargel, L. & Mutnick, A.H. et al (2001) Comprehensive Pharmacy Review, 4th Edition. Baltimore: Lippencott Williams & Wilkins
Beevers D.G, Lip GY.H, O'Brien, E. (2007) BMJ Books: ABC of Hypertension, 5th Edition. Oxford: Blackwell Publishing Ltd.
British Hypertension Society & Royal College of Physicians (2006) Hypertension – Management of adults in primary care, London: Royal College of Physicians.
Lüllmann (2000) Color Atlas of Pharmacology, 2nd Edition. Stuttgart: Thieme.
Bray, J.J, Cragg, P.A et al (1999) Lecture notes on Human Physiology, 4th Edition. New Zealand: Blackwell Science.
Miller SA, Accardi JR (2008), Angiotensin II vaccine: a novel approach in the treatment of hypertension. Expert opinion on biological therapy. Nov;8(11):1669-73. Review.