Blood Pressure Regulation and Dysregulation

Introduction

Blood pressure measurement is an important component of clinical assessment, as everybody in the healthcare profession knows. Although pressure exerted by the blood is seen in other places (BP in the pulmonary circulation, central venous pressure, peripheral venous pressure, capillary pressure), the BP routinely measured is the arterial blood pressure of the systemic circulation. Arterial BP needs to be adequate for proper tissue perfusion, bringing oxygen, nutrients, hormones and electrolytes to the cells & to clear them of carbon dioxide and wastes. If BP is too low, tissue perfusion becomes inadequate, causing tissue hypoxia, acidosis, and disturbed function. Severe cases may present as shock. If BP is too high, it can cause the vessels to burst. Also, overperfusion can cause organ damage, pulmonary oedema, and generalised oedema.

BP is maintained within normal limits by various mechanisms involving the autonomic nerves, hormones and local factors. When regulation becomes ineffective, (dysregulation), disease states ensue. The effects of dysregulation may be transient and dismissed as insignificant or sustained and come under notice.

The following are clinical vignettes of blood pressure dysregulation.

 

Normal Blood Pressure

Although the heart pumps out blood only during systole, blood flow is continuous because of the motion created by elastic recoil of vessels during diastole. The adult systolic pressure is considered to be between 90-120 mm Hg and diastolic blood pressure between 60-90 mm Hg. The systolic blood pressure is contributed mainly by cardiac output and diastolic blood pressure by elastic recoil.

Variations in blood pressure

Physiological variations

Since heart rate is a determinant of blood pressure, physiological variations in blood pressure occur with changes in heart rate, which fluctuates readily. Thus, blood pressure (especially systolic BP) rises in exercise, excitement, in hot environments, raised BMR, and consumption of caffeine-containing drinks. There is also a circadian variation in blood pressure, the highest readings being obtained in the late evening and lowest readings observed during sleep. The reduction in blood pressure during sleep is termed “dipping”. Women usually have lower BP than men. Blood pressure is much lower at birth (about 50/30 mm Hg), rising steadily to reach adult values by adolescence. It is therefore extremely important to measure blood pressure at the same time of day in a thermally comfortable room after adequate rest, and preferably having abstained from caffeine- containing drinks; and to take gender and age into consideration.

Posture influences blood pressure. The effect of gravity is venous pooling in dependent parts of the body. Thus, blood pressure is raised in readings with the arm below heart level.  Standing up causes an initial drop in BP because of venous pooling in the legs; the sympathetic system is activated and BP is raised to levels above supine BP. Assumption of the left lateral position from supine position lowers the BP by 20-30 mm Hg. (In the “roll over test” done in the third trimester, a rise of more than 20 mm Hg on changing from left lateral to supine position is taken as positive for predicting pregnancy-induced hypertension/ pre-eclampsia.)

The systolic BP may rise in the third trimester of pregnancy due to increased blood volume; and diastolic blood pressure may be lower due to progesterone which causes relaxation of smooth muscles.  Blood pressure tends to rise with age. When blood vessels become thickened and arteries become less elastic with age, the diastolic blood pressure rises. SBP higher than  120 mm Hg and DBP >80 mm Hg is now considered as hypertension.

Fig.1- Physiological variations in arterial blood pressure

Source- unidentified

Pathological variations

BP variations may result from pathological conditions and present as low, high or fluctuations in BP or as failure of cardiovascular reflexes that normally correct BP altered by challenges like exercise, postural changes, fluid loss. The failure of regulation may be termed “dysregulation” and results from dysfunction of the autonomic system, endocrine disorders affecting sodium and water homeostasis, involvement of the renin-angiotensin system (RAS) and syndromes affecting renal function.

Regulation of blood pressure

Blood pressure is defined as the lateral pressure exerted on the wall of the blood vessel by the contained blood. This pressure is the product of how much blood comes in (a determinant of the cardiac output) and how much blood is prevented from leaving (peripheral resistance). Thus, Blood Pressure (BP) = Cardiac Output x Total peripheral resistance. (TPR)

Cardiac output is a product of heart rate (HR) and stroke volume (SV). TPR is maintained by arteriolar tone which is a function of the alpha adrenergic sympathetic stimuli originating from the vasomotor centre (VMC). Superimposed on this inherent tone are the influences of local and circulating hormones, chemicals, temperature and blood gases. The sympathetic nervous system also influences HR and SV. Stroke volume is determined by (a) the end –diastolic volume (EDV) (also termed the “preload” which favours ventricular contraction ) which is dependent on venous return (b) myocardial contractility which depends on the state of the cardiac muscle, sympathetic activity, pH (c) resistance offered by the aortic valve (aortic impedance; also known as “after load” which increases cardiac workload). Venous return is increased by increased blood volume, inspiration (“thoracic pump”), contraction of leg muscles (“muscle pump”), venoconstriction (sympathetic effect), lying down posture (about 700 ml added ).

Fig.2- Determinants of arterial blood pressure

TPR is maintained by its inherent vascular tone which is an alpha adrenergic effect. Vasoactive substances influence vascular tone .

Table 1– Vasoactive substances

Because blood pressure variations occur continuously throughout the 24 hours, mechanisms to regulate it and keep it within the “set point” need to be in place. These homeostatic processes occur as short-term regulations (“moment-to-moment” regulation) mediated through the baroreceptors (arterial and aortic sinuses) and peripheral chemoreceptors

(arterial and aortic bodies); and long-term regulations mediated through the renin-angiotensin system (RAS).  The thirst and ADH mechanisms also influence blood pressure indirectly, through regulation of blood volume.

Short-term regulation of blood pressure

The short-term regulation depends on switch on/ switch off of the sympathetic nervous system and the balance between it and the vagus. The effect of sympathetic stimulation is   (a) an increase in heart rate (positive chronotropic effect), stroke volume (positive inotropic effect) and conduction rate (positive dromotropic effect). (b) venoconstriction (facilitates venous return) and arteriolar vasoconstriction (increases TPR) (c)on the adrenal medulla (“sympathoadrenal axis”) where it causes release of catecholamines which in turn cause an increase in heart rate, stroke volume, and vasoconstriction. Vagal stimulation exerts a negative chronotropic, inotropic and dromotropic effect. It is noteworthy that the parasympathetic system does not directly cause vasodilation because it does not innervate blood vessels except those of salivary glands, glands of the gastrointestinal tract and erectile tissue in males.

1. The baroreceptor reflex

Baroreceptors present in the aortic and carotid sinus are responsive to stretch.They are stimulated when blood pressure rises, and stimulates (a) the inhibitory neurone and (b) dorsal motor nucleus of the vagus in the vasomotor centre. The inhibitory neurone inhibits discharge of the descending neurone which stimulates the sympathetic neurones, switching off sympathetic discharge. At the same time, the vagus is activated to exert negative inotropic & chronotropic effects on the heart. When blood pressure falls, the discharge from the baroreceptors fall, and the   inhibition of the sympathetic system is removed, thus: switching on” the effects of sympathetic stimulation. The peripheral chemoreceptors also send impulses to the vasomotor centre and activate sympathetic discharge.

Fig.3- The baroceptor reflex.

2.The oculocardiac reflex ¹

Pressure on the eyeball or nearby structures causes bradycardia and hypotension. Arrhythmias  ( junctional rhythms, heart block) and cardiac arrest  have been reported  in extreme cases). The reflex has most often been encountered during ophthalmologic procedures such as strabismus surgery, though it has also been seen in cases of facial trauma, regional anesthetic nerve blocks, and mechanical stimulation. A fall in heart rate by more than 10-20% is clinically significant.

3. Bezold-Jarisch Reflex²

This is also known as the  “Veratridine Reflex” and was discovered during experiments to test parasympathetic function.  Injection of veratridine into the left ventricle caused a triad of hypotension, bradycardia, reduced respiratory rate/apnoea.

Clinically, it may occur with administration of anaesthetic agents, rapid intravenous infusion of some agents, recovery from inferior MI, profound blood loss or hypovolaemia in the presence of vigorous ventricular contraction.   Drugs which can trigger this reflex are nicotine, capsaicin, ANP, prostanoids, nitrovasodilators, AT1 antagonists, serotonin agonists , verapamil, adenosine.

It is thought to protect the heart during extreme conditions such as excessive ventricular contraction in a hypovolaemic state. It reduces cardiac workload and prevents further damage to a heart contracting too forcefully when the ventricle is nearly empty.

4.Bainbridge Reflex

An increase in venous return and atrial stretch causes an increase in heart rate and contractility, preventing damming of blood in atria, veins and pulmonary circulation.

5.Cushing Reflex ( Cushing’s Triad)

An increase in intracranial pressure ( due to brain injury, haemorrhage or tumours) causes the triad of hypertension, bradycardia and irregular respiration.Raised ICP impedes cerebral perfusion. This is compensated by a rise in BP which avtivates the baroceptors. Bradycardia results.  Pressure on the respiratory centres cause irregular respiration. N.B. HR and BP usually go in the same direction but are in opposite directions in this case.

It is a late and ominous sign of ICP, often indicating impending herniation. Immediate medical intervention is crucial.

6. Cardiac arrest caused by sudden inrush of water into nose In London in the late 20^th Century, the “Brides in the Bath” murders were committed by George Joseph Smith ³ ( who used other aliases to marry different women  ) who drowned three of his wives in bathtubs to collect financial benefits. No signs of foul play were seen, and no case was opened against him at first but the cases made the headlines and the similarity of the cases and the same man in the pictures  drew suspicion. Experiments  by Scotland Yard later revealed that he would have held the ankles and  yanked the women up suddenly. Their heads went under water , and the sudden inrush of water into the mouth & nose caused a blackout.

Long -term regulation of blood pressure

The renin -angiotensin system (RAS) is central to the long-term regulation of blood pressure. A fall in blood volume or blood pressure stimulates the juxtaglomerular apparatus in the kidneys to release renin which acts on angiotensinogen, an alpha2 globulin produced by the liver, to form angiotensin I. Angiotensin I (ANG I) is cleaved into angiotensin II (ANG II) by the angiotensin converting enzyme (ACE) present in the lungs. ANG II is the most potent circulating vasoconstrictor identified. It also stimulates aldosterone release from the adrenal cortex, promoting water and sodium retention, increase in blood volume, venous return, stroke volume and cardiac output.

When there is an expansion of ECF volume e.g after drinking large amounts of water to allay thirst induced by ingestion of salty food, the increase in venous return to the right atrium causes release of atrial natriuretic peptide (ANP) which causes natriuresis and diuresis.

 

Fig.4- Long-term regulation of blood pressure

Blood Pressure Dysregulation

Dysregulation of BP may manifest as transient or sustained inability to maintain BP within normal limits. This may be caused by under- or overactivity of the sympathetic system  ( dysautonomia/ dysfunction of the ANS) or hormones regulating BP : aldosterone, catecholamines, renin. Failure of BP homeostasis can present as transient or sustained fall/ rise of BP , or fluctuations. Hypotension may be seen in excessive fluid loss, sodium loss / inefficient retention of sodium ( salt-losing nephropathy e.g. Bartter Syndrome, Gitelman Syndrome, chronic tubulointerstitial disease; Addison’s disease), postural challenge ( orthostatic hypotension) . Hypertension may be  primary ( “ essential hypertension”) or secondary ( renal/ endocrine causes) ; the former contributes to 95% of cases. Renal ischaemia / renal artery stenosis ( “Goldblatt kidneys”) causes renin release and hypertension (“high renin hypertension”). Sodium retention and volume expansion inhibit the RAS. Hypertension resulting from this is termed “low renin hypertension”.

1.Postural Orthostatic Tachycardia Syndrome (POTS)⁴ is a specific form of dysautonomia. It is defined by a sustained increase in heart rate of at least 30 beats per minute in adults (40 bpm in adolescents) within 10 minutes of standing, without a significant drop in blood    pressure. It predominantly affects younger adults (especially women 15-50 years ) and is associated with orthostatic intolerance causing light-headedness, palpitations, fatigue and sometimes syncope. It can be idiopathic or secondary (viral infections, autoimmune disorders, prolonged bedrest, autonomic neuropathy, blood volume depletion, connective tissue disorders).

2. Orthostatic Hypotension (OH) ^5,6

OH is a sudden drop of BP caused by autonomic reflex failure, central or peripheral nervous system lesions, cardiac dysfunction, volume depletion, adverse medication effects, or  viral infections.  The main cause may be neuropathic, cardiogenic or mixed. Neuropathic causes include Parkinsonism, Shy-Drager Syndrome (multiple system atrophy ) and diabetic neuropathy. Hypothyroidism and Addison’s disease also present with OH . Medications that can cause OH include alpha- and beta blockers and others.

• Classical OH is present when a sustained reduction of systolic BP (SBP) ≥20 mm Hg or diastolic BP (DBP) ≥10 mm Hg within 3 minutes of active standing or on a head-up tilt (HUT) test ≥60°.
• Variants of OH include smaller, but symptomatic, reduction in SBP when the supine SBP is low (90–100 mm Hg) but drops well below this.
• In patients with supine hypertension (Standing BP is higher than supine BP in normal people, but reversed in autonomic neuropathy), higher diagnostic thresholds i,e. SBP/DBP decline ≥30/15 mm Hg may be more appropriate because the magnitude of the orthostatic BP fall depends upon baseline BP.
• Prevalence strongly correlated with age, ranging from <5% below age 50 to 20% above age 70
• OH is commonly seen in the elderly. When a person gets up suddenly, the BP falls due to venous pooling in the leg veins. The  sympathetic system can  restore the BP to normal very quickly in young people but the reflex is slow in the elderly.

Shy-Drager Syndrome⁷

First described in 1960 and reclassified in 1980 as multiple system atrophy (MSA) to better reflect its broad neurological impact, it is a rare neurodegenerative disorder affecting mainly males of 50-60 and is characterized by tremors, slow movement, muscle rigidity, postural instability (collectively known as Parkinsonism parkinsonism), autonomic dysfunction and ataxia. There is progressive degeneration of neurons in several parts of the brain including the basal ganglia, inferior olivary nucleus and cerebellum. Dysfunction of the autonomic nervous system commonly manifests as orthostatic hypotension, impotence, anhidrosis, dry mouth, urinary retention, incontinence, palsy of the vocal cords.

The integrity of the ANS can be assessed by head-up tilt (HUT), 3- minute stationary standing, 24-hour BP monitoring or the Valsalva manoeuvre. Sometimes, autonomic dysfunction is only discovered when a patient faints on the toilet bowl (straining at defaecation is similar to performing the Valsalva Manoeuvre i.e. forced expiration against a closed glottis.

Phase 1- pressure on great veins increases venous return; heart rate falls (Baroreceptor reflex)

Phase 2- venous return falls and BP falls, but is sustained by an increase in HR.

Phase 3- with sudden release of pressure, the great veins expand and BP falls .HR rises.

Phase 4- the fall in BP activates the baroceptor reflex and BP is raised to normal (sympathetic). HR falls as a consequence of BP rising ( vagus action).

Hypertension

Secondary hypertension

Renal causes of hypertension are caused through the excessive production of renin (“high renin hypertension”) or “low renin hypertension” which  results from ECF volume expansion as a result of excessive cortisol production as in Cushing’s Syndrome (cortisol in large amounts exhibits mineralocorticoid activity) or aldosterone production as in congenital adrenal hyperplasia. Hypertension caused by ingestion of candy containing liquorice, or drugs (prednisolone, oral contraceptives ) are reversible. Tumours like phaeochromocytomas cause hypertension by releasing catecholamines inappropriate to the needs of the body. Overactivity of the sympathetic nervous system causes hypertension.

Essential hypertension

The causes of essential hypertension have not been satisfactorily elucidated, but many factors have been proposed. Included are age, genes (being of African or Caribbean origin ), high salt intake, sedentary lifestyles, obesity, chronic sleep deprivation, alcohol, smoking^8.

1. Age – It is a common observation that BP rises after 60. The American Heart Association estimated that almost 80 per cent of adults over 75 have hypertension. Thickening of arteries, loss of elasticity and unhealthy lifestyles are contributory factors.
2. Genes- Intense research has identified the genes causing hypertension.Hypertension is a key feature of some rare genetic disorders, including familial hyperaldosteronism, pseudohypoaldo -steronism type 2, Liddle syndrome, Bartter syndrome, Gitelman syndrome, and some  tumors⁹. Inbreeding between rats with higher blood pressures produced the Dahl salt-sensitive rats at the 19^th Cross-transplantation of kidneys between normotensive and SHR(spontaneously hypertensive rats) has shown that the “pressure follows the kidneys” i.e. the SHRs became normotensive and the normotensive rats developed hypertension.
3. Salt-sensitivity – High salt intake has long been implicated in the pathogenesis of hypertension. It was noted that the rise in blood pressure with age is not seen in communities ingesting less than 50 mmol of sodium per day^10,11. Guyton ¹¹ explained the rise in blood pressure associated with high salt intake as a reflex vasoconstriction to the high perfusion rates resulting from increased ECF volume; the raised blood pressure facilitates natriuresis and diuresis. However, this explanation may not fit all cases. ECF volume expansion is not demonstrable in all cases and other factors may play a role. There seems to be a subset of salt sensitivity because not all hypertensive patients benefit from salt restriction. A recent study from the USA reported that out of 56.8% of population having hypertension or salt sensitivity or both, 30.4% was hypertensive, of which only 11.6 % was salt-sensitive⁸. Endothelial dysfunction has been implicated ⁹and gene mutations and oxidative stress have been demonstrated in SHR (spontaneously hypertensive rats) ¹²
4. Sedentary lifestyles –Being inactive can lead to high blood pressure, elevated cholesterol, and increased risk of heart disease and stroke. Reduced movement impairs circulation, promoting atherosclerosis and other cardiovascular issues.
5. Obesity-A 2020 review estimates that obesity accounts for  65-78% of cases of primary hypertension. Obesity-induced hypertension can result from various mechanisms, including an overactive nervous system, kidney pressure, and resistance to hormones like leptin and insulin. Leptin is a substance released by fat cells to cause satiety. Resistance to leptin by the brain abolishes the sensation of satiety. Insulin resistance results in high insulin levels which favour sodium reabsorption in the kidneys In cases of visceral obesity, pressure on the kidneys stimulates renin release and activation of the RAS.
6. Chronic sleep deprivation-BP dips by 10-20% during sleep. Sleep deprivation prevents this dipping and the heart loses the chance to relax. Sleep loss favours cortisol secretion , stimulation of sympathetic system and insulin resistance. Sleep loss also causes endothelial dysfunction and body fluids homeostasis.
7. Alcohol- Possible pathophysiologic mechanisms involve endothelial dysfunction, vasoconstriction, sympathetic activation, and activation of the renin-angiotensin-aldosterone system.
8. Smoking – Smoking stimulates the sympathetic nervous system , cause damage to the endothelium, and induces inflammation and oxidative stress. It also accelerates atherosclerosis and activates the RAS.
9. The brain RAS – has also been proposed as a contributor to the pathogenesis of hypertension.

(10).Overactivity of the sympathetic system

The overall picture of pathogenesis involves interaction between genetic and environmental factors influencing sodium homeostasis, vascular structure and reactivity,

Principles of management

Management of dysregulation is towards treating the cause and controlling the BP. In the case of hypertension, alpha blockers can counteract vasoconstriction, beta blockers slow the heart and inhibit renin secretion . Angiotensin converting enzyme inhibitors block conversion of ANG I into ANG II (which is more potent than ANG I) and angiotensin receptor inhibitors block the actions of angiotensin. Calcium channel blockers also inhibits vasoconstriction.

References

1. Katz,S.& Rosenbaum,A (2012).Oculocardiac reflex. A Review. Journal of Pediatric Ophthalmology & Strabismus. 49(6),346-351.
2. Bezold-Jarisch Reflex-StatPearls(NCBI Bookshelf, 2025 update).https://www,ncbi.nlm.nih.gov/books/NBK557611)
3. George Joseph Smith-overview of the case and its significance –Wikipedia
4. Arnold, A.C., Ng,J., Raj,S.R. and Shibao, C. (2018). Postural tachycardia syndrome – Diagnosis, physiology and prognosis. Autonomic Neuroscience 215,3-11.
5. Fedorowski, A. (2019). Orthostatic hypotension: pathophysiology, diagnosis and treatment. Journal of Internal Medicine .285(4).373-390.
6. Mayo Clinic (2023). Orthostatic Hypotension(postural hypotension).https://www.mayoclinicorg.
7. Mayo Clinic (2023). Multiple System Atrophy- symptoms and causes. https://www. mayoclinicorg.
8. Carretero OA &OParil S (2000). Essential Hypertension . 101. 329-335.
9. Genetics Home Reference. https://ghr.nlm.nih.gov/condition/hypertension
10. Hollenberg NK, Martinez G, McCullough M, Meinking T, Passan D, Preston M, Rivera A, Taplin D &Vicaria-Clement ( 1997). Aging, Acculturation, Salt Intake, and Hypertension in the Kuna of Panama. 1997;29:171–176
11. Guyton AC. Blood pressure control: special role of the kidneys and body fluids. 1991;252:1813–1816
12. Leckie BJ. Polymorphisms of the renin gene promoter in spontaneously hypertensive and Wistar-Kyoto rats. ClinExpPharmacol Physiol. 2001;28:60–63

Author information

MBBS(Rgn); MSc (Mdy); PhD (Lond); FRCP(Edin)(Hon); FRCP(Lond.)(Hon) Cert.in Leadership for Physician Educators (Harvard Business School)

Former Professor & Head, Department of Physiology, Institute of Medicine 1; Former Professor of Physiology, The International Medical University, Kuala Lumpur.