PATPHYSYOLOGY OF HYPERTENSION

Some of the causes of hypertension are known (e.g., renal or hormonal

abnormalities; !B2,3), but these forms make up only about 510% of all cases. In all others
the diagnosis by exclusion is primary or essential hypertension (!B1). Apart from a
genetic component, more women than men and more urbanites than country dwellers are
affected by primary H. In addition, chronic psychological stress, be it job-related (pilot, bus
driver) or personality-based (e.g., frustrated fighter type), can induce hypertension.
Especially in salt-sensitive people (ca. 13 of patients with primary H.; increased incidence
when there is a family history) the high NaCl intake (ca. 1015 g/d = 170250 mmol/d) in the
western industrialized countries might play an important role. While the organism is well
protected against Na+ loss (or diminished extracellular volume) through an increase in
aldosterone, those with an increased salt sensitivity are apparently relatively unprotected
against a high NaCl intake. In these patients, aldosterone release is so strongly inhibited
even at normal Na+ intake (> 100mmol/d) that it cannot be lowered any further. A diet
with low NaCl intake would in this case bring NaCl balance into the aldosterone regulatory
range. The actual connection between NaCl sensitivity and primary H. has not been
fully elucidated, but the possibility is being considered that responsiveness to
catecholamines is raised in people sensitive to NaCl. This results, for example, on
psychological stress, in a greater than normal rise in blood pressure, on the one hand, due
directly to the effect of increased cardiac stimulation (!B, upper right) and, on the other
hand, indirectly as a result of increased renal absorption and thus retention of Na+ (rise in
extracellular volume leads to hyperdynamic H.). The increased blood pressure leads to
pressure diuresis with increased Na+ excretion, restoring Na+ balance (Guyton). This
mechanism also exists in healthy people, but the pressure increase required for excretion of
large amounts of NaCl is much lower (!C, a ! b). In primary H. (as in disorders of renal
function) the NaCl-dependent increase in blood pressure is greater than normal (!C, c ! d). A
diet that is low in Na+ can thus lower (not yet fixed) H. in these cases (C, c ! e). A
simultaneously elevated K+ supply accentuates this effect for unknown reasons. The cellular
mechanism of salt sensitivity still awaits clarification. It is possible that changes in cellular
Na+ transport are important. In fact cellular Na+ concentration is raised in primary H., which
decreases the driving force for the 3 Na+/Ca2+ exchange carrier in the cell membrane, as a
result of which the intracellular Ca2+ concentration rises, which in turn increases the tone of
the vasoconstrictor muscles (Blaustein). It is possible that digitalislike inhibitors of Na+-K+ATPase are involved (ouabain?). They may be present in larger amounts, or there may be a
special sensitivity to them in primary H. Atriopeptin (= atrial natriuretic peptide [ANP]),
which has vasodilator and natriuretic effects, is probably not involved in the development of
primary H. Although the concentration of renin is not elevated in primary H., blood pressure
can be reduced even in primary H. by inhibiting the angiotensin-converting enzyme (ACE
inhibitors;
Neurogenic hypertension. Encephalitis, cerebral edemas or hemorrhage, and brain
tumors may lead to a massive rise in blood pressure via central nervous stimulation of the
sympathetic nervous system. An abnormally high central stimulation of cardiac action as
part of the hyperkinetic heart syndrome may also cause H.
The consequences of hypertension (!E) most importantly result from
atherosclerotic damage in arterial vessels (!p. 236ff.), which can be observed well by means
of fundoscopy. Because of the resulting increase in flow resistance, every form of
hypertension ultimately creates a vicious circle. Vascular damage finally leads to ischemia of
various organs and tissues (myocardium, brain, kidneys, mesenteric vessels, legs), renal
ischemia accelerating the vicious circle. Damage to the vascular walls together with
hypertension can, for example, lead to brain hemorrhage (stroke) and in the large arteries
(e.g., aorta) to the formation of aneurysms and ultimately their rupture (!p. 238). Life
expectancy is therefore markedly reduced.

A number of renal diseases can ultimately lead to the destruction of renal tissue (!
p.102ff., 114). If the residual renal tissue is not in a position to adequately fulfill its tasks, the
picture of renal failure evolves. Reduced renal excretion is particularly significant. The
decreased GFR leads to an inversely proportional rise in the plasma level of creatinine (!A,
top; see also p. 94). The plasma concentration of reabsorbed substances also rises, but
less markedly, because Renal tubular reabsorption is impaired in renal failure. The
reabsorption of Na+ and water is inhibited in renal failure by a variety of factors, such as
natriuretic hormone, PTH, and vanadate (!p.112). The reduced reabsorption of Na+ in the
proximal tubules also directly or indirectly decreases the reabsorption of other substances,
such as phosphate, uric acid, HCO3 , Ca2+, urea, glucose, and amino acids. The
reabsorption of phosphate is also inhibited by PTH. Reduced NaCl reabsorption in the
ascending limb compromises the concentrating mechanism (!p.100). The large supply of
volume and NaCl from parts of the proximal nephron promotes the reabsorption of Na+
distally and aids in the secretion of K+ and H+ in the distal nephron and in the collecting
duct. As a result, the plasma concentration of electrolytes can remain practically normal
even if GFR is markedly reduced (compensated renal insufficiency). Disorders occur only
once GFR has fallen to less than a quarter of the normal level. However, this compensation
is carried out at the cost of the regulatory range, in that the damaged kidney is unable
adequately to increase the excretion of water, Na+, K+, H+, phosphate, etc. (e.g., if oral
intake is increased). It is probably the disruption in renal water and electrolyte excretion that
is responsible, at least partially, for the development of most of symptoms of chronic renal
failure. Excess volume and the changed electrolyte concentrations lead to edemas,
hypertension, osteomalacia, acidosis, pruritus, and arthritis, either directly or via the
activation of hormones (!p.112). Also, abnormalities of the excitatory cells
(polyneuropathy, confusion, coma, seizures, cerebral edemas), of gastrointestinal
function (nausea, peptic ulcer, diarrhea), and of blood cells (hemolysis, abnormal
leukocyte function, abnormal blood clotting) are due to this. While uric acid can be
precipitated at high concentrations, especially in the joints, and thus cause gout (!p. 250),
sufficiently high concentrations of uric acid are only rarely achieved in renal failure. The role
of reduced elimination of so-called uremia toxins (e.g., acetone, 2,3-butyleneglycol,
guanidinosuccinic acid, methylguanidine, indoles, phenols, aliphatic and aromatic amines,
etc.) as well as of so-called middle molecules (lipids or peptides with a molecular weight of
3002000 Da) in producing the symptoms of renal failure remains the subject of
considerable debate. High concentrations of urea can destabilize proteins and bring about
cell shrinkage. But its effect is partly canceled by the cellular uptake of stabilizing osmolytes
(especially betaine, glycerophosphorylcholine). The impaired renal production of
erythropoietin leads to the development of renal anemia (!p. 30ff.), while the reduced
formation of calcitriol contributes to abnormalities of mineral metabolism (!p.112).
Depending on the cause and course of the disease, the intrarenal formation of renin and of
prostaglandins can be raised (!p.114) or reduced (death of renin- or prostaglandin-producing
cells). Increased formation of renin promotes, while its reduced formation inhibits, the
development of hypertension, a frequent occurrence in renal failure (!p.112ff.).
Prostaglandins, on the other hand, are more likely to cause vasodilation and a fall in blood
pressure (!p. 296). The loss of renal inactivation of hormones (!p. 92) may slow down
hormonal regulatory cycles. It is not clear, however, what the role of these changes is in the
development of symptoms. The reduced consumption of fatty acids by the kidney
contributes to hyperlipidemia, while reduced gluconeogenesis favors the developmentof
hypoglycemia.
Reduced renal elimination of water and electrolytes is particularly important in the
development of symptoms of renal failure (see also p.110). The extracellular volume
expands if there is an excess of NaCl and water (!A), and hypervolemia as well as edemas
develop (!p.122); pulmonary edema being the most dangerous complication (!p. 80). If it is
predominantly water which is in excess, the osmotically driven entry of water increases the
intracellular volume (!A) and there is a danger of cerebral edema (!p. 358). The
hypervolemia results in the release of atrial natriuretic factor (ANF) and probably also of

ouabain. The latter inhibits Na+/K+- ATPase (!A1). Vanadate (VNO4), which is largely
excreted by the kidney, has a similar effect. Its clearance is about the same as GFR and its
plasma level is markedly raised in renal failure. Inhibition of Na+/K+-ATPase causes
reduced Na+reabsorption in the kidney. Additionally, the intracellular K+ concentration falls
in cells from diverse tissues and the cells depolarize. The intracellular concentration of Na+
rises. This impairs 3Na+/Ca2+ exchange (!A2), and thus the intracellular concentration of
Ca2+ also increases. The consequences of depolarization are abnormal neuromuscular
excitability, cellular accumulation of Cl, and cell swelling (!A; see also p.10). The
increased Ca2+ concentration causes vasoconstriction as well as increased release of
hormones (e.g., gastrin, insulin) and increased hormonal effects (e.g., epinephrine).
Abnormalities of mineral metabolism also contribute greatly to the symptoms of renal
failure (!B). If the GFR is reduced to less than 20% of normal rate, less phosphate is filtered
than is absorbed through the gut. Even if the entire amount of filtered phosphate is
eliminated, i.e., there is no reabsorption, renal elimination cannot keep up with intestinal
absorption, and the plasma concentration of phosphate rises. When the solubility is
exceeded, phosphate combines with Ca2+ to form poorly soluble calcium phosphate. The
precipitated calcium phosphate is deposited in the joints and skin (causing joint pains or
pruritus, respectively).
When Ca2+ forms a complex with phosphate, the concentration of Ca2+ is lowered.
The hypocalcemia stimulates the release of PTH from the parathyroid gland, mobilizing
calciumphosphate from bone (!B). The result is demineralization of bone (osteomalacia).
Normally PTH makes it possible, by simultaneous inhibition of renal reabsorption of
phosphate, for the plasma concentration of phosphate to fall so that, despite mobilization of
calcium phosphate from bone, the solubility product in plasma is not exceeded and Ca2+
concentration can increase. In renal insufficiency, however, renal excretion cannot be
enhanced, plasma phosphate concentration increases, CaHPO4 is precipitated, and plasma
Ca2+ concentration remains low. The stimulus for PTH release therefore continues. Under
this persisting secretory stimulus the parathyroid glands hypertrophy and, in a vicious circle,
release ever larger amounts of PTH. As the receptors for PTH are, in addition to those in the
kidney and bones, in many other organs (nervous system, stomach, blood cells, gonads) it is
assumed that PTH plays a role in the development of abnormalities in these organs. In fact,
removal of the parathyroid glands is thought to significantly improve numerous symptoms of
renal failure. The formation of calcitriol is reduced in renal failure, which also plays a part in
causing the abnormalities of mineral metabolism. Normally this hormone stimulates the
absorption of calcium and phosphate in the gut (!B). Although calcitriol deficiency reduces
the intestinal absorption of phosphate, it aggravates the hypocalcemia. There are receptors
for calcitriol in various organs. Calcitriol substitution does not necessarily improve the
symptoms and endangers the patient with renal failure by stimulating the intestinal
absorption of phosphate.
Silbernagl, Stefan & Florian Lang. 2000. Color Atlas of Patophysiology. New York: Thieme p.
110-114