Renin – Angiotensin – Aldosterone System
Activation of the renin – angiotensin – aldosterone system is an important mechanism in the pathophysiology of heart failure as part of the counter-regulatory neurohormonal response to impaired cardiac output. In conjunction with sympathetic drive, there is an increase in peripheral vasoconstriction mediated by increased sympathetic tone and angiotensin II coupled with the salt and water retention induced by elevated aldosterone concentrations. Together, these increase preload and afterload on the heart, further compromising impaired ventricular function and setting up a vicious circle of heart failure.
Angiotensin – converting enzyme inhibitor drugs (ACE inhibitors) block this increase in aldosterone production and are effective drugs in the clinical management of chronic heart failure. In randomized controlled trials, ACE inhibitors have been shown to improve symptoms and reduce the incidence of further cardiac events including hospital readmission for heart failure, myocardial infarction and death.
Renin is synthesized and stored in the juxtaglomerular cells of the kidney. These are located in the walls of the afferent arterioles which supply the glomeruli (Fig. 36a). These arterioles also contain baroreceptors, which fire off in response to changes in flow rate and pressure. The cells of the macula densa are sensitive to changes in urinary cations such as Ca2+, Na2+ and Cl−. The afferent arterioles, the juxtaglomerular cells and the macula densa are together termed the juxtaglomerular apparatus.
Release. Renin is an enzyme with a molecular weight of about 40 kDa which is released in response to a rise in blood osmolarity or to hypovolaemia, although there are different theories as to what the physiological stimuli to release are. The theories are that:
1. the macula densa cells monitor changes in cations and pass this information to the adjacent juxtaglomerular cells;
2. the baroreceptors in the afferent arterioles fire off in response to changes in the mean renal perfusion pressure (the baroreceptors may be part of the juxtaglomerular cells themselves);
3. there is autonomic innervation of juxtaglomerular cells (sympathetic stimulation releases renin).
It is possible that all three theories are significant in the regula- tion of renin release.
Action. Renin cleaves angiotensinogen to angiotensin I in the plasma and kidney (Fig. 36b). Angiotensinogen is a globulin with a molecular weight of about 60 kDa, which is synthesized continuously in the liver and released in the circulation. Angiotensin I is converted into the biologically active form, the octapeptide angiotensin II, by a converting enzyme which occurs in plasma, vascular endothelial cells, kidney, lung and many other tissues. Angiotensin-converting enzyme (ACE) has another function in the inactivation of a potent vasodilator called bradykinin.
Angiotensin II is the most potent natural vasoconstrictor so far discovered. The hormone is rapidly inactivated by angiotensinase enzymes in the peripheral capillaries. One of the break-down metabolites, called angiotensin III, occurs in large amounts in the adrenal gland, and has been found to stimulate aldosterone release without significant vasopressor effect. Angiotensin III is a heptapeptide, resulting from the removal of the N-terminal aspartic acid from angiotensin II.
Actions of angiotensin II
1 Vascular smooth muscle and heart. Angiotensin II has a potent and direct vasoconstrictor effect on vascular muscle, and plays a critical role in the regulation of arterial blood pressure. There are marked regional differences in constrictor responses to angiotensin II in different vascular beds. Blood vessels in the kidney, mesenteric plexus and the skin are highly responsive to angiotensin II, while those in the brain, lungs and skeletal muscle respond less to administered peptide. In the heart, angi-otensin II acts on atrial and ventricular myocytes during the plateau phase of the action potential, to increase Ca2+ entry through voltage-gated channels, thereby prolonging the action potential, which increases the force of contraction of the heart.
2 Kidney. Angiotensin II regulates glomerular permeability, tubular Na+ and water reabsorption and renal haemodynamics. Angiotensin II has three important renal actions:
(a) It constricts the renal arterioles, especially the efferent arterioles, which lowers the glomerular filtration rate proportionately more than renal blood flow. This causes an increase in the osmolarity of blood feeding into the peritubular capillaries, which drives solutes and water back into the tubular cell and thence to the bloodstream.
(b) Angiotensin II has been shown to constrict glomerular mesangial cells, which also contributes to the fall in glomerular filtration rate.
(c) Angiotensin II has a direct action on the tubule cells to stimulate Na+ reabsorption.
3 Adrenal cortex. Angiotensin II alone, or through conversion to angiotensin III, acts on the glomerulosa cells to increase aldosterone synthesis.
4 Nervous system. Angiotensin II binds to specific presynaptic receptors on sympathetic nerve terminals to enhance norepinephrine release. It has been shown to depolarize adrenal medullary chromaffin cells, causing release of epinephrine, and, when injected directly into the brain, causes an increase in salt and thirst appetite. Angiotensin stimulates vasopressin release from the posterior pituitary gland, an effect potentiated by dehydration.
5 Water absorption. Angiotensin II stimulates Na+ and water absorption from the lumen of the gastrointestinal tract (GIT) at low doses. During dehydration, haemorrhage or salt loss, angiotensin II acts on the small intestine to limit loss, while aldosterone acts predominantly upon the large intestine to limit loss.
6 Cell proliferation. Angiotensin II has been shown to have trophic effects on smooth muscle vascular cells, fibroblasts, adrenocortical cells and human fetal kidney mesangial cells. The peptide appears to stimulate the production of specific proteins such as α-actin, and may play a role in repair following vascular injury.
Receptor subtypes. Angiotensin II receptor subtypes have been discovered using different analogues of angiotensin II. The AT1 receptor, acting through G proteins and the IP3 second messenger system, mediates the increase in blood pressure in extracellular volume and cell proliferation. The AT2 receptor may mediate cell proliferation.
Tissue distribution of receptor subtypes. Aortic smooth muscle cells, GIT, kidney, liver, lung, placenta and urinary bladder express exclusively AT1 receptors. Both AT1 and AT2 receptors are expressed in the brain, where AT1 receptors may mediate the central actions of angiotensin II on blood pressure, water and electrolyte balance, the renal arterioles, adrenal cells, heart and uterus. There is evidence for the existence of even more subtypes of angiotensin II receptors.
More recent studies have identified the presence of angiotensin II receptors on the nuclear membrane of cardiomyocytes, which activate NFk ß expression. This suggests a role for angiotensin directly on cardiac function.