Since the first identification of renin by Tigerstedt and Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system is characterized by an increased complexity, as evidenced by the discovery of new functional components and pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions. Recently, the research efforts studying these noncardiovascular effects of the RAS have intensified, and a large body of data are now available to support the existence of numerous organ-based RAS exerting diverse physiological effects. ANG II has direct effects at the cellular level and can influence, for example, cell growth and differentiation, but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions may be important in many organ systems and can mediate important physiological stimuli. Transgenic overexpression and knock-out strategies of RAS genes in animals have also shown a central functional role of the RAS in prenatal development. Taken together, these findings may become increasingly important in the study of organ physiology but also for a fresh look at the implications of these findings for organ pathophysiology.

Physiology of local renin-angiotensin systems.

Regulation of noradrenaline release by presynaptic receptor systems.

Renin-angiotensin system: biochemistry and mechanisms of action.

Background. Hypertension is a frequent complication of chronic renal failure, but its causes are not fully understood. There is indirect evidence that increased activity of the sympathetic nervous system might contribute to hypertension in patients with end-stage renal disease, but sympathetic-nerve discharge has not been measured directly in patients or animals with chronic renal failure. Methods. We recorded the rate of postganglionic sympathetic-nerve discharge to the blood vessels in skeletal muscle by means of microelectrodes inserted into the peroneal nerve in 18 patients with native kidneys who were undergoing long-term treatment with hemodialysis (of whom 14 had hypertension), 5 patients receiving hemodialysis who had undergone bilateral nephrectomy (of whom 1 had hypertension), and 11 normal subjects. Results. The mean (±SE) rate of sympathetic-nerve discharge was 2.5 times higher in the patients receiving hemodialysis who had not undergone nephrectomy than in the normal subjects (58±3 v...

https://www.nejm.org/doi/pdf/10.1056/NEJM199212313272704

Sympathetic overactivity in patients with chronic renal failure.

The purpose of this study was to relate baroreflex sensitivity to age and arterial pressure in 61 male and 20 female untreated subjects, aged 19-66 years, whose mean arterial pressures ranged from 70 to 150 mm Hg. In this selected group of subjects there was no correlation between age and arterial pressure. The index of sensitivity used was the increase in pulse interval which occurs reflexly in response to a rise in systolic pressure induced by the intravenous injection of phenylephrine and is measured as the increase in pulse interval in milliseconds per mm Hg rise in systolic blood pressure. It ranged from 1.9 to 48.9 msec/mm Hg. Increasing age and arterial pressure act independently to reduce baroreflex sensitivity. Eight subjects who had normal blood pressure at the time of testing but whose pressure had been elevated in the past, had reflex sensitivities significantly less than expected in persons of the same age and mean arterial pressure. The heart rate in these subjects was not significantly different from that in the controls; the heart rate of the 12 hypertensive subjects aged under 40 years was significantly faster than that of age-matched normotensive subjects but not that of older hypertensive subjects.

Effect of age and high blood pressure on baroreflex sensitivity in man.

The results of these experiments indicate that the carotid and aortic baroceptor mechanisms are reset to the hypertensive pressure levels of animals with chronic perinephritic hypertension. Thus, seemingly, the buffer reflexes tend to maintain, rather than prevent, the chronic phase of renal hypertension and are, presumably, an important component in the mechanism of chronic renal hypertension.

Baroceptor Function in Chronic Renal Hypertension

• During recent years the nature of the considerable contribution of the sympathetic nervous system to renal hypertension has become somewhat more clear, due in part to the unexpected discoveries that angiotensin is not simply a direct vasoconstrictor agent but is almost ubiquitous in its actions. Among these actions are several on the sympathetic nervous system that appear to intensify its effects on the peripheral vascular system. It stimulates release of catechols from the adrenal medulla (1); at certain dose levels it facilitates ganglionic transmission (2); and it sensitizes the neurovascular effector so that the effects of sympathetic vasomotor discharge are augmented (3). This latter effect may depend in part on prevention of reuptake of released norepinephrine (4). For a long time it was considered unlikely that angiotensin had any effect on the central nervous system since theoretically it does not cross the blood-brain barrier. Then Bickerton and Buckley (5), in 1961, cross-perfused the head of a recipient dog, isolated from its own circulation and connected to the body only by the spinal cord, with blood from a donor animal. When angiotensin was injected into the circulation of the donor animal it raised the systemic arterial pressure in the recipient's trunk as well as in the donor animal. Because

Cardiovascular Effects of Angiotensin Mediated by the Central Nervous System

Increased vasomotor discharge induced by bleeding caused renal release of renin in anesthetized dogs whether or not there was measurable change in either arterial pressure or total renal blood flow. Release of renin was prevented by ganglion blockade or local anesthesia of the renal nerves. Hemorrhage-induced release of renin occurred more consistently in dogs fed a low-sodium diet than in those fed a standard kennel diet. Stimulation of sympathetic vasomotor discharge by occlusion of the common carotid arteries, while renal perfusion pressure was kept constant, also caused release of renin, as did infusions of norepinephrine, tyramine, or DMPP. Isoproterenol, angiotensin, vasopressin, serotonin, or acetylcholine infused into the renal artery did not cause release of renin. It is concluded that neural stimuli are capable of causing release of renin in the absence of gross change in renal perfusion pressure or flow.

Neural Stimulation of Release of Renin

Renin secretion was found to be controlled by a renal baroreceptor rather than by ischemia. Development of a sensitive assay technique that detects renin in small quantities of renal venous and peripheral arterial plasma has permitted the demonstration that the rate of renin secretion varies inversely with the level of arterial pressure independently of renal blood flow. When mean renal perfusion pressure was reduced 5 to 40 mm Hg by a constricting band around the aorta above the level of the renal arteries, increased renin secretion commenced within 60 seeonds. Reductions of this magnitude did not necessarily cause mean perfusion pressure to fall below control levels of diastolic perfusion pressure. Rises in perfusion pressure had the reverse effect, reducing the rate of renin secretion again without measurable change in renal blood flow. Compression of the kidney within an oncometer by an applied forece of from 15 to 40 mm Hg also caused increases in the rate of renin secretion in the absence of change in total renal blood flow. Reduction of pulse pressure alone did not provoke secretion of renin, nor did reduced oxygen tension, or renal ischemia. Rise in perfusion pressure due to occlusion of the common carotid arteries was associated with reduction in the rate of renin secretion. A small amount of renin was secreted continuously under the conditions of these experiments; physiologic changes in mean perfusion pressure served to alter the rate. This suggests that a renal baroreceptor mechanism regulates renin secretion under normal circumstances and that arterial pressure tends to stabilize at a level at which renin secretion is minimal.

Control of Renin Secretion

Long-term infusion of amounts of angiotensin insufficient at the beginning to raise arterial pressure results, after several days in sustained arterial hypertension in unanesthetized dogs. This hypertension is to a large degree dependent on environmental stimuli, and results chiefly from increase in peripheral resistance. As in dogs with renal hypertension, there is increased pressor responsiveness to tyramine. This indirect action of angiotensin to increase total peripheral resistance and arterial pressure by an action on the sympathetic nervous system, along with an upward resetting of the carotid sinus buffering mechanism, might logically account for the neural component of chronic renal hypertension. Such a proposal integrates the humoral and neural elements of the mosaic describing the mechanisms of tissue perfusion.

https://science.sciencemag.org/content/sci/149/3690/1394.full.pdf

James W. Mccubbin

Papers

Baroceptor Function in Chronic Renal Hypertension

Cardiovascular Effects of Angiotensin Mediated by the Central Nervous System

Neural Stimulation of Release of Renin

Control of Renin Secretion

Arterial Hypertension Elicited by Subpressor Amounts of Angiotensin