The Renin-Angiotensin System
Angiotensin II, an octapeptide, is the most active endogenous vasoconstrictor agent identified to date, with an especially marked influence on the renal vasculature. A marked reduction in blood flow to the kidney occurs with doses that are well below those required to induce a pressor response (Mandel & Sapirstein 1962, Schmid 1962, DeBono et al. 1963, Hollenberg et al. 1972, 1975, 1976). A number of reviews have stressed the possibility that angiotensin functions as a renal hormone (Schmid 1962, Brown et al. 1972, sokabe 1974).
Renin, a proteolytic enzyme, is produced primarily in the renal cortex, with much smaller amounts being found in the uterus, placenta, salivary glands, brain and some blood vessels (Smeby & Bumpus 1968). In the kidney it is synthesized in specialized cells in the juxtaglomerular apparatus in intimate contact with the vascular pole of the glomerulus; thus secretion occurs immediately adjacent to the afferent and efferent arterioles (Barajas 1972).
The renin acts on an oc-globulin that serves as substrate to split off an inactive precursor decapeptide, angiotensin I. A specific converting enzyme, recently demonstrated to be present in the juxtaglomerular apparatus of the kidney (Granger et al. 1972, Leekie et al. 1972), splits two amino acids off the decapeptide to form the active moiety, angiotensin 11.
Because the largest concentration of converting enzyme is found in the lung, it was until recently believed that conversion occurred only there (Ng & Vane 1967). On this basis the function of angiotensin II was considered to be primarily systemic, rather than intrarenal.
Three unrelated lines of evidence have evolved in the last 5 years which suggest, conversely, that there is a critical intrarenal focus for conversion and that angiotensin II is indeed a local renal vascular hormone. First, while the total amount of converting enzyme in the kidney is considerably smaller than that in the lung, the available converting-enzyme activity in the kidney is sharply localized to the juxtaglomerular apparatus, the area in which renin is released (Granger et al. 1972, Leckie et al. 1972).
Secondly, lymph draining the kidney contains considerably higher concentrations of angiotensin II than are found in either arterial or renal venous blood: it must have been generated Within the kidney (Bailie et al. 1971, 1972). Thirdly, specific competitive antagonists to converting enzyme-have been identified. Infusion of these agents into the renal artery blocks the local action of angiotensin I but not angiotensin II (DiSalvo et al. 1971).
Angiotensin I, therefore, must require conversion to angiotensin II for renal action, and that conversion must occur within the kidney. Taken in all, these observations demonstrate the capacity of the kidney to generate angiotensin II and the probability that it is generated in a strategic locus, adjacent to the afferent and efferent arterioles.
Homer Smith (1951) emphasized that the evolution of the kidney is essentially the evolution of salt and water regulation of the body. Viewed from this perspective, the phylogeny of the renin-angiotensin-aldosterone system provides insight into its role in the body economy and in the control of renal function.
Sokabe et al. (1968) demonstrated in euryhaline fish and eels placed in fresh water a striking increase in urine flow and glomerular filtration rate associated with an increase in the renin activity of the kidney; whereas adaptation to the salinity of sea water was associated with a decrease in urine flow, glomerular filtration rate and intrarenal renin activity.
Malvin and Vander (1967) were unable to demonstrate changes in plasma renin activity in marine teleosts and cetaceae during acute or chronic adaptation to fresh water, perhaps consistent with a more important intrarenal than systemic role of renin in these organisms.
Sokabe et al. concluded from their data that the renin-angiotensin system may regulate glomerular filtration rate in teleosts: renin secreted from the granular cells into the afferent arteriole formed angiotensin, which in turn constricted the efferent arteriole increasing glomerular filtration rate.
Renin activity and juxtaglomerular granules are not found in the kidneys of the most primitive living vertebrates, the cyclostomes and elasmobranchs (Nishimura et al. 1973). They confirmed, however, their presence in teleosts and tetrapods. A macula densa was never visualized in these fishes.
The amphibian, phylogenetically, represents the first vertebrate to venture from the protective environment of water and salt to air, where the defence of extracellular fluid volume takes on a new challenge. Capelli et al. (1970) pointed out that the appearance of the recurrent nephron and the macula densa in the amphibian may ‘represent the beginnings of a structural element within the nephron to aid electrolyte and volume homeostasis by sampling fluids reaching the distal segments of the nephron’.
There is little doubt that the renin-angiotensin system plays an important role in electrolyte homeostasis by controlling mineralo-corticoid secretion in the mammal, and Bern (1967) concluded that aldosterone ‘may be an invention of land living vertebrates’, appearing late in phylogeny. It seems likely from this overview that the renin-angiotensin system arose as a control mechanism for the kidney and that its role broadened with increasingly more ambitious ventures into new and more hostile environments (Sokabe 1974).
In view of the remarkable amount of attention focused on the role of the renin-angiotensin system in the control of aldosterone secretion, it is surprising that so little attention has been paid to a probable primary role of angiotensin as a local, renal hormone.
The amount of angiotensin required to reduce renal blood flow is astonishingly minute: as little as 0-1 ng/kg/min infused intravenously in normal subjects on a high sodium intake-ma dose which is only about 3 per cent of that required to raise blood pressure-systematically reduces renal blood flow (Hollenberg et al. 1976b).
The consequent change in plasma angiotensin II concentration is less than 3 pg/ml, well within the range of physiological fluctuation. Given the probability that angiotensin II is generated within the kidney, reviewed above, it would be astonishing if it did not have an important influence on the renal vasculature.
Angiotensin II induces a larger reduction in blood flow than in glomerular filtration rate in the isolated, perfused kidney (Krahe et al 1970, Regoli & Gauthier 1971), in the intact kidney m animals (Furuyama et al. 1967, Navar & Langford 1974) and in man (Bock & Krecke 1958, Finnerty 1962, Hollenberg et al. 1976b).
These studies performed on the kidney of the rabbit, cat, dog and man suggest an increase in the filtration fraction due to a predominant efferent arteriolar action, as was suggested in more primitive species by Sokabe et al. (1968). There is, in general, a good correlation between the reduction in renal blood flow, glomerular filtration rate and urine flow in animals (Schmid 1968, Navar & Langford 1974) and in man (Bock & Kucke 1958, Aurell 1969, Hollenberg et al. 1976b).
McGiff and Fasy (1965) concluded that the renal vascular response to angiotensin involved the sympathetic nervous system, since the responsiveness was reduced by denervation and also by guanethidine which prevents neural release of norepinephrine. The mechanism was not straightforward, however, since neither ganglionic nor oc-adrenergic blocking agents modified the response to angiotensin II.
Disalvo and Fell (1970) could find no influence of acute or chronic denervation or chronic reserpine treatment on the renal vascular response to angiotensin and suggested, therefore, that the renal vasoconstrictor action was largely independent of the renal vasomotor innervation. Alpha-adrenergic blockade also did not influence the response to angiotensin in normal man (Hollenberg et al. 1975).
In the normal animal and man (Brown & Peart 1962, Laragh et al. 1963, Navar & Langford 1974), a reduction in blood flow is accompanied by a reduction in urine flow rate and electrolyte excretion, with a striking reduction in urine sodium. This response is already evident with even the smallest angiotensin II dose required to influence the renal vasculature (Hollenberg et al. 1976).
In a number of circumstances, including some patients with essential hypertension (Brown & Peart 1962, Villarreal et al. 1967) or hepatic cirrhosis (Laragh et al. 1963, Gutman et al. 1973), angiotensin induces a diuresis and natriuresis, a response which only occurs with doses which raise blood pressure (Lever 1965).
Villarreal et al. (1967) found that some patients with essential hypertension responded to angiotensin with a striking diuresis. In these patients filtration rate tended to rise, with little or no blood flow reduction. In the other patients, in whom an antidiuresis occurred, both blood flow and filtration rate fell strikingly. Gutman et al. (1973) also demonstrated that renal blood flow fell and filtration fraction rose in nearly all patients with cirrhosis who did not respond to angiotensin with a natriuresis, but changed little in those who did.
Both observations are consistent with Schmid’s findings in the dog (1968). Renal vascular responses to angiotensin II are reduced markedly during the continuous exposure to large amounts of angiotensin, either exogenous (Furuyama et al. 1967, Kiil et al. 1969,
Caldicott at at. 1970) or endogenous, when the renin-angiotensin system is activated by restriction of sodium intake (Hollenberg et al. 1972, 1975), restriction of potassium intake (Hollen~ berg et al. 1975), or by oral contraceptive agents in the presence of any diet (Hollenberg et al. 19760). A similar phenomenon has been seen in the dog (Burger et al. 1976), where induction of anaesthesia with barbiturate activated the renin-angiotensin system and reduced both renal blood flow and the renal vascular response to angiotensin II strikingly. The blunting of the renal vascular response may reflect occupation of receptors by angiotensin, thus reducing the response to an additional administered agent (Thurston & Laragh 1975).
The recent development of pharmacologic agents which interrupt the renin angiotensin axis has made it possible to define further the role of angiotensin in determining the state of the renal vasculature. When renal blood flow is reduced by restriction of sodium intake in the dog (Freeman et al. 1973, Burger et al. 1976) or in the rabbit (Mimran et al. 1974, Warren & Ledingham 1975) the administration of an agent such as proprano101 which prevents renin release; a nonapeptide, SQ 20881 which prevents conversion of angiotensin I to angiotensin II; or a structural analogue of angiotensin II which acts as a competitive antagonist, increases renal blood flow.
None of these agents does so when the renin-angiotensin system is suppressed by a high salt intake. We have made similar observations in man. Pharmacological interruption of the renin-angiotensin system has reversed in part or in total the renal vascular responses in anaesthesia and trauma (Burger et al. 1976); in thoracic inferior vena cava obstruction (Freeman et al. 1973); in experimental heart failure (Freeman et al. 1975c); in haemorrhagic shock (Jakschik et al. 1974, Lachance et al. 1974); in impaired reflow following haemorrhagic hypo-f tension (Frega et al. 1973); and in'renal hypertension (Zimmerman 1973, Satoh & Zimmerman 1975).
Where assessed, glomerular filtration rate did not increase in parallel with the increase in renal blood flow (Freeman et al. 1973, 1975, Mimran et al. 1974, Bailie & Barbour 1975, Ishikawa & Hollenberg 1976). While this may reflect a predominant action of the blockers on the efferent arteriode-an interpretation which would certainly be consistent with available evidence on the primary locus of angiotensin action-all of the studies were complicated by a striking fall in blood pressure, which may have blunted the influence on glomerular filtration rate.
The blood pressure reduction during pharmacologic interruption of the renin-angiotensin system occurs not only in patients with secondary hypertension in whom the renin-angiotensin system is activated, but also in animals with activation of the renin-angiotensin system and 3 normal or reduced blood pressure (Freeman et al. 1973, 1975, Mimran et al. 1974, Ishikawa & Hollenberg 1976) and in patients with cirrhosis of the liver (Schroeder et al. 1975) and congestive heart failure (our unpublished observations). The resultant hypotension represents a limiting factor in the therapeutic potential of the angiotensin antagonists.
Several observations, however, have suggested that the renal vascular receptor for angiotensin II may differ sufficiently from other systemic vascular angiotensin receptors that more specific antagonists may be forthcoming. First, the renal vasculature is an order of magnitude more sensitive to angiotensin II than most vascular beds (Mandel & Sapirstein 1962). Secondly, 1-sar 8-ala angiotensin II, a structural analogue which acts as a partial agonist, produces only a modest pressor response and yet induces striking, doserelated renal vasoconstriction (Hollenberg et al. l976b).
Other vascular beds are much less responsive. Freeman et al. (1975) demonstrated an identical dose-response curve of the renal vasculature to angiotensin II and to a substance until recently considered to be a relatively inactive metabolite, the l-des-asp angiotensin heptapeptide. This observation was confirmed by Taub et al. (1975) and extended with the demonstration that angiotensin II and its l~des-asp heptapeptide analogue (‘angiotensin III’) showed total cross-tachyphylaxis and were equally sensitive to the antagonist action of octapeptide and heptapeptide analogues.
The heptapeptide analogues blocked the renal vasculature as effectively as did octapeptide analogues, but had a much smaller tendency to induce hypotension in, for example, the dog with partial thoracic caval occlusion, presumably because of a reduced affinity for angiotensin receptors in other vascular beds. Should these observations be generally applicable, these agents may be useful in reversing renal ischaemia in a host of conditions characterized by activation of the renin-angiotensin system, a reduction in renal blood flow and blunting of the vascular response to angiotensin.
These conditions include congestive heart failure, cirrhosis of the liver, complications of pregnancy, the renal response to trauma and shock, and selected patients with essential and secondary hypertension.
Taken in all, the available evidence suggests that angiotensin plays an important role in the control of the renal circulation and perhaps that this is its original, primitive function. Through its vascular action angiotensin has an important action on filtration and tubular reabsorption. The possibility that angiotensin has an additional, intraglomerular action was reviewed earlier.
Even more circumstantial but compelling evidence suggests that angiotensin also contributes to the renal response in a host of conditions characterized by renal vasoconstriction, a reduction in filtration rate and sodium retention.
The renin acts on an oc-globulin that serves as substrate to split off an inactive precursor decapeptide, angiotensin I. A specific converting enzyme, recently demonstrated to be present in the juxtaglomerular apparatus of the kidney (Granger et al. 1972, Leekie et al. 1972), splits two amino acids off the decapeptide to form the active moiety, angiotensin 11.
Because the largest concentration of converting enzyme is found in the lung, it was until recently believed that conversion occurred only there (Ng & Vane 1967). On this basis the function of angiotensin II was considered to be primarily systemic, rather than intrarenal.
Three unrelated lines of evidence have evolved in the last 5 years which suggest, conversely, that there is a critical intrarenal focus for conversion and that angiotensin II is indeed a local renal vascular hormone. First, while the total amount of converting enzyme in the kidney is considerably smaller than that in the lung, the available converting-enzyme activity in the kidney is sharply localized to the juxtaglomerular apparatus, the area in which renin is released (Granger et al. 1972, Leckie et al. 1972).
Secondly, lymph draining the kidney contains considerably higher concentrations of angiotensin II than are found in either arterial or renal venous blood: it must have been generated Within the kidney (Bailie et al. 1971, 1972). Thirdly, specific competitive antagonists to converting enzyme-have been identified. Infusion of these agents into the renal artery blocks the local action of angiotensin I but not angiotensin II (DiSalvo et al. 1971).
Angiotensin I, therefore, must require conversion to angiotensin II for renal action, and that conversion must occur within the kidney. Taken in all, these observations demonstrate the capacity of the kidney to generate angiotensin II and the probability that it is generated in a strategic locus, adjacent to the afferent and efferent arterioles.
Homer Smith (1951) emphasized that the evolution of the kidney is essentially the evolution of salt and water regulation of the body. Viewed from this perspective, the phylogeny of the renin-angiotensin-aldosterone system provides insight into its role in the body economy and in the control of renal function.
Sokabe et al. (1968) demonstrated in euryhaline fish and eels placed in fresh water a striking increase in urine flow and glomerular filtration rate associated with an increase in the renin activity of the kidney; whereas adaptation to the salinity of sea water was associated with a decrease in urine flow, glomerular filtration rate and intrarenal renin activity.
Malvin and Vander (1967) were unable to demonstrate changes in plasma renin activity in marine teleosts and cetaceae during acute or chronic adaptation to fresh water, perhaps consistent with a more important intrarenal than systemic role of renin in these organisms.
Sokabe et al. concluded from their data that the renin-angiotensin system may regulate glomerular filtration rate in teleosts: renin secreted from the granular cells into the afferent arteriole formed angiotensin, which in turn constricted the efferent arteriole increasing glomerular filtration rate.
Renin activity and juxtaglomerular granules are not found in the kidneys of the most primitive living vertebrates, the cyclostomes and elasmobranchs (Nishimura et al. 1973). They confirmed, however, their presence in teleosts and tetrapods. A macula densa was never visualized in these fishes.
The amphibian, phylogenetically, represents the first vertebrate to venture from the protective environment of water and salt to air, where the defence of extracellular fluid volume takes on a new challenge. Capelli et al. (1970) pointed out that the appearance of the recurrent nephron and the macula densa in the amphibian may ‘represent the beginnings of a structural element within the nephron to aid electrolyte and volume homeostasis by sampling fluids reaching the distal segments of the nephron’.
There is little doubt that the renin-angiotensin system plays an important role in electrolyte homeostasis by controlling mineralo-corticoid secretion in the mammal, and Bern (1967) concluded that aldosterone ‘may be an invention of land living vertebrates’, appearing late in phylogeny. It seems likely from this overview that the renin-angiotensin system arose as a control mechanism for the kidney and that its role broadened with increasingly more ambitious ventures into new and more hostile environments (Sokabe 1974).
In view of the remarkable amount of attention focused on the role of the renin-angiotensin system in the control of aldosterone secretion, it is surprising that so little attention has been paid to a probable primary role of angiotensin as a local, renal hormone.
The amount of angiotensin required to reduce renal blood flow is astonishingly minute: as little as 0-1 ng/kg/min infused intravenously in normal subjects on a high sodium intake-ma dose which is only about 3 per cent of that required to raise blood pressure-systematically reduces renal blood flow (Hollenberg et al. 1976b).
The consequent change in plasma angiotensin II concentration is less than 3 pg/ml, well within the range of physiological fluctuation. Given the probability that angiotensin II is generated within the kidney, reviewed above, it would be astonishing if it did not have an important influence on the renal vasculature.
Angiotensin II induces a larger reduction in blood flow than in glomerular filtration rate in the isolated, perfused kidney (Krahe et al 1970, Regoli & Gauthier 1971), in the intact kidney m animals (Furuyama et al. 1967, Navar & Langford 1974) and in man (Bock & Krecke 1958, Finnerty 1962, Hollenberg et al. 1976b).
These studies performed on the kidney of the rabbit, cat, dog and man suggest an increase in the filtration fraction due to a predominant efferent arteriolar action, as was suggested in more primitive species by Sokabe et al. (1968). There is, in general, a good correlation between the reduction in renal blood flow, glomerular filtration rate and urine flow in animals (Schmid 1968, Navar & Langford 1974) and in man (Bock & Kucke 1958, Aurell 1969, Hollenberg et al. 1976b).
McGiff and Fasy (1965) concluded that the renal vascular response to angiotensin involved the sympathetic nervous system, since the responsiveness was reduced by denervation and also by guanethidine which prevents neural release of norepinephrine. The mechanism was not straightforward, however, since neither ganglionic nor oc-adrenergic blocking agents modified the response to angiotensin II.
Disalvo and Fell (1970) could find no influence of acute or chronic denervation or chronic reserpine treatment on the renal vascular response to angiotensin and suggested, therefore, that the renal vasoconstrictor action was largely independent of the renal vasomotor innervation. Alpha-adrenergic blockade also did not influence the response to angiotensin in normal man (Hollenberg et al. 1975).
In the normal animal and man (Brown & Peart 1962, Laragh et al. 1963, Navar & Langford 1974), a reduction in blood flow is accompanied by a reduction in urine flow rate and electrolyte excretion, with a striking reduction in urine sodium. This response is already evident with even the smallest angiotensin II dose required to influence the renal vasculature (Hollenberg et al. 1976).
In a number of circumstances, including some patients with essential hypertension (Brown & Peart 1962, Villarreal et al. 1967) or hepatic cirrhosis (Laragh et al. 1963, Gutman et al. 1973), angiotensin induces a diuresis and natriuresis, a response which only occurs with doses which raise blood pressure (Lever 1965).
Villarreal et al. (1967) found that some patients with essential hypertension responded to angiotensin with a striking diuresis. In these patients filtration rate tended to rise, with little or no blood flow reduction. In the other patients, in whom an antidiuresis occurred, both blood flow and filtration rate fell strikingly. Gutman et al. (1973) also demonstrated that renal blood flow fell and filtration fraction rose in nearly all patients with cirrhosis who did not respond to angiotensin with a natriuresis, but changed little in those who did.
Both observations are consistent with Schmid’s findings in the dog (1968). Renal vascular responses to angiotensin II are reduced markedly during the continuous exposure to large amounts of angiotensin, either exogenous (Furuyama et al. 1967, Kiil et al. 1969,
Caldicott at at. 1970) or endogenous, when the renin-angiotensin system is activated by restriction of sodium intake (Hollenberg et al. 1972, 1975), restriction of potassium intake (Hollen~ berg et al. 1975), or by oral contraceptive agents in the presence of any diet (Hollenberg et al. 19760). A similar phenomenon has been seen in the dog (Burger et al. 1976), where induction of anaesthesia with barbiturate activated the renin-angiotensin system and reduced both renal blood flow and the renal vascular response to angiotensin II strikingly. The blunting of the renal vascular response may reflect occupation of receptors by angiotensin, thus reducing the response to an additional administered agent (Thurston & Laragh 1975).
The recent development of pharmacologic agents which interrupt the renin angiotensin axis has made it possible to define further the role of angiotensin in determining the state of the renal vasculature. When renal blood flow is reduced by restriction of sodium intake in the dog (Freeman et al. 1973, Burger et al. 1976) or in the rabbit (Mimran et al. 1974, Warren & Ledingham 1975) the administration of an agent such as proprano101 which prevents renin release; a nonapeptide, SQ 20881 which prevents conversion of angiotensin I to angiotensin II; or a structural analogue of angiotensin II which acts as a competitive antagonist, increases renal blood flow.
None of these agents does so when the renin-angiotensin system is suppressed by a high salt intake. We have made similar observations in man. Pharmacological interruption of the renin-angiotensin system has reversed in part or in total the renal vascular responses in anaesthesia and trauma (Burger et al. 1976); in thoracic inferior vena cava obstruction (Freeman et al. 1973); in experimental heart failure (Freeman et al. 1975c); in haemorrhagic shock (Jakschik et al. 1974, Lachance et al. 1974); in impaired reflow following haemorrhagic hypo-f tension (Frega et al. 1973); and in'renal hypertension (Zimmerman 1973, Satoh & Zimmerman 1975).
Where assessed, glomerular filtration rate did not increase in parallel with the increase in renal blood flow (Freeman et al. 1973, 1975, Mimran et al. 1974, Bailie & Barbour 1975, Ishikawa & Hollenberg 1976). While this may reflect a predominant action of the blockers on the efferent arteriode-an interpretation which would certainly be consistent with available evidence on the primary locus of angiotensin action-all of the studies were complicated by a striking fall in blood pressure, which may have blunted the influence on glomerular filtration rate.
The blood pressure reduction during pharmacologic interruption of the renin-angiotensin system occurs not only in patients with secondary hypertension in whom the renin-angiotensin system is activated, but also in animals with activation of the renin-angiotensin system and 3 normal or reduced blood pressure (Freeman et al. 1973, 1975, Mimran et al. 1974, Ishikawa & Hollenberg 1976) and in patients with cirrhosis of the liver (Schroeder et al. 1975) and congestive heart failure (our unpublished observations). The resultant hypotension represents a limiting factor in the therapeutic potential of the angiotensin antagonists.
Several observations, however, have suggested that the renal vascular receptor for angiotensin II may differ sufficiently from other systemic vascular angiotensin receptors that more specific antagonists may be forthcoming. First, the renal vasculature is an order of magnitude more sensitive to angiotensin II than most vascular beds (Mandel & Sapirstein 1962). Secondly, 1-sar 8-ala angiotensin II, a structural analogue which acts as a partial agonist, produces only a modest pressor response and yet induces striking, doserelated renal vasoconstriction (Hollenberg et al. l976b).
Other vascular beds are much less responsive. Freeman et al. (1975) demonstrated an identical dose-response curve of the renal vasculature to angiotensin II and to a substance until recently considered to be a relatively inactive metabolite, the l-des-asp angiotensin heptapeptide. This observation was confirmed by Taub et al. (1975) and extended with the demonstration that angiotensin II and its l~des-asp heptapeptide analogue (‘angiotensin III’) showed total cross-tachyphylaxis and were equally sensitive to the antagonist action of octapeptide and heptapeptide analogues.
The heptapeptide analogues blocked the renal vasculature as effectively as did octapeptide analogues, but had a much smaller tendency to induce hypotension in, for example, the dog with partial thoracic caval occlusion, presumably because of a reduced affinity for angiotensin receptors in other vascular beds. Should these observations be generally applicable, these agents may be useful in reversing renal ischaemia in a host of conditions characterized by activation of the renin-angiotensin system, a reduction in renal blood flow and blunting of the vascular response to angiotensin.
These conditions include congestive heart failure, cirrhosis of the liver, complications of pregnancy, the renal response to trauma and shock, and selected patients with essential and secondary hypertension.
Taken in all, the available evidence suggests that angiotensin plays an important role in the control of the renal circulation and perhaps that this is its original, primitive function. Through its vascular action angiotensin has an important action on filtration and tubular reabsorption. The possibility that angiotensin has an additional, intraglomerular action was reviewed earlier.
Even more circumstantial but compelling evidence suggests that angiotensin also contributes to the renal response in a host of conditions characterized by renal vasoconstriction, a reduction in filtration rate and sodium retention.
Given the potential role that renin and angio-tensin play in the control of renal haemodynamics, the factors which determine renin release must be relevant to the control of the renal circulation. Recent reviews of the subject (Vander 1967, Davis & Freeman 1976) have indicated that at least three mechanisms control renin release from the kidney. First, pressure delivery to the juxtaglomerular apparatus represents an important determinant of renin release.
Second, sodium delivery to or transport within the macula densa region of the distal tubule represents a major contributing factor. Third, sympathetic activity operating upon beta receptors in the juxtaglomerular apparatus also promotes renin release. Conversely, the angiotensin concentration in the region of the juxtaglomerular apparatus blunts renin release, providing a homeostatic feedback control mechanism.
While there has been considerable debate concerning which factor has primacy, it is important to recognize that changes in pressure delivery to the region of the juxtaglomerular apparatus, sympathetic activity, and sodium reaching the distal tubule are not mutually exclusive phenomena, but rather might be expected to act in concert.
When a volume deficit is perceived, all three factors are likely to play a role in promoting renin release. A parallel reduction in renal blood flow is a consequence as well as a cause of the activation of the renin-angiotensin system.
Second, sodium delivery to or transport within the macula densa region of the distal tubule represents a major contributing factor. Third, sympathetic activity operating upon beta receptors in the juxtaglomerular apparatus also promotes renin release. Conversely, the angiotensin concentration in the region of the juxtaglomerular apparatus blunts renin release, providing a homeostatic feedback control mechanism.
While there has been considerable debate concerning which factor has primacy, it is important to recognize that changes in pressure delivery to the region of the juxtaglomerular apparatus, sympathetic activity, and sodium reaching the distal tubule are not mutually exclusive phenomena, but rather might be expected to act in concert.
When a volume deficit is perceived, all three factors are likely to play a role in promoting renin release. A parallel reduction in renal blood flow is a consequence as well as a cause of the activation of the renin-angiotensin system.