Other Endogenous Vasoactive Factors and Metabolic Products
There has long been interest in the role of the products of metabolism as determinants of vascular tone in various vascular beds (Furchgott 1966, Haddy & Scott 1970). Such products, including both specific substances such as the adenine nucleotides, lactic acid, hydrogen, potassium and magnesium ions and a general increase in osmotically active metabolites, dilate most vascular beds.
It is potentially important that all of these agents are vasoconstrictors only in the special case of the renal vasculature (Johnson & Lepley 1966, Haddy & Scott 1970, Caldicott & Hollenberg 1970, Wexler & Kao 1970). The reduction in renal blood flow that characteristically occurs in shock, after a period of renal ischaemia or with heavy exercise may be attributable to the products of metabolism.
It is potentially important that all of these agents are vasoconstrictors only in the special case of the renal vasculature (Johnson & Lepley 1966, Haddy & Scott 1970, Caldicott & Hollenberg 1970, Wexler & Kao 1970). The reduction in renal blood flow that characteristically occurs in shock, after a period of renal ischaemia or with heavy exercise may be attributable to the products of metabolism.
Before concluding that metabolic processes play an important role as a determinant of cortical perfusion, it is well to recall the lavish perfusion that the cortex enjoys: an average flow per gram of 3-5 ml/min exceeds by several fold the how per gram in Such metabolically active organs as the heart, brain, liver and skeletal muscle during exercise.
Perfusion is therefore clearly in excess of the ‘grocery function’ of a vascular supply in providing oxygen and substrate for oxidative processes. Indeed, the kidney is unique in that blood flow is ultimately a major determinant of oxygen utilization (Thaysen et al. 1961, Thurau 1964), whereas in most systems oxygen demand determines the level of perfusion and thus oxygen delivery.
Perfusion is therefore clearly in excess of the ‘grocery function’ of a vascular supply in providing oxygen and substrate for oxidative processes. Indeed, the kidney is unique in that blood flow is ultimately a major determinant of oxygen utilization (Thaysen et al. 1961, Thurau 1964), whereas in most systems oxygen demand determines the level of perfusion and thus oxygen delivery.
The major metabolic cost of renal function is the support of active tubular transport processes, especially those responsible for reabsorption of sodium. An increase in renal blood flow, to the extent that it is followed by an increase in glomerular filtration rate, will increase oxygen consumption. This is because an increase in filtration rate represents an increase in the total solute load presented to the tubules for reabsorption (Thurau 1964).
It is apparent that oxygen delivery must only rarely represent a rate-limiting step for function in the cortex, with its very high blood flow. One wonders whether the term ischaemia, frequently used to describe the renal cortex in a number of abnormal states, should be used in a manner analogous to that used for myocardium. When renal blood flow is reduced to 25 per cent of normal, the blood flow is equivalent to that of the normal myocardium. Moreover, total renal work is sharply reduced, because at such low flow rates the rate of glomerular filtration, and thus the load presented to the tubules for reabsorption, is sharply diminished.
It is apparent that oxygen delivery must only rarely represent a rate-limiting step for function in the cortex, with its very high blood flow. One wonders whether the term ischaemia, frequently used to describe the renal cortex in a number of abnormal states, should be used in a manner analogous to that used for myocardium. When renal blood flow is reduced to 25 per cent of normal, the blood flow is equivalent to that of the normal myocardium. Moreover, total renal work is sharply reduced, because at such low flow rates the rate of glomerular filtration, and thus the load presented to the tubules for reabsorption, is sharply diminished.
This development is clearly applicable only in the case of the renal cortex, where the plentiful renal blood flow provides an oxygen supply considerably in excess of local needs. Blood flow in the outer and inner medulla, on the other hand, is not plentiful, and it may well be that local flow in these regions is determined by local metabolic requirements. Direct evidence is gradually becoming available. Both the oxygen saturation of blood (Thurau 1964) and tissue p02 (Baumgartl et al. 1972) are considerably lower in the medulla than in the cortex.
The extracellular sodium concentration in the outer medulla is the primary determinant of local substrate oxidation (Aboduly & Lee 1971). Since that, in turn, must retiect predominantly the rate of sodium transport by the ascending limb of Henle’s loop, it seems likely that outer medullary blood flow is coupled to loop function. This may account for the apparent effect of loop diuretics on outer medullary blood flow (Birtch et al. 1967, Epstein et al. 1971).
The extracellular sodium concentration in the outer medulla is the primary determinant of local substrate oxidation (Aboduly & Lee 1971). Since that, in turn, must retiect predominantly the rate of sodium transport by the ascending limb of Henle’s loop, it seems likely that outer medullary blood flow is coupled to loop function. This may account for the apparent effect of loop diuretics on outer medullary blood flow (Birtch et al. 1967, Epstein et al. 1971).
A number of additional endogenous factors may play a role in the control of the renal circulation under certain circumstances. Activation of the complement cascade results in the release of the vasoactive substance anaphylatoxin, which is a cleavage product of the fifth complement component. This agent has a broad range of smooth muscle action, including a prominent vasoconstrictor influence on the kidney (von Friedberg et al. 1964, Jensen et al. 1972).
Fibrinopeptides are low-molecular weight polypeptides which are generated during the clotting cascade (Bayley et al. 1967) and which also have a number of smooth-muscle actions. In View of the potential importance of intravascular coagulation in states ranging from disseminated intravascular coagulation and the Shwartzman phenomenon to acute renal failure and glomerulonephritis, it would not be surprising if this class of agent acted as a determinant of renal perfusion in these settings.
The striking changes in renal blood flow, filtration rate and renal sodium handling which occur during pregnancy (Bucht 1951, Sims & Krantz 1958, Wesson 1969) have led to a series of systematic studies on the influence of oestrogens and progesterone on renal blood flow.‘ Neither bilateral oophorectomy nor the acute administration of even large doses of oestrogen alters renal perfusion in humans (Dean et al. 1945, Dignam et al. 1956, Chesley & Tepper 1967).
Large doses were reported to increase renal blood flow in the dog (Dance et al. 1959), but this was not reproducible (Johnson et al. 1972, Barnes 1973). Conversely, progesterone was reported to increase renal plasma flow in humans (Chesley & Tepper 1967) but not in the dog (Barnes 1973). Oral contraceptive agents, which contain both an oestrogen and progestin, reduced renal blood flow substantially in normal young women (Hollenberg et al. 19760), probably by way of activation of the renin-angiotensin system.
Their predominant action appears to involve the influence of oestrogen on the synthesis of renin substrate by the liver. Progestin in the oral contraceptive agents might also exert an indirect influence on the renin-angiotensin system, since these agents antagonize the action of aldosterone on the distal tubule of the kidney, and thus promote sodium excretion.
The sodium loss would also tend to stimulate renin secretion. It is probable that this pair of actions working in concert combine to produce the profound influence of oral contraceptive agents on renal perfusion. The increase in renal blood flow during pregnancy probably reflects a dominant action of progesterone.
Large doses were reported to increase renal blood flow in the dog (Dance et al. 1959), but this was not reproducible (Johnson et al. 1972, Barnes 1973). Conversely, progesterone was reported to increase renal plasma flow in humans (Chesley & Tepper 1967) but not in the dog (Barnes 1973). Oral contraceptive agents, which contain both an oestrogen and progestin, reduced renal blood flow substantially in normal young women (Hollenberg et al. 19760), probably by way of activation of the renin-angiotensin system.
Their predominant action appears to involve the influence of oestrogen on the synthesis of renin substrate by the liver. Progestin in the oral contraceptive agents might also exert an indirect influence on the renin-angiotensin system, since these agents antagonize the action of aldosterone on the distal tubule of the kidney, and thus promote sodium excretion.
The sodium loss would also tend to stimulate renin secretion. It is probable that this pair of actions working in concert combine to produce the profound influence of oral contraceptive agents on renal perfusion. The increase in renal blood flow during pregnancy probably reflects a dominant action of progesterone.