Prostaglandins and the Kidney
Prostaglandins are a family of biologically active lipids synthesized in viva from a number of essential fatty acid precursors, especially arachidonic acid (Bergstrom et al. 1968). Although they were identified in the early 1930s, only in the last decade have they generated widespread interest, especially in relation to the kidney.
They have been detected in almost every tissue and body fluid, but the concentrations are especially high in the kidney (Lee et al. 1967, Crowshaw 1971); their production increases in response to an astonishingly diverse array of stimuli; a remarkably broad spectrum of effects occurs in virtually every system in response to minute amounts.
A powerful new tool for exploring the role of prostaglandins arose from the discovery that non-steroidal anti-inflammatory agents such as aspirin, indomethacin and meclofenamate interfere with prostaglandin synthesis (Vane 1971). Synthesis of the prostaglandins is accomplished sequentially by a series of microsomal enzymes referred to as ‘prostaglandin synthetase’ (Flower 1974).
While there are a number of classes and subclasses of prostaglandins, the most abundant, the most intensively studied and the most likely to be of physiological importance on the basis of current evidence are those of the E and F series. In the kidney the predominant prostaglandin is PGE1, with smaller but measurable quantities of PG 2 alfa (Lee et al. 1967, Crowshaw 1971, Larsson & Anggard 1973).
All investigators agree that the bulk of prostaglandin biosynthesis occurs in the renal medulla. While cortical synthesis of prostaglandins was initially denied (Crowshaw 1970, 1971) improved techniques subsequently demonstrated both significant biosynthesis in the renal cortex and that the renal cortex has much the
They have been detected in almost every tissue and body fluid, but the concentrations are especially high in the kidney (Lee et al. 1967, Crowshaw 1971); their production increases in response to an astonishingly diverse array of stimuli; a remarkably broad spectrum of effects occurs in virtually every system in response to minute amounts.
A powerful new tool for exploring the role of prostaglandins arose from the discovery that non-steroidal anti-inflammatory agents such as aspirin, indomethacin and meclofenamate interfere with prostaglandin synthesis (Vane 1971). Synthesis of the prostaglandins is accomplished sequentially by a series of microsomal enzymes referred to as ‘prostaglandin synthetase’ (Flower 1974).
While there are a number of classes and subclasses of prostaglandins, the most abundant, the most intensively studied and the most likely to be of physiological importance on the basis of current evidence are those of the E and F series. In the kidney the predominant prostaglandin is PGE1, with smaller but measurable quantities of PG 2 alfa (Lee et al. 1967, Crowshaw 1971, Larsson & Anggard 1973).
All investigators agree that the bulk of prostaglandin biosynthesis occurs in the renal medulla. While cortical synthesis of prostaglandins was initially denied (Crowshaw 1970, 1971) improved techniques subsequently demonstrated both significant biosynthesis in the renal cortex and that the renal cortex has much the
highest concentration of the enzyme which degrades the prostaglandins, 15-hydroxyprosta-glandin dehydrogenase (Larsson & Anggard 1973). There is continued debate on whether prostaglandin A, which Lee et al. (1967) identified in the kidney, is normally present, or represents an artifact which is formed chemically by dehydration and isomerization only during extraction (Vane & McGiff 1975) as originally suspected by Lee et al. (1967).
This is of some importance, since prostaglandins of the E and F series disappear rapidly from the circulation in their passage through the lung (Ferreira & Vane 1967) and thus are unlikely to have systemic effects. Prostaglandins of the A series are more resistant to destruction in the lung-and thus could subserve a systemic function (Lee 1972, 1974).
This is of some importance, since prostaglandins of the E and F series disappear rapidly from the circulation in their passage through the lung (Ferreira & Vane 1967) and thus are unlikely to have systemic effects. Prostaglandins of the A series are more resistant to destruction in the lung-and thus could subserve a systemic function (Lee 1972, 1974).
Major attention has been focused on the renal vascular effects of prostaglandins (Johnston et al. 1967, Bergstrom et al. 1968, Burger & Herd 1971, Itskovitz & McGiff 1974). Species differences exist, providing one difficulty in generalizing on their role. Prostaglandins of the E and A series are vasodilators in the rabbit, dog and man (Johnston et a! 1967, Hornych et al. 1973, Itskovitz & McGiff 1974, Malik & McGiff 1975) but are constrictors in the rat (Malik & McGiff 1975).
Prostaglandin F205, the second most prominent renal prostaglandin, has little influence on the renal vasculature in the dog, even in very high concentration (McGiff & Itskovitz 1973) but is an active renal vasoconstrictor in the rat and rabbit (Malik & McGiff 1975). In the dog the maximal renal blood flovv response to prostaglandin E1 is identical to that of the most active dilators, acetylcholine and bradykinin, and considerably in excess of all other active vasodilators tested, suggesting that it is capable of inducing maximal generalized renal vasodilatation (Abe & McNay 1970, Ozer & Hollenberg 1974).
Little is known of their inhuence in man, with the exception of prostaglandin A1 which is an active renal vasodilator (Hornyeh et al. 1973). With the exception of prostaglandin A1, all of the prostaglandins are metabolized effectively by the lung and thus are relatively inactive on intravenous administration, accounting for the paucity of information available on their actions in man.
Prostaglandin F205, the second most prominent renal prostaglandin, has little influence on the renal vasculature in the dog, even in very high concentration (McGiff & Itskovitz 1973) but is an active renal vasoconstrictor in the rat and rabbit (Malik & McGiff 1975). In the dog the maximal renal blood flovv response to prostaglandin E1 is identical to that of the most active dilators, acetylcholine and bradykinin, and considerably in excess of all other active vasodilators tested, suggesting that it is capable of inducing maximal generalized renal vasodilatation (Abe & McNay 1970, Ozer & Hollenberg 1974).
Little is known of their inhuence in man, with the exception of prostaglandin A1 which is an active renal vasodilator (Hornyeh et al. 1973). With the exception of prostaglandin A1, all of the prostaglandins are metabolized effectively by the lung and thus are relatively inactive on intravenous administration, accounting for the paucity of information available on their actions in man.
The high concentration of the major classes of prostaglandins in the kidney, their location in the renal medulla, their remarkable influence on renal blood flow and sodium excretion and the influence of synthetase inhibitors on a number of these functions have led to much speculation concerning the role of prostaglandins in normal renal function and disease.
Lonigro et al. (1973) found that synthetase inhibitors reduced renal blood flow in the anaesthetized dog, and demonstrated an excellent correlation between the reduction in prostaglandin E efflux and the change in renal blood flow, which suggested a tonic renal vasodilator influence of prostaglandins. The possible role played by anaesthesia in these results is discussed below.
Because the E series are vasodilators and result in a natriuresis it has been suggested that they may mediate the renal vascular and functional response to changing sodium intake (Johnston et al. 1967, Lee 1972, Fulgraff et al. 1974). The intrarenal site of synthesis and release of PGE and the effect of synthetase inhibitors on cortical how distribution led Itskovitz et al. (1974) to suggest that the prostaglandins are a major determinant of inner cortical and medullary blood flow.
Similar evidence has been used to suggest that the prostaglandins participate in renal autoregulation (Herbaczynska-Cedro & Vane 1973); in renal reactive hyperemia (Herbaczynska-Cedro & Vane 1974); in the renal response to haemorrhage and shock (Selkurt 1974, Bell et al. 1974, Data et al. 1976) and as a modulator of renal vascular responses to other endogenous vascular hormones, especially angiotensin and norepinephrine (Vane & McGiff 1975), as discussed below.
Lonigro et al. (1973) found that synthetase inhibitors reduced renal blood flow in the anaesthetized dog, and demonstrated an excellent correlation between the reduction in prostaglandin E efflux and the change in renal blood flow, which suggested a tonic renal vasodilator influence of prostaglandins. The possible role played by anaesthesia in these results is discussed below.
Because the E series are vasodilators and result in a natriuresis it has been suggested that they may mediate the renal vascular and functional response to changing sodium intake (Johnston et al. 1967, Lee 1972, Fulgraff et al. 1974). The intrarenal site of synthesis and release of PGE and the effect of synthetase inhibitors on cortical how distribution led Itskovitz et al. (1974) to suggest that the prostaglandins are a major determinant of inner cortical and medullary blood flow.
Similar evidence has been used to suggest that the prostaglandins participate in renal autoregulation (Herbaczynska-Cedro & Vane 1973); in renal reactive hyperemia (Herbaczynska-Cedro & Vane 1974); in the renal response to haemorrhage and shock (Selkurt 1974, Bell et al. 1974, Data et al. 1976) and as a modulator of renal vascular responses to other endogenous vascular hormones, especially angiotensin and norepinephrine (Vane & McGiff 1975), as discussed below.
In support of these hypotheses, several groups have demonstrated that the administration of arachidonic acid, the major prostaglandin precursor, also produces renal vasodilatation and a natriuresis in the dog (Bolger et al. 1975; Tannenbaum et al. 1975, Chang, LOT. et al. 1975) with a preferential increase in inner cortical perfusion (Chang, R.L.S. et al. 1975). In further support, the renal effects of arachidonic acid were inhibited by prostaglandin synthetase inhibitors (Bolger et al. 1975, Tannenbaum et al. 1975).
All studies reviewed on both the direct effects of prostaglandins per se, the influence of synthetase inhibitors and of arachidonic acid were performed in the anaesthetized dog. Before concluding that prostaglandins mediate many or all of these responses, it is important to note that Zins (1975) and Swain et al. (1975) independently discovered that prostaglandin synthetase inhibitors in adequate dosage did not influence resting renal blood flow or its intrarenal distribution in the conscious dog-man observation which was confirmed by Kirschenbaum and Stein (1976).
Swain er al. did note in conscious dogs and primates that both indomethacin and meclofenamate reduced reactive hyperaemia after arterial occlusion and enhanced“ the vascular response to the vasoconstrictors. methoxamine and angiotensin 11. They concluded that in the conscious animal prostaglandins play a minor role in the control of the renal circulation at rest, but might play a more important role in mediating the renal response to reactive hyperaemia and to vasoconstriction.
Swain er al. did note in conscious dogs and primates that both indomethacin and meclofenamate reduced reactive hyperaemia after arterial occlusion and enhanced“ the vascular response to the vasoconstrictors. methoxamine and angiotensin 11. They concluded that in the conscious animal prostaglandins play a minor role in the control of the renal circulation at rest, but might play a more important role in mediating the renal response to reactive hyperaemia and to vasoconstriction.
It is also reasonable to ask how specific the prostaglandin synthetase inhibitors are, since so many hypotheses have been predicated on their influence. Flower (1974) pointed out that these agents have a host of actions on other enzyme systems, and suggested that caution was warranted in interpreting their inducnce, even when unrelated synthetase inhibitors induced a similar response.
Particularly in high dosesas often used in the studies cited-indomethacin has had apparently non-specific effects on a number of smooth-muscle preparations (Northover 1968, Farmer et al. 1974). While it might be argued that any action of synthetase inhibitors in any smooth-muscle preparation reflected an influence on the prostaglandin system, this seems particularly unlikely in the experiments reported by Northover (1968), who demonstrated that the contractile effects of calcium and barium on smooth muscle were antagonized by indomethacin in moderately high concentration.
It is most unlikely that prostaglandins act distal to the calcium step in excitation-contraction coupling. Sanner ( 1974) has recently reviewed three principal types of specilic competitive prostaglandin antagonists which may prove useful in defining the physiological role of prostaglandins.
Particularly in high dosesas often used in the studies cited-indomethacin has had apparently non-specific effects on a number of smooth-muscle preparations (Northover 1968, Farmer et al. 1974). While it might be argued that any action of synthetase inhibitors in any smooth-muscle preparation reflected an influence on the prostaglandin system, this seems particularly unlikely in the experiments reported by Northover (1968), who demonstrated that the contractile effects of calcium and barium on smooth muscle were antagonized by indomethacin in moderately high concentration.
It is most unlikely that prostaglandins act distal to the calcium step in excitation-contraction coupling. Sanner ( 1974) has recently reviewed three principal types of specilic competitive prostaglandin antagonists which may prove useful in defining the physiological role of prostaglandins.
The possibility that prostaglandins participate in the control of the renal circulation by modulating responses to other vasoactive agents has also received considerable attention. McGiff and Itskovitz (1964) reported a striking loss of renal vascular responses to angiotensin II during renal ischaemia, which they later attributed to an offsetting influence of prostaglandins released during ischaemia (Itskovitz & McGiff 1974).
Angiotensin has a major influence on prostaglandin release which parallels the poorly sustained renal vascular response (McGiffet al. 1970). Moreover, prostaglandin synthetase inhibitors enhance the renal vascular effects of angiotensin (Aiken & Vane 1973); and there is evidence from studies with competitive antagonists to angiotensin that angiotensin mediates the prostaglandin release (Satoh & Zimmerman 1975).
Angiotensin has a major influence on prostaglandin release which parallels the poorly sustained renal vascular response (McGiffet al. 1970). Moreover, prostaglandin synthetase inhibitors enhance the renal vascular effects of angiotensin (Aiken & Vane 1973); and there is evidence from studies with competitive antagonists to angiotensin that angiotensin mediates the prostaglandin release (Satoh & Zimmerman 1975).
There has also been interest in prostaglandins as modulators of adrenergic transmission and responses to norepinephrine in the kidney. McGiff er al. (1972) reported that norepinephrine also induced a poorly sustained response in the kidney, which was associated with prostaglandin E release. In contrast, they found that renal nerve stimulation produced neither prostaglandin release nor early rapid recovery of renal blood flow and urine flow.
Dunham and Zimmerman, conversely, reported that nerve stimulation did induce renal prostaglandin release in the dog (1970), which was confirmed by Davis and Horton (1972) in the rabbit. Frame 61 al. (1974) reported that prostaglandin E2 inhibited markedly the vascular responses to nerve stimulation whereas responses to norepinephrine were not altered significantly. In situ, on the other hand, the renal vascular response to both nerve stimulation and norepinephrine was inhibited by PGE.
They concluded that PGE acted as a modulator primarily at the prejunctional level of adrenergic transmission, but with an additional postjunctional effect; i.e. that PGE modified both catecholamine release and, once they had been released, modified their action. Some of the difficulties may involve species differences, since Malik and McGiff(1975) confirmed that in the rabbit kidney prostaglandins of the E and A series inhibited vasoconstrictor responses to sympathetic nerve stimulation but did not alter those to norepinephrine.
Moreover, they extended the study to Show that in the rat kidney prostaglandins of the E and A series were not only active constrictors, they also enhanced the vasoconstrictor response to sympathetic nervous stimulation. Taken in all it is difficult to define a single theme, largely because of the striking species differences and the variable influence of anaesthesia.
Dunham and Zimmerman, conversely, reported that nerve stimulation did induce renal prostaglandin release in the dog (1970), which was confirmed by Davis and Horton (1972) in the rabbit. Frame 61 al. (1974) reported that prostaglandin E2 inhibited markedly the vascular responses to nerve stimulation whereas responses to norepinephrine were not altered significantly. In situ, on the other hand, the renal vascular response to both nerve stimulation and norepinephrine was inhibited by PGE.
They concluded that PGE acted as a modulator primarily at the prejunctional level of adrenergic transmission, but with an additional postjunctional effect; i.e. that PGE modified both catecholamine release and, once they had been released, modified their action. Some of the difficulties may involve species differences, since Malik and McGiff(1975) confirmed that in the rabbit kidney prostaglandins of the E and A series inhibited vasoconstrictor responses to sympathetic nerve stimulation but did not alter those to norepinephrine.
Moreover, they extended the study to Show that in the rat kidney prostaglandins of the E and A series were not only active constrictors, they also enhanced the vasoconstrictor response to sympathetic nervous stimulation. Taken in all it is difficult to define a single theme, largely because of the striking species differences and the variable influence of anaesthesia.
An important logical difficulty has been raised by these studies. They are internally inconsistent. McGiff and co-workers have used identical techniques, findings and logic to suggest that the poorly sustained responses to both angiotensin (1970) and norepinephrine (1972) are attributable to the resultant prostaglandin release, and offsetting vasodilatation.
If this were so, one would anticipate total cross-tachyphylaxis between the two agents, i.e. the poorly sustained response to angiotensin should be associated with a reduction in response to norepinephrine, and vice versa. In fact, angiotensin tachyphylaxis in the dog kidney, the species in which their studies were done, is associated with a well-sustained response to norepinephrine (Caldicott & Hollenberg 1971, Taub et at. 1975).
Despite the evidence supporting the role for prostaglandin as a modulator of responses to norepinephrine and angiotensin, a simple model in which prostaglandin release directly offsets the action of the primary constrictor obviously cannot be applied. A more complex model is required.
If this were so, one would anticipate total cross-tachyphylaxis between the two agents, i.e. the poorly sustained response to angiotensin should be associated with a reduction in response to norepinephrine, and vice versa. In fact, angiotensin tachyphylaxis in the dog kidney, the species in which their studies were done, is associated with a well-sustained response to norepinephrine (Caldicott & Hollenberg 1971, Taub et at. 1975).
Despite the evidence supporting the role for prostaglandin as a modulator of responses to norepinephrine and angiotensin, a simple model in which prostaglandin release directly offsets the action of the primary constrictor obviously cannot be applied. A more complex model is required.
To summarize, the remarkable activity of the prostaglandins, their high concentration in the kidney, changes in their release under a number of circumstances, and the influence of prostaglandin synthetase inhibitors on renal perfusion and function have raised the possibility that prostaglandins play an important role in the control and modulation of renal perfusion and function.
Despite the impressive array of information, it is impossible to conclude at this juncture that prostaglandins play a key role in View of a number of reports which suggest caution. Complicating factors include the important role that anaesthesia plays; the striking species differences in both the primary response to prostaglandins and their modulator influence; the fact that the synthetase inhibitors lack complete specificity; and the difficulty that investigators have had in duplicating some observations.
Despite the impressive array of information, it is impossible to conclude at this juncture that prostaglandins play a key role in View of a number of reports which suggest caution. Complicating factors include the important role that anaesthesia plays; the striking species differences in both the primary response to prostaglandins and their modulator influence; the fact that the synthetase inhibitors lack complete specificity; and the difficulty that investigators have had in duplicating some observations.
The same caution is required before concluding that prostaglandins play an important role in the control of blood pressure, sodium homeostasis or other systemic functionsmsince the evidence in these areas is even more marginal.