Adrenergic Factors
The kidney receives a rich nerve supply from the sympathetic nervous system, as indicated in the preceding chapter. While it is traditional to discuss the role of local, neural release of catecholamines and of circulating catecholamines together, the latter rarely play much of a role quantitatively in controlling the renal circulation (Celander l954).
The distribution within the kidney of the sympathetic neurone supply has received considerable attention: norepinephrine-containing nerves are found in the major arterial vessels in the cortex, up to the afferent arterioles and the juxtaglomerular apparatus (Nilsson 1965, Mc. Kenna & Angelakos 1968, Fourman 1970, Ljungqvist & Wagermark 1970, Norvell et al. 1970). All studies agree that neither the intraglomerular capillaries nor the tubules appear to have such an innervation.
There is still debate concerning the sympathetic nerve supply of the efferent arterioles, which Fourman (1970) and Ljungqvist and Wagermark (1970) identified, and the others denied. Why equally experienced investigators using similar techniques find divergent results is uncertain; but they cannot be attributed to species or technique differences. The presence of a postglomerular innervation has important functional implications, reviewed below.
The distribution within the kidney of the sympathetic neurone supply has received considerable attention: norepinephrine-containing nerves are found in the major arterial vessels in the cortex, up to the afferent arterioles and the juxtaglomerular apparatus (Nilsson 1965, Mc. Kenna & Angelakos 1968, Fourman 1970, Ljungqvist & Wagermark 1970, Norvell et al. 1970). All studies agree that neither the intraglomerular capillaries nor the tubules appear to have such an innervation.
There is still debate concerning the sympathetic nerve supply of the efferent arterioles, which Fourman (1970) and Ljungqvist and Wagermark (1970) identified, and the others denied. Why equally experienced investigators using similar techniques find divergent results is uncertain; but they cannot be attributed to species or technique differences. The presence of a postglomerular innervation has important functional implications, reviewed below.
It is over 100 years since Claude Bernard (1858) reported that stimulation of the efferent end of the sectioned distal splanchnic nerve resulted in oliguria or anuria with blanching of the kidney’s surface. In the light of current interest in the role of the sympathetic nerves in renal sodium handling, it is of some interest that he also discovered that lesions of the reticular substance in the floor of the fourth ventricle in the medulla led to a diuresis with increased chloride excretion.
Despite the striking capacity of the renal circulation to respond to sympathetic nervous system activity, most observations suggest that in the normal state in animals and in recumbent man there is no resting sympathetic tone to the kidney (Smith 1951, Pappenheimer 1960, Hollenberg et al. 1971, Millard et al. 1972, Burger et al. 1976).
Active renal vasoconstriction mediated by norepinephrine and thus preventable by denervation or reversed by alpha adrenergic blocking agents does occur in response to emotional-or aversive conditions in animals and man (Wolf et al. 1948, Smith 1951, Schramm et a. 1975), and in life threatening situations such as haemorrhage, severe heart failure or asphyxia: increasing degrees of stress result in an increasing response (Celander 1954, Pappenheimer 1960, Hollenberg 1965, Millard et al. 1972).
While indirect, the available evidence suggests that with severe cardiovascular disarray the response of the renal vasculature to sympathetic activity may be sufficiently intense to reduce the rate of filtration sharply, and oliguria results (Nickerson 1962, Li1~ lehei et al. 1964, Hollenberg 1965). At least for a short time direct stimulation of the sympathetic nerves at a physiological frequency can arrest renal blood flow completely (DiSalvo & Fell 1971).
For reasons that are not yet clear, in anaesthetized animals the renal vascular response to activation of the sympathetic nerves, whether central (Feigl et al. 1964) or peripheral (Study & Shipley 1950, DiSalvo & Fell 1971), may be poorly sustained. Conversely, Hoff et al. (1951) and Pomeranz et al. (1968) reported a well-sustained response to sympathetic nerve stimulation in unanaesthetized animals.
The possibility that an offsetting prostaglandin release is involved and accounts for the difference between anaesthetized and conscious animals is reviewed below. Stimulation of the sympathetic nerves to the kidney also induces renal sodium retention and renin release, both of which occur at stimulus frequencies well below those required to induce a measurable change in renal perfusion or filtration rate (LaGrange et al. 1973).
Despite the striking capacity of the renal circulation to respond to sympathetic nervous system activity, most observations suggest that in the normal state in animals and in recumbent man there is no resting sympathetic tone to the kidney (Smith 1951, Pappenheimer 1960, Hollenberg et al. 1971, Millard et al. 1972, Burger et al. 1976).
Active renal vasoconstriction mediated by norepinephrine and thus preventable by denervation or reversed by alpha adrenergic blocking agents does occur in response to emotional-or aversive conditions in animals and man (Wolf et al. 1948, Smith 1951, Schramm et a. 1975), and in life threatening situations such as haemorrhage, severe heart failure or asphyxia: increasing degrees of stress result in an increasing response (Celander 1954, Pappenheimer 1960, Hollenberg 1965, Millard et al. 1972).
While indirect, the available evidence suggests that with severe cardiovascular disarray the response of the renal vasculature to sympathetic activity may be sufficiently intense to reduce the rate of filtration sharply, and oliguria results (Nickerson 1962, Li1~ lehei et al. 1964, Hollenberg 1965). At least for a short time direct stimulation of the sympathetic nerves at a physiological frequency can arrest renal blood flow completely (DiSalvo & Fell 1971).
For reasons that are not yet clear, in anaesthetized animals the renal vascular response to activation of the sympathetic nerves, whether central (Feigl et al. 1964) or peripheral (Study & Shipley 1950, DiSalvo & Fell 1971), may be poorly sustained. Conversely, Hoff et al. (1951) and Pomeranz et al. (1968) reported a well-sustained response to sympathetic nerve stimulation in unanaesthetized animals.
The possibility that an offsetting prostaglandin release is involved and accounts for the difference between anaesthetized and conscious animals is reviewed below. Stimulation of the sympathetic nerves to the kidney also induces renal sodium retention and renin release, both of which occur at stimulus frequencies well below those required to induce a measurable change in renal perfusion or filtration rate (LaGrange et al. 1973).
The precise quantitative relationship between the drop in the renal blood flow and glomerular filtration rate is of considerable interest. Both fall, but the reduction in renal blood flow generally exceeds that of the filtration rate so that the fraction of plasma delivered to the glomeruli which is filtered rises sharply (Selkurt 1946, Study & Shipley 1950).
Norepinephrine administered intravenously also has a larger influence on renal blood flow than on glomerular filtration rate (Myers et al. 1975a). It is traditional to ascribe the rise in filtration fraction to an active, relatively larger increase in postglomerular resistance-but, this explanation is inconsistent with the known anatomy. Much of the available evidence denies a sympathetic innervation of the efferent vessels.
While the frequently cited increase in efferent resistance is hallowed by tradition, perhaps an alternative explanation should be sought. It is of historical interest that Richards and his colleagues, who first developed the micropuncture technique, as reviewed earlier, did so on the basis of this puzzle. Their purpose was to explore the effects of epinephrine on the efferent vessels (Schmidt 1969).
They fashioned micropuncture pipettes in order to place epinephrine directly on efferent arterioles, but the implications of being able to sample glomerular filtrate directly (which became apparent during the early course of their experiments) led them away from their primary goal; in fact the direct test has never been made. An alternative possibility arises from the characteristics of the outer and inner cortical nephrons.
Outer cortical nephrons differ from those in the inner cortex in having a much higher perfusion rate and lower filtration rate per glomerulus (Jamison 1970, de Rouffignac & Bonvalet 1972). A number of observations suggest, moreover, that a relatively larger reduction in outer cortical perfusion occurs in response to activation of the sympathetic nervous system and to norepinephrine (Pomeranz et al. 1968, Carriere 1969, Hollenberg et al. 1972).
Barger and Herd (1971) attributed the striking superficial cortical ischaemia which occurs with threshold sympathetic stimulation to the unusual sensitivity of the superficial cortical arteries. Increased frequency of stimulation results in a more diffuse and even reduction of cortical perfusion.
The sensitivity of the outer cortical vessels was denied by Stein et al. (197321) who demonstrated an unchanged fraction of total renal blood flow to the outer cortex during sympathetic nerve stimulation, but in View of the considerably higher flow rate in the outer cortex, the Same fractional reduction in outer and inner cortical perfusion rates will reflect a much larger absolute reduction in flow rate in the outer cortex. Moreover, threshold sensitivity was not tested.
Norepinephrine administered intravenously also has a larger influence on renal blood flow than on glomerular filtration rate (Myers et al. 1975a). It is traditional to ascribe the rise in filtration fraction to an active, relatively larger increase in postglomerular resistance-but, this explanation is inconsistent with the known anatomy. Much of the available evidence denies a sympathetic innervation of the efferent vessels.
While the frequently cited increase in efferent resistance is hallowed by tradition, perhaps an alternative explanation should be sought. It is of historical interest that Richards and his colleagues, who first developed the micropuncture technique, as reviewed earlier, did so on the basis of this puzzle. Their purpose was to explore the effects of epinephrine on the efferent vessels (Schmidt 1969).
They fashioned micropuncture pipettes in order to place epinephrine directly on efferent arterioles, but the implications of being able to sample glomerular filtrate directly (which became apparent during the early course of their experiments) led them away from their primary goal; in fact the direct test has never been made. An alternative possibility arises from the characteristics of the outer and inner cortical nephrons.
Outer cortical nephrons differ from those in the inner cortex in having a much higher perfusion rate and lower filtration rate per glomerulus (Jamison 1970, de Rouffignac & Bonvalet 1972). A number of observations suggest, moreover, that a relatively larger reduction in outer cortical perfusion occurs in response to activation of the sympathetic nervous system and to norepinephrine (Pomeranz et al. 1968, Carriere 1969, Hollenberg et al. 1972).
Barger and Herd (1971) attributed the striking superficial cortical ischaemia which occurs with threshold sympathetic stimulation to the unusual sensitivity of the superficial cortical arteries. Increased frequency of stimulation results in a more diffuse and even reduction of cortical perfusion.
The sensitivity of the outer cortical vessels was denied by Stein et al. (197321) who demonstrated an unchanged fraction of total renal blood flow to the outer cortex during sympathetic nerve stimulation, but in View of the considerably higher flow rate in the outer cortex, the Same fractional reduction in outer and inner cortical perfusion rates will reflect a much larger absolute reduction in flow rate in the outer cortex. Moreover, threshold sensitivity was not tested.
A larger reduction of flow delivery to outer cortical nephrons, which have a lower filtration fraction, would thus result in a larger reduction in total blood flow than in glomerular filtration rate, and an increase in the calculated filtration fraction, without preferential constriction of postglomerular arterioles.
The reflex and central nervous system factors determining the degree of activation of sympathetic activity to the kidney are complex. Clearly intense activation occurs with a major stimulus, such as that provided by asphyxia or severe haemorrhage (Daniel et al. 1952, Celander 1954, Pappenheimer 1960, Nickerson 1962, Lillehei et al. 1964, Hollenberg 1965).
More modest stimuli, sufficient to activate sympathetic activity to other regions, frequently fail to induce renal vasoconstriction (Folkow et al. 1961). In part this may be attributable to the fact that mild sympathetic activity can modify intrarenal perfusion patterns without a demonstrable change in total renal blood flow (Pomeranz et al. 1968).
It has become apparent in the last decade, however, that we can no longer think of the sympathetic nervous system in an all-or-none sense: regionally differentiated activation probably representing outflow from different central neurone pools has been well demonstrated in many systems, including the renal vasculature (Hix 1958, Folkow et al. 1961, Bagshaw et al. 1971, Wilson et al. 1971, Clement et al. 1972, Kendrick‘et al. 1972, Ninomiya er al.
More modest stimuli, sufficient to activate sympathetic activity to other regions, frequently fail to induce renal vasoconstriction (Folkow et al. 1961). In part this may be attributable to the fact that mild sympathetic activity can modify intrarenal perfusion patterns without a demonstrable change in total renal blood flow (Pomeranz et al. 1968).
It has become apparent in the last decade, however, that we can no longer think of the sympathetic nervous system in an all-or-none sense: regionally differentiated activation probably representing outflow from different central neurone pools has been well demonstrated in many systems, including the renal vasculature (Hix 1958, Folkow et al. 1961, Bagshaw et al. 1971, Wilson et al. 1971, Clement et al. 1972, Kendrick‘et al. 1972, Ninomiya er al.
1973, Pelletier & Shepherd 1975). The renal vasculature shows special sensitivity to some afferent stimuli, and multiple stimuli may summate to induce renal vasoconstriction whereas other vascular beds are frequently activated by a single stimulus.
It may well be relevant that stimuli which preferentially modify intrathoracic pressure or tension in the central chambers either directly or indirectly, by way of changes in the ventilatory pattern (Folkow et al. 1961) or acidosis (Kendrick et al. 1972), appear to exert a preferential action on the renal vasculature.
The nerves in the atria and great vessels in the thorax have been identified as an important element in the ‘volume’ receptor which influences antidiuretic hormone release, renin release and sodium and water handling by the kidney (GOetz et al. 1975). Kahl et al. (1974) demonstrated immediate, neurally mediated renal vasoconstriction in response to left atrial hypotension, whereas an increase in left atrial pressure had little influence on renal vasomotor tone unless the initial tone was unusually high.
It would not be surprising if sodium and water homeostasis and renin-angiotensin system activity were integrated centrally with nervous system control of the renal circulation-all are influenced strikingly by receptors in the intrathoracic region.
The nerves in the atria and great vessels in the thorax have been identified as an important element in the ‘volume’ receptor which influences antidiuretic hormone release, renin release and sodium and water handling by the kidney (GOetz et al. 1975). Kahl et al. (1974) demonstrated immediate, neurally mediated renal vasoconstriction in response to left atrial hypotension, whereas an increase in left atrial pressure had little influence on renal vasomotor tone unless the initial tone was unusually high.
It would not be surprising if sodium and water homeostasis and renin-angiotensin system activity were integrated centrally with nervous system control of the renal circulation-all are influenced strikingly by receptors in the intrathoracic region.
The precise influence of the arterial baroreceptor system on the renal vasculature is less clear. On the one hand the data of Vatner et al. (1970), Kendrick et al. (1972), Passmore et al. (1975) and Pelletier and Shepherd (1975) suggested at most a modest influence of baroreceptor activity on the kidney’s bloOd supply in comparison to other vascular beds when blood flow was used as the index. On the other hand direct measurements of sympathetic nerve activity to the kidney suggested an important baroreceptor component (Wilson et al. 1971, Ninomiya et al. 1973).
Given the role of neural activity as a determinant of 4 renin release it is possible that the nerve impulses are not directed to the arterioles but rather to the juxtaglomerular apparatus-a possibility that apparently remains untested in these studies. Taken in all, the available evidence suggests that baroreceptor input from the high-pressure side of the circulation plays a much smaller role than input from the thoracic, low-pressure (volume) side of the circulation as a determinant of renal perfusion and function. Volume has primacy as a determinant of sympathetic activity to the kidney, as it does in many other aspects of renal function.
Given the role of neural activity as a determinant of 4 renin release it is possible that the nerve impulses are not directed to the arterioles but rather to the juxtaglomerular apparatus-a possibility that apparently remains untested in these studies. Taken in all, the available evidence suggests that baroreceptor input from the high-pressure side of the circulation plays a much smaller role than input from the thoracic, low-pressure (volume) side of the circulation as a determinant of renal perfusion and function. Volume has primacy as a determinant of sympathetic activity to the kidney, as it does in many other aspects of renal function.