The role of the kidney
in spontaneous
hypertension
Thomas G. Coleman, Ph.D. R. Davis Manning, Jr., Ph.D. Roger A. Norman, Jr., Ph.D. James DeClue, Ph.D. Jackson, Miss.
Renal dysfunction is critically involved in many forms of human and experimental hypertension. Spontaneously hypertensive rats may have a similar defect. Interpretation of recent data is complicated by the fact that many different colonies of spontaneously hypertensive rats have been studied. Some are local creations while others are representative of the several more standard strains. The Okamoto strain is the best known and most widely disseminated; a strain developed by Dahl and colleagues at Brookhaven remains normotensive until subjected to high sodium intake; the New Zealand strain has been distinguished by a less than total incidence of hypertension. Each strain has descended from a single unique pair of animals. Because the hypertension that occurs in each of the colonies is the result of an unusual genetic trait in the original animals, there is little guarantee that the same specific physiologic mechanisms are involved in each of the different hypertensions. For example, two different hypothetical groups of animals could develop hypertension: one hypertension due to an inherited primary aldosteronism, and the other due to an inherited pheochromocytoma. Even though comparable elevations in blood pressure were observed and the adrenal glands were known to be intimately involved in both forms of hypertension, there would be few additional similarities. The unique origins of the different strains now being studied may prevent From the Mississippi Received
Department of Physiology and School of Medicine, Jackson. for publication
University
Feb. 4, 1974.
Reprint requests to: Dr. Thomas ogy and Biophysics, University Jackson, Miss. 39216.
94
Biophysics,
G. Coleman, of Mississippi
Department School
of Physiolof Medicine,
of
generalization; however, if potential differences among strains are kept in mind, several working hypotheses can be examined. Of many possible theories, two directly relate primary renal dysfunction to spontaneous hypertension. One theory is that increased extrinsic influences upon the kidney, particularly from the sympathetic nervous system, cause depressed renal function leading to hypertension. A second theory is that intrinsic or inherent renal dysfunction leads to hypertension. The point that these two theories have in common is that a renal defect produces elevated pressure, almost, as it will be argued later, as if the animals have inherited a diffuse intrarenal Goldblatt clamp. The distinction between the two theories is that in the former (increased extrinsic infIuence) hypertension would be expected to occur even if a recipient animal were given a replacement kidney from a genetically normotensive animal, while in the latter (inherent renal dysfunction) hypertension would be expected to follow the kidney in renal transplant experiments. Possible role of the sympathetic nerves. There is evidence both for and against the contention that increased sympathetic activity is critically involved in the genesis of spontaneous hypertension, with most attention being focused on the Okamoto strain. Some variability in sympathetic function and catecholamine stores has’been observed,lp2 but the irregularities do not convincingly account for the increase in pressure especially via arterial vasoconstriction. Pfeffer, Frohlich, and Pfeffer3 have identified an increased beta-sympathetic state that particularly affects cardiodynamics. Increased cardiac stimulation may contribute to the final hemodynamic picture observed, but it is apparently
January,
1975, Vol. 89, No. 1, pp. 94-98
Spontaneous hypertension and the kidney
not essential for the development of hypertension.‘Immunosympathectomy decreases blood pressure in both Okamoto5 and New Zealand6 rats in a somewhat greater proportion than in normotensive rats, but it does not prevent a marked increase in blood pressure as the animal matures. Adrenal medullectomy does not decrease blood pressure in the Okamoto strain.7 Hexamethonium has been widely used to produce an acute blood pressure decrease in spontaneously hypertensive rats,6,8-10but this data may not confirm an exaggerated, neurogenic arterial vasoconstriction for several reasons. One is that hexamethonium also decreases blood pressure in experimentally hypertensive animals where increased sympathetic activity is most probably not involved.*pn Second, the primary hypotensive potency of hexamethonium results from severe depression of cardiac output; peripheral resistance changes little following administration of the drug? Data from environmental experiments support sympathetic involvement in spontaneous hypertension. Spontaneously hypertensive rats have been shown to have an increased cardiovascular reactivity to irritating stimuli,2*12 while, on the other hand, chronically maintaining the animals in a quiet, dark environment slows the development of the hypertension.13 A theory that reconciles this variety of data is that increased sympathetic nerve activity in the spontaneously hypertensive rat has a specific, pronounced effect on renal function that is greater than any effect on the general vasculature. In Okamoto animals, direct electrical recordings from the splanchnic nerveI and also indirect studies15s10have shown splanchnic nerve traffic to be increased up to five times that of control rats. The direct anatomic connection between the splanchnic sympathetic trunk and the renal sympathetic nerves suggests that renal function is compromised. At least acutely, experiments have shown that sympathetic nerve stimulation markedly decreases sodium excretionl?; increased arterial pressure would be required to re-establish salt and water homeostasis. The evidence, in toto, suggests that in the Okamoto and New Zealand strains, increased sympathetic activity could cause or exacerbate the hypertension, particularly via depressed renal function, but a possible crucial role of inherent renal dysfunction is definitely not elimi-
American Heart Journal
nated by this data. In contrast, in the Dahl strain there is rather convincing evidence that hypertension is caused solely by an intrinsic renal defect. Evidence for an inherent renal defect. The crux of kidney transplant protocols is that kidneys are exchanged among spontaneously hypertensive and normotensive animals and subsequent blood pressure changes are noted. One preliminary report, presumably using the Okamoto strain, stated that hypertension did not follow transplantation of the hypertensive kidney.‘* In contrast, Bianchi and colleagues,19 in a separate strain, found that hypertension did move with the transplanted kidney. Similarly, Dahl and Herne20 have observed that hypertension followed the transplanted kidney when kidneys were exchanged between hypertensive and normotensive animals. There is additional evidence for an inherent renal defect in Dahl’s strain of hypertensive rats. This strain, designated “salt-sensitive,” becomes hypertensive when placed on a high-salt diet but remains normotensive on a normal diet. During normal salt intake and before hypertension has ever developed, Jaffe and co-workers2’ have observed a mild, nonuniform focal constriction of the early afferent arterioles. The constriction is not observed in a companion strain of “salt-resistant” animals, a strain that remains normotensive on all salt intakes. But in the saltsensitive animals, the hypertensive response to high-salt diet includes further encroachment of the lesion upon the lumen of the afferent arteriole, as if an intrarenal response to the highsalt diet was creating a wealth of diffuse, minute Goldblatt clamps. Renal blood flow and glomerular filtration rate are normal after the development of hypertension,22 evidence for a considerably elevated renal afferent resistance. This alteration in renal morphology and function is irreversible in that hypertension persists after the salt-rich diet is discontinued.% There is also some indication of renal dysfunction in the Okamoto strain, but it may not be due to intrinsic causes. Kidney weight in these animals is normal2 and no morphologic abnormalities have yet been discovered.2 Folkow and co-workers24 have measured a decreased renal resistance in isolated Okamoto kidneys perfused at low pressure. The renal vasculature in these preparations appears abnormally stiff and it may
95
Coleman
et al.
be that at higher perfusion pressures the renal resistance is, in fact, greater than normal. In other studies of Okamoto rats, blood flow through the kidneys in situ has been observed to be low26*26even at the very high arterial pressures that commonly occur. Similarity between spontaneous and Goldblatt hypekension. The blood pressure of Okamoto
animals is remarkably insensitive to the level of salt intake, with hypertension developing on both low and normal salt intakes.27-2g Similarly, even though Dahl’s strain of rats is called saltsensitive, the animals’ arterial pressures are remarkably salt-insensitive after a high-salt diet has been administered for a requisite, but short, amount of time23-the hypertension persists when the animals are subsequently placed on a low-salt diet. The lack of pressure sensitivity to salt intake in these strains is nearly identical to the Goldblatt-clamped rat that has allof its renal tissue distal to a renal artery constriction; most commonly, the preparation consists of unilateral renal artery clamping in combination with contralateral nephrectomy. Parallelism between spontaneous and Goldblatt animals is further developed by the apparent lack of involvement of the reninangiotensin system in both forms of hypertension. With Goldblatt clamping, the abrupt application of a clamp provokes temporary renin release, but this subsides as the hypertension develops and the pressure distal to the clamp rises toward normal values. After the initial transients, plasma renin activity is quite normal. There is no comparable abruptness in the onset of hypertension of the spontaneously hypertensive rat, and this may allow the renin-angiotensin system to remain primarily dormant in these animals. Possible role of fluid volumes. Experience with anephric patients has shown that rather small changes in fluid volumes can have a pronounced effect on arterial pressure. Similarly, the early sodium and water retention in G.oldblatt hypertension gives way to only the slightest of abnormalities in the chronic state. In both instances, a strong argument can be made for an important role of fluid retention in the onset of hypertension; the argument is that overhydration causes & increased cardiac output which in turn triggers an autoregulatory response.30,31 Demonstration of the same sequence of events in spontaneously hypertensive rats has been difficult. Fluid
96
volume measurement in Okamoto,32”3 New Zealand,34 and Dah134 rats has not revealed comparable overhydration. There are two critical considerations: (1) absolute fluid volume is important in the circulation only in relation to the compliance of the vasculature that it is contained in, and this compliance may be decreasing as spontaneous hypertension develops; and (2) the gradual onset of spontaneous hypertension may allow very subtle overhydration to play a more important role in elevating pressure than previously s%petted. The vasculature:
hypertension
vs. growth.
Growth is a physiologic process which demands increased vasculature, while hypertension is a disease which produces decreased vasculature. Decreased vasculature and, therefore, increased resistance, is probably the result of the physioiogic response of overperfused tissues36 and, later, pathologic effects.2 The conflict between growth’s demands for increased vascularity and the disease process might be resolved within the spontaneously hypertensive rat by retardation in the normal development of the animal’s vasculature. It is interesting to note that these animals do not grow particularly rapidly, as if an inadequately developed circulation is not capable of supporting the normal rate of accumulation of body mass. The mature, spontaneously hypertensive rat shows a decreased number of arterioles2~37 and venules38 when compared to normotensive control animals. Normal absolute fluid volume plus decreased compliance could equal relative overhydration. It is not clear, though, if vascular change plays a role in the onset of elevated pressure or if it follows, and is caused by, the elevated pressure. Transient volume changes. Sudden changes in renal function can produce easily identified increases in fluid volumes during the onset of hypertension. The spontaneously hypertensive rat does not usually undergo any abrupt changes comparable to those produced by experimental intervention in other animal models, e.g., the sudden decrease in renal function that occurs with renal artery clamping. There are two observations in spontaneous hypertension, however, that have been made during abrupt changes in the animal’s status and suggest that fluid volume retention may have a direct role in the etiology of this hypertension. One observation is that after cessation of successful antihypertensive therapy
January, 1975, Vol. 89, No. 1
Spontaneous
in the Okamoto strain, the resulting rapid elevation in blood pressure is associated with increasing blood volume and extracellular fluid volume.39 Similarly, increased extracellular fluid volume has been observed immediately following the implantation of hypertension-producing kidneys into normotensive rats.40 In both cases, fluid retention coincides with the development of hypertension in a previously normotensive animal. Extrapolating from this short-term data, salt and water retention may be important in the more subtle elevation in pressure that normally occurs.
There is direct and indirect evidence that the kidneys are involved in the onset of hypertension in spontaneously hypertensive animals. In the Dahl strain, rather convincing evidence exists for a primary, inherent renal defect that is worsened by high dietary salt. In the Okamoto and New Zealand strains, an intrinsic defect may be provoked by increased sympathetic nerve activity. Similarities between all of these strains and Goldblatt hypertension suggest a fluid volume abnormality, but the gradual onset of elevated pressure and continuing growth during development of hypertension may obscure critical volume changes. Theoretically, arterial pressure, somewhat independent of intermediate steps, will reach the level which is dictated by renal function as being necessary for the maintenance of salt and water homeostasis. While widespread use of different spontaneously hypertensive strains may currently be complicating our understanding of the intermediate steps, studies of dissimilar strains should in time, enhance our understanding of the many different facets of long-term blood pressure control.
9.
10.
11.
12.
13.
14.
15. 16.
17.
18.
19.
20.
REFERENCES 1.
2. 3.
4. 5.
Louis, W. J., Spector, S., Tabei, R., and Sjoerdsma, A.: Synthesis and turnover of norepinephrine in the heart of spontaneously hypertensive rat, Circ. Res. 24~85, 1969. Okamoto, K.: Spontaneous hypertension in rats, Int. Rev. Exp. Pathol. 7:227, 1969. Pfeffer, M. A., Frohlich, E. D., and Pfeffer, J. M.: Disparity in autonomic control of cardiac performance in spontaneously hypertensive rats, Circulation 48 (5uppl. 4): 45, 1973. Pfeffer, M. A.: Personal communication. Folkow, B., Hallback, M., Lundgren, Y., and Weiss, L.: The effects of “immunosympathectomy” on blood pressure and vascular “reactivity” in normal and spon-
American
Heart Journal
21.
22.
23.
24.
hypertension
and the kidney
taneously hypertensive rats, Acta Phyxiol. Stand. 84:512,1972. Clark, D. W. J.: Effects of immunosympathectomy on development of high blood pressure in genetically hypertensive rats, Circ. Res. 28:330, 1971. Aoki, K., Takikawa, K., and Hotta, K.: Role of adrenal cortex and medulla in hypertension, Nature New Biol. 241:122, 1973. Laverty, R., and Smirk, F. H.: Observations on the pathogenesis of spontaneous inherited hypertension and constricted renal artery hypertension in rats, Circ. Res. 9:455, 1961. Iriuchijima. J.: Cardiac output and total peripheral resistance in spontaneously hypertensive rats, Jap. Heart J. l&267,1973. Aoki, K.: Experimental studies on the relationship between endocrine organs and hypertension in spontaneously hypertensive rats, Jap. Heart J. 4~443, 1963. Sturtevant, F. M.: Response of metacorticoid hypertension to bistrium, apresoline, veriloid, and serpentina, Proc. Sot. Exn. Biol. Med. 84~101. 1953. Folkow, B., Hallback, M., and Weiss, L.: Cardiovascular responses to acute mental “stress” in spontaneously bypertensive rats, Acta Physiol. Stand. 8437A, 1972. Brody, M. J., Lais, L. T., and Bhatnager, R. K.: Development of hypertension in spontaneously hypertensive rat: inhibition by dark adaptation, Circulation 48 (Suppl. 4): 45, 1973. Okamoto, K., Nosaka, S., Yamori, Y., and Matsumoto, M.: Participation of neural factor in the pathogenesis of hypertension in the spontaneously h,vpertensive rat, Jap. Heart J. 8:16&l, 1967. Iriuchijima, J.: Sympathetic discharge rate in spontaneously hypertensive rats, Jap. Heart J. 14:350, 1973. Ozaki, M., Hotta, K., and Aoki, K.: Catecholamine content and metabolism in the brainstem and adrenal gland in the spontaneously hypertensive rat, in Spontaneous hypertension, Okamoto, K., editor, Berlin, 1972, Springer-Verlag. Block, M. A., Wakim, K. G., and Mann, F. C.: Renal function during stimulation of the renal nerves, Am. J. Physiol. 169:670, 1952. Coburn, R. J., Manger, W. M., Dufton, S., Gallo, G., and Manger, C. C., III: Absence of renal participation in genesis of hypertension in spontaneously hypertensive rats, Clin. Res. 20589, 1972. Bianchi, G., Fox, U., Di Francesco, G., Bardi, U., and Radice, M.: The hypertensive role of the kidney in spontaneously hypertensive rats, Europ. J. Clin. Invest. 3:213, 1973. Dahl, L. K., and Herne, M.: Genetic influence of the kidney on blood pressure: evidence from chronic renal homografts in rats. Presented at annual meeting of the American Heart Association Council for High Blood Pressure Research, Cleveland, 1973. Jaffe, D., Sutherland, L. E., Barker, D,. and Dahl, L. K.: Effects of chronic excess salt ingestion: morphological findings in kidneys of rats with different genetic susceptibilities to hypertension, Arch. Pathol. 90:1, 1970. Ben-Ishay, D., Knudsen, K. D., and Dahl, L. K.: Renal function studies in the early stage of salt hypertension in rats, Proc. Sot. Exp. Biol. Med. 126:515, 1967. Dahl, L. K., Knudsen, K. D., Heine, M. A., and Leith, G. J.: Effects of chronic salt ingestion. Modification of experimental hypertension in the rat by variations in the diet, Circ. Res. 22:11, 1968. Folkow, B., Hallback, M., Lundgren, Y., and Weiss, L.: Renal vascular resistance in spontaneously hypertensive rats, Acta Physiol. Stand. 8396. 1971.
97
Coleman
et al.
Albrecht, I., Viiek, M., and Kiedek, J.: The hemodynamits of the rat during ontogenesis, with special reference to the age factor in the development of hypertension, in Spontaneous hypertension, Okamoto, K., editor, Berlin, 1972, Springer-Verlag. 26. Redel, D., Dahners, H. W., Breull, W., and Flohr, H.: Nierendurchblutung bei spontaner hypertonie der Ratte, Pflug. Arch. 339:R43, 1973. 21. Baer, L., Knowlton, A., and Laragh, J. H.: The role of sodium balance and the pituitary-adrenal axis in the hypertension of spontaneously hypertensive rats, in Spontaneous hypertension, Okamoto, K., editor, Berlin, 1972, Springer-Verlag. 28. Aoki, K., Yamori, Y., Ooshima, A., and Okamoto, K.: Effects of high- or low-sodium intake in spontaneously hypertensive rats, Jap. Circ. J. 36:539, 1972. 29. Louis, W. J., Tabei, R., and Spector, S.: Effects of sodium intake on inherited hypertension in the rat, Lancet 2:1283, 1971. 30. Bianchi, G., Tenconi, L. T., and Lucca, R.: Effect in the conscious dog of constriction of the renal artery to a sole remaining kidney on the hemodynamics, sodium balance, body fluid volumes, plasma renin concentration, and pressor responsiveness to angiotensin, Clin. Sci. 36:741, 1970. 31. Coleman, T. G., Bower, J. D., Langford, H. G., and Guyton, A. C.: Regulation of arterial pressure in the anephric state, Circulation 42509, 1970. 32. Sen, S., Hoffman, G. C., Stowe, N. T., Smeby, R. R., and Bumpus, F. M.: Erythrocytosis in spontaneously hypertensive rats, J. Clin. Invest. 61:710, 1972. 25.
98
Nagaoka, A., Iwatsuka, H., Suzuoki, Z., and Okamoto, K.: Electrolyte metabolism in substrains of spontaneously hypertensive rats, Jap. Heart J. 14~157, 1973. 34. Gresson, C. R., Bird, D. L., and Simpson, F. 0.: Plasma volume, total body sodium, and total body water volume in young genetically hypertensive rats, Life Sci. 12:393, 1973. 35. Schackow, E., and Dahl, L. K.: Effects of chronic excess salt ingestion: lack of gross salt retention in salt-hypertension, Proc. Sot. Exp. Biol. Med. 122:952, 1966. M., Lundgren, Y., and Weiss, L.: 36. Folkow, B., Hallblck, Time course and extent of structural adaption of the resistance vessels in renal hypertensive rats as compared with spontaneous hypertensive rats, Acta Physiol. Stand. 67:10A, 1973. 37. Hutchins, P. M., and Darnell, A. E.: Microcirculatory dimensions in spontaneously hypertensive rats, Microvasc. Res. 4:325, 1972. 36. Hutchins, P. M., and Darnell, A. E.: Observation of a decreased number of small arterioles in spontaneously hypertensive rats, Presented at Annual Meeting of the American Heart Association Council for High Blood Pressure Research, Cleveland, 1973. 39. Freis, E. D., Ragan, D., Pillsbury, H., III, and Mathews, M.: Alteration of the course of hypertension in the spontaneously hypertensive rat, Circ.-Res. 31:1, 1972. 40. Bianchi. G.. and Fox. U.: The hvoertensive role of the kidney in spontaneously hypertensive rats, Presented at the Second International Workshop on the Relationship Between Cardiac Output and Hypertension, Cleveland, Ohio, 1973. 33.
January,
1976, Vol. 89, No. 1
in spontaneous
hypertension
Thomas G. Coleman, Ph.D. R. Davis Manning, Jr., Ph.D. Roger A. Norman, Jr., Ph.D. James DeClue, Ph.D. Jackson, Miss.
Renal dysfunction is critically involved in many forms of human and experimental hypertension. Spontaneously hypertensive rats may have a similar defect. Interpretation of recent data is complicated by the fact that many different colonies of spontaneously hypertensive rats have been studied. Some are local creations while others are representative of the several more standard strains. The Okamoto strain is the best known and most widely disseminated; a strain developed by Dahl and colleagues at Brookhaven remains normotensive until subjected to high sodium intake; the New Zealand strain has been distinguished by a less than total incidence of hypertension. Each strain has descended from a single unique pair of animals. Because the hypertension that occurs in each of the colonies is the result of an unusual genetic trait in the original animals, there is little guarantee that the same specific physiologic mechanisms are involved in each of the different hypertensions. For example, two different hypothetical groups of animals could develop hypertension: one hypertension due to an inherited primary aldosteronism, and the other due to an inherited pheochromocytoma. Even though comparable elevations in blood pressure were observed and the adrenal glands were known to be intimately involved in both forms of hypertension, there would be few additional similarities. The unique origins of the different strains now being studied may prevent From the Mississippi Received
Department of Physiology and School of Medicine, Jackson. for publication
University
Feb. 4, 1974.
Reprint requests to: Dr. Thomas ogy and Biophysics, University Jackson, Miss. 39216.
94
Biophysics,
G. Coleman, of Mississippi
Department School
of Physiolof Medicine,
of
generalization; however, if potential differences among strains are kept in mind, several working hypotheses can be examined. Of many possible theories, two directly relate primary renal dysfunction to spontaneous hypertension. One theory is that increased extrinsic influences upon the kidney, particularly from the sympathetic nervous system, cause depressed renal function leading to hypertension. A second theory is that intrinsic or inherent renal dysfunction leads to hypertension. The point that these two theories have in common is that a renal defect produces elevated pressure, almost, as it will be argued later, as if the animals have inherited a diffuse intrarenal Goldblatt clamp. The distinction between the two theories is that in the former (increased extrinsic infIuence) hypertension would be expected to occur even if a recipient animal were given a replacement kidney from a genetically normotensive animal, while in the latter (inherent renal dysfunction) hypertension would be expected to follow the kidney in renal transplant experiments. Possible role of the sympathetic nerves. There is evidence both for and against the contention that increased sympathetic activity is critically involved in the genesis of spontaneous hypertension, with most attention being focused on the Okamoto strain. Some variability in sympathetic function and catecholamine stores has’been observed,lp2 but the irregularities do not convincingly account for the increase in pressure especially via arterial vasoconstriction. Pfeffer, Frohlich, and Pfeffer3 have identified an increased beta-sympathetic state that particularly affects cardiodynamics. Increased cardiac stimulation may contribute to the final hemodynamic picture observed, but it is apparently
January,
1975, Vol. 89, No. 1, pp. 94-98
Spontaneous hypertension and the kidney
not essential for the development of hypertension.‘Immunosympathectomy decreases blood pressure in both Okamoto5 and New Zealand6 rats in a somewhat greater proportion than in normotensive rats, but it does not prevent a marked increase in blood pressure as the animal matures. Adrenal medullectomy does not decrease blood pressure in the Okamoto strain.7 Hexamethonium has been widely used to produce an acute blood pressure decrease in spontaneously hypertensive rats,6,8-10but this data may not confirm an exaggerated, neurogenic arterial vasoconstriction for several reasons. One is that hexamethonium also decreases blood pressure in experimentally hypertensive animals where increased sympathetic activity is most probably not involved.*pn Second, the primary hypotensive potency of hexamethonium results from severe depression of cardiac output; peripheral resistance changes little following administration of the drug? Data from environmental experiments support sympathetic involvement in spontaneous hypertension. Spontaneously hypertensive rats have been shown to have an increased cardiovascular reactivity to irritating stimuli,2*12 while, on the other hand, chronically maintaining the animals in a quiet, dark environment slows the development of the hypertension.13 A theory that reconciles this variety of data is that increased sympathetic nerve activity in the spontaneously hypertensive rat has a specific, pronounced effect on renal function that is greater than any effect on the general vasculature. In Okamoto animals, direct electrical recordings from the splanchnic nerveI and also indirect studies15s10have shown splanchnic nerve traffic to be increased up to five times that of control rats. The direct anatomic connection between the splanchnic sympathetic trunk and the renal sympathetic nerves suggests that renal function is compromised. At least acutely, experiments have shown that sympathetic nerve stimulation markedly decreases sodium excretionl?; increased arterial pressure would be required to re-establish salt and water homeostasis. The evidence, in toto, suggests that in the Okamoto and New Zealand strains, increased sympathetic activity could cause or exacerbate the hypertension, particularly via depressed renal function, but a possible crucial role of inherent renal dysfunction is definitely not elimi-
American Heart Journal
nated by this data. In contrast, in the Dahl strain there is rather convincing evidence that hypertension is caused solely by an intrinsic renal defect. Evidence for an inherent renal defect. The crux of kidney transplant protocols is that kidneys are exchanged among spontaneously hypertensive and normotensive animals and subsequent blood pressure changes are noted. One preliminary report, presumably using the Okamoto strain, stated that hypertension did not follow transplantation of the hypertensive kidney.‘* In contrast, Bianchi and colleagues,19 in a separate strain, found that hypertension did move with the transplanted kidney. Similarly, Dahl and Herne20 have observed that hypertension followed the transplanted kidney when kidneys were exchanged between hypertensive and normotensive animals. There is additional evidence for an inherent renal defect in Dahl’s strain of hypertensive rats. This strain, designated “salt-sensitive,” becomes hypertensive when placed on a high-salt diet but remains normotensive on a normal diet. During normal salt intake and before hypertension has ever developed, Jaffe and co-workers2’ have observed a mild, nonuniform focal constriction of the early afferent arterioles. The constriction is not observed in a companion strain of “salt-resistant” animals, a strain that remains normotensive on all salt intakes. But in the saltsensitive animals, the hypertensive response to high-salt diet includes further encroachment of the lesion upon the lumen of the afferent arteriole, as if an intrarenal response to the highsalt diet was creating a wealth of diffuse, minute Goldblatt clamps. Renal blood flow and glomerular filtration rate are normal after the development of hypertension,22 evidence for a considerably elevated renal afferent resistance. This alteration in renal morphology and function is irreversible in that hypertension persists after the salt-rich diet is discontinued.% There is also some indication of renal dysfunction in the Okamoto strain, but it may not be due to intrinsic causes. Kidney weight in these animals is normal2 and no morphologic abnormalities have yet been discovered.2 Folkow and co-workers24 have measured a decreased renal resistance in isolated Okamoto kidneys perfused at low pressure. The renal vasculature in these preparations appears abnormally stiff and it may
95
Coleman
et al.
be that at higher perfusion pressures the renal resistance is, in fact, greater than normal. In other studies of Okamoto rats, blood flow through the kidneys in situ has been observed to be low26*26even at the very high arterial pressures that commonly occur. Similarity between spontaneous and Goldblatt hypekension. The blood pressure of Okamoto
animals is remarkably insensitive to the level of salt intake, with hypertension developing on both low and normal salt intakes.27-2g Similarly, even though Dahl’s strain of rats is called saltsensitive, the animals’ arterial pressures are remarkably salt-insensitive after a high-salt diet has been administered for a requisite, but short, amount of time23-the hypertension persists when the animals are subsequently placed on a low-salt diet. The lack of pressure sensitivity to salt intake in these strains is nearly identical to the Goldblatt-clamped rat that has allof its renal tissue distal to a renal artery constriction; most commonly, the preparation consists of unilateral renal artery clamping in combination with contralateral nephrectomy. Parallelism between spontaneous and Goldblatt animals is further developed by the apparent lack of involvement of the reninangiotensin system in both forms of hypertension. With Goldblatt clamping, the abrupt application of a clamp provokes temporary renin release, but this subsides as the hypertension develops and the pressure distal to the clamp rises toward normal values. After the initial transients, plasma renin activity is quite normal. There is no comparable abruptness in the onset of hypertension of the spontaneously hypertensive rat, and this may allow the renin-angiotensin system to remain primarily dormant in these animals. Possible role of fluid volumes. Experience with anephric patients has shown that rather small changes in fluid volumes can have a pronounced effect on arterial pressure. Similarly, the early sodium and water retention in G.oldblatt hypertension gives way to only the slightest of abnormalities in the chronic state. In both instances, a strong argument can be made for an important role of fluid retention in the onset of hypertension; the argument is that overhydration causes & increased cardiac output which in turn triggers an autoregulatory response.30,31 Demonstration of the same sequence of events in spontaneously hypertensive rats has been difficult. Fluid
96
volume measurement in Okamoto,32”3 New Zealand,34 and Dah134 rats has not revealed comparable overhydration. There are two critical considerations: (1) absolute fluid volume is important in the circulation only in relation to the compliance of the vasculature that it is contained in, and this compliance may be decreasing as spontaneous hypertension develops; and (2) the gradual onset of spontaneous hypertension may allow very subtle overhydration to play a more important role in elevating pressure than previously s%petted. The vasculature:
hypertension
vs. growth.
Growth is a physiologic process which demands increased vasculature, while hypertension is a disease which produces decreased vasculature. Decreased vasculature and, therefore, increased resistance, is probably the result of the physioiogic response of overperfused tissues36 and, later, pathologic effects.2 The conflict between growth’s demands for increased vascularity and the disease process might be resolved within the spontaneously hypertensive rat by retardation in the normal development of the animal’s vasculature. It is interesting to note that these animals do not grow particularly rapidly, as if an inadequately developed circulation is not capable of supporting the normal rate of accumulation of body mass. The mature, spontaneously hypertensive rat shows a decreased number of arterioles2~37 and venules38 when compared to normotensive control animals. Normal absolute fluid volume plus decreased compliance could equal relative overhydration. It is not clear, though, if vascular change plays a role in the onset of elevated pressure or if it follows, and is caused by, the elevated pressure. Transient volume changes. Sudden changes in renal function can produce easily identified increases in fluid volumes during the onset of hypertension. The spontaneously hypertensive rat does not usually undergo any abrupt changes comparable to those produced by experimental intervention in other animal models, e.g., the sudden decrease in renal function that occurs with renal artery clamping. There are two observations in spontaneous hypertension, however, that have been made during abrupt changes in the animal’s status and suggest that fluid volume retention may have a direct role in the etiology of this hypertension. One observation is that after cessation of successful antihypertensive therapy
January, 1975, Vol. 89, No. 1
Spontaneous
in the Okamoto strain, the resulting rapid elevation in blood pressure is associated with increasing blood volume and extracellular fluid volume.39 Similarly, increased extracellular fluid volume has been observed immediately following the implantation of hypertension-producing kidneys into normotensive rats.40 In both cases, fluid retention coincides with the development of hypertension in a previously normotensive animal. Extrapolating from this short-term data, salt and water retention may be important in the more subtle elevation in pressure that normally occurs.
There is direct and indirect evidence that the kidneys are involved in the onset of hypertension in spontaneously hypertensive animals. In the Dahl strain, rather convincing evidence exists for a primary, inherent renal defect that is worsened by high dietary salt. In the Okamoto and New Zealand strains, an intrinsic defect may be provoked by increased sympathetic nerve activity. Similarities between all of these strains and Goldblatt hypertension suggest a fluid volume abnormality, but the gradual onset of elevated pressure and continuing growth during development of hypertension may obscure critical volume changes. Theoretically, arterial pressure, somewhat independent of intermediate steps, will reach the level which is dictated by renal function as being necessary for the maintenance of salt and water homeostasis. While widespread use of different spontaneously hypertensive strains may currently be complicating our understanding of the intermediate steps, studies of dissimilar strains should in time, enhance our understanding of the many different facets of long-term blood pressure control.
9.
10.
11.
12.
13.
14.
15. 16.
17.
18.
19.
20.
REFERENCES 1.
2. 3.
4. 5.
Louis, W. J., Spector, S., Tabei, R., and Sjoerdsma, A.: Synthesis and turnover of norepinephrine in the heart of spontaneously hypertensive rat, Circ. Res. 24~85, 1969. Okamoto, K.: Spontaneous hypertension in rats, Int. Rev. Exp. Pathol. 7:227, 1969. Pfeffer, M. A., Frohlich, E. D., and Pfeffer, J. M.: Disparity in autonomic control of cardiac performance in spontaneously hypertensive rats, Circulation 48 (5uppl. 4): 45, 1973. Pfeffer, M. A.: Personal communication. Folkow, B., Hallback, M., Lundgren, Y., and Weiss, L.: The effects of “immunosympathectomy” on blood pressure and vascular “reactivity” in normal and spon-
American
Heart Journal
21.
22.
23.
24.
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January,
1976, Vol. 89, No. 1
