Renal circulation in genetic experimental hypertension

RENAL CIRCULATION IN GENETIC EXPERIMENTAL HYPERTENSION

Alain Bataillard, Ming Lo, and Jean Sassard

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rat M o d e l s o f Genetic H y p e r t e n s i o n . . . . . . . . . . . . . . . . . . . . . . . . . . Genetically H y p e r t e n s i v e Rat Strains . . . . . . . . . . . . . . . . . . . . . . . . T h e H y p e r t e n s i o n - P r o n e Rat Strains . . . . . . . . . . . . . . . . . . . . . . . . M e t h o d s for the M e a s u r e m e n t o f Renal B l o o d Flow in Rats . . . . . . . . . . . . . . Techniques Using Microspheres ........................... P u l s e d D o p p l e r Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ultrasonic T r a n s i t - T i m e Techniques . . . . . . . . . . . . . . . . . . . . . . . . . L a s e r Doppler M e t h o d s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E x p e r i m e n t a l Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R e n a l Circulation in Genetically Hypertensive Rats . . . . . . . . . . . . . . . . . . G H Rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dahl Salt-Sensitive Rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S H R Rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M i l a n Hypertensive Rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . L y o n Rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Advances in Organ Biology Volume 9, pages 317-329. Copyright © 2000 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 0-7623-0617-3

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ALAIN BATAILLARD,MING LO, and JEANSASSARD INTRODUCTION

Starting with Richard Bright (1784-1858) who observed in patients the association of renal disease with left ventricle hypertrophy, the kidney has been recognized as being central--both as a cause and as a victim--in hypertension. More recent experiments involving cross-transplantation of kidneys from genetically hypertensive rats to normotensive recipients showed that kidneys transferred at least a large part of the hypertension (Dahl et al., 1974; Bianchi et al., 1974; Rettig et al., 1990) thus emphasizing their primary role. As a consequence, renal function and especially the circulation have been extensively studied in the various models of genetic hypertension. After a short description of the models, the methods available for studying the renal circulation and the data so far obtained will be summarized. Despite the interest of the genetically hypertensive mouse strain selected by Schlager (1974), the size of this animal still makes it difficult to correctly appraise renal functions. Therefore, this review is restricted to rat models of genetic hypertension.

RAT MODELS OF GENETIC HYPERTENSION The models can be divided into two categories.

Genetically Hypertensive Rat Strains These strains have been obtained by inbreeding albino rats, mostly of the Wistar strain, selected on the basis of their spontaneous baseline systolic blood pressure (BP) level, usually measured by tail-cuff plethysmography in the preheated conscious animal. Those strains are, by order of appearance:

The New Zealand Genetically Hypertensive (GH) Strain This was the first strain to be obtained, by Sir Horace Smirk (Smirk and Hall, 1958). GH rats are compared to random-bred normotensive (GN) rats which descend from the stock used to select GH animals.

The Spontaneously Hypertensive Rat (SHR) Strain This strain was established by Okamoto and Aoki (1963) in Kyoto, then generously distributed to the NIH and thereafter throughout the world by Pr Y. Yamori. The normotensive control strain, the Wistar-Kyoto strain (WKY), descends from the stock of origin of the SHR but has not been simultaneously selected with them. It must be noted that there are some genetic and phenotypic differences between the different colonies of SHR and WKY rats due to their widespread use (Nabika et al., 1991).

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The Lyon Hypertensive Rat (LH) Strain This is the only one which is comprised of three simultaneously selected rat strains: one hypertensive (LH), one normotensive (LN), and one selected to exhibit a low BP level (LL) (Dupont et al., 1973). Since the BP of LL rats does not differ from that of LN, both strains can be used as controls for the LH animals. Therefore, LH rats are the only ones that can be compared to two simultaneously selected genetically pure and different control strains. This has proved to be of interest as it allows differences which can be observed between LH and LN, which are possibly related to hypertension (in that case LH differ in the same way from both LN and LL controls) to be distinguished from those which are not (in that case LH differ from LN or LL rats but not from both). The other special characteristics of the Lyon model are (1) its Sprague-Dawley origin instead of Wistar and (2) the fact that in LH rats hypertension is uniquely associated with increased body weight, a spontaneous elevation in plasma cholesterol and insulin/glucose ratio, and a marked proteinuria.

The Milan Hypertensive Strain (MHS) of Rats MHS rats are of Wistar origin and can be compared to genetically pure normotensire (MNS) controls which have not been simultaneously selected (Bianchi et al., 1974).

The Hypertension-Prone Rat Strains In these cases, the rats are not selected on the basis of a spontaneously greaterthan-average BP but on the basis of their BP response to known hypertensive maneuvers. The idea of obtaining such rats arose from the observation by Dahl that the response of random-bred rats to high salt intake was variable and genetically determined (Dahl et al., 1962).

The Dahl Salt-Sensitive (DS) Rat Strain Using Sprague-Dawley rats, Dahl selected animals which were sensitive (DS) or resistant (DR) to the effects of a high-salt (8% NaCI in food) diet (Rapp, 1984). They exist as two different colonies. One remained in the original laboratory at Brookhaven and is not inbred. The second was derived by J. Rapp (JR) from the original colony and is now fully inbred at least in some research centers. The DS animals in the second strain develop a marked hypertension when given salt. However, even when maintained on a normal salt diet, DS rats spontaneously exhibit a higher BP than DR.

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The Sabra Hypertensive-Prone Rat (SBH) Strain This strain was developed by Ben-Ishay et al. (1972). It comprises rats which become hypertensive (SBH) or remain normotensive (SBN) when, after uninephrectomy, they are given DOCA (25 rag, subcutaneously) and NaC1 1% to drink. In conclusion, a wide range of rat models of genetic hypertension are offered to the investigator. All have advantages and disadvantages. In any case, the greatest attention has to be paid to the choice of the normotensive controls. In addition, it must be clear that the single comparison between one hypertensive and one normotensive strain will reveal a huge number of genetically determined differences. Obviously, very few of them are really linked to hypertension. The identification of factors linked to hypertension requires the use of several normotensive control strains and/or the development of a large population of hybrids of the second generation followed by the determination of the relationship between any given phenotype and the BP level in this population.

METHODS FOR THE MEASUREMENT OF: RENAL BLOOD FLOW IN RATS The appraisal of renal hemodynamics in rats is rather complex. Since anesthetics markedly influence RBF for long periods of time (Petersen et al., 1991), experiments should, as far as possible, avoid anesthetized animals. In addition, when measurements are performed in conscious rats, these rats are preferably studied unrestrained and the experiments should allow a recovery delay of at least 1 week after surgical preparation.

Techniques UsingMicrospheres Basically, these techniques involve the intravenous injection of microspheres which have a diameter approximately twice that of an erythrocyte and are trapped by the organs in amounts proportional to the flow they receive. The animals are then killed and the organ content in microspheres easily measured since they are labeled either with cobalt-57 (Domenech et al., 1969) or with a fluorescent (Glenny et al., 1993) or colored dye (Kowallik et al., 1991). The major advantage of this technique is that it measures simultaneously the blood flow in all of the organs which are dissected, providing an accurate view of the way the cardiac output is distributed. However, it gives only one time poin: and requires the death of the animals.

Pulsed DopplerTechniques Adapted to the rat by Haywood et al. (1981), this technique uses the Doppler phenomenon which is the change in the frequency of an ultrasonic wave after reflection on a moving target. Since the change in frequency is proportional to the

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speed of the target, this technique allows measurement of the velocity of the red blood cells. It is called pulsed Doppler as the emission of ultrasounds is pulsed, the same crystal functioning as an emitter and a receiver. This technique has been widely applied after the pioneering work of the late Professor M.J. Brody. It is suited to obtaining simultaneously several blood flows in conscious rats. The crystals are easy to place and cheap. The major limitations are linked to the theoretical basis of the technique. Since it measures red blood cell velocity, pulsed Doppler values may be altered by changes in the hematocrit and the shape of the vessel. Therefore this technique cannot give absolute values of blood flow (Grady and Bullivant, 1992), and is restricted to the quantification of spontaneous or evoked changes in blood flow compared to the baseline value obtained in a given animal. Despite these limitations, pulsed Doppler has been extensively used and provided many interesting findings, such as the fact that compared to other vasculatures, RBF is less variable. However, even RBF is more spontaneously variable than BP (Ferrari et al., 1993), thus suggesting that BP may be stabilized at the expense of RBF variations (see also Zhafig et al., 1995).

Ultrasonic Transit-Time Techniques The purpose of these techniques was to avoid the major disadvantages of the pulsed Doppler method, namely, being influenced by changes in the position of the probe and the shape of the vessel. Transit-time flow probes do not rely on the Doppler principle. Instead, they use large crystals which generate ultrasonic waves and calculate the transit time of these waves between an upstream and a downstream signal. Therefore, they allow a direct measurement of the flow, irrespective of its composition and of the size of the vessel. Initially designed for large animal studies, miniaturized probes are now available and the accuracy of the technique in the rat has been carefully studied (Welch et al., 1995). Absolute flow values can be obtained and several probes can be placed in the same animal. The limits are the size of the probes and their price. However, this technique may well represent the most reliable technique actually available for studies in conscious rats.

Laser Doppler Methods Laser Doppler methods (Nilsson et al., 1980) allow measurement of capillary red cell blood flow in a very restricted area (1 mm 3) of an organ. Although the results in the rat kidney have been correlated to more direct estimates of local capillary flow using 51Cr-labeling erythrocytes (Roman and Smits, 1986), it is not yet possible to apply any other method of blood flow measurement to the small areas investigated by the laser Doppler technique. It is thus impossible to really calibrate laser Doppler probes. In addition it has to be emphasized that (1) laser Doppler, as well as pulsed Doppler, does not directly measure BF and (2) the areas studied by laser Doppler are so small that the extrapolation to an organ, or even a part of it, is hazardous. Finally this technique remains extremely difficult to apply to conscious rats.

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EXPERIMENTAL C O N D I T I O N S The renal circulation and renal function of genetically hypertensive rats can be studied in various experimental conditions. Schematically, from the more integrative to the more reductionist ones, they are as follows: • The conscious unrestrained animal, which has to be studied far away from the time of surgical preparation so as to avoid the influence of anesthesia (Petersen et al., 1991), and also to allow fibrosis to develop which fixes the flow probes in a stable geometry around the renal artery. • The anesthetized animal which allows an easy development of acute protocols. The data may be confounded by the influence of anesthetics, which have marked effects on cardiovascular and renal functions. Of course, similar effects are expected to occur in normotensive controls, but it is impossible to rule out the existence of different sensitivities to anesthesia in normotensive compared to hypertensive rats. In any case it is necessary to pay great attention to the stability of the body temperature and of the blood gases of the animals. • The "isolated" kidney perfused in situ. In this technique the kidney is maintained in strictly fixed conditions, which allows us to use the term "isolated," but it remains in situ and perfused with the blood of the animal. One of the most interesting has been developed by Roman and Cowley (1985) to study the pressure natriuresis function. It consists of rats which have been uninephrectomized and adrenalectomized 1 week before the experiment. After anesthesia, the remaining kidney is exposed and the remaining adrenal excised. Very importantly, a hormone cocktail is infused to maintain stable the most important hormones that control urinary sodium excretion. Finally two inflatable balloon cuffs are placed around the aorta, above and below the renal artery. They allow modification of renal perfusion pressure and thus determination of its influence on intrinsic renal function. • The isolated kidney perfused in vitro. Several techniques can be used which differ by (1) the composition of the perfusate: physiological solution with or without a colloid osmotic agent to improve sodium reabsorption and/or red blood cells; (2) the use of recirculating perfusate or single-pass perfusion. We have mostly used single-pass perfusions with Krebs-Henseleit added with polygelin as a colloid osmotic agent according to Schmidt and Imbs (1980). This preparation is stable for more than 2 hours. It is noteworthy that (1) the vasculature is maximally dilated so it is necessary to preconstrict it prior to any maneuver which may induce vasodilation; (2) the tubular sodium reabsorption remains below 90%, which makes this preparation more suitable for the study of responses of the renal vasculature than of the control of sodium excretion.

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RENAL CIRCULATION IN GENETICALLY HYPERTENSIVE RATS GH Rats According to the re¥iew of Simpson et al. (1994), GH do not exhibit marked alterations in renal morphology compared to controls, at least in terms of those characteristics which, being present in young animals, are likely to initiate the hypertensive process. The renal circulation of adult GH rats was studied using the washout of a radioactive gas (133Xe) injected in the anesthetized rat. At the kidney level, the disappearance rate of the 133Xeallows identification of three compartments of RBF: one fast (85% of the total), one slow (10%) and a last one (5%). These three flows do not have a defined anatomical or functional basis except that the third compartment is probably extrarenal. In GH rats, the fast compartment but not the slow one was lower than in controls. As a consequence, the total RBF was decreased (-20%) and the renal vascular resistance increased twofold in GH rats. Participation of the renin-angiotensin system in this decreased RBF was strongly suggested by the observation that saralasin, an antagonist at angiotensin II receptors, increased, and angiotensin II decreased, RBF more markedly in GH than in GN rats.

Dahl Salt-Sensitive Rats This model has been widely studied in various experimental conditions, all data converging to point to the existence of preglomerular vasoconstriction in DS rats. Using the isolated perfused preparation, Steele and Challoner-Hue (1988) described that DS kidneys differed from DR by an increased vascular resistance without change in glomerular filtration rate, regardless of whether or not the rats were exposed to a high salt diet. Roman (1986) showed that the in situ perfused kidneys of salt-loaded animals exhibited increased vascular resistance, decreased glomerular filtration rate, natriuresis, and slope of the pressure-natriuresis curve relative to DS rats on a low-salt diet. In vivo, Boegehold et al. (1991) using microspheres demonstrated that vascular resistance was elevated in all organs of DS rats but that this increase was especially prominent in the kidneys. Recently Churchill et al. (1995) elegantly showed that the renal vasoconstriction seen in DS rats was, in part, genetically determined. These authors cross transplanted kidneys from DS to DR and vice versa. After salt loading, DS rats with a DR kidney and DR rats with a DS kidney had the same BR However, the DS kidney still exhibited reduced blood flow, glomerular filtration rate, and urinary kallikrein excretion. This study suggests that, in Dahl's model, (1) hypertension is not fully explained by renal factors and (2) the abnormalities in the renal circulation and kallikrein excretion are genetically determined.

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SHR Rats It is impossible to summarize'here the huge number of studies devoted to the renal circulation of SHRs. Consequently we have chosen to focus on some which appeared to us to be the most relevant. Using isolated kidneys perfused with physiological solution with added albumin, Firth et al. (1989) showed that, at various perfusion pressures, SHR kidneys had significantly lower RBF, glomerular filtration rate, natriuresis and fractional excretion of sodium and lithium than WKY ones. The conclusion was that in SHRs a preglomerular vasoconstriction existed, together with increased sodium reabsorption which predominated in the proximal tubules. Interestingly, Uyehara and Gellai (1993) in similar experiments showed that this preglomerular vasoconstriction preceded the full development of hypertension as it was present in 4 week-old SHRs. An elegant series of studies by Arendshorst's group demonstrated that when SHR kidneys were perfused in situ with blood: (1) There exists an elevated preglomerular vessel tone as shown by a lower RBF and glomerular filtration rate which is linked to hypersensitivity of these vessels to the effects of angiotensin II (Arendshorst et al., 1990). (2) This hypersensitivity to angiotensin II could be related to a defective release of vasodilatory prostaglandins as the difference between SHR and WKY responses to angiotensin II disappears after cyclooxygenase blockade with indomethacin (Arendshorst et al., 1990). A defect in the action of other vasodilatory compounds was also suggested as it appeared that theadenylate cyclase activation was diminished (Chatziantoniou et al., 1993) probably due to an altered coupling through G proteins (Chatziantoniou et al., 1995). One interesting question concerns the specificity of this hypersensitivity of preglomerular vessels to angiotensin II. The results are controversial. For example, Kost and Jackson (1993) showed that it was not shared with periarterial nerve stimulation and not secondary to the vascular hypertrophy induced by hypertension as it persists in SHRs made normotensive with captopril. On the contrary, Feng and Arendshorst (1996), under similar experimental conditions, found that SHR renal vessels were also more sensitive to the constricting action of arginine vasopressin V1 receptor stimulation. In contrast to these experiments, Roman (1987) using his own technique did not find that the SHR kidneys had lower RBF and filtration at any given renal perfusion pressure. However, he showed a shift of the pressure-natriuresis curve toward high pressure levels. More recently, using the laser Doppler technique (Roman, 1990), he reported the observation of lower papillary blood flow in SHR, associated with lower interstitial fluid pressure. These alterations, which did not affect the total RBF, could account for the pressure-natriuresis curve shift. The differences between the findings of these two leading groups are interesting as they point out the importance of experimental conditions. In effect, the most likely explanation for the above-described discrepancy is that in Roman's preparation, but not in Arendshorst's, most of the neurohumoral factors which control renal resistance and sodium reabsorption are fixed. Whatever these differences, it re-

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mains, as postulated by Anderson (1994), that the abnormalities of preglomerular vessels could be of major importance for the development of hypertension in SHRs. This position is strengthened by the observation that in F2 hybrids of an SHR x WKY cross, the diameter of the afferent glomerular arteriole negatively correlated with the BP level (Norrelund et al., 1994).

Milan Hypertensive Rats Using kidneys isolated from 4-week-old MHS rats, perfused with a physiological solution withadded albumin, Salvati et al. (1987) reported a surprising greater RBF, glomerular filtration rate, and tubular sodium reabsorption when compared to MNS controls. With the same preparation it appeared that the slope of the pressurenatriuresis curve was identical in the two strains, thus reinforcing the importance of an enhanced sodium reabsorption since the filtered load is much greater in MHS than in MNS rats. When kidneys were perfused in situ with blood, young MHS still exhibited greater glomerular filtration rate and diuresis than MNS. These differences disappeared with the development of hypertension. On this basis, Bianchi's group developed a series of biochemical studies concerning the Na + handling by the tubules (for review see Bianchi et al., 1994) and showed that in MHS the maximum velocity of Na +, K+-ATPase, Na+/H + countertransport, and Na+/K+ cotransport was greater than in MNS, all of which would likely contribute to an increased tubular reabsorption of sodium. Finally, using red blood cells as a model of renal tubular cells, this group identified a point mutation in the a subunit of the cytoskeleton protein adducin. Interestingly, this mutation cosegregated with blood pressure in MHS x MNS second-generation hybrids and explained 50% of the hypertension. Very recently, the group reported that the same mutation partly controlled the sensitivity of hypertensive patients to a diuretic treatement (Glorioso et al., 1997).

Lyon Rats Three different approaches were used to assess renal functions in LH rats compared either to LL or to LN and LL controls. Using isolated kidneys, single pass perfused with a physiological solution with added colloid osmotic agent, Liu et al. (1991) found that LH kidneys differed from controls in that they had greater renal vascular resistance, and lesser glomerular filtration rate and urinary sodium excretion. Medeiros et al. (1992), with the same preparation submitted to various perfusion pressure levels, found a markedly lesser slope of the pressure-natriuresis curve in LH than in LN and LL controls. However, when the natriuresis was plotted against flow instead of pressure, the slope of the curve did not differ among LH and controls (unpublished data). This strengthens the prominent role of the preglomerular vasoconstriction existing in LH kidneys. Using the technique of Roman, Liu et al., (1996) confirmed the existence in LH kidneys of a preglomerular vasoconstriction associated with a blunted pressure-

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natriuresis curve. Interestingly, they demonstrated that most of these abnormalities were dependent on an active renin-angiotensin system as: (1) the higher renal vascular resistance, the lower glomerular filtration rate and most of the abnormalities of the pressure-natriuresis curve disappeared when LH rats were made normotensive by means of chronic treatment with perindopril, an angiotensin-converting enzyme inhibitor (see Figure 1); (2) in perindopril-treated rats the infusion of angiotensin II induced greater reductions in flow, filtration, and sodium excretion in LH than in LN kidneys. Finally, in anesthetized rats, the microsphere technique confirmed that LH rats differed from LN and LL controls by a prominent renal vasoconstriction which disappeared if they were perindopril treated, and reappeared when angiotensin II was chronically infused by means of a minipump (P. Lantelme, personal communication).

CONCLUSION In conclusion, two things are noteworthy. First, due to the very important role of the renal circulation, a technical effort is required so that RBF and its local components (cortical, medullary, papillary) can be measured accurately in conscious unrestrained animals. Second, most of the studies point to the existence of preglomerular vasoconstriction in genetically hypertensive rats. The mechanisms of this preglomerular vasoconstriction, which makes genetic hypertension close to a "multiple, micro-Goldblatt renal hypertension," represent one of the most exciting areas of hypertension research.

SUMMARY This chapter focused on rat models of genetic hypertension since (1) they are widely used and (2) they allow renal function and especially RBF to be measured with a relative accuracy. The various techniques used to obtain RBF (microspheres, pulsed Doppler, ultrasonic transit time, and laser Doppler methods) are presented with their major advantages and limitations. The most frequently used experimental conditions are described since they largely influence the data. Finally, the results obtained in various strains of genetically hypertensive rats are summarized with a special emphasis on the existence ofpreglomerular vasoconstriction in most of these strains, which makes them close to a "multiple, micro-Goldblatt renal hypertension."

REFERENCES Anderson, W.R (1994). Is hypertrophyof the walls of pre-glomerularvesselsresponsiblefor hypertension in spontaneouslyhypertensiverats? Blood Pressure 3 (Suppl. 5), 57-60. Arendshorst, WJ., Chatziantoniou, C., and Daniels, E (1990). Role of angiotensin in the renal vasoconstrictionobservedduringthe developmentof genetichypertension.KidneyInt.38 (Suppl. 30), $92-$96.

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Ben-Ishay, D., Saliternick, R., and Welner, A. (1972). Separation of two strains of rats with inbred dissimilar sensitivity to DOCA-salt hypertension. Experientia 28, 1321-1322. Bianchi, G., Fux, U., and Imbasciati, E. (1974). The development of a new strain of spontaneously hypertensive rats. Life Sci. 14, 339-347. Bianchi, G., Barber, B.R., Torielli, L., and Ferrari, P. (1994). The Milan hypertensive strain of rats. In: Textbook of Hypertension (Swales, J.D., ed.). Blackwell Scientific, Oxford, pp. 457-460. Boegehold, M.A., Huffman, L.J., and Hedge, G.A. (1991). Peripheral vascular resistance and regional blood flows in hypertensive Dahl rats. Am. J. Physiol. 261, R934-R938. Chatziantoniou, C., Ruan, X., and Arendshorst, W.J. (1993). Interactions of cAMP-mediated vasodilators with angiotensin II in rat kidney during hypertension. Am. J. Physiol. 265, F845-F852. Chatziantoniou, C., Ruan, X., and Arendshorst, W.J. (1995). Defective G protein activation of the cAMP pathway in rat kidney during genetic hypertension. Proc. Natl. Acad. Sci. USA 92, 2924-2928. Churchill, P.C., Churchill, M.C., Bidani, A.K., and Rabito, S.E (1995). Kallikrein excretion in Dahl salt-sensitive and salt-resistant rats with native and transplanted kidneys. Am. J. Physiol. 269, F710-F717. Dahl, L.K., Heine, M., and Tassinari, L. (1962). Effects of chronic excess salt ingestion: Evidence that genetic factors play an important role in the susceptibility to experimental hypertension. J. Exp. Med. 6, 1173-1190. Dahl, L.K., Heine, M., and Thompson, K. (1974). Genetic influence of the kidneys on blood pressure: Evidence from chronic renal homografts in rats with opposite predispositions to hypertension. Circ. Res. 34, 94-101. Domenech, R.J., Hoffman, J.I.E., Noble, M.I.M., Saunders, K.B., Henson, J.R., and Subijanto, S. (1969). Total and regional coronary blood flow measured by radioactive microspheres in conscious and anesthetized dogs. Circ. Res. 25, 581-596. Dupont, J., Froment, A., Milon, H., and Vincent, M. (1973). Selection of three strains of rats with spontaneously different levels of blood pressure. Biomedicine 19, 36-41. Feng, J.J., and Arendshorst, W.J. (1996). Enhanced renal vasoconstriction induced by vasopressin in SHR is mediated by V1 receptors. Am. L Physiol. 271, F304-F313. Ferrari, A.U., Daffonchio, A., Gerosa, S., Franzelli, C., Paleari, P., Ventura, C., DiRienzo, M., and Mancia, G. (1993). Spontaneous variability of regional haemodynamics in unanaesthetized rats. J. Hypertens. 1 I, 535-541. Ferrari, P., Cusi, D., and Barber, B.R. (1982). Erythrocyte membrane and renal function in relation to hypertension in rats of the Milan hypertensive strain. Clin. Sci. 63, 61s-64s. Firth, J.D., Raine, A.E.G., and Ledingham, J.G.G. (1989). Sodium and lithium handling in the isolated hypertensive rat kidney. Clin. Sci. 76, 335-341. Glenny, R.W., Bernard, S., and Brinkley, M. (1993). Validation of fluorescent-labeled microspheres for measurement of regional organ perfusion. J. Appl. Physiol. 74, 2585-2587. Glorioso, N., Stella, P., Cusi, D., Bariassina, C., Righetti, M., Troffa, C., Pinna Parpaglia, P., Soro, A., Manunta, P., and Bianchi, G. (1997). ct-Adducin genotype predicts the hypotensive response to diuretic treatment in essential hypertensive patients. Abstr. 8th Eur. Meeting on Hypertension, Milan. Grady, H.C., and Bullivant, E.M.A. (1992). Renal blood flow varies during normal activity in conscious unrestrained rats. Am. J. Physiol. 262, R926-R932. Haywood, J.R., Shaffer, R.A., Fastenow, C., Fink, G.D., and Brody, M.J. (1981). Regional blood flow measurement with pulsed Doppler flowmeter in conscious rat. Am. J. Physiol. 241, H273-H278. Kost, C.K., and Jackson, E.K. (1993). Enhanced renal angiotensin II subtype 1 receptor responses in the spontaneously hypertensive rat. Hypertension 21,420-431. Kowallik, P., Schulz, R., Guth, B.D., Schade, A., Paffhausen, W., Gross, R., and Heusch, G. (1991). Measurement of regional myocardial blood flow with multiple colored microspheres. Circulation 83, 974-982. Liu, K.L., Aissa, A.H., Lartal, M.C., Benzoni, D., Vincent, M., and Sassard, J. (1991). Adrenergic stimulation of renal prostanoids in the Lyon hypertensive rat. Hypertension 17, 296-302.

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