INTRODUCTION

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INCREASED GLOMERULAR capillary pressure (P_gc) seems to be a major pathogenetic factor in the development of glomerular sclerosis in hypertensive renal disease in rats (29). Lowering of the increased P_gc by different regimes has been shown to attenuate glomerular degeneration and preserve renal function (2, 5, 8, 12, 13, 21, 34, 36). The effect on P_gc of different antihypertensive drugs is therefore of considerable interest.

P_gc is a function of the balance between afferent and efferent vascular resistances, as well as the level of systemic blood pressure. Variations in P_gc during everyday transitory fluctuations of the systemic blood pressure may be prevented by adjusting the renal vascular resistance (RVR), mainly involving the afferent vessels (25). In experimental conditions, autoregulation keeps both renal blood flow (RBF) and P_gc constant within a wide range of acute pressure variations. When hypertension becomes chronic, the set point of autoregulation is reversibly reset toward higher blood pressures, whereas the capacity of autoregulation seems to be maintained (20). However, an increase in P_gc seems to follow long-standing hypertension (18).

Animal experiments have demonstrated significantly different effects of antihypertensive drugs on afferent and efferent RVR, P_gc, and RBF autoregulation in different experimental settings (1, 2, 8, 10, 12, 23, 26, 36). A comparative study of the effect of antihypertensive drugs on these parameters when the blood pressure is reduced to the same level for all drugs has not been carried out. The intention of the present study was therefore to compare the effects on P_gc, afferent and efferent resistances, and RBF autoregulation of antihypertensive drugs at doses that lowered mean arterial pressure (MAP) to similar levels. Furthermore, the main part of the study was conducted in uninephrectomized spontaneously hypertensive rats (SHR), a model of renal hypertrophy and sclerosis with intact RBF autoregulation. The drugs we used were two calcium channel antagonists (dihydropyridin derivative and phenylalkylamin), an ₁-receptor blocker, and an angiotensin-converting enzyme (ACE) inhibitor.

In the normal situation, RBF and P_gc are autoregulated within the same limits. As the calcium channel antagonists abolish RBF and probably also P_gc autoregulation, we would expect that P_gc becomes a function of MAP when the kidneys are exposed to calcium channel antagonists. To further investigate the relationship between MAP and P_gc, experiments were conducted in which P_gc was measured over a wide range of renal perfusion pressures.

The study shows that the effect on P_gc differs among these antihypertensive drugs and is critically dose dependent when calcium channel antagonists are used, because these drugs abolish autoregulation.

	MATERIAL AND METHODS

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Animals. A total of 87 male SHR (Mol:SHR; Möllegaard, Skensved, Denmark) were used in the experiments. They were fed the supplier's standard maintenance chow, containing (in percent) 0.2 sodium, 1.0 potassium, 0.9 calcium, and 19 crude protein (Altromin-Stålstandard, Nittedal, Norway). Four animals were housed in each cage, with a 12:12-h light-dark cycle. In the main part of this study, nephrectomy (right kidney) was carried out during pentobarbital sodium anesthesia in the rats at 16 wk of age, and the hemodynamic studies were done 10 wk later. Forty-two uninephrectomized rats in six groups were used to measure P_gc at a MAP of ~120 mmHg, and 27 animals in four groups were later on supplemented to study P_gc at a MAP of ~85 mmHg.

The effects of the main antihypertensive drugs in animals with both kidneys intact were studied in three groups (18 animals) of 30-wk-old SHR. MAP in these animals was reduced to ~100 mmHg.

The experiments described have been performed in accordance with and under the approval of the Norwegian State Board for Biological Experiments with Living Animals.

Preparation. After anesthesia with Inactin (120 mg/kg body wt; Byk-Gulden, Constance, Germany), the animals were placed on a thermostat-regulated (37°C) heating pad, one PP-50 catheter was introduced into the left femoral vein for infusions, and another was introduced into the left femoral artery for blood sampling and continuous systemic blood pressure measurement by a Hewlett-Packard pressure transducer (model 1280C) connected to a Hewlett-Packard recorder (model 8811A). A continuous infusion of Ringer acetate (Travenol Laboratories, Halden, Norway) with 2% bovine serum albumin (7 ml · kg body wt¹ · h¹; Sigma Chemical, St. Louis, MO) was started. The arterial hematocrit was measured in 0.1-ml blood samples, one drawn initially and one drawn after the second stop-flow measurement to secure adequate fluid replacement. Plasma samples were frozen for later measurement of oncotic pressure.

The trachea was cannulated with a PP-260 catheter. After a left subcostal incision, an adjustable clamp was placed on the abdominal aorta above the renal artery to adjust renal perfusion pressure. Care was taken not to damage the renal nerves while dissecting the renal artery free from the surroundings, and RBF was measured by a small ultrasound-Doppler silicon rubber probe with internal diameter of 0.8 mm, connected to a 10-MHz pulsed-Doppler meter (Alfred; Vingmed Sound, Horten, Norway) placed on the renal artery. The value for RBF after 10 min of stable recording was used in the calculations. Calibration of the flow probe was carried out as described before (19).

Measurement of RBF autoregulation. RBF was recorded during reduction of the arterial perfusion pressure in steps of 10-15 mmHg from the control value to a pressure of 60 mmHg. The last recording before a fall in RBF of >0.2 ml · min¹ · kidney¹ lasting more than 30 s was defined as the lower pressure limit of RBF autoregulation. Absence of RBF autoregulation was defined to be present when a small pressure reduction produced a lasting reduction of RBF. In these rats, control pressure and the lower pressure limit of RBF autoregulation were defined as equal. The ability to reduce RVR during pressure reduction was calculated in percent of control in all groups.

After an initial measurement of RBF autoregulation, the kidney was allowed to recover at control pressure for ~15 min. The infusion of Ringer acetate was then changed to an infusion of an antihypertensive drug diluted in Ringer containing 2% bovine serum albumin. In this main part of the study, an individualized dose was given to reduce systemic arterial pressure to ~120 mmHg. The drugs (average doses per kilogram of body weight; range in parentheses) used were the -receptor blocker doxazosin, 16 µg (13-27 µg); the ACE inhibitor enalapril, 4 mg (2.6-5.2 mg); and the calcium-channel antagonists nifedipine, 50 µg (25-100 µg), or verapamil, 1.12 mg (0.75-1.26 mg). The drugs were delivered as sustained intravenous infusions for 30 min. Ringer solution was given to two control groups. In one group, P_gc was measured without any intervention. In the other, MAP was reduced to ~120 mmHg by means of an aortic clamp. For all groups, n = 7.

In a separate set of animals divided into four groups, MAP was reduced to ~85 mmHg and only enalapril and nifedipine were used in addition to two control groups. The animals were given nifedipine in an average dose of 0.72 ± 0.16 mg/kg body wt (n = 6) or enalapril in an average dose of 10.3 ± 1.1 mg/kg body wt (n = 7). Enalapril had to be supplemented with an aortic constriction in some of the animals to reach the intended blood pressure reduction. The control groups (n = 7) got Ringer solution. In one group, an aortic constriction was used to reduce MAP to ~85 mmHg; in the other group, the animals were studied at control pressure.

After the drug infusion was completed, a new steady state was obtained, and a second recording of RBF autoregulation was performed. The animals were then prepared for micropuncture.

To test the effect of antihypertensives on P_gc in animals with both kidneys intact, P_gc was measured in 30-wk-old SHR with MAP reduced to ~100 mmHg. The animals were given the ACE inhibitor ramipril (4 mg/kg body wt, n = 6) or nifedipine (30 mg/kg body wt, n = 6) by gastric gavage once a day, 5 days a week for 15 wk, to reduce systemic arterial blood pressure to ~100 mmHg, i.e., below the lower pressure limit of RBF autoregulation. Both drugs were given in 3% metylcellulose, and this was also given to the controls (n = 6). They were prepared for micropuncture as described above, with the difference that 50 mg/kg body wt pentobarbital sodium was used to induce anesthesia, and the RBF autoregulation procedure was not performed.

Micropuncture and stop-flow measurements. Stop-flow measurements were performed as described by Gertz et al. (11). The kidney was dissected free from its surroundings, with no attempts made to denervate it. It was placed in a Lucite cup with its dorsal aspect facing upward and immobilized by cotton moistened in saline. The ureter was cannulated with a PP-10 catheter to visualize small droplets of urine as a marker of a filtrating kidney. The open abdomen was then covered with mineral oil (viscous paraffin, E. Merck, Darmstadt, Germany), and the kidney was continuously irrigated with warmed Ringer acetate.

Micropuncture was performed with glass pipettes with sharpened tips of 3-6 µm diameter. The micropipettes were mounted in micromanipulators (Ernst Leitz, Wetzler, Germany), and the punctures were performed under a stereomicroscope (model M54; Wild, Herbrugg, Switzerland) at a ×50 magnification and a fiberoptic light source (Intralux 5000; Volpi, Zürich, Switzerland). The micropipettes used to measure intratubular pressure were filled with 0.5 M NaCl colored with Evans blue (E. Merck) and neutralized with NaHCO₃ to prevent precipitation. They were connected to a servocontrolled counterpressure pump system (Institute of Physiology, Univ. of Bergen), with a setup slightly modified from that described by Intaglietta et al. (16). An arbitrary tubule was punctured, and free-flow pressure was measured. Small amounts of fluid colored with Evans blue were injected to identify the tubule as proximal, i.e., when it was possible to see three or more tubular loops filled with blue color. The tubule was then punctured distal to the pressure-measuring pipette with a pipette filled with castor oil colored with Sudan black B (E. Merck) to stop the tubular flow. When the oil meniscus had been stable for 30 s, the pressure measured was defined as the stop-flow pressure. Three to six tubules were punctured in each animal.

Plasma colloid osmotic pressure was measured from arterial blood samples taken during the experiments by means of the membrane osmometer described by Aukland and Johnsen (3).

RVR was calculated using the formulas R_a = MAP  P_gc/RBF to find the resistance proximal (R_a) and R_e = P_gc  5/RBF for resistance distal (R_e) to the glomerular capillaries. When R_e was estimated, the venous pressure was assumed to be 5 mmHg (22).

Statistics. The results are presented as means ± SE. One-way analysis of variance was performed among the groups, and, where differences were found, Scheffé's F-test was performed for analyses of significance. Student's t-test for paired varieties was used to compare parameters before and after infusion of antihypertensive drugs in the same animals. In the three groups of animals with both kidneys intact, Student's t-test for impaired varieties adjusted with the Bonferroni method was performed for analyses of significance. P < 0.05 was considered to be statistically significant.

	RESULTS

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RBF autoregulation. The preinfusion MAP was similar in all groups of uninephrectomized SHR. The postinfusion MAP values were all significantly different from controls (P < 0.01) but not from each other (Table 1). Infusion of Ringer solution in the control group did not affect MAP (161 ± 3 vs. 152 ± 6 mmHg).

RBF did not change in the control group, but it increased in all the drug-treated groups. Calcium channel antagonists increased RBF more than doxazosin or enalapril (P < 0.05, Table 1).

RBF autoregulation was present in all the animals before the infusion of antihypertensive drugs and the lower pressure limit of RBF autoregulation was not different between the groups (Fig. 1 and Table 1). Infusion of doxazosin and enalapril reduced the lower pressure limits from 111 ± 5 to 100 ± 3 mmHg (P < 0.02) and from 111 ± 2 to 91 ± 3 mmHg (P < 0.001), respectively. These postinfusion lower pressure limits were different from each other (P < 0.05) and also lower than the lower pressure limit of the untreated control group (P < 0.05). In the animals given nifedipine, RBF autoregulation was abolished, and RBF fell linearly as the pressure was reduced. The RBF autoregulatory range before infusion was from 169 ± 4 to 108 ± 3 mmHg (P < 0.001), whereas the lower pressure limit of RBF autoregulation after infusion was equal to the MAP (120 ± 3 mmHg). In the animals given verapamil, the autoregulatory range before infusion was from 161 ± 5 to 110 ± 3 mmHg (P < 0.001), whereas, following infusion, it was reduced to 119 ± 4 vs. 115 ± 3 mmHg [not significant (NS)]. One of the seven animals in the verapamil group showed autoregulation of RBF. If this animal were excluded, the curve for RBF autoregulation in the verapamil group would fit a straight line as with nifedipine. The lower pressure limit of RBF autoregulation did not change after infusion of Ringer solution in the control group (118 ± 5 vs. 114 ± 5 mmHg).

View larger version (26K): [in this window] [in a new window]   Fig. 1.   Renal blood flow (ml · min1 · g kidney wt1) autoregulation in uninephrectomized spontaneously hypertensive rats (SHR) before infusion and after 30 min of infusion of different antihypertensive drugs to reduce mean arterial blood pressure (MAP) to ~120 mmHg. A: control group given Ringer solution. B: 16 µg/kg body wt doxazosin. C: 50 µg/kg body wt nifedipine. D: 4 mg/kg body wt enalapril. E: 1.12 mg/kg body wt verapamil. Data are means ± SE.

Table 2 shows that RVR decreased in all groups. No differences were present between the groups before infusions, but RVR fell significantly in all groups after drug infusions compared with control. The RVR at the lower pressure limit of RBF autoregulation was reduced, except in the groups given calcium channel antagonists.

Glomerular hemodynamics. After the infusions, P_gc was 46.7 ± 1.5 mmHg in controls without intervention, 45.8 ± 1.0 mmHg in controls with aortic clamp, 43.6 ± 1.4 mmHg in the group given doxazosin (NS), 41.3 ± 0.8 mmHg in the group given enalapril (P < 0.01), 53.7 ± 1.4 mmHg after nifedipine (P < 0.01), and 54.8 ± 1.2 mmHg in the group given verapamil (P < 0.001) (Fig. 2 and Table 3). Both groups given calcium channel antagonists had higher P_gc than the groups given doxazosin and enalapril (P < 0.001), and there were no differences between the effects of the two calcium channel antagonists. The differences in P_gc between the groups were due to differences in the stop-flow pressure. Stop-flow pressure in the enalapril group was significantly lower (P < 0.05), and stop-flow pressure in the calcium channel inhibitor groups was significantly higher (P < 0.001) than the other groups. The free-flow proximal tubular hydrostatic pressure after infusions with antihypertensive agents did not differ among the groups.

View larger version (21K): [in this window] [in a new window]   Fig. 2.   A: MAP (mmHg) before infusion of drugs and during micropuncture experiments in uninephrectomized SHR. B: glomerular capillary pressure (mmHg) after drug infusion. C: resistances in the afferent arteriole (Ra, ml · min1 · g kidney wt1) and the efferent arteriole (Re, ml · min1 · g kidney wt1). C, control group given Ringer solution; C (clamp), control group given Ringer solution and mean arterial pressure reduced to ~120 mmHg with a mechanical clamp above the renal artery; D, doxazosin; E, enalapril; N, nifedipine; V, verapamil. Doses of the different drugs are given in the legend of Fig. 1. Data are means ± SE. * P < 0.05, ** P < 0.001 compared with control without intervention (A) and with control at ~120 mmHg (B and C).

Except for enalapril, all the antihypertensive agents reduced R_a compared with control. The calcium channel antagonists reduced R_a more than doxazosin (P < 0.01) and enalapril (P < 0.02), whereas only enalapril reduced R_e compared with control (P < 0.05).

In two other groups, enalapril and nifedipine treatments were used to reduce MAP to 84 ± 2 and 87 ± 2 mmHg, respectively (P < 0.001 vs. untreated controls). In the first untreated control group, MAP was 140 ± 3 mmHg, and RBF was 5.4 ± 0.4 ml · min¹ · g kidney wt¹. In the second control group, MAP was reduced to 85 ± 2 mmHg by an aortic constriction, and RBF fell to 4.0 ± 0.3 ml · min¹ · g kidney wt¹. RBF increased initially after infusion of both drugs but decreased to 4.4 ± 0.5 ml · min¹ · g kidney wt¹ in the enalapril group and 5.2 ± 0.2 ml · min¹ · g kidney wt¹ in the nifedipine group during reduction of MAP. P_gc was 43.3 ± 1.3 mmHg in the untreated group with MAP of 140 mmHg, 37.4 ± 0.7 mmHg in the group where MAP was reduced to 85 mmHg by an aortic clamp (P < 0.05), 38.5 ± 0.9 mmHg in the enalapril-treated group (P < 0.05), and 43.3 ± 1.7 mmHg in the nifedipine-treated group (P > 0.5 vs. untreated and P < 0.05 vs. control at MAP of 85 mmHg).

The relationship between MAP and P_gc during reduction of MAP with an aortic clamp, during ACE inhibition, or during treatment with a calcium channel antagonist is shown in Fig. 3. P_gc was unchanged during pressure reduction with an aortic clamp from ~160 to ~120 mmHg. At systemic arterial pressure of 85 mmHg, the P_gc was significantly reduced. ACE inhibition reduced P_gc at all levels of arterial pressure, whereas nifedipine treatment increased P_gc when systemic arterial pressure was reduced to 120 mmHg. When systemic arterial pressure was further reduced to 87 mmHg with nifedipine treatment, P_gc was normalized.

View larger version (23K): [in this window] [in a new window]   Fig. 3.   Summary of the main findings of this study. Some of these data have already been presented in Table 1, Fig. 2, or text. Effects on renal blood flow (ml · min1 · g kidney wt1) and intraglomerular capillary pressure (mmHg) after reducing MAP in uninephrectomized SHR from control MAP at ~160 to ~120 or ~85 mmHg with a calcium channel antagonists (nifedipine, A), an angiotensin-converting enzyme (ACE) inhibitor (enalapril, B), or a mechanical clamp above the renal artery in animals infused with Ringer solution (C). Bars represent separate groups of animals, except for the control group at MAP ~160 mmHg in A-C. In this group, MAP fell slightly during the experimental procedure; bar represents values from 135 to 160 mmHg. Data are means ± SE. ** P < 0.001, compared with control at ~160 mmHg.

In still three other groups, we wanted to examine whether the observations we did in nephrectomized animals could also be seen in animals with both kidneys intact. The two-kidney control group had a systemic blood pressure of 159 ± 6 mmHg. Ramipril treatment reduced the pressure to 110 ± 6 mmHg (P < 0.001) and nifedipine to 99 ± 5 mmHg (P < 0.001). RBF in the control group was 5.6 ± 0.9 ml · min¹ · g kidney wt¹, rose in the ramipril-treated animals to 6.9 ± 1.0 ml · min¹ · g kidney wt¹ (NS), and fell in the nifedipine group to 3.8 ± 0.5 ml · min¹ · g kidney wt¹ (NS). P_gc was 44.5 ± 1.5 mmHg in controls, 38.0 ± 1.3 mmHg in the ramipril group (P < 0.002), and 42.7 ± 2.7 mmHg in the nifedipine group (NS).

Basic data. Basic data for the uninephrectomized SHR are given in Table 3. The animals in the doxazosin group were slightly heavier than those in the nifedipine group. Kidney weight, the number of infusions given, and total duration of the experiments (not shown) were not different among the groups. Hematocrit rose in the enalapril group (P < 0.01) and fell in the doxazosin group (P < 0.05) during the experiment.

	DISCUSSION

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The present study demonstrates clearly that the most commonly used antihypertensive drugs have different effects on autoregulation of P_gc and RBF in SHR with glomerulosclerosis. Enalapril reduced the P_gc at all pressure levels studied, despite increased RBF at 120 mmHg. RBF autoregulation was reset to lower pressure levels. These observations were in marked contrast to the findings after treatment with nifedipine. This drug substantially increased P_gc and RBF when the blood pressure was reduced from control situation to a systemic blood pressure of 120 mmHg, whereas both these parameters were normalized when the blood pressure was reduced to 85 mmHg. RBF autoregulation was abolished. Doxazosin increased blood flow but had no major impact on P_gc at any level of blood pressure reduction. Similar to enalapril, RBF autoregulation was reset to lower pressure levels.

Glomerulosclerosis is a common complication to high blood pressure, and increased P_gc, as well as glomerular size, is involved in the pathogenesis of these changes (18). In this study, we decided to use uninephrectomized SHR as our main model, because unilateral nephrectomy is known to increase the amount of glomerulosclerosis, and this could consequently give a better model for hypertensive renal damage. However, we also included one group of SHR with both kidneys intact and less glomerulosclerosis and examined these rats after long-term treatment with nifedipine or an ACE inhibitor. The results are basically not different, and it is therefore reasonable to suggest that antihypertensive therapy would change renal hemodynamics in SHR in a similar way, more or less independent of the amount of glomerulosclerosis.

There is good evidence that renal vessels in general and especially in SHR are more sensitive to catecholamines, angiotensin II, and also calcium channel antagonists than the systemic resistance vessels (23). In the case of the calcium channel antagonists, this implies that these drugs may ameliorate renal autoregulation at drug concentrations too small to reduce the systemic blood pressure. In such circumstances, the P_gc will increase. When the dose of calcium channel antagonist is great enough to abolish autoregulation completely, the P_gc will vary pari passu with the systemic blood pressure. Our study shows that even a substantial pressure reduction during calcium channel antagonist treatment resulted in an increased P_gc. These observations were in contrast to the effects of the ACE inhibitors, which decreased P_gc at a comparable pressure reduction. However, when nifedipine was given in a dose great enough to reduce the arterial blood pressure further, P_gc became normal. Reports on different results of calcium channel antagonist treatment on P_gc (increased in Ref. 5, normal in Refs. 8 and 17, reduced in Ref. 1), as well as the progression of experimental chronic renal diseases (beneficial in Refs. 8 and 14, negative in Refs. 5, 12, 34, and 36), may be explained by this dynamic relationship between P_gc and the systemic blood pressure when renal autoregulation is absent.

The calcium channel antagonists reduced RVR significantly more than the other drugs. In fact, the calcium channel antagonists reduced the total RVR numerically to a value similar to that at the lower pressure limit of RBF autoregulation in the groups treated with enalapril and doxazosin (Table 2). This increased reduction in the calcium channel treated group was significant for the preglomerular resistance (Fig. 2). As reported by others, the calcium channel antagonists affect mainly the afferent arteriole (6, 10). This was also seen during treatment with the ₁-receptor blocker, however, with preserved capacity for autoregulation.

In the enalapril- and doxazosin-treated groups, dilation of the afferent arteriole was probably induced by the autoregulatory reaction on the lowered systemic blood pressure but probably also by a direct pharmacological effect on the arteriolar smooth muscle cells and the macula densa feedback response. Both angiotensin II and catecholamines have been shown to constrict preglomerular vessels in isolated arteries (9), in isolated kidneys (33), and in vivo (7). The effect on the afferent resistance in this study might also have been caused by a macula densa feedback response during the autoregulatory adaptation to the reduced systemic blood pressure. This response was possibly less than normal. A reduction of the systemic blood pressure seems by itself to reduce the macula densa response (32). Inhibiting the effects of nerve stimulation and angiotensin II might in addition have a negative effect on this response (31). This indicates that the autoregulatory response to the pressure drop in these experiments was less than normal, thus partially attenuating the dilatory effect of the ACE and ₁-receptor inhibitors on the afferent arteriole. This was not the case for the calcium channel antagonists, which have been shown to abolish the macula densa response (24).

The preserved capacity of autoregulation in the enalapril and doxazosin groups indicates that the set point of autoregulation was reset to the left when the systemic pressure was reduced. This is in accordance with earlier reports on preserved autoregulation during resetting, caused by ACE inhibition or nervous stimulation (20, 26). The effect of the calcium channel antagonists on renal autoregulation confirms observations by others (26). The preserved autoregulation of RBF in SHR with glomerulosclerosis during ₁-receptor blockade is a new observation.

The reduced P_gc in the enalapril group was probably caused mainly by the effect on the efferent resistance. The unaltered P_gc in presence of reduced afferent resistance in the doxazosin group indicates that the efferent resistance also was reduced in this group, although it did not reach statistical significance. Similar to angiotensin II, nervous stimulation has been reported to affect both afferent and efferent resistances (15). In situations with increased sympathetic nerve stimulation, ₁-receptor blockers therefore might also affect the efferent resistance significantly and secondarily the P_gc (27). The effect of nervous stimulation also may be facilitated by increased angiotensin II levels because angiotensin II seems to be an important mediator of the contraction of resistance vessels during nervous stimulation in rats (30). Thus ₁-receptor blockade may also have a potential of P_gc reduction by dilating postglomerular vessels. This has been observed in an acute study where terazosin was used (35), but it could not be seen after chronic treatment for 3 wk with the same agent (28). The decreases in hematocrit and plasma colloid osmotic pressure in the doxazosin group in our study indicate a slight expansion of the extracellular volume and consequently a decreased sympathetic activity during micropuncture in this group. This might have reduced the effect of ₁-receptor blockade on P_gc. In contrast, the calcium channel antagonists have a potential effect of reducing P_gc only through reduction of the systemic blood pressure, because these drugs do not affect the efferent resistance.

Caution must be taken when comparing the results in this study with findings in two other models. In the remnant kidney model, the kidneys have vastly increased P_gc and substantially reduced or abolished autoregulation of RBF (4). In such kidneys, P_gc is mainly a direct function of the systemic pressure. As shown by Griffin et al. (13), the development of glomerulosclerosis in remnant kidneys is linearly correlated to the blood pressure, irrespective of the type of antihypertensive treatment. In another study in this model by the same authors (12), they found a reduced ability to autoregulate RBF. This was not altered by enalapril, but nifedipine abolished RBF autoregulation. Long-term treatment with either nifedipine or enalapril reduced MAP significantly, but only enalapril protected against glomerulosclerosis. The flaw of this study was a significantly lower MAP in the enalapril than in the nifedipine group.

In the deoxycorticosterone acetate (DOCA) hypertensive rat model, autoregulation of RBF is also abolished or reduced in the initial stage, and both calcium channel antagonists and ACE inhibitors have been shown to be without effect on the P_gc in such animals at minor systemic pressure reductions (29).

The model of unilateral nephrectomy was used to study drug effects in a model of hypertension and glomerulosclerosis. However, data are also included here that indicate that long-term treatment with nifedipine and the ACE inhibitor ramipril in a two-kidney SHR model induced similar hemodynamic effects when systemic blood pressure was reduced to low values.

From the considerations stated above, the preferable antihypertensive agents should not only reduce arterial blood pressure but also preserve RBF autoregulation and a normal P_gc. Antihypertensive drugs that abolish RBF autoregulation could be deleterious to the kidney if the systemic blood pressure is not reduced sufficiently. Consequently, one may expect that monotherapy with nifedipine or verapamil may accelerate nephrosclerosis in individuals with hypertension if the effect on systemic arterial blood pressure is only minor.