(Hypertension. 1997;30:968-974.)
© 1997 American Heart Association, Inc.
Articles |
Lovastatin Prevents Development of Hypertension in Spontaneously Hypertensive Rats
From the Department of Physiology, Medical College of Wisconsin, Milwaukee.
Correspondence to Richard J. Roman, PhD, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
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Abstract |
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Abstract The present study evaluated the effects of lovastatin on renal function and the development of hypertension in spontaneously hypertensive rats (SHR). Four-week-old SHR were given lovastatin (10 mg/kg) or vehicle twice daily by gavage. After 4 weeks of treatment, mean arterial pressure was significantly lower in lovastatin-treated SHR (131±4 mm Hg, n=5) than in control animals (160±4 mm Hg, n=12) (P<.05). The fall in arterial pressure in lovastatin-treated rats was accompanied by changes in renal function. The slope of the relationship between arterial pressure and sodium excretion was threefold greater in lovastatin-treated SHR (n=6) than in control rats (n=6), and this was associated with significant elevations in renal medullary blood flow and renal interstitial hydrostatic pressure. Glomerular filtration rate was 17% higher in lovastatin-treated SHR (n=6) than in control rats (n=6) (0.94±0.05 versus 0.81±0.07 mL/min per g of kidney weight, P<.05). The wall-to-lumen area ratio of renal arterioles was significantly reduced in lovastatin-treated SHR compared with vehicle-treated rats (0.86±0.05 versus 1.08±0.04 for vessels with inner diameters <50 µm and 0.62±0.02 versus 0.75±0.04 for vessels with inner diameters of 50 to 100 µm, P<.05). These results indicate that chronic treatment with lovastatin shifts the relations between renal medullary blood flow, renal interstitial pressure, sodium excretion, and renal perfusion pressure to lower levels of arterial pressure and attenuates the development of hypertension and renal vascular hypertrophy in SHR.
Key Words: lovastatin • hypertension • rats, inbred SHR • natriuresis • hypertrophy
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Introduction |
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Recent studies have indicated that hypertension and abnormalities in lipid metabolism are related. For example, the prevalence of serum cholesterol values >6.0 mmol/L is twice as high in hypertensive as in normotensive patients.1 2 Hypertension, dyslipidemia, and insulin resistance also cosegregate in families, and the concordance rate for hypertension and obesity is higher in monozygotic versus dizygotic twins.3 4 Furthermore, genetic studies have suggested that hypertension and dyslipidemia are inherited syndromes that may represent 12% to 16% of the hypertensive population.5 6
Despite the apparent association between hypertension and dyslipidemia, relatively little is known about the effects of antilipidemic therapy on blood pressure or in reducing renal and vascular end-organ damage in hypertension. In a recent study, we found that chronic treatment with the antilipidemic agent clofibrate prevented the development of hypertension in Dahl salt-sensitive rats.7 The antihypertensive effects of clofibrate appeared to be secondary to induction of the renal metabolism of arachidonic acid by P4504A enzymes and changes in the renal handling of sodium.7 However, there are other reports indicating that antilipidemic agents such as the HMG-CoA reductase inhibitors, which are not known to alter the expression of P4504A genes, also attenuate the development of hypertension in Dahl salt-sensitive rats.8 These findings suggest that HMG-CoA reductase inhibitors may exert antihypertensive effects through some unknown mechanism.
The effects of lipid-lowering agents on blood pressure in SHR, a non–salt-sensitive model of hypertension, have not been studied previously. The purpose of the present study was to determine whether the HMG-CoA reductase inhibitor lovastatin affects the development of hypertension in SHR. In addition, the effects of lovastatin on renal function were examined in these animals, because there is considerable evidence that the development of hypertension in SHR is associated with changes in renal vascular tone, renal medullary blood flow, and resetting of the pressure-natriuresis relationship to higher levels of perfusion pressure.9 10
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Methods |
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Measurement of Arterial Pressure
Experiments were performed on 4-week-old SHR purchased from Harlan Sprague Dawley Laboratories. The rats were housed in an animal care facility at the Medical College of Wisconsin that is approved by the American Association for Accreditation of Laboratory Animal Care and had free access to food and water throughout the experiment. All protocols involving animals received prior approval from the Animal Care Committee of the Medical College of Wisconsin.
The rats were divided into four groups: the first two groups were given lovastatin (10 mg/kg) or vehicle twice daily by gavage and the other two groups were treated with hydralazine (100 mg/L) or vehicle in drinking water. Hydralazine was used as a control to distinguish whether the effects of lovastatin to reduce hypertrophy of the renal vasculature were secondary to its effect to lower blood pressure. Because no significant differences in arterial pressure or renal histology were observed in the two vehicle-treated groups, the results were pooled and presented together.
After 4 weeks of treatment with lovastatin, vehicle, or hydralazine, the rats were anesthetized with an injection of ketamine (50 mg/kg IM) and xylazine (2 mg/kg IM), and a catheter was implanted in the femoral artery for measurement of arterial pressure. The catheter was exteriorized at the back of the neck and brought out through a stainless steel spring and swivel device. After a 3-day recovery period, arterial pressure was directly measured between 9 and 12 AM with a pressure transducer and a computerized recording system for 3 h/d on three consecutive days while the animal was conscious in its home cage. The signals were sampled at 30 Hz, and heart rate, systolic and diastolic pressures, and MAPs were determined at 1-minute intervals and reduced to a mean value for the entire recording session. After 3 days of blood pressure measurements, 1 mL of blood was collected for determination of plasma cholesterol and triglyceride concentrations.
Histology
At the end of the experiments, the rats were
anesthetized with injection of pentobarbital (60 mg/kg
IP). Following a midline abdominal incision, the mesenteric and celiac
arteries and the aorta above the renal arteries were tied off, and the
kidneys were flushed with 10 mL isotonic 0.9% NaCl solution through a
catheter inserted in the aorta below the renal arteries. The kidneys
were then removed, fixed in 10% formalin, and embedded in paraffin.
Tissue sections (2 µm thick) were cut from each kidney and
stained with hematoxylin and eosin.
A morphometric method as described by Lee et al11 was used
to evaluate the degree of vascular hypertrophy in renal
arterioles. This method is based on the observations that the wall area
and the circumferential length of the IEL of arteries from SHR are not
altered by changes in distending pressure or tone in these
vessels.11 12 Briefly, the length of the IEL and the media
area of the arterial wall were measured with a
video-imaging system, which consisted of an Olympus microscope, a color
video camera, a color monitor, a PC, and IMAGE-1 software (Universal
Imaging Corporation). An image of a vessel was acquired and displayed
on the monitor. A line was traced over the IEL and outer boundary of
the medial layer, and the length and area of the IEL (Li
and Ai) and the outer boundary (Lo and
Ao) of the vessel media were thus determined. Repetitive
tracings by two investigators yielded values that varied by 5%,
indicating that the measurements were repeatable and accurate. The ID
of the vessel (Di) was calculated as Li/
,
and the wall area (intima+media) was calculated as
Aw=Ao-Ai. The outer diameter of
the medial layer was calculated according to the formula
Do=2x
(Li2/42+Aw/)|.
The wall-to-lumen area ratio was calculated as
Ratio=4xAw/(xDi2). Only
arteries with a nearly round shape or a uniform medial wall thickness
were sampled to minimize the influence of the eccentricity of the
section cuts. About 3 to 9 vessels were sampled from each section. A
total of 
100 vessels were sampled from kidneys of vehicle-,
lovastatin-, and hydralazine-treated rats. Vessels
were sampled from tissue slides in a blinded manner and traced
independently by two investigators.
Clearance Studies
These experiments were performed in separate groups of
4-week-old SHR chronically treated with lovastatin (n=6) or
vehicle (n=6) for 4 weeks. The pressure-natriuresis relation was
characterized in these rats as described previously.13
Briefly, the rats were anesthetized with injections of
ketamine (30 mg/kg IM) and thiobutylbarbitol (50
mg/kg IM) and placed on a thermostatically controlled warming
table to maintain body temperature at 37°C. Cannulas were placed in
the right jugular vein for IV infusion and in the right femoral artery
for measurement of arterial pressure. Both ureters were
cannulated for the collection of urine. An adjustable clamp was placed
on the aorta above the left renal artery, and ligatures were placed
loosely around the superior mesenteric and celiac arteries so that RPP
could be manipulated above and below control. The rats received an
intravenous infusion of 0.9% NaCl, containing 2% BSA, at
a rate of 6 mL/h. 3H-Inulin (1 µCi/mL) was included in
the perfusion solution for the measurement of GFR. After surgery and a
30-minute equilibration period, RPP was lowered by partial occlusion of
the abdominal aorta to 110 mm Hg in
lovastatin-treated rats and to 130 mm Hg in
vehicle-treated rats. Urine and plasma samples were collected and GFR,
urine flow, and sodium excretion were measured during a 30-minute
period. RPP was then elevated by 20 mm Hg by partial release of
the clamp on the abdominal aorta, and after a 10-minute equilibration,
urine and plasma samples were collected during a 20-minute period. RPP
was raised another 20 mm Hg by tying off the mesenteric and
celiac arteries and adjusting the clamp on the abdominal aorta. Urine
and plasma samples then were collected after a 10-minute equilibration.
Finally, RPP was elevated to 170 mm Hg in
lovastatin-treated SHR and 200 mm Hg in
vehicle-treated SHR by full release of the clamp on the aorta. After a
10-minute equilibration, urine and plasma samples were again
collected.
Measurement of Cortical and Papillary Blood Flow and
Interstitial Hydrostatic Pressure
The relations between renal cortical and papillary blood flow,
RIHP, and RPP were determined in separate groups of SHR chronically
treated with lovastatin (n=6) or vehicle (n=6) for 4 weeks.
One week before the acute experiment, the rats were
anesthetized with ketamine (50 mg/kg IM) and
acepromazine (1 mg/kg IM), and the right kidney was exposed
through a flank incision. A small amount of renal cortical tissue
overlying the papilla on the dorsal surface of the left kidney was
surgically removed, as previously described by Roman and
Kaldunski.10 The kidney was reinserted into the body, the
incisions were closed, and the animal was allowed 1 week of recovery.
The creation of this papillary window allowed the later exposure of the
renal papilla after removal of the ureter. On the day of the acute
experiment, the rats were anesthetized with ketamine
(30 mg/kg) and thiobutylbarbitol (50 mg/kg) and
surgically prepared as described above in "Clearance Studies." In
addition, the left kidney was immobilized by placing it
dorsal side up in a kidney cup positioned above the abdominal aorta.
The tip of the papilla was exposed by a longitudinal incision in the
ureter from the tip to the base of the papilla. Cortical and papillary
blood flow signals were measured with a dual-channel, laser-Doppler
flowmeter (model Pf3, Perimed). The papillary blood flow was
recorded by a fiberoptic probe (Special Probe 315:47, Perimed,
1 mm in diameter) placed 1 mm from the tip of the papilla.
Cortical blood flow was measured by a probe (Special Probe 315:47,
Perimed, 1 mm in diameter) placed on the dorsal surface of the
kidney. RIHP was measured with a capsule implanted in the renal
interstitium as described previously.14 Briefly, the
capsule was constructed by insertion of a 0.5x2-mm piece of
polyethylene matrix material (0.35 mm pore size, Bel-Art
Associates) in a catheter (outside diameter 0.89 mm, SV31, Dural
Plastics). The matrix material was secured in the catheter using a 6-0
suture. A small hole, 1 mm in diameter and 3 mm deep, was
created in the renal cortex using an electrocautery needle. After the
bleeding was stopped, the capsule was inserted in the hole and sealed
in place with cyanoacrylate adhesive. The catheter was flushed with 20
µL of saline, and the pressure was recorded with a transducer
(P23, Gould Statham Instruments) and a Grass polygraph calibrated
between 1 and 20 mm Hg.
After surgery and a 1-hour equilibration period, the relations between cortical flow, papillary flow, RIHP, and RPP were determined. RPP was first increased to 150 mm Hg by tying the mesenteric artery and the celiac artery, and cortical and papillary blood flow signals were recorded as pressure was varied from 150 to 70 mm Hg in steps of 20 mm Hg by gradual tightening of the clamp on the aorta above the renal artery. Five minutes was allowed after RPP was adjusted to obtain a new steady state level of blood flow and interstitial pressure.
Statistics
Data are presented as mean±SEM. The significance of
differences in mean values within and between groups was determined
with an ANOVA for repeated measures with multiple independent factors
followed by a Duncan's multiple range test. A probability level of
P<.05 (two-tailed test) was considered
significant.
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Results |
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The effect of lovastatin on the development of hypertension in SHR is presented in Fig 1
. MAP averaged 160±4 mm Hg in
control SHR (n=12) but only 131±4 mm Hg in SHR chronically
treated with lovastatin (20 mg/kg per day, n=5)
(P<.05). Mean body weight was similar in the control and
lovastatin-treated groups (281±5 versus 276±6 g). Plasma
cholesterol concentration was 33% lower in
lovastatin-treated rats than that seen in the control
animals (1.03±0.06 versus 1.56±0.18 mmol/L,
P<.05), whereas plasma triglyceride
concentration was not significantly different in the two groups
(1.0±0.1 mmol/L in the lovastatin-treated
group versus 1.1±0.1 mmol/L in the control rats).
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The effects of lovastatin on the pressure-natriuresis
relation are presented in Fig 2.
GFR was autoregulated as RPP was varied above or below the control
values in either lovastatin- or vehicle-treated rats (Fig 2A). GFR within the autoregulatory range of RPP was 17% higher in
lovastatin-treated rats than in vehicle-treated animals
(0.94±0.05 versus 0.81±0.07 mL/min per g kidney wt,
P<.05). In addition, the lower limit of GFR autoregulation
range was shifted to lower pressure by 20 mm Hg in rats treated
with lovastatin. The pressure-natriuretic (Fig 2B) and pressure-diuretic (Fig 2C) relations were shifted
toward lower perfusion pressure in lovastatin-treated SHR
compared with the relations seen in vehicle-treated rats
(P<.05). At each level of RPP, urine flow and sodium
excretion were significantly higher in lovastatin-treated
than in control rats. The enhanced pressure-natriuretic
relationship in lovastatin-treated SHR was not solely due
to the elevation in GFR and the filtered load of sodium but also due to
an inhibition of tubular sodium reabsorption, as evidenced by a higher
fractional sodium excretion at each RPP in
lovastatin-treated rats than in control animals (Fig 3).
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The effects of lovastatin on the relations between RPP,
cortical and medullary blood flow, and RIHP are depicted in Fig 4. Papillary blood flow (Fig 4A) was not
autoregulated when RPP was varied from 70 to 150 mm Hg in either
group, and it was significantly higher in
lovastatin-treated than in control rats at each level of
RPP studied. Cortical blood flow (Fig 4B) was well autoregulated in
both groups, and baseline values of cortical blood flow were not
significantly different in lovastatin- and vehicle-treated
rats. However, the lower limit of autoregulation range of cortical
blood flow was 20 mm Hg lower in
lovastatin-treated rats than in the control animals. As
shown in Fig 4C, RIHP also was not autoregulated in either group, and
it was slightly but significantly higher in
lovastatin-treated than in control rats at RPP>120
mm Hg.
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The effects of lovastatin and hydralazine on the
structure of renal arteries in SHR were examined in this study. Fig 5 illustrates the typical
histological appearance of preglomerular
arterioles in vehicle-, hydralazine-, or
lovastatin-treated rats. The wall of
preglomerular arterioles (Fig 5A) was thickened and the
lumen was encroached upon in vehicle-treated rats, and these structural
abnormalities were not significantly altered after chronic treatment
with hydralazine (Fig 5B). However, the hypertrophy
of renal arterioles was attenuated in rats chronically treated with
lovastatin (Fig 5C). A summary of the effects of
lovastatin and hydralazine on the wall
(intima+media)–to–lumen area ratio of renal arteries in SHR is
presented in Fig 6. The results
were divided into four groups according to the ID of the vessels
studied, ie, preglomerular arterioles (ID <50 µm),
arterioles (ID 50 to 100 µm), small arteries (ID 100 to 150
µm), and large arteries (ID >150 µm). Chronic treatment with
lovastatin significantly reduced the wall-to-lumen area
ratio in the preglomerular arterioles and arterioles by
20% and 17%, respectively. However, there was no significant change
in this ratio in larger arteries (ID >100 µm). Chronic
treatment with hydralazine had no significant effect on
wall-to-lumen area ratio in different branches of the renal
arterial tree, although hydralazine was just as
effective as lovastatin in lowering arterial
pressure in these animals (Fig 1
).
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Discussion |
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The present study examined the effects of lovastatin on the development of hypertension in SHR. Chronic treatment of young SHR (4 weeks old) for 4 weeks with lovastatin (20 mg/kg per day) significantly blunted the development of hypertension. MAPs in the treated group averaged 29 mm Hg less than those seen in vehicle-treated animals. These results, together with previous reports that HMG-CoA reductase inhibitors8 and other antilipidemic agents7 markedly attenuate the development of hypertension in Dahl salt-sensitive rats, support the view that antilipidemic therapy might have antihypertensive effects in genetic models of hypertension.
The dosage (20 mg/kg per day) of lovastatin used in this study is about four to five times higher than that used in previous studies on rats with renal diseases.8 15 16 17 This dose was chosen by referencing to the concentrations of lovastatin needed to effectively inhibit VSM cell growth in vitro and in vivo.18 19 Previous toxicity studies have indicated that this drug is not hepatotoxic in rats even at doses as high as 200 mg/kg per day.20 In our studies, the lovastatin-treated rats ate and gained weight normally. These observations suggest that the prevention of hypertension in SHR seen in the present study is not likely due to some generalized toxic effect of lovastatin.
The mechanisms by which lovastatin and other antilipidemic agents attenuate the development of hypertension are unknown. Previous studies have indicated that the development of hypertension in SHR is associated with a shift in the pressure-natriuresis relationship to higher pressure, reduced renal medullary blood flow and renal interstitial pressure, and an elevation in renal vascular resistance.9 10 Moreover, several classes of antihypertensive agents, such as converting enzyme inhibitors,21 calcium channel blockers,13 and atrial natriuretic peptides,22 have been shown to increase medullary blood flow and normalize the pressure-natriuresis relationship in SHR. We therefore evaluated whether the antihypertensive effect of chronic lovastatin treatment in SHR was associated with changes in renal function.
The present results indicate that lovastatin alters renal function in SHR. The pressure-natriuretic response was markedly enhanced in SHR chronically treated with lovastatin. Part of this was due to an increase in GFR and the filtered load of sodium in the lovastatin-treated animals. However, tubular reabsorption of sodium was also inhibited in the lovastatin-treated rats, because fractional excretion of sodium was significantly greater in lovastatin- versus vehicle-treated rats. Similarly, Kline and McLennan23 have reported that chronic treatment of SHR with hydralazine shifts the pressure-natriuretic curve to lower perfusion pressure. The shift in the pressure-natriuretic relation to lower pressure in lovastatin-treated SHR was associated with increases in renal medullary blood flow and renal interstitial pressure. These findings are consistent with previous findings that other antihypertensive agents, notably calcium channel blockers,13 converting enzyme inhibitors,21 and atrial natriuretic peptide,22 have a similar action to selectively dilate the renal medullary circulation, increase renal interstitial pressure, and shift the pressure-natriuretic relationship to a lower level of arterial pressure in SHR. Elevations in renal medullary blood flow are thought to inhibit net sodium reabsorption by raising RIHP and promoting passive back-diffusion of sodium through the paracellular pathway into the proximal tubule and/or the thin descending limb, particularly in deep nephrons.24 Thus, the rise in medullary blood flow may contribute to the increased fractional sodium excretion seen in lovastatin-treated rats. However, other actions, such as changes in the activity of the renin-angiotensin-aldosterone system or direct effects of lovastatin on tubular epithelial cells, cannot be excluded, because lovastatin alters the activity of key elements of signal transduction pathways through mechanisms discussed in more detail below.
Previous studies have indicated that there is hypertrophy
of the vascular wall in different arterial beds in
SHR.25 26 27 28 Indeed, structural changes in the vasculature
have formed the core of the hypothesis that arterial
hypertrophy and subsequent narrowing of the vascular lumen
may be responsible for the development of hypertension in
SHR.29 In this regard, it is interesting to note that
chronic treatment with lovastatin reduced the wall-to-lumen
area ratio of renal arterioles in SHR. These morphological changes in
the preglomerular arterioles are consistent with
the present finding that the lower limit for autoregulation of
renal blood flow and GFR was shifted to lower perfusion pressures by
20 mm Hg in lovastatin-treated SHR compared with
the values seen in vehicle-treated rats. These findings are also in
agreement with previous reports that lovastatin and other
antilipidemic agents attenuate kidney injury and the development of
glomerulosclerosis and proteinuria in Dahl
salt-sensitive rats8 and in other models of progressive
glomerulosclerosis, ie, rats with reduced renal
mass, and Zucker obese rats.15 16 17
The mechanism by which lovastatin prevents hypertrophy of the renal vasculature remains to be determined, but it is probably not due to its antihypertensive effect alone. Indeed, in the present study we found that chronic treatment of SHR with hydralazine did not prevent the hypertrophy of the preglomerular vascular wall even though it was as effective as lovastatin in lowering blood pressure in SHR. Similarly, other investigators have previously shown that lowering blood pressure in SHR with hydralazine30 31 even before birth or triple therapy32 33 did not prevent vascular hypertrophy in the kidney and in other vascular beds. All these observations support the idea that some factors other than high blood pressure may contribute to the pathogenesis of renal vascular hypertrophy in SHR. The exact underlying mechanisms responsible for vascular hypertrophy in SHR remain unknown.
Plasma cholesterol concentration was 33% lower in lovastatin-treated rats than in control animals, but it remains unclear whether the effects of lovastatin in preventing renal vascular hypertrophy and the development of hypertension in SHR are related to its hypolipidemic action. The plasma lipid concentrations are not elevated in SHR,34 and it is not known whether a reduction of cholesterol concentration from the normal baseline level has any effect on the growth and proliferation of VSM cells.
One possible mechanism by which lovastatin may affect vascular growth might be related to the ability of this drug to inhibit the synthesis of mevalonate. Mevalonate not only is involved in the synthesis of cholesterol but also is the precursor for the synthesis of isoprenoids, which are important for the posttranslational isoprenylation of many proteins involved in signal transduction pathways.35 One class of these proteins includes the low-molecular-weight GTP binding proteins (ras and rho), which have been increasingly shown to play a central role in the growth signal transduction pathway36 and more recently been reported to modulate vascular reactivity by modifying the activity of voltage-gated calcium channels37 and the calcium sensitivity of the contractile mechanism in VSM cells.38 39 Lovastatin has been shown to reduce small G protein activity and inhibit the proliferation of VSM cells in vitro and in vivo.18 19 Moreover, lovastatin inhibits Ca2+ influx in response to vasopressin in VSM cells.40 Thus, it is conceivable that chronic treatment with lovastatin may reduce vascular hypertrophy and reactivity in the kidney by interfering with the synthesis of mevalonate and the isoprenylation and activity of signal transduction proteins. The reduction of preglomerular arteriolar tone in the kidney would be expected to lower blood pressure by increasing GFR, renal medullary blood flow, and renal interstitial pressure and promoting the excretion of sodium and water at lower levels of RPP.
In summary, the present study indicates that chronic treatment of SHR with lovastatin increases renal medullary blood flow and renal interstitial pressure, resets the pressure-natriuresis relation to a lower level of RPP, and markedly attenuates the development of hypertension and preglomerular vascular hypertrophy in SHR.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by a grant from the National Heart, Lung, and Blood Institute (HL-36279). Jian Jiang was a recipient of the Predoctoral Fellowship Award from the American Heart Association, Wisconsin Affiliate. The authors wish to thank Dr Aipin Zou for his help and Mary Kaldunski for providing excellent technical assistance in these experiments.
Received February 12, 1997; first decision March 5, 1997; accepted March 5, 1997.
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