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(Hypertension. 1996;27:1115-1120.)
© 1996 American Heart Association, Inc.
Articles |
Preweanling Administration of Terazosin Decreases Blood Pressure of Hypertensive Rats in Adulthood
From the Department of Psychology, University of Virginia, Charlottesville.
Correspondence to Richard McCarty, PhD, Department of Psychology, 102 Gilmer Hall, University of Virginia, Charlottesville, VA 22903-2477. E-mail rcm@virginia.edu.
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Abstract |
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Abstract To examine the contribution of the sympathetic nervous system to the development of hypertension, we injected spontaneously hypertensive rat (SHR) pups and normotensive Wistar-Kyoto rat (WKY) pups twice daily with saline (1.0 mL/kg SC) or terazosin (0.5 mg/kg SC), an
1-adrenoceptor antagonist,
from postnatal day 1 through 21. We determined the effectiveness and
duration of action of this terazosin dose in pilot studies with adult
SHR and WKY. Body weights of WKY pups were greater than body weights of
SHR pups from postnatal day 1 through 21. In addition, body weights of
terazosin-treated pups of both strains were comparable to
body weights of saline-injected littermate controls. Indirectly
measured systolic pressures of terazosin-treated SHR were
reduced significantly at 60 and 90 days of age but not at 30 days of
age compared with saline-injected littermate controls. Terazosin
did not affect systolic pressures of WKY, measured at 30, 60,
and 90 days of age. At 100 days of age, in chronically catheterized
rats, mean arterial pressures of terazosin-treated SHR
were reduced significantly compared with those of saline-injected
littermate controls. In contrast, terazosin did not affect mean
arterial pressures of WKY at 100 days of age. Finally,
preweanling treatment with terazosin did not alter patterns of open
field behavior of adult SHR or WKY. SHR were significantly more active
and reared more frequently compared with WKY. These findings indicate
that the time between birth and weaning at 21 days of age is critical
for the full expression of the hypertensive phenotype in SHR.
Chronic blockade of 1-adrenoceptors during the
preweanling period in SHR may reduce vascular hypertrophy,
leading to long-term reductions in arterial pressure.
Key Words: rats, inbred SHR • nervous system, sympathetic • development • muscle, smooth, vascular • adrenergic receptors • phenotype
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Introduction |
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For more than 30 years, the SHR, along with its normotensive WKY control, has been used as an animal model of human essential hypertension.1 2 One important line of research with SHR has involved the identification of factors responsible for the progressive increases in arterial pressure that are especially evident beginning soon after the rats are weaned at 3 to 4 weeks of age.3 4
It is well established that the sympathetic nervous system plays an important role in the initiation of BP increases in SHR. Treatment of neonatal SHR with the catecholamine neurotoxin 6-hydroxydopamine, with guanethidine, or with an antibody to NGF is effective in preventing the development of hypertension.5 6 7 Donohue, Head, and coworkers8 9 10 have extended these findings by focusing on the relationship between sympathetic hyperinnervation of peripheral resistance vessels and vascular smooth muscle hyperplasia and hypertrophy. They have also demonstrated an association between elevated levels of NGF mRNA and tissue hypernoradrenergic innervation in neonatal SHR.11 These findings have led to the formulation of the trophic hypothesis, in which elevated levels of NGF in resistance vessels of SHR promote vascular smooth muscle hyperplasia and hypertrophy and increased peripheral vascular resistance.12 13
One approach to short-circuiting the development of vascular
hypertrophy in SHR is to block peripheral
sympathetic neurotransmission to vascular smooth muscle cells with an
1-adrenoceptor antagonist. By preventing
excessive sympathetic input to resistance vessels, one would expect to
prevent or reduce substantially the development of vascular
hypertrophy and hypertension. Several such attempts have
been made, but the results to date have not been promising. For
example, terazosin, a water-soluble 1-adrenoceptor
antagonist,14 15 16 was administered to SHR in
their drinking water from 4.5 to 12 weeks of age, but the drug
treatment did not prevent the development of hypertension or of
vascular hypertrophy.17 Similarly, oral
administration of doxazosin, a selective 1-adrenoceptor
antagonist, to SHR from 4 to 5 weeks of age until 16 weeks
of age did not influence the normal course of BP
increases.18 Finally, administration of prazosin once a
day from 5 to 10 weeks of age had no effect on the development of adult
BP of SHR.19 In contrast, slight but significant
decreases in BP of SHR have been reported after long-term treatment
of adult rats with bunazosin, a selective 1-adrenoceptor
antagonist.20 21
A major limitation of previous studies involving long-term treatment with adrenoceptor antagonists has been the age of rats when the drug was administered. In three of the studies cited above, SHR were 4 to 5 weeks of age at the beginning of drug treatment, and in the other two studies, SHR were well into adulthood at the start of the experiments. However, sympathetic hyperinnervation and vascular smooth muscle hyperplasia are evident in SHR as early as the first week of life.3 13 22 23 Thus, structural alterations in the vasculature of SHR are well under way before rats are weaned at 3 to 4 weeks of age. If drug administration is delayed until SHR are 4 weeks of age or older, it may be too late to interrupt sympathetically mediated contributions to the development of hypertension.
In the present study, we sought to address several of these methodological shortcomings of previous studies by administering terazosin twice daily to SHR and WKY pups beginning on the day after birth and continuing until rats were weaned on postnatal day 21. We found that preweanling terazosin administration was attended by dramatic reductions in the BP of SHR that persisted until at least 100 days of age. In contrast, preweanling terazosin administration had no effect on the adult BP of WKY.
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Methods |
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In a series of pilot studies, we determined a terazosin dose that would effectively block pressor responses to an intravenous bolus injection of phenylephrine in conscious SHR and WKY. Comparing across a dose range of 0.1 to 2.5 mg/kg, we determined that 0.5 mg/kg terazosin was more than 90% effective in blocking pressor responses to phenylephrine (5.0 µg IV per rat) in adult SHR and WKY. We then characterized acute changes in BP and HR of conscious male SHR and WKY (15 to 20 weeks of age) after a single dose of terazosin (0.5 mg/kg SC). In a separate group of rats, we also quantified pressor responses to phenylephrine at hourly intervals to 24 hours after injection. All rats in these two pilot studies were anesthetized with methohexital sodium (Brevital, Eli Lilly, 60 mg/kg IP) and prepared with chronic tail artery catheters on the day before measurement of MAP and HR.24 In addition, rats in the second study were also prepared with chronic jugular catheters for intravenous administration of phenylephrine (5.0 µg per rat). The reader is referred to an earlier report for a complete description of the chronic catheter procedures and use of phenylephrine as a pressor agent in conscious rats.25
SHR and WKY breeders were maintained in our laboratory from breeding stock originally purchased from Taconic Farms, Germantown, NY. In our vivarium, adult breeders were housed individually in suspended wire cages that were provided with laboratory chow (Ralston Purina) and tap water ad libitum. The vivarium room was kept on a 12-hour light/dark cycle, with lights on at 7 AM, and ambient temperature was maintained at 22±1°C.
Breeder rats of both strains were at least 70 days old before mating. Rats were screened for resting systolic BP with tail-cuff plethysmography. In this procedure, rats were restrained in clear Plexiglas tubes, and ambient temperature was maintained at less than 27°C. A tail cuff with a photosensitive cell was placed around the base of each rat's tail. Changes in pressure applied to the cuff and systolic pressure pulses were simultaneously transduced and amplified by an amplifier (model 29, IITC). The output from the amplifier was displayed on a dual-channel chart recorder.
Each rat was in a restraint tube for at least 10 minutes before BP recording and was then returned to its home cage within 50 minutes. Precautions were taken to ensure that rats were calm when BP recordings were made. If satisfactory tracings could not be obtained, rats were returned to their home cages and tested later in the same day or early the following day. Systolic BP values for each rat at each time point were based on an average of three to five tracings spaced at least 2 minutes apart. An average systolic BP of at least 150 mm Hg was required for all SHR breeders and one of not more than 130 mm Hg for all WKY breeders. All BP measures were obtained between 10 AM and 3 PM.
Three to four SHR and WKY females were mated with one male of the same strain for 1 to 2 weeks and were then isolated in polypropylene maternity cages (45x25x15 cm) when visibly pregnant. The date of birth for litters (postnatal day 0) was designated as the day on which pups were present by 5 PM. On postnatal day 1, litters were culled to eight pups each, maximizing the number of males. Four male pups were selected at random; two of them were assigned to a saline-injected control group (1.0 mL/kg total volume SC) and the other two received terazosin (0.5 mg/kg SC). An indelible marker was used to place black identification bands on the backs of the pups; these marks were enhanced as necessary over the preweanling period. Injections of saline or terazosin (prepared freshly before each series of injections) were given twice daily in the early morning (8 to 10 AM) and late afternoon (4 to 6 PM) on postnatal day 1 through 21. Body weights of pups were measured to the nearest 0.1 g immediately before each injection.
After weaning at 21 days of age, the two saline-injected pups and two terazosin-injected pups from each litter were housed together in polypropylene cages, with chow, tap water, and bedding material freely available at all times. At later ages, pups were housed in groups of two, with one saline-injected and one terazosin-injected pup in each cage.
Body weights and indirect systolic BPs were measured at 30, 60, and 90 days of age in one saline-injected and one terazosin-injected rat from each SHR and WKY litter (n=11 rats per strain per treatment group). Systolic BP was measured as described above for breeder rats. The remaining saline-injected and terazosin-injected rats from each litter were left undisturbed until 100 days of age (n=12 rats per strain per treatment group). At that time, each rat was anesthetized with methohexital sodium as described above, and a PE-50 catheter was inserted into the ventral tail artery. The catheter was then run under the skin and exited in the midscapular region. For protection, the catheter was covered by a spring wire and the entire assembly was secured to each rat with an adhesive tape collar. Rats were allowed to recover fully from anesthesia and were then housed individually in clear plastic cages (25x25x15 cm) that contained bedding material, tap water, and chow. The PE-50 catheter was led out the top-center of the cage and secured such that each rat had freedom of movement about the cage. MAP and HR were measured in rats from 9 AM to noon on the day after surgery. At the time of MAP and HR measurement, the end of the catheter was attached to a Statham pressure transducer, and MAP tracings were recorded on a Grass multichannel polygraph. HR was measured by a cardiotachometer triggered by the arterial pulse pressure signal. Cardiovascular measures were recorded over a 2- to 3-minute period while rats were resting and undisturbed in their home cages.
The saline-treated and terazosin-treated SHR and WKY from the indirect BP groups (n=11 rats per strain per treatment group) were also tested in an open field arena at 75 to 80 days of age for assessment of behavioral responses to a novel environment. The open field enclosure (125x125x25 cm) was made of plywood painted flat black. The floor of the enclosure was divided by lines into 25 squares of equal size (25x25x25 cm). During a single 3-minute test period, each rat was observed, and the number of squares entered (crossing a boundary line with two paws and leaving the square that was previously occupied) and the number of rears onto the hind legs were recorded.
All data are presented as mean±SE for the indicated numbers of rats. Data from saline-injected and terazosin-injected SHR and WKY were analyzed by a 2x2 ANOVA, and comparisons within strains (saline versus terazosin) were made with two-tailed t tests. Each litter contributed only one rat per cell of the experiments for maintenance of the independence of observations.26
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Results |
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One hour after terazosin administration to adult SHR, resting MAP fell profoundly, by more than 30 mm Hg. MAP values of SHR remained significantly below preinjection values for at least 6 hours after injection (P<.05). In WKY, MAP was more moderately reduced by less than 10 mm Hg 1 hour after acute administration of terazosin and remained within 7 mm Hg of preinjection MAP values for 2 to 24 hours after terazosin (Fig 1
). Significant decreases in
MAP values of WKY were noted at 1, 3, 4, 5, 6, and 12 hours after
terazosin (P<.05).
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Terazosin was also effective in blocking pressor responses to
phenylephrine in adult rats. Before terazosin
administration, SHR and WKY displayed average MAP increments of 50 to
55 mm Hg above basal values after intravenous
administration of phenylephrine. One hour after acute
administration of terazosin, pressor responses to
phenylephrine were reduced by more than 85% in rats of
both strains (P<.001). Pressor responses to
phenylephrine remained significantly blunted compared with
control values for up to 6 hours after terazosin administration in rats
of both strains (P<.05) (Fig 2). These
findings served as the basis for our design of subsequent studies with
preweanling SHR and WKY and suggested to us that twice-daily
administration of terazosin to preweanling rats would greatly reduce
1-adrenoceptor–mediated
cardiovascular responses for at least 6 to 8 hours
after each of the two daily terazosin injections.
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Systolic BP values of SHR breeder males and females were significantly greater than values for WKY breeder males and females (P<.001).
Administration of terazosin twice daily to SHR and WKY pups on
postnatal day 1 through 21 did not affect age-related increases in
body weights [F(20,1350)=0.53, P>.90]. WKY weighed
significantly more than SHR on the day after birth, and this strain
difference was maintained throughout the preweanling period
[F(1,65)=4.75, P<.03]. Terazosin-treated pups of both
strains weighed slightly less than their saline-injected littermate
controls beginning at postnatal days 8 to 9 and continuing through
postnatal day 21. However, these slight differences in body weight
within strains did not attain statistical significance [F(1,65)=0.23,
P>.60] (Fig 3).
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Fig 4 presents data for indirect systolic
BPs of control and terazosin-treated SHR and WKY at 30, 60, and 90
days of age. At 30 days of age, systolic BPs of control SHR and
WKY were not significantly different [F(1,40)=1.37,
P>.20]. In addition, terazosin did not affect
systolic BPs of 30-day-old rats of either strain
[F(1,40)=0.87, P>.30]. In contrast, at 60 and 90 days of
age, systolic BPs of SHR controls were significantly greater
than values for WKY controls [F(1,40)=50.2, P<.001 and
F(1,40)=152.8, P<.001, respectively]. In addition, there
was a significant main effect of terazosin treatment on
systolic BPs at 60 [F(1,40)=21.5, P<.001] and 90
[F(1,40)=8.12, P<.01] days of age. The strainxdrug
interaction was significant at 60 days of age [F(1,40)=13.2,
P<.001] and approached significance at 90 days of age
[F(1,40)=3.82, P=.058]. Systolic BPs of SHR were
reduced significantly compared with those of their saline-injected
littermate controls at 60 and 90 days of age (both P<.05).
However, terazosin treatment did not affect systolic BPs of WKY
at either 60 or 90 days of age (Fig 4).
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Basal MAP and HR values of conscious, freely behaving SHR and WKY were
measured via indwelling tail artery catheters at 100 days of age. There
were significant main effects of strain [F(1,44)=195.1,
P<.001] and drug treatment [F(1,44)=12.3,
P<.001] and a significant strainxdrug treatment
interaction [F(1,44)=12.3, P<.01] on MAP at 100 days of
age. SHR had significantly greater MAPs compared with WKY, and
terazosin effected a significant reduction in MAPs of SHR but had no
effect on MAPs of WKY (Fig 5). Basal MAPs were 160±4
mm Hg for saline-injected SHR and 137±3 mm Hg for
terazosin-treated SHR. In contrast, basal MAPs were 109±2 mm Hg
for saline-injected WKY and 106±2 mm Hg for
terazosin-injected WKY.
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There was a significant main effect of strain on basal HR values [F(1,44)=42.4, P<.001], with SHR having higher basal HRs compared with WKY. Preweanling administration of terazosin did not affect basal HRs in rats of either strain [F(1,44)=2.53, P>.10]. Basal HRs were 326±3 beats per minute in saline-injected SHR and 319±5 beats per minute in terazosin-treated SHR. Basal HRs were 290±9 beats per minute in saline-treated WKY and 280±4 beats per minute in terazosin-treated WKY.
SHR were significantly more active [F(1,44)=20.9, P<.001]
and reared more frequently [F(1,44)=62.9, P<.001] in an
open field test chamber compared with WKY. These strain differences in
behavior were unaffected by preweanling terazosin administration
(P>.30) (Fig 6).
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Discussion |
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The present study demonstrates that expression of the cardiovascular phenotype in adult SHR can be altered by preweanling administration of terazosin. Specifically, SHR that received twice-daily injections of terazosin from the day after birth until weaning on postnatal day 21 had significant reductions in arterial pressure that were evident as early as 60 days of age and persisted well into adulthood compared with saline-injected littermate controls. This drug effect was selective for genetically hypertensive rats, as revealed by a lack of effect of preweanling terazosin on normotensive WKY. In addition, it is important to note that terazosin-treated SHR exhibited normal patterns of weight gain during the preweanling period and into adulthood and maintained their strain-specific behavioral responses to a novel environment when tested at 75 to 80 days of age.
Several aspects of our drug treatment protocol differ from earlier
studies and may partly explain the significant effect of terazosin on
adult BPs of SHR reported here. First, we administered terazosin via
subcutaneous injections twice daily rather than administering the drug
in each mother's drinking water. This approach gave us an opportunity
to control the timing of drug delivery and amount of drug each rat pup
received. This degree of control over drug delivery in studies that
have used delivery of drug to nursing pups via the mother's drinking
water is simply not possible. In addition, dissolving a drug in the
drinking water of the mother opens the possibility of a host of
indirect effects of the drug on the pups as a result of changes in the
mother's BP, constituents in her milk, or alterations in her behavior.
Such indirect effects are difficult if not impossible to control.
Second, we limited the time of drug delivery to the pups to postnatal
day 1 through 21. Earlier studies have begun administration of various
1-adrenoceptor antagonists after weaning
(typically at 4 to 5 weeks of age) and continued it for several weeks.
Each of these studies has failed to report a drug treatment effect on
adult BPs of SHR.17 18 19
The present findings, along with previous research, provide
compelling evidence that a delay in administration of an
1-adrenoceptor antagonist to SHR until after
weaning fails to block adrenergically mediated
cardiovascular processes that occur between birth and
weaning that are critical for the full expression of the hypertensive
phenotype in adulthood. The approach taken in the current study
was to limit drug administration to a time during early development
when the sympathetic nervous system is known to play an important role
in initiating elevations in arterial BP.
One cautionary note regarding the method of drug administration used in
the present study relates to the percentage of time each day that
an effective blockade of 1-adrenoceptors occurred. Our
pilot studies in adult rats indicated that a single subcutaneous
injection of terazosin resulted in effective blockade of
phenylephrine-induced pressor responses for 6 to 8
hours after injection. Thus, our regimen of twice-daily injections
of terazosin may have achieved effective blockade of vascular
1-adrenoceptors in developing SHR pups for at least 12
to 16 hours per day. It is also possible that terazosin acts on central
1-adrenoceptors to effect a reduction in central
sympathetic outflow. This is especially true in rats soon after birth
when the blood-brain barrier is poorly formed.
What mechanism or mechanisms might explain the ability of terazosin to affect adult BPs of SHR well beyond the cessation of drug administration? At present, we favor the view that preweanling terazosin administration interrupts the pathophysiological interactions of noradrenergic nerves, vascular smooth muscle cells, and NGF. NGF is released from vascular smooth muscle cells and is critical for the development of noradrenergic neurons.27 A series of studies by Donohue, Head, and coworkers8 9 10 has revealed that neonatal SHR have greater sympathetic innervation of blood vessels and greater vascular smooth muscle hypertrophy and hyperplasia compared with age-matched WKY. They have also shown that levels of NGF protein and NGF mRNA are elevated in vascular tissues from SHR compared with levels in tissues from WKY.9 11 28 More recently, Spitsbergen, Tuttle, and coworkers29 30 demonstrated that SHR vascular smooth muscle cells maintained in culture released greater amounts of NGF after adrenergic stimulation compared with WKY cells. Taken together, these findings suggest that preweanling terazosin administration has the potential for minimizing the pathophysiological interactions between sympathetic neurons and vascular smooth muscle cells that lead in later life to permanent elevations in peripheral vascular resistance in SHR.
Several neural and hormonal systems appear to play important roles in the development of the hypertensive phenotype in SHR. Of particular interest has been the role of the renin-angiotensin-aldosterone system in the development of hypertension in SHR. Several laboratories have demonstrated that long-term treatment with captopril, an angiotensin converting enzyme inhibitor, prevents the development of high BP in SHR.31 32 33 34 Similarly, early administration of the angiotensin type 1 receptor antagonist A-81988 attenuated the development of hypertension in SHR.35 In addition, treatment of SHR with nitrendipine, a calcium channel blocker, from 4 to 8 weeks of age delayed the development of high BP.36 In contrast, early blockade of bradykinin receptors increased adult BPs of normotensive rats.37
Adult BPs of SHR may also be reduced by nonpharmacological treatments carried out early in life.4 For example, SHR pups reared by normotensive WKY, Wistar, or Sprague-Dawley foster mothers from birth to weaning display significant reductions in BP in adulthood.38 39 40 41 42 43 In contrast, adult BPs of normotensive rat pups are unaffected if they are reared by SHR foster mothers. These effects of the maternal environment appear to occur during the first 2 postnatal weeks and may reflect strain differences in the milk provided by hypertensive and normotensive mothers.44 45
Several converging lines of evidence point to the preweanling period as a sensitive period for influencing adult cardiovascular phenotype in genetically hypertensive animals.46 Arterial pressure is regulated by a complex interplay of neural and hormonal systems, and no single system assumes dominance over all others. In addition, each of these BP regulatory systems has its own characteristic developmental trajectory and its own sensitive period for influencing adult cardiovascular phenotype. Therapeutic interventions must be designed such that the system of interest is inhibited during its sensitive period of development if there is to be a long-lasting reduction in adult BP. Depending on the BP regulatory system under study, drug interventions may include the prenatal and early postnatal periods, may be limited to the time between birth and weaning (eg, the preweanling period), may encompass portions of the preweanling period and the time immediately after weanling, or may occur in the weeks after weaning. Although simultaneous blockade of several BP regulatory systems during early development may exert a greater effect on BP reduction in adulthood than any single intervention, we are unaware of any studies that have attempted to pharmacologically block the activities of multiple BP regulatory systems during early development.
In summary, our findings indicate that blockade of
1-adrenoceptors with terazosin that was limited to the
time between birth and weaning at 3 weeks of age resulted in
long-term reductions in adult BPs of SHR. These results suggest
that terazosin prevents in part the hypertrophy and
hyperplasia of vascular smooth muscle cells in SHR by blocking the
effects of norepinephrine released from developing
sympathetic nerve terminals.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported in part by a grant from the American Heart Association, Virginia Affiliate. J.H.L. was a postdoctoral trainee supported in part by a Training Grant in Neurobiological and Behavioral Development (HD 07323). We thank Abbott Laboratories for kindly providing the terazosin used in this study.
Received September 14, 1995; first decision October 10, 1995; accepted January 29, 1996.
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