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CARDIOVASCULAR
Department of Pharmacology, The Brody School of Medicine at East Carolina University, Greenville, North Carolina.
Received December 20, 2002; accepted February 27, 2003.
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Abstract |
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50% of baseline on day 5 and a cumulative elevation in MAP.
The inverse BRS and MAP responses required daily administration of CsA because
neither response was evident throughout the 5-day observation period after a
single dose of CsA. Plasma testosterone levels were similar in all groups,
whereas the body weight decreased approximately 10% in the CsA group on day 5.
These findings suggest 1) CsA attenuation of BRS is relatively rapid and
cumulative; 2) the attenuation of BRS may contribute to the delayed, but not
to the acute, pressor elicited by CsA; and 3) the cumulative reduction in BRS
caused by short-term (5-day) CsA treatment is not testosterone-related.
).
However, CsA also causes serious cardiovascular disorders such as secondary
hypertension (Schachter, 1988;
Sander et al., 1996), which
comprises an acute phase developing with the first dose
(Sturrock et al., 1993) and
chronic phase during long-term administration
(Olivari et al., 1989).
CsA-induced hypertension is a major contributing factor to cardiovascular
morbidity and mortality in the transplant population
(Sander et al., 1996) and is,
therefore, a major limiting factor for the use of CsA.
In rats, i.v. CsA produces a rapid elevation in blood pressure (BP) that
resembles the acute CsA-induced hypertension in humans
(Moeller et al., 1988;
Lyson et al., 1994). Although
evidence suggests that the acute pressor response to CsA is sympathetically
mediated (Moeller et al.,
1988; Lyson et al.,
1994), other findings argue against this possibility
(Kaye et al., 1993;
Stein et al., 1995).
Nonetheless, whether the attenuation of BRS contributes to the acute pressor
effect of CsA has not been investigated. Notably, CsA-induced inhibition of
BRS has been implicated in the chronic pressor effect of the drug
(Gerhardt et al., 1999;
Lucini et al., 2000). Other
proposed mechanisms include 1) endothelial dysfunction
(Oriji and Keiser, 1999) and
direct vasoconstriction (Xue et al.,
1987; Lo Russo et al.,
1997), 2) induction of endothelin release
(Grieff et al., 1993), 3)
inhibition of endothelin inactivating peptidase
(Janas et al., 1994), and 4)
activation of afferent nerve firing from subdiaphragmatic region with a reflex
sympathetic activation, which was shown to be related to calcineurin enzyme
inhibition (Moss et al., 1985;
Zhang et al., 2000;
Zhang and Victor, 2000).
The mechanism by which CsA inhibits BRS is not fully understood. Recent
evidence suggests that a reduction in serum testosterone level contributes to
the inhibition of BRS caused by chronic CsA administration
(El-Mas et al., 2002). This
conclusion is based on the findings that chronic CsA causes a reduction in
serum testosterone (Rajfer et al.,
1987; Krueger et al.,
1991) and the ability of testosterone to enhance BRS
(El-Mas et al., 2001).
Epidemiological studies have revealed similar incidence of CsA-evoked
hypertension in female and male patients
(Fernandez-Miranda et al.,
2002), but it is not known whether the magnitude of hypertension
is influenced by gender. Nonetheless, whether a rapid inhibitory effect of CsA
on BRS occurs in rodents and whether such effect is secondary to a reduction
in serum testosterone has not been investigated. Furthermore, the reported
findings on the effects of a single dose
(Ryuzaki et al., 1997) or
multiple doses (>10 days) of CsA (El-Mas
et al., 2002) on mean arterial pressure (MAP) were based on the
use of doses, formulation, and route of administration that are not relevant
to the clinical use of CsA.
The main objective of the present study was to investigate the acute and
short-term effects of CsA on MAP and BRS using the clinically prescribed
formulation and route of administration (i.v. infusion). Because measurements
of MAP and BRS were made daily in the same animal over the 5-day course of the
study, we determined the temporal relationship between CsA-induced inhibition
of BRS and the acute and chronic pressor responses. Because our experimental
design and the use of the clinical formulation of CsA lead to a relatively
rapid and cumulative inhibition of BRS, a second objective of the study was to
determine whether the substantial (50%) inhibition in BRS was a
consequence of CsA induced reduction in serum testosterone levels. To achieve
these goals, MAP and BRS (Oxford method) were measured in conscious freely
moving Sprague-Dawley male rats before and after daily administration of CsA,
vehicle, or saline for five consecutive days. Finally, an additional group of
rats received a single dose of CsA followed by vehicle for the remaining 4
days to determine whether 1) the acute (single-dose) effects of CsA on BP, HR,
and body weight are fully reversible, and 2) the sustained reduction in BRS
and increase in MAP require daily treatment with CsA. Body weights of the rats
were recorded daily, and blood samples were collected for measurement of
plasma testosterone levels at the conclusion of the study (5th day).
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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). Briefly,
the rats were anesthetized with methohexital sodium (50 mg/kg i.p.). Catheters
(polyethylene-10 connected to polyethylene-50), filled with heparinized saline
(100 U/ml), were placed in the abdominal aorta and vena cava via the femoral
artery and vein for measurement of BP and i.v. administration of drugs,
respectively. The catheters were inserted about 5 cm into the femoral vessels
and secured in place with sutures. Finally, the catheters were tunneled s.c.,
exteriorized at the back of the neck between the scapulae, and plugged by
stainless steel pins. Incisions were closed by surgical staples and swabbed
with povidone-iodine solution. Each rat received an s.c. injection of
buprenorphine hydrochloride (Buprenex; 0.3 ng/rat) to control pain and an i.p.
injection of 50,000 U/kg penicillin G benzathine and penicillin G procaine in
an aqueous suspension (Durapen) and was housed in a separate cage. Each
experiment started 2 days later, by connecting the arterial catheter to a
pressure transducer (Gould-Statham, Oxnard, CA). Blood pressure and heart rate
(HR) were recorded and analyzed using PolyView PRO/32 data acquisition and
analysis system (Grass Instrument Division, Astro-Med, Inc., West Warwick,
RI). BP and HR were also displayed on a polygraph (model 7D; Grass
Instruments, Quincy, MA). One of the venous catheters was used to infuse CsA,
vehicle, or saline. The other venous catheter was used to inject phenylephrine
for the measurement of BRS. Experiments were performed in strict accordance
with institutional animal care and use guidelines, and in accordance with the
principles and guidelines of the National Institutes of Health Guide for the
Care and Use of Laboratory Animals.
Measurement of Plasma Testosterone
A blood sample (0.6 ml) was withdrawn from the arterial catheter of each
rat at specified hour (6:00–8:00 PM) on the 5th day (last day) of the
experiment after baroreflex testing. Plasma testosterone level was measured by
a commercially available radioimmunoassay Coat-A-Count total testosterone kit
purchased from Diagnostic Products (Los Angeles, CA).
Protocols and Experimental Groups
Effect of Cyclosporine on Baroreceptor Reflex Control of HR. Four
groups of rats (cumulative cyclosporine, n = 6; single-dose
cyclosporine, n = 6; vehicle, n = 6; and saline, n
= 4) weighing 300 to 350 g were used in this study to investigate the effect
of cyclosporine on BP and baroreflex HR response in conscious unrestrained
rats. On the day of the experiment, the rats were allowed to acclimatize to
laboratory conditions for at least 2 h before experimentation. Subsequently,
the arterial catheter was connected to a pressure transducer for measurement
of BP and HR. A period of 30 min was then allowed for further stabilization of
BP and HR. Baroreflex curves were constructed in all rats by the i.v. bolus
injection of randomized doses of PE (1–16 µg/kg) at 5-min intervals
as in our previous study (Abdel-Rahman,
1994). Phenylephrine was dissolved in saline and administered in
varying volumes of a stock concentration (36 µg/ml) of PE to achieve the
desired doses. The peak changes in MAP and HR, obtained after PE injections,
were used for the construction of the baroreflex curves. Then the rat in a
particular group received i.v. infusion of cyclosporine (15 mg/kg), vehicle
(195 mg/kg Cremophor EL + 96.9 mg/kg ethanol) or saline through the
intravenous catheter over 10 min using CMA/100 microinfusion pump. The group
assigned a single dose regimen, received 15 mg/kg CsA on day 1 and vehicle
over the consecutive 4 days. Twenty minutes after the end of infusion, another
baroreflex curve, completed in approximately 1 h, was constructed as described
above. Each experiment lasted approximately 2.5 h. These procedures were
repeated for five consecutive days and on the 5th day blood samples (0.6 ml)
were collected from the femoral artery, for measurements of serum testosterone
level at specified time, to avoid the daily variation of plasma testosterone
(Moeller et al., 1988;
Leal and Moreira, 1997).
Drugs
Phenylephrine hydrochloride (Sigma-Aldrich, St. Louis, MO), methohexital
sodium (Eli Lilly & Co., Indianapolis, IN), Buprenex (buprenorphine
hydrochloride; Rickitt & Colman, Richmond, VA), Sandimmune injection (50
mg/ml cyclosporine; Novartis Pharmaceuticals Co., East Hanover, NJ), Cremophor
EL (Sigma-Aldrich), povidone-iodine solution (Norton Co., Rockford, IL), and
Durapen (penicillin G benzathine and penicillin G procaine; Vedco, Overland
Park, KS) were purchased from commercial vendors.
Statistical Analysis
Values are expressed as means ± S.E.M. The relationship between
increases in MAP [MAP = diastolic pressure + one-third (systolic - diastolic
pressures)] and associated decreases in HR was assessed by regression analysis
for individual animals, as described in our previous studies
(Abdel-Rahman, 1994). The
regression coefficient (slope of the regression line) expressed as beats per
minute per millimeter of Hg was taken as an index of BRS. Analysis of variance
followed by Fisher's least significant difference post hoc analysis was used
for multiple comparisons. This test was used to analyze the effects of
cyclosporine administration on MAP, HR, baroreflex, body weight, and plasma
testosterone levels. The Student's t test was used in the analysis of
unpaired data. Probability levels less than 0.05 was considered
significant.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Effect of Cyclosporine on Baroreceptor Reflex Control of HR (BRS). Baroreflex curves, relating decrease in HR to phenylephrine-induced increase in MAP, were constructed (Fig. 4), and the slopes of the linear regression line represented the BRS (Fig. 5). At any given rise in MAP, the reflex bradycardic response remained unchanged after the infusion of vehicle or saline throughout the 5 days of the experiment (see example in Fig. 4, A and B). However, in the CsA-treated group at any given rise in MAP, the reflex bradycardia was significantly (p < 0.05) reduced starting with the 2nd dose (Fig. 4C); there was no significant change in the BRS after the 1st dose (day 1; Fig. 4C). The CsA induced inhibition of BRS was cumulative (Figs. 4C and 5D). Starting with a basal BRS value of -1.86 ± 0.15 beats/min/mm Hg, daily CsA administration resulted in a progressive reduction in BRS, which became -0.97 ± 0.04 beats/min/mm Hg (47% reduction) by the 5th day (Fig. 5D). In the group that received single-dose CsA, BRS value did not change during the 5-day observation period (Fig. 5C). The correlation coefficients of the regression lines were highly significant and ranged from 0.935 to 0.995.
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As shown in Fig. 3B, CsA caused a significant (p < 0.05) reduction in body weight amounting to 10% by the 5th day. Again, this reduction was cumulative. In the single-dose CsA group, there was a slight but nonsignificant reduction in body weight (Fig. 3B). The body weights of the saline and vehicle groups showed a slight increase over the same time period (Fig. 3B).
Effect of Cyclosporine on Plasma Testosterone Level. Analysis of the blood samples collected on the 5th day of the experiment revealed no significant differences in plasma testosterone levels between the rats that received CsA, vehicle, or saline (32.2 ± 14.4, 45.4 ± 19.6, and 35.7 ± 9.0 ng/dl, respectively).
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Discussion |
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In most of the reported studies, CsA was administered s.c. in oil and in
high doses (>15 mg/kg/day) for extended periods, 11 to 28 days. MAP, HR,
and BRS were measured only at the conclusion of the study
(El-Mas et al., 2002), and in
some instances, blood pressure was measured by the tail cuff method
(Oriji and Keiser, 1999). Even
when the i.v. route was used, a single dose of CsA was administered
(Ryuzaki et al., 1997). To
establish clinical relevance, we investigated the daily effects of CsA on
blood pressure and BRS in conscious unrestrained rats. Furthermore, we used
the clinical CsA formulation (Sandimmune) and administered the drug by i.v.
infusion to establish a model system that permits generation of information
that might bear scientific and clinical implications. We measured MAP and
constructed baroreflex curves before and after daily infusion of CsA or its
vehicle for 5 days. Because the vehicle contained Cremophor EL and alcohol, it
was important to include another control (saline) group in the study.
Notably, the dose of CsA used in the present study was higher than the
clinically used dose (15 versus 5 mg/kg), which may limit the clinical
relevance of the present findings. It must be remembered, however, that
because the dose used in the present study is equal to
(Krueger et al., 1991;
Jaramillo-Juarez et al., 2000)
or slightly higher (Moss et al.,
1985; Zhang et al.,
2000) and even smaller
(Ryuzaki et al., 1997) than
the doses of CsA administered to experimental animals in reported studies, the
present findings may have scientific implications. We observed an acute
pressor response caused by the first dose of CsA that was not associated with
any change in BRS, which rules out a role for BRS in the acute pressor effect
of CsA. Our findings are consistent with reported acute increases in MAP
produced by CsA infusion in rats (Morgan
et al., 1991; Lyson et al.,
1994), although in these studies BRS was not measured. It is
unlikely that CsA-induced reduction in BRS contributes to the acute pressor
response caused by CsA. In support of this notion, sinoaortic denervation
failed to affect the pressor response elicited by CsA infusion
(Lyson et al., 1994).
Furthermore, CsA-induced hypertension seems to be mediated by synapsin, stored
in the renal afferent nerve endings, because in the synapsin knockout mice CsA
failed to induce hypertension (Zhang et
al., 2000). On the other hand, our findings are not consistent
with reported findings where an acute CsA infusion (20 mg/kg over 30 min)
caused attenuation in baroreflex control of sympathetic discharge and no
change in BP in rabbits (Ryuzaki et al.,
1997). The difference in the BP and BRS responses could be
attributed to species differences and the reflex response, HR in the present
study versus sympathetic discharge in the reported study
(Ryuzaki et al., 1997).
Notably, the acute pressor effect obtained in the present study resembles a
similar effect in humans (Schachter,
1988; Sturrock et al.,
1993; Sander et al.,
1996). It remains to be investigated, however, whether the
clinically used dose of CsA produces similar effects on blood pressure and BRS
in our model system to support the clinical relevance of our findings.
The present study is the first to report that CsA attenuates BRS in a
progressive manner starting with the second dose, and reaching approximately
50% reduction by the 5th day. The possibility must be considered that the
increase in blood pressure and the decrease in heart rate caused by acute CsA
administration might have contributed to the observed reduction in BRS in the
present study. This possibility is unlikely because BRS did not change after
the first dose of CsA in the presence of elevated blood pressure (Figs.
1 and
5D) nor in BRS in the group
that received a single dose of CsA on day 1 and the vehicle over the following
4 days. Furthermore, the BRS values in the vehicle- or saline-treated rats did
not change over the 5-day period. Notably, the progressive reductions in BRS
in CsA-treated rats were associated with cumulative increases in baseline MAP.
Whether this relationship is causal remains to be investigated. It is
noteworthy that in the absence of any change in the BRS of the rats that
received a single dose of CsA, MAP also remained unchanged compared with
control (saline or vehicle) values on the 2nd through the 5th day of the
study. It may be argued that the lack of inhibition of BRS in the group that
received the single dose of CsA was due to a lower baseline value compared
with the group that received the cumulative dose regimen. This is unlikely for
two reasons. First, CsA did not reduce BRS after the first dose in the group
that received the cumulative regimen in spite of a significantly higher
baseline BRS (Fig. 5). Second,
by the 5th day, the BRS in the group that received cumulative CsA was
significantly lower than the BRS value in the group that received the single
dose, indicating that the starting low baseline value in the latter group was
not a limiting factor. Furthermore, in some models of hypertension, a
reduction in BRS contributes to the consequent elevation in blood pressure
(Gordon and Mark, 1983;
Abdel-Rahman and Wooles, 1987).
Together, it is likely that the chronic pressor response caused by CsA is a
consequence of the attenuation of BRS.
The mechanism of a relatively rapid (2-day) CsA-induced attenuation of BRS
is not known. A recent study attributed a 50% reduction in BRS caused by CsA
to a reduction in serum testosterone
(El-Mas et al., 2002). Because
we obtained a similar reduction in BRS at much earlier time (5 versus 11
days), we decided to determine whether the testosterone link also applies to
our findings. We started with the measurements of plasma testosterone levels
after 5 days of CsA administration. The lack of a change in serum testosterone
level precludes a role for this hormone in the early (<5 days) attenuation
of BRS caused by CsA in our study. Notably, to rule out any effect of diurnal
variation in plasma testosterone levels, blood samples were withdrawn from all
rats at a specified time on the 5th day
(Moeller et al., 1988;
Leal and Moreira, 1997).
Results of the present study demonstrated, for the first time, a temporal
relationship between the time-dependent increases in baseline heart rate and
blood pressure and the decline in BRS observed in the rats that received
cumulative CsA treatment (Table
1; Figs. 3 and
5). The progressive increases
in baseline blood pressure and heart rate become more apparent when
comparisons are made with the appropriate control (vehicle) values. This is
particularly important given the present findings that the vehicle, Cremophor
EL, elicited a depressor response (Table
1; Fig. 3A), which
has been attributed to inhibition of the diacylglycerol-protein kinase C
pathway (Zhao et al., 1989).
The chronic pressor response seen with the cumulative CsA treatment could be
due to one or more of the CsA-reported effects
(Cartier et al., 1994), which
include 1) reduced release of nitric oxide mediated by muscarinic receptor
activation, 2) increased production of endothelium related constricting
factors mediated by serotonin receptors, and 3) increased vascular sensitivity
to circulating catecholamines. Notably, the chronic pressor effect of CsA,
which seems to be masked somewhat by the depressor effect of the vehicle, must
be distinguished from the acute pressor effect caused, at least partly, by
enhancing sympathetic activity (Sander et
al., 1996). It is also important to comment on the inverse
relationship between baseline heart rate and BRS observed after cumulative
administration of CsA. Interestingly, in a previous study, we observed a
similar relationship between baseline heart rate and BRS in normotensive
humans when BRS was measured by the same method used in the present study
(Abdel-Rahman et al., 1994).
The mechanism by which CsA produces incremental increase in heart rate is not
known. It is possible, however, that this response observed in the present
study and after 13-day treatment with CsA
(El-Mas et al., 2002) is
secondary to the progressive attenuation of BRS. Nonetheless, because the
inverse relationship between baseline heart rate and BRS observed in the
present study and in our previous study
(Abdel-Rahman et al., 1994) is
based on association, it is also possible that the reduced BRS is secondary to
the higher baseline heart rate. As discussed above, chronic CsA administration
caused a reduction in vasodilation elicited by muscarinic receptor activation
(Cartier et al., 1994). A
similar interaction, whether direct or indirect, between chronic CsA and
cardiac muscarinic receptor, if exists, may well explain the cumulative
increase in baseline heart rate as well as the associated reduction in BRS.
Further studies are needed to investigate this possibility. It is notable that
CsA effects seem to involve the pharmacokinetic profile of CsA rather than the
mere plasma level of the drug because the increases in heart rate and the
associated reductions in BRS started to occur on the 3rd day of treatment.
Neither response occurred after the acute administration of CsA or when the
effects of a single dose CsA were followed over the 5-day observation period
and compared with the appropriate control (vehicle) values.
Results of the present study demonstrated consistent bradycardic responses
along with the reproducible and similar pressor responses elicited by CsA,
which suggests these HR responses are baroreflex-mediated. In support of this
notion is the gradual reduction in the bradycardic response that paralleled
the progressive reduction in BRS over the 5-day observation period. It may be
argued that the reduction in BRS in the CsA group was a secondary event to the
pressor response because hypertension is associated with attenuated BRS
(Goldstein, 1983). Our
findings argue against this possibility because the acute (first dose) pressor
response elicited by CsA was not associated with any change in BRS.
In the present study, we used CsA in the clinically available formulation,
which contains Cremophor EL and ethanol. It is noteworthy that in reported
studies, including our own, ethanol elicits dose-related attenuation of BRS.
It is unlikely, however, that the amount of ethanol (0.1 g/kg/day)
administered along with CsA, in our study, contributed to the attenuation of
BRS for two reasons. First, we have shown in previous studies that ethanol in
doses less than 0.25 g/kg has no effect on BRS
(Abdel-Rahman, 1994). Second,
the vehicle used in the present study, which contains the same amount of
ethanol had no effect, compared with saline, on BRS over the 5-day treatment
period. Finally, results of the present study showed a gradual reduction in
body weight, which reached 10% by the 5th day. The reasons for the reduction
in body weight in CsA-treated animals are not fully understood. However, our
findings agree with the reported findings, which demonstrated similar loss in
body weight that was attributed to anorexia and increased catabolism
(Farthing and Clark, 1981) or
to acid-base imbalance induced by CsA
(Jaramillo-Juarez et al.,
2000).
In summary, CsA induced progressive attenuation in BRS along with cumulative elevation of MAP over the 5-day course of the study in conscious unrestrained rats. On the other hand, the acute (first dose) pressor response observed during CsA infusion, which was reproducible over the 5-day treatment period, was not associated with any alteration in BRS. Furthermore, CsA had no effect on plasma testosterone levels after 5 days of daily treatment, which rules out a role for serum testosterone in the progressive attenuation of BRS. The present findings suggest that CsA-evoked reduction of BRS, which requires at least two daily doses of the drug, seems to contribute to the cumulative (chronic) but not to the acute elevation in blood pressure.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: CsA, cyclosporin A; BP, blood pressure; BRS, baroreflex sensitivity; MAP, mean arterial pressure; HR, heart rate; PE, phenylephrine.
Address correspondence to: Dr. Abdel A. Abdel-Rahman, Department of Pharmacology, The Brody School of Medicine, East Carolina University, Greenville, NC 27858. E-mail: abdelrahmana{at}mail.ecu.edu
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, p < 0.05 compared with vehicle, saline, and
single-dose CsA, respectively. Baseline body weight in the single-dose CsA,
cumulative CsA, vehicle, and saline groups was 350 ± 10, 287 ±
12, 338 ± 11, and 314 ± 19 g, respectively.
) and
after (
) the infusion of saline (A) or vehicle (B) on the 1st day of
study and before (baseline, 
) CsA (15 mg/kg) treatments (C). Values are means ± S.E.
) and after (