(Hypertension. 2000;36:376.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
ß-Adrenoceptor Dysfunction After Inhibition of NO Synthesis
From the Departments of Pharmacology (E.J.W., A.K.J., S.J.L.) and Psychology (A.K.J.) and The Cardiovascular Center (E.J.W., A.K.J.), University of Iowa, Iowa City.
Correspondence to Stephen J. Lewis, PhD, Department of Pharmacology, University of Iowa, Iowa City, IA 52242. E-mail stephen-lewis{at}uiowa.edu
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Abstract |
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Abstract—Gs protein–coupled ß-adrenoceptors rapidly desensitize on exposure to agonists in reconstituted membrane preparations, whereas rapid tachyphylaxis to ß-adrenoceptor–mediated vasodilation does not readily occur in vivo. This study examined the possibility that endothelium-derived nitrosyl factors prevent the rapid desensitization of ß-adrenoceptors in the vascular smooth muscle of resistance arteries in pentobarbital-anesthetized rats. The fall in mean arterial blood pressure and in hindquarter vascular resistance produced by the ß-adrenoceptor agonist isoproterenol (ISO, 0.1 to 10 µg/kg IV) was slightly but significantly smaller in rats treated with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 100 µmol/kg IV) than in saline-treated rats. The ISO-induced fall in mesenteric resistance was similar in L-NAME–treated and in saline-treated rats. The fall in hindquarter vascular resistance and in mesenteric resistance produced by ISO (8x10 µg/kg IV) was subject to tachyphylaxis on repeated injection in rats treated with L-NAME (100 µmol/kg IV) but not in rats treated with saline. Injections of L-S-nitrosocysteine (1200 nmol/kg IV), a lipophobic S-nitrosothiol, before each injection of ISO (10 µg/kg IV) prevented tachyphylaxis to ISO in L-NAME–treated rats. The vasodilator effects of ISO (0.1 to 10 µg/kg IV) in L-NAME–treated rats that received 8 injections of ISO (10 µg/kg IV) were markedly smaller than in L-NAME–treated rats that received 8 injections of saline. These results indicate that (1) the vasodilator actions of ISO in pentobarbital-anesthetized rats only minimally involve the release of endothelium-derived nitrosyl factors, (2) the effects of ISO are subject to development of tachyphylaxis in L-NAME–treated rats, and (3) tachyphylaxis to ISO is prevented by L-S-nitrosocysteine. These findings suggest that endothelium-derived nitrosyl factors may prevent desensitization of ß-adrenoceptors in vivo.
Key Words: adrenergic receptor agonists • hemodynamics • nitric oxide • rats
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Introduction |
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On exposure to catecholamines or the ß-adrenoceptor (ß-AR) agonist isoproterenol (ISO), Gs protein–coupled ß-ARs are rapidly (in minutes) desensitized in isolated cells and in reconstituted receptor–Gs protein preparations.1 2 3 4 Rapid desensitization involves phosphorylation of ß-ARs by cAMP-dependent protein kinase and by G protein–coupled receptor kinases, known as ß-AR kinases .2 3 4 Phosphorylated ß-ARs cannot be coupled with Gs proteins and are sequestered into intracellular organelles, where they are dephosphorylated before reincorporation into plasma membranes.2 3 4 In contrast, the vasodilation produced by ISO in human forearm arteries does not diminish during a 4-hour infusion.5 These findings suggest that (1) rapid desensitization of ß-ARs in vivo is prevented by endogenous factors not present in isolated cells or in reconstituted ß-AR–Gs protein preparations,1 2 3 4 and/or (2) the absence of these factors precludes resensitization of ß-ARs.
On the basis of findings with pituitary adenylate cyclase–activating polypeptide-27, a Gs protein–coupled receptor agonist,6 7 8 the hypothesis underlying the present study is that endothelium-derived NO–containing factors (NOFs), such as L-S-nitrosocysteine (L-SNC),9 10 11 prevent rapid desensitization of ß-ARs in vascular smooth muscle in resistance vessels in vivo by mechanisms other than the generation of cGMP. The main goal of the present study was to determine whether ISO-mediated vasodilation is subject to rapid tachyphylaxis after inhibition of NO synthesis. In the context of these studies, rapid tachyphylaxis is defined as the progressive loss of response elicited by second or subsequent doses of ISO. The specific aims were to determine (1) the role of endothelium-derived NOFs in the vasodilator responses elicited by systemic injections of ISO in pentobarbital-anesthetized rats, (2) whether ISO-induced vasodilation was subject to tachyphylaxis after inhibition of NO synthesis, and (3) whether administration of L-SNC would prevent tachyphylaxis to ISO after inhibition of NO synthesis.
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Methods |
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Animals and Surgical Procedures
The protocols were approved by the University of Iowa Animal Care and Use Committee. Male Sprague-Dawley rats (Harlan, Indianapolis, Ind), weighing 250 to 350 g, were used in the present study. Each rat was anesthetized with pentobarbital (50 mg/kg IP). A polyethylene catheter was placed in a femoral vein to administer drugs, and a polyethylene catheter was placed in the lower abdominal aorta via the femoral artery to record mean arterial blood pressure (MAP). The rats were supplemented with pentobarbital (5 mg/kg IV) as needed. A midline laparotomy was performed, and a pulsed Doppler flow probe was placed around the lower abdominal aorta to measure hindquarter blood flow velocity and to determine hindquarter vascular resistance (HQR).6 7 8 A Doppler flow probe was also placed around the superior mesenteric artery to measure mesenteric blood flow and to determine mesenteric vascular resistance (MR).6 7 8 HQR (mm Hg/kHz) at any one point in time was determined by dividing the MAP (mm Hg) value by the hindquarter blood flow velocity (kHz) value. MR (mm Hg/kHz) at any one point in time was determined by dividing the MAP (mm Hg) value by the mesenteric blood flow (kHz) value. The HQR value at the peak of each ISO-induced response is expressed as a percentage of the MR value immediately before ISO was given. The same is true for MR. The peak changes in HQR and MR did not necessarily occur at the same time, although they were usually within 5 to 10 seconds of one another. The MAP values at the times of peak changes in HQR and MR were virtually identical to one another. Accordingly, the physiographic recordings were scanned to establish the maximal changes in HQR and MR. Note that a fall in vascular resistance denotes a vasodilation in peripheral resistance arteries, whereas an increase in vascular resistance denotes a vasoconstriction in these arteries. Details of the Doppler technique, including construction of the probes, the reliability of the method for estimation of flow velocity, and suitability of determining percent changes in vascular resistance have been described previously.12 In Figure 1, the arithmetic changes in vascular resistances were presented to support experimental findings. Rat body temperatures were kept at 37°C by a thermostat-controlled heating pad. Rats breathed room air supplemented with humidified 95% O2/5% CO2 via a face mask.
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Experimental Protocols
All drugs were given as intravenous bolus
injections. The responses elicited by each injection of ISO or L-SNC
were allowed to fully recover before the next injection was given. The
responses elicited by the NO synthesis inhibitor
NG-nitro-L-arginine
methyl ester (L-NAME) reached plateau levels by 15 to 20 minutes. As
such, the first injection of ISO was given 20 minutes after the
injection of L-NAME (or saline). The groups are described below on the
basis of the treatments they received.
Saline-I
The saline-I group (n=6) received saline (0.9% NaCl IV), ISO
(0.1 to 10 µg/kg IV, first dose-response [DR] curve), 8 injections
of saline, and then ISO (0.1 to 10 µg/kg IV, second DR
curve).
Saline-II
The saline-II group (n=5) received saline, ISO (0.1 to 10
µg/kg IV), 8 injections of ISO (10 µg/kg IV), and ISO (0.1 to 10
µg/kg IV).
L-NAME-I
The L-NAME-I group (n=5) received L-NAME (100 µmol/kg
IV), ISO (0.1 to 10 µg/kg IV), 8 injections of saline, and then ISO
(0.1 to 10 µg/kg IV).
L-NAME-II
The L-NAME-II group (n=5) received L-NAME (100 µmol/kg
IV), ISO (0.1 to 10 µg/kg IV), 8 injections of ISO (10 µg/kg IV),
and then ISO (0.1 to 10 µg/kg IV).
L-NAME-III
The L-NAME-III group (n=5) received L-NAME (100 µmol/kg
IV) and ISO (0.1 to 10 µg/kg IV). The rats then received L-SNC (1200
nmol/kg IV), which produced a fall in MAP and vascular resistance. Once
the hemodynamic effects of L-SNC had subsided, the rats
received ISO (10 µg/kg IV). This was repeated until rats had received
8 injections of L-SNC and ISO.
These experiments lasted for 
3 hours. Specifically, the first set of
ISO injections (0.1 to 10 µg/kg IV, first DR curve) took 30
minutes to administer. The 8 injections of saline, or ISO (10 µg/kg
IV) with and without injections of L-SNC (1200 nmol/kg IV), took 2
hours to administer. The second set of ISO injections (0.1 to 10
µg/kg IV, second DR curve) also took 30 minutes to administer. The
L-NAME–induced plateaus in MAP and vascular resistances were sustained
throughout the experiments. A supplemental dose of L-NAME (50
µmol/kg IV) was given halfway through the experiments to ensure that
these plateau values were maintained.
Drugs
All drugs were obtained from Sigma Chemical Co, except sodium
pentobarbital, which was obtained from Abbott Laboratories. L-SNC was
prepared as described previously.7 All drugs were
dissolved and/or diluted for injection in sterile saline.
Statistical Analyses
The data are presented as mean±SEM. The single SEM term
on each DR curve was determined by the following formula:
(EMS/n)1/2, where EMS is the error mean square
term from ANOVA, and n is the number of animals.6 7 8 The
data were analyzed by repeated-measures ANOVA,13
followed by the Student modified t test with the Bonferroni
correction for multiple comparisons between means; the modified EMS
term from the ANOVA was used.6 7 8
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Results |
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Effects of Saline or L-NAME on Resting Hemodynamic Variables
Resting variables in the 5 groups of rats used in the present study are summarized in the Table. Resting variables were sampled until precise estimates were obtained. The values obtained before or after injection of saline or L-NAME (100 µmol/kg IV) were averaged. In subsequent phases, preinjection values for each injection of ISO or saline were determined and averaged because they were similar to one another. The initial injection of saline did not affect resting variables, and these variables remained constant thereafter. L-NAME produced substantial increases in MAP and vascular resistances. The L-NAME–induced responses were similar in each group and remained constant thereafter. However, resting HQR values recorded during the second ISO DR curve in L-NAME–treated rats were lower than those before the injections of L-SNC because of the long-lasting effects of the last injection of L-SNC.
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Effects of L-NAME on the Hemodynamic Actions
of ISO
The responses elicited by ISO (0.1 to 10.0 µg/kg IV, first DR
curve) were determined in 2 groups of saline-treated rats and in 3
groups of L-NAME (100 µmol/kg IV)–treated rats. The data from
the 2 saline-treated groups of rats (n=11 rats in total) were combined
as were the data from the 3 L-NAME–treated groups of rats (n=15 rats).
The effects of L-NAME were similar in each group (P>0.05
for all between-group comparisons). The responses elicited by ISO were
similar in the 2 saline-treated groups and in the 3 L-NAME–treated
groups (P>0.05 for all between-group comparisons). Resting
MAP, HQR, and MR values in saline-treated rats were 116±2
mm Hg, 108±9 mm Hg/kHz, and 66±5 mm Hg/kHz,
respectively. Resting MAP, HQR, and MR values in L-NAME–treated rats
were 156±3 mm Hg, 220±22 mm Hg/kHz, and 85±7
mm Hg/kHz, respectively. The values in L-NAME–treated rats were
higher than the values in saline-treated rats (P<0.05 for
all comparisons). Arithmetic and percent changes in MAP and resistances
elicited by ISO (0.1 to 10 µg/kg IV) in saline-treated and in
L-NAME–treated rats are summarized in Figure 1. ISO elicited a
dose-dependent fall in MAP in both groups. The arithmetic fall in MAP
elicited by ISO was similar in both groups. However, the percent fall
in MAP elicited by 1.0 to 10 µg/kg doses of ISO was smaller in
L-NAME–treated rats. ISO elicited a dose-dependent fall in HQR in both
groups. The arithmetic fall in HQR elicited by 1.0 to 10 µg/kg doses
of ISO was greater in L-NAME–treated rats, whereas the percent fall in
HQR elicited by 0.5 to 10 µg/kg doses of ISO was smaller in
L-NAME–treated rats. ISO produced a dose-dependent fall in MR. The
arithmetic and percent falls in MR were similar in saline-treated and
L-NAME–treated rats. The responses elicited by ISO (0.1 to 10 µg/kg
IV) in saline-treated rats lasted for 1 minute (lower doses) to 10
minutes (higher doses). The durations of the ISO-induced responses were
similar in saline-treated and in L-NAME–treated rats, except when the
magnitudes of the responses were diminished in L-NAME–treated
rats.
Responses Produced by Repeated Injections of ISO in
Saline-Pretreated Rats
The first injection of ISO (10 µg/kg IV) elicited a fall in MAP
(-59±2%), HQR (-64±4%), and MR (-65±5%) in saline-treated rats
(P<0.05 for all responses). Subsequent injections elicited
similar responses (P>0.05 for all comparisons to first
injection response, data not shown). The duration of the fall in MAP,
HQR, and MR elicited by each injection of ISO lasted for 10 minutes.
The durations of the responses produced by each injection were similar
to one another in these saline-treated rats (P>0.05 for all
comparisons, data not shown).
Responses Produced by Repeated Injections of ISO in
L-NAME–Pretreated Rats
The responses elicited by 8 injections of ISO (10 µg/kg IV) in
L-NAME–treated rats are summarized in Figure 2. The first injection of ISO produced a
significant fall in MAP (-43±4%), HQR (-44±4%), and MR
(-62±5%). The falls in MAP and HQR were smaller than those in
saline-treated rats (P<0.05), whereas the fall in MR was
similar in both groups (P>0.05). Subsequent injections of
ISO produced progressively smaller falls in MAP, HQR, and MR in
L-NAME–treated rats. Because preinjection values remained constant
during these injections, the progressive loss of response to ISO was
also evident when expressed as arithmetic changes. The responses
elicited by the first few injections of ISO (10 µg/kg IV) lasted for
10 minutes. The durations of the responses elicited by later
injections of ISO were shorter (P<0.05 for all
comparisons), probably because the maximal ISO-induced responses were
diminished in these L-NAME–treated rats.
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Effects of L-SNC on Tachyphylaxis to ISO in L-NAME–Pretreated
Rats
The first injection of L-SNC (1200 nmol/kg IV) elicited a
pronounced fall in MAP (-68±2%), HQR (-73±2%), and MR (-72±2%)
in L-NAME–treated rats (P<0.05 for all responses). Each
subsequent injection of L-SNC elicited similar responses
(P>0.05 for all comparisons to first injection responses,
data not shown). The responses elicited by 8 injections of ISO (10
µg/kg IV) in L-NAME–treated rats that received L-SNC (1200 nmol/kg
IV) before each injection of ISO are summarized in Figure 3. The first injection of ISO elicited a
significant (P<0.05) fall in MAP (-46±4%), HQR
(-59±6%), and MR (-58±7%). These responses were similar to those
in L-NAME–treated rats that did not receive L-SNC (P>0.05
for all comparisons). Subsequent injections of ISO elicited similar
responses in these L-SNC–treated rats.
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Comparison of the First and Second ISO DR Curves in
Saline-Pretreated Rats
The percent changes in MAP and vascular resistances elicited by
the first and second ISO DR curves (0.1 to 10 µg/kg IV) in
saline-treated rats are summarized in Figure 4. The 2 ISO DR curves were similar in
rats that received 8 injections of saline between the ISO DR curves.
The responses elicited by the lowest dose of ISO (second ISO DR curve)
were reduced in rats that received 8 injections of ISO (10.0 µg/kg
IV) between the ISO DR curves. The responses elicited by the higher
doses of ISO (second ISO DR curve) were not diminished. The responses
elicited by ISO (0.1 to 10 µg/kg IV) lasted for 1 minute (lower
doses) to 10 minutes (higher doses). These responses were usually of
lesser duration in L-NAME–treated rats because the maximal ISO-induced
responses were diminished (see below).
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Comparison of the First and Second ISO DR Curves in
L-NAME–Pretreated Rats
The first and second ISO DR curves (0.1 to 10 µg/kg IV) in
L-NAME (100 µmol/kg IV)–treated rats that received 8 injections
of saline between the 2 DR curves are summarized in the left panels of
Figure 5. The 2 DR curves were identical;
however, the fall in MAP elicited by 1.0 µg/kg of ISO (2nd ISO DR)
was smaller than before the 8 injections of saline. The first and
second ISO DR curves (0.1 to 10 µg/kg IV) in L-NAME (100
µmol/kg IV)–treated rats that received 8 injections of ISO (10
µg/kg IV) between the 2 DR curves are summarized in the right panels
of Figure 5. The responses elicited by each dose of ISO (second
DR curve) were markedly smaller than the values before the 8 injections
of ISO (first DR curve). Again, preinjection values remained constant
during these injections, and the loss of response to ISO would be
evident if expressed as arithmetic changes.
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Effects of Prior Injections of L-SNC on the Second ISO DR Curves in
L-NAME–Pretreated Rats
The first and second ISO DR curves (0.1 to 10 µg/kg IV) in
L-NAME (100 µmol/kg IV)–treated rats that received L-SNC (1200
nmol/kg IV) before each of the 8 injections of ISO (10 µg/kg IV) are
summarized in Figure 6. The falls in MAP
elicited by the 5.0 and 10.0 µg/kg doses of ISO (second ISO DR curve)
were smaller than those before the 8 injections of ISO and L-SNC. The
fall in HQR elicited by the 10 µg/kg dose of ISO (2nd DR curve) was
smaller than that before the 8 injections of ISO and L-SNC (first DR
curve). The ISO-induced changes in MR were similar before and after
administration of the 8 doses of ISO and L-SNC. As such, the loss of
response to ISO (second DR) was markedly less than that observed in
L-NAME–treated rats that did not receive the injections of L-SNC (see
Figures 3 and 4 for comparisons).
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Discussion |
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Role of Endothelium-Derived NOFs in the Hemodynamic Actions of ISO
The present study confirms that ISO produces a dose-dependent fall in MAP and vascular resistance in pentobarbital-anesthetized rats.13 The percent fall in HQR produced by ISO (first DR curve) was slightly smaller in L-NAME–treated than in saline-treated rats, whereas the ISO-induced fall in MR was not. Although there is evidence that the vasodilator actions of ISO involve endothelium-derived NOFs,14 15 16 17 it appears that these factors do not play a major role in mediating the vasodilator effects of ISO in pentobarbital-anesthetized rats.
Lack of Tachyphylaxis to the Hemodynamic Actions of
ISO in Saline-Pretreated Rats
The ISO (10 µmol/kg IV)–induced responses did not diminish
on repeated injections in saline-treated rats. Moreover, the ISO DR
curves were similar before and after the 8 injections of ISO (10
µmol/kg IV). These results support evidence that the dilator effects
of ISO in human arteries are not subject to tachyphylaxis with
short-term administration.5 However, ISO may have
desensitized ß-ARs, because agonists can elicit maximal responses
despite marked reductions in the affinity and/or density of
ß-ARs.1 The lack of tachyphylaxis to ISO may be because
(1) cAMP-dependent protein kinase and ß-AR kinases do not
phosphorylate ß-ARs in vivo, (2) 8 injections of ISO
(10 µmol/kg IV) do not desensitize enough ß-ARs for
tachyphylaxis to be evident, or (3) desensitized ß-ARs are rapidly
resensitized.
Tachyphylaxis to the Hemodynamic Actions of ISO in
L-NAME-Pretreated Rats
The first and second ISO DR curves were similar to one another in
L-NAME–treated rats that received injections of saline between the DR
curves. This demonstrates that a loss of response to ISO did not occur
over time. The vasodilator effects of ISO (10 µmol/kg IV) were
subject to tachyphylaxis on repeated injection in L-NAME–treated rats.
Moreover, the second DR curves were more shallow than the DR curves in
these rats. This suggests that endothelium-derived NOFs
prevent the desensitization of ß-ARs or play a vital role in the
resensitization of ß-ARs.2 3 4 Long-term administration
of ß-AR agonists results in tachyphylaxis.1 18 19 20 21 22 This
may involve the uncoupling of ß-ARs from Gs
proteins18 and the sequestration of ß-ARs into
organelles.1 18 19 20 21 22 The rapid tachyphylaxis to ISO in
L-NAME–treated rats may involve the above processes.
L-SNC Prevents Tachyphylaxis to ISO in L-NAME–Pretreated
Rats
L-SNC prevented tachyphylaxis to pituitary adenylate
cyclase–activating polypeptide-27 in L-NAME–treated rats, whereas
the NO donor, sodium nitroprusside, or the membrane-permeable cGMP
analogue, 8-(4-chlorophenylthiol)-cGMP, did not.7 The
finding that L-SNC prevented tachyphylaxis to the
hemodynamic actions of ISO in L-NAME–treated rats
supports the contention that tachyphylaxis to ISO occurs because the
vasculature is not exposed to endothelium-derived NOFs
and not because of a deficiency of NO/cGMP. L-SNC alters the activity
of functional proteins by nitrosation of amino acids in these
proteins.10 23 24 25 Accordingly, L-SNC may prevent
tachyphylaxis to ISO by nitrosation of ß-ARs, cAMP-dependent protein
kinase, or ß-AR kinases or may facilitate the resensitization of
ß-ARs. The ability of S-nitrosothiols to activate
stereoselective recognition sites in plasma
membranes26 27 28 may also play a role in preventing
tachyphylaxis to ISO.
Summary
The present study provides evidence that
endothelium-derived NOFs prevent tachyphylaxis to ISO
in vivo. Tachyphylaxis to ISO in L-NAME–treated rats may involve
desensitization of ß-ARs. The lack of exposure to NOFs may explain
why rapid desensitization of ß-ARs readily occurs in isolated cells
and reconstituted receptor–Gs protein
preparations,1 2 3 4 whereas tachyphylaxis to ISO does not
readily occur on repeated injection in saline-treated rats.
Hypertension29 and diabetes30 are associated
with endothelial cell dysfunction and a loss of
Gs protein–coupled receptor-mediated
vasodilation. The loss of vasodilator potency of
Gs protein–coupled receptor agonists in these
disease states may involve desensitization of receptors that is due to
the reduced release of
endothelium-derived31 and neurogenically
derived32 33 34 35 NOFs. The possibility that L-SNC may prevent
the desensitization of ß-ARs awaits appropriate molecular studies,
which may confirm whether L-SNC prevents ISO-induced
phosphorylation/desensitization of ß-ARs.
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Acknowledgments |
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This work was supported in part by grants from the National Institutes of Health (HL-14388, HL-57472, and DK-54759), from NASA (NAG5-6171), and from the Office of Naval Research (N00014-97-1-0145). We wish to acknowledge the expert assistance of Mike Burcham in the preparation of the figures.
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Footnotes |
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Reprint requests to Alan Kim Johnson, PhD, Department of Psychology, 11 Seashore Hall, University of Iowa, Iowa City, IA 52242-1407.
Received February 28, 2000; first decision March 23, 2000; accepted April 3, 2000.
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