(Hypertension. 1999;33:467-471.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Effects of Vasodilatory ß-Adrenoceptor Antagonists on Endothelium-Derived Nitric Oxide Release in Rat Kidney
From the Second Department of Internal Medicine, Faculty of Medicine (M.K., Y.H., H.H., H.N., Y.S., D.N., E.S., M.O.), and Faculty of Pharmaceutical Sciences (K.K., T.N.), University of Tokyo (Japan).
Correspondence to Yasunobu Hirata, MD, The Second Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail hirata-2im{at}h.u-tokyo.ac.jp
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Abstract |
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Abstract—The mechanisms for the vascular actions of vasodilatory ß-blockers remain undetermined. For some kinds of ß-blockers, the involvement of nitric oxide (NO) has been suggested. We studied the effects of vasodilatory ß-blockers on renal perfusion pressure (RPP) and NO release in the rat kidney. Infusion of bopindolol, celiprolol, and nebivolol caused a dose-dependent reduction in RPP and an increase in NO release (RPP: bopindolol 10-6 mol/L, -23±2%; celiprolol 10-4 mol/L, -27±2%; nebivolol 10-5 mol/L, -35±3%; NO: bopindolol 10-6 mol/L, +33±2; celiprolol 10-4 mol/L, +41±2; nebivolol 10-5 mol/L, +45±5 fmol · min-1 · g kidney-1, mean±SEM). Metergoline (10-6 mol/L), a 5-hydroxytryptamine (5-HT)1/2 antagonist, or NAN-190 (10-6 mol/L), a 5-HT1A antagonist, almost completely abolished the vasorelaxation and NO release caused by bopindolol, celiprolol, and nebivolol. However, neither propranolol nor bisoprolol decreased RPP. Celiprolol and nebivolol caused vasodilation in the rat thoracic aorta, and it was markedly reduced by endothelial denudation, N
-nitro-L-arginine methyl ester
(10-4 mol/L), or NAN-190 (10-6 mol/L). In
deoxycorticosterone acetate-salt hypertensive rats, 4-week
administration of celiprolol (50 mg · kg-1 ·
d-1 IV) restored the responses regarding RPP and NO
release to acetylcholine. These results suggest that several
ß-blockers exert their vasodilatory action through the
5-HT1A receptor/NO pathway and that treatment with these
ß-blockers may protect against endothelial injury
in hypertension.
Key Words: nitric oxide • kidney • receptors, adrenergic, beta • 5-hydroxytryptamine
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The mechanism for vasodilation by some ß-adrenoceptor antagonists (ß-blockers) is not fully understood. It has been partly explained by intrinsic sympathomimetic activity (ISA).1 Celiprolol2 and dilevalol3 are known to stimulate ß2-adrenoceptors. Other mechanisms, such as the blockade of calcium channels by betaxolol4 and the blockade of
-adrenoceptors, have been reported, suggesting that the
mechanisms for vasodilator ß-blockers may be
heterogeneous.
Although vasodilatory ß-blockers have little negative
chronotropic actions, previous studies have shown that the long-term
administration of bucindolol or carvedilol is beneficial in terms of
ventricular function and mortality rate in congestive heart
failure,5 6 probably because of the reduction in cardiac
afterload and the increase in coronary blood flow. Recent
studies have also suggested that several sorts of vasodilatory
ß-blockers, such as tertatolol and nebivolol, exert their effects
partly via endothelium-derived nitric oxide (NO)
release because their vasodilator effects are
endothelium dependent and are suppressed by
N-nitro-L-arginine, an NO synthase
(NOS) inhibitor; by hemoglobin, a scavenger of NO; or by
methylene blue, a soluble guanylate cyclase
inhibitor.7 8 9 10 If NO were involved in the
effects of vasodilatory ß-blockers, we could expect these to exert
nitrate-like effects and prevent cardiovascular
complications, including ischemic organ damage. However, the
mechanisms for their NO-releasing activity are largely unknown.
Differences in the pharmacological properties of these ß-blockers
such as ISA, lipid solubility, cardioselectivity,
and membrane-stabilizing activity do not seem to explain systematically
the reported NO-releasing activity of carteolol,11
nebivolol8 10 and tertatolol.7 9 The
mechanisms have been speculated to be an
2-agonistic activity in the case of
carteolol11 and a 5-hydroxytryptamine
(5-HT)–agonistic activity in the case of tertatolol.9
In the present study, we investigated whether endothelium-derived NO was involved in the vasodilation caused by ß-blockers and, if that were the case, which properties of ß-blockers were responsible for their NO-releasing effect. Thus, we examined the endothelium-dependency of the vasodilatory effects of ß-blockers on vascular tone and NO release in the isolated perfused rat kidney and thoracic aorta. Moreover, we investigated whether vasodilatory ß-blockers could prevent endothelial dysfunction in hypertension.
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Methods |
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Measurement of Perfusion Pressure and NO Release in Isolated Perfused Kidney
Male Wistar rats, weighing 316±7 g, were anesthetized with pentobarbital sodium (40 mg/kg IP). The kidneys were isolated and perfused as described elsewhere.12 The kidneys were perfused at a constant flow of 5 mL/min with a Krebs-Henseleit buffer containing 10-6 mol/L phenylephrine and 10-5 mol/L indomethacin to maintain renal perfusion pressure (RPP) at
100 mm Hg. When
agents used interacted with 1-adrenoceptors,
their effects were also examined using 10-8.5
mol/L angiotensin II–containing perfusate. The effluent perfusate from the renal vein was obtained continuously (2 mL/min), mixed with a chemiluminescence probe, and then forwarded into a chemiluminescence analyzer as previously described13 to measure NO output.
Sixty minutes after the kidney was isolated, we examined the effects of
celiprolol and other ß-blockers on RPP and NO release in a cumulative
manner at 10-minute intervals. To examine the
endothelium-dependency of the action of ß-blockers,
we also examined the effects of pretreatments with
N-nitro-L-arginine methyl ester
(L-NAME) or E-4021
(1-[6-chloro-4-(3,4-methylbenzyl)amino-quinazolin-2-yl]piperdine-4-carboxylate),
a cGMP-specific type V phosphodiesterase
inhibitor.14 Furthermore, we studied whether
the action of ß-blockers was exerted through adrenergic receptors or
5-HT receptors, using the antagonists and agonists of each
type of receptors.
Measurement of Tension in Aortic Ring Segments
Vascular responses of the thoracic aorta from 12-week-old, male
Wistar rats were tested in organ chambers. Briefly, the rats were
anesthetized by injection of sodium pentobarbital (40 mg/kg
body weight IP). The thoracic aorta was excised and cut into rings
(4 mm in length). Aortic rings were mounted in organ chambers
filled with 25 mL of an oxygenated modified Krebs-Ringer
bicarbonate solution at 37°C. Isometric tension was recorded with
a force transducer (Oriental).
The aortic rings were precontracted with prostaglandin
F2 (10-6 mol/L), and
responses to celiprolol and nebivolol at 70% of the maximal
contraction obtained in each individual ring were studied in the
presence or absence of vascular endothelium. The
endothelium of each aortic ring was removed by rubbing
them gently with a stainless needle. To evaluate the role of the
NO/cGMP pathway and 5-HT receptors, the responses to ß-blockers were
tested in the presence of 10-4 mol/L L-NAME
or 10-6 mol/L NAN-190
(1-[2-methoxyphenyl]-4-[4(2-phthalimido)butyl]-piperazine), a
5-HT1A antagonist.
Effects of Celiprolol in DOCA-Salt Hypertensive Rats
We next examined the in vivo effects of celiprolol in DOCA-salt
hypertensive rats in which endothelial function has
been suggested to be impaired.12 To evaluate
endothelial function, the kidneys were isolated, and
the effects of acetylcholine (ACh) on RPP and NO release were examined.
Six-week-old male Wistar rats were uninephrectomized, and silicone
pellets containing deoxycorticosterone acetate (DOCA; 200 mg/kg) were
implanted subcutaneously under ether anesthesia. The rats
were then given normal saline (0.9%) for 4 weeks so that they
developed hypertension (DOCA-salt hypertensive rats). Systolic
blood pressure was measured by the tail-cuff method. DOCA-salt
hypertensive rats were intravenously given celiprolol (50
mg · kg-1 · d-1)
or vehicle for 4 weeks via an osmotic minipump (Alzet 2 ML4; Alza Co),
which was implanted together with the DOCA pellets. All animal studies
were performed in conformance with the university guidelines for animal
experiments.
Drugs and Chemicals
Bisoprolol, bopindolol, celiprolol, nebivolol, and E-4021 were
kindly donated by Tanabe Seiyaku Co, Novartis Pharma KK, Nippon
Shinyaku Co, Meiji Seika Co, and Eisai Co, respectively.
Statistical Analysis
All values are presented as the mean±SEM. Data were
analyzed with one-way ANOVA followed by the
Student-Newman-Keuls test. Differences with P<0.05 were
considered statistically significant.
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Results |
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Effects of ß-Blockers on RPP and NO in Isolated Kidney
We studied the effects of propranolol, bisoprolol, bopindolol, celiprolol, and nebivolol on RPP and NO release in the isolated perfused rat kidney. As shown in Figure 1
and 2,
celiprolol decreased RPP in a dose-dependent manner. This vasodilation
was associated with a significant increase in NO release. These effects
were also observed in the kidneys pretreated with
10-8.5 mol/L angiotensin II (data
not shown). Bopindolol and nebivolol also reduced RPP and increased NO
release in a dose-dependent manner (Figure 3). However, neither
propranolol nor bisoprolol had such vasodilatory effects in
the isolated kidney (propranolol
10-6 mol/L, -1±2%; bisoprolol
10-6 mol/L, -5±2%).
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P<0.01 vs normal rats (n=5 for each group).
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As shown in Figure 2
, pretreatment with
10-4 mol/L L-NAME markedly attenuated the
responses to the infusion of celiprolol. The vasodilation in response
to celiprolol, especially at the lower concentrations employed in this
study, was enhanced by pretreatment with 10-8
mol/L E-4021, but NO release induced by celiprolol and nebivolol was
unaltered by E-4021.
Effects of Adrenoceptor Antagonists and
5-Hydroxytryptamine Receptor Antagonists on
the Action of ß-Blockers in Isolated Kidney
It is possible that celiprolol may cause vasodilation through a
ß2- or an 2-agonistic
action. The vasodilation and NO release observed in response to the
lower concentrations of celiprolol were significantly reduced by
pretreatment with 10-6 mol/L
propranolol but not by pretreatment with
10-7 mol/L yohimbine, an
2-adrenoceptor antagonist (Figure 2). Yohimbine alone had no effects on RPP or NO release (data
not shown). We also studied the effects of 5-HT receptor
antagonists on the action of the 3 ß-blockers in the
isolated rat kidney. Pretreatment with 10-6
mol/L metergoline, a 5-HT1/2
antagonist, and with 10-6 mol/L
NAN-190, a 5-HT1A receptor
antagonist, almost completely inhibited the changes in RPP
and NO in response to celiprolol (Figures 1 and 2).
Similar suppressive effects of 5-HT antagonists on the RPP
reduction and NO release induced by bopindolol or nevibolol were
observed (Figure 3).
Effects of ß-Blockers on Rat Thoracic Aorta
To explore whether ß-blockers exert vasodilatory effects on
other vessels, we performed tension studies using the isolated rat
thoracic aorta. As shown in Figure 4, celiprolol and nebivolol caused vasorelaxation of the
endothelium-intact aorta in a dose-dependent manner.
Endothelial denudation significantly attenuated these
responses. Furthermore, in the presence of L-NAME
(10-4 mol/L) or NAN-190, vasorelaxation of the
endothelium-intact aorta by celiprolol or nebivolol was
markedly blunted.
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Effects of Adrenoceptor Agonists and a 5-HT1A Receptor
Agonist in Isolated Kidney
We also examined the effects of clonidine (an
2-agonist), dobutamine (a
ß1-agonist), salbutamol (a
ß2-agonist), and
(±)-8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT), a
selective 5-HT1A receptor agonist, on vascular
tone and NO release in the isolated perfused rat kidney. As shown in
Figure 5, clonidine caused NO release and
vasoconstriction in a dose-dependent manner (ie, it did not mimic the
effects of vasodilatory ß-blockers). Salbutamol caused vasorelaxation
dose-dependently, but the dilation was associated with a very small
increase of NO release. Dobutamine caused little changes in
RPP or NO release (data not shown). On the other hand, infusion of
8-OH-DPAT substantially reduced RPP and increased NO in a
dose-dependent manner.
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Effects of Celiprolol in DOCA-Salt Hypertensive Rats
Although several ß-blockers actually dilated renal vessels at
least in part via an NO-dependent mechanism, it remains to be
determined whether such an NO-releasing property protects the vascular
endothelium from various insults such as hypertension.
We therefore examined the in vivo effects of celiprolol in DOCA-salt
hypertensive rats. Four-week treatment with DOCA and saline
significantly elevated systolic blood pressure in
uninephrectomized rats (control, 124±3 mm Hg; DOCA-vehicle,
188±6 mm Hg; P<0.01). Intravenous
administration of celiprolol (50 mg ·
kg-1 · d-1) to
DOCA-salt hypertensive rats for 4 weeks slightly but significantly
lowered systolic blood pressure (164±6 mm Hg,
P<0.05 versus DOCA-vehicle). In the isolated perfused
kidney of DOCA-salt–treated rats, ACh-evoked vasorelaxation
(10-8 mol/L ACh, DOCA-salt -20±2% versus
control -37±4%, P<0.01) and NO release
(10-8 mol/L ACh, DOCA-salt +3±1 versus control
+16±2 fmol · min-1 · g
kidney-1, P<0.01) were markedly
attenuated compared with control rats. However, administration of
celiprolol to DOCA-salt rats significantly increased the responses to
ACh (10-8 mol/L ACh, RPP -41±2%, NO release
+19±2 fmol · min-1 · g
kidney-1, both P<0.01 versus
DOCA-salt rats treated with vehicle).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, bopindolol, celiprolol, and nebivolol caused vasodilation of the rat renal vasculature, which was associated with an increase of NO release in a dose-dependent manner. Pretreatment with L-NAME and E-4021 resulted in attenuation and potentiation of the vasodilatory effects of these ß-blockers, respectively, suggesting that the NO/cGMP pathway plays a role in renal vasorelaxation induced by these 3 ß-blockers. Moreover, we observed that in the rat aorta, the vasorelaxation induced by these ß-blockers was at least in part endothelium dependent.
It seemed unlikely that the 3 ß-blockers had directly activated endothelial NOS via ß-adrenoceptor antagonism itself because the tissues we used in the experiment were not innervated and no ß-adrenoceptor agonists were contained in the perfusate. We speculated at first that partial agonistic activity was involved in the mechanism or mechanisms by which these 3 ß-blockers activated endothelial NOS because celiprolol has been reported to stimulate ß2-adrenoceptors.2 It has been shown that the stimulation of ß1- and ß2-adrenoceptors activates endothelial NOS and that NO plays a role in the vasodilator effects of ß-adrenergic stimulants.15 16 17 On the other hand, some investigators have shown that the role of NO is of little importance in ß-adrenoceptor–mediated vasorelaxation.18 19
In the presence of 10-6 mol/L propranolol, which is a nonselective ß-blocker, the vasodilatory effects of celiprolol at the lower doses used in this study were significantly attenuated in the isolated rat kidney, suggesting that ISA is ascribable at least in part for the vasodilatory effects of celiprolol. Thus, we also investigated whether stimulation of ß-adrenoceptors caused NO release to explain the potent endothelial NOS-activating properties of the 3 vasodilating ß-blockers. Salbutamol augmented NO release significantly, but the extent was very small. The lack of effect of dobutamine on RPP and NO may have been due to the scarcity of ß1-receptors in the renal vasculature. Clonidine augmented NO release but caused vasoconstriction. Furthermore, 10-5 mol/L yohimbine did not affect the celiprolol-induced vasorelaxation and NO release. These findings suggest that partial agonistic actions of adrenergic receptors do not explain the endothelium-dependent vasorelaxant activity of these ß-blockers.
Although the effects of 5-HT on the cardiovascular system are complex, stimulation of 5-HT1 receptors is thought to cause endothelium-dependent relaxation, most likely via NO release.20 It is well established that 5-HT receptors, especially 5-HT1A receptors, can bind certain ß-blockers, such as propranolol and pindolol, with high affinity.21 Propranolol has shown to bind stereoselectively to 5-HT1 sites and exert an antagonizing action.21 Therefore, the blocking effects of propranolol on the celiprolol-induced changes in RPP and NO may be due to another property of propranolol: the blockade of 5-HT1 receptors. As for the effects of metergoline, a 5-HT1/2 antagonist, and NAN-190, a 5-HT1A antagonist, on the effects of the 3 ß-blockers on the renal vasculature, metergoline and NAN-190 almost completely abolished vasodilation and NO release induced by celiprolol, bopindolol, and nebivolol. Verbeuren et al9 have shown that vasorelaxation caused by tertatolol in the isolated perfused rat kidney was markedly attenuated by BMY 7378, a 5-HT1A receptor antagonist. Furthermore, 8-OH-DPAT, a 5-HT1A agonist, increased vasodilation and NO release in a dose-dependent manner, confirming that several vasodilatory ß-blockers exert their vascular action through the 5-HT1A receptor/NO pathway. Such pharmacological cross-reactivity between ß-adrenoceptors and 5-HT receptors suggests a structural similarity of the ligand-binding site between the 2 kinds of receptors. The gene for the human 5-HT1A receptor was first cloned by low stringency Southern blots using the ß2-adrenoceptor gene as a probe.22 It has also been demonstrated that a mutation of asparagine 385 in the seventh transmembrane domain of the human 5-HT1A receptor decreased its affinity for pindolol and that asparagine 385 may be a critical site for the cross-reactivity.23
Moreover, the present study has shown that celiprolol exerts beneficial effects in rats with endothelial dysfunction in the early phase of hypertension. Consistent with our results, long-term treatment with celiprolol, even at its subdepressor dose (5 mg · kg-1 · d-1 PO), has been reported to restore endothelial dysfunction of mesenteric arteries of spontaneously hypertensive rats,24 suggesting that the beneficial effects of celiprolol in hypertension are not only due to reduction in blood pressure. Therefore, stimulation of NO release caused by celiprolol may be a mechanism underlying its vascular action.
In conclusion, several kinds of ß-blockers are potent stimulators of endothelial NOS and exert this effect via 5-HT1A receptors. This property may contribute to protect the endothelium from hypertension.
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Acknowledgments |
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This study was supported in part by Grants-in-Aid 07557055 and 09281206 from the Ministry of Education, Culture and Science of Japan.
Received September 15, 1998; first decision October 14, 1998; accepted October 28, 1998.
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