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(Hypertension. 1999;34:222-228.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Impaired Isoproterenol-Induced Hyperpolarization in Isolated Mesenteric Arteries of Aged Rats
From the Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Correspondence to Koji Fujii, MD, PhD, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. E-mail fujii{at}intmed2.med.kyushu-u.ac.jp
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Abstract |
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Abstract—Stimulation of vascular ß-adrenoceptors leads to membrane hyperpolarization, presumably via the ß-adrenoceptor/Gs protein/adenylate cyclase signaling cascade; the ionic mechanisms of this phenomenon remain unclear. ß-Adrenoceptor–mediated vascular relaxation is impaired with aging; however, little is known concerning whether ß-adrenoceptor–mediated hyperpolarization is altered with aging. We sought to determine the ionic mechanisms of isoproterenol-induced hyperpolarization in the rat mesenteric resistance artery, as well as the age-related changes in isoproterenol-induced hyperpolarization and their underlying mechanisms. Isoproterenol-induced hyperpolarization was inhibited by high-K+ solution and glibenclamide (10-6 mol/L), an inhibitor of ATP-sensitive K+ channels (KATP), but not by apamin, iberiotoxin, or charybdotoxin, inhibitors of Ca2+-activated K+ channels. Isoproterenol-induced hyperpolarization was markedly less in aged rats (
24 months) than in adults rats (12 to 20
weeks) (3x10-6 mol/L; -3.1 versus -9.9 mV;
P<0.001; n=8 to 9). Cholera toxin (10-9
g/mL), an activator of Gs, evoked
hyperpolarization only in adult rats.
Hyperpolarization to forskolin, a direct
activator of adenylate cyclase, was also
reduced to some extent in aged rats (10-5 mol/L; -8.8
versus -13 mV; P<0.05; n=6), whereas
hyperpolarization to levcromakalim, a
KATP opener, was comparable in both groups. These findings
suggest that isoproterenol elicits
hyperpolarization via an opening of
KATP in the rat resistance artery and that
isoproterenol-induced hyperpolarization is
attenuated in aged rats mainly because of a defective coupling of
ß-adrenoceptors to adenylate cyclase and partly because
of a defect at the level of adenylate cyclase, but not
because of an alteration of KATP per se.
Key Words: receptors, adrenergic, beta • hyperpolarization • potassium channels • aging • muscle, smooth, vascular
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Introduction |
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Stimulation of ß-adrenoceptors leads to vascular relaxation, which involves the following signaling cascade: ß-adrenoceptor/stimulatory guanine nucleotide regulatory protein (Gs protein)/adenylate cyclase/cAMP.1 2 3 4 In addition, ß-agonists, eg, isoproterenol or norepinephrine, induce membrane hyperpolarization in various smooth muscle cells,5 6 7 8 and such hyperpolarization has been demonstrated to play an important role in the regulation of membrane potential of smooth muscle cells.6 9 Several recent studies suggest possible involvement of K+ channels in this hyperpolarization10 11 12 ; however, controversy exists regarding the type of K+ channels involved.10 11 12
ß-Adrenoceptor–mediated vasodilatation is impaired with aging in both humans13 14 and animals.15 16 17 18 19 Several mechanisms have been proposed to account for this impairment, such as defective Gs protein18 20 and abnormality of cAMP-dependent protein kinase A (PKA).15 17 On the other hand, little is known about whether ß-adrenoceptor–mediated hyperpolarization alters with aging.
The first goal of this study was to determine ionic mechanisms of isoproterenol-induced hyperpolarization in the rat mesenteric resistance artery, and the second goal was to evaluate age-related changes in isoproterenol-induced hyperpolarization and their underlying mechanisms.
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Methods |
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Preparation of Arteries
Twelve- to 20-week-old and 24- to 26-month-old male Wistar-Kyoto rats were used in the present study. The rats were originally purchased from Charles River Co, Ltd (Atsugi, Japan) and maintained at the animal center of Kyushu University. They had free access to tap water and were fed a normal rat chow. The study protocol was approved by the Animal Experimentation Ethics Committee of Kyushu University. Systolic blood pressure was measured by the tail-cuff method. Rats were anesthetized with ether and exsanguinated. The mesenteric vascular bed was excised and placed on a plate containing cold Krebs' solution. The third or fourth branches of the arteries (external diameter, 100 to 150 µm) were cut and cleaned of adherent connective tissue. In some preparations, the endothelium was removed by rubbing the intimal surface with small rugged pins. The absence of the endothelium was verified by the lack of hyperpolarization to acetylcholine.21
Recording of Membrane Potentials
The arteries were placed in an experimental chamber (capacity, 2
mL). Tissues were carefully pinned to a rubber bed fixed at the bottom
of the chamber and were superfused with Krebs' solution (36°C)
bubbled with 95% O2 and 5%
CO2 (pH 7.3 to 7.4) at a rate of 3 mL/min. The
arteries were allowed to equilibrate for 60 minutes before
recordings were started. Membrane potentials were recorded
with glass capillary microelectrodes filled with 3 mol/L KCl and with
tip resistances of 50 to 80 M
and tip potentials of <4
mV.21 22 Microelectrodes were impaled into the smooth
muscle cell from the adventitial side. Criteria for successful
impalement were an abrupt drop in voltage on entry of the
microelectrode into the cell, a stable membrane potential for 2
minutes, and a sharp return of the membrane potential to zero on
withdrawal of the electrode. Electric responses were monitored on
an oscilloscope (VC-11, Nihon Kohden Co Ltd) and recorded with a
pen writing recorder (RJG-4002, Nihon Kohden Co Ltd).
Solutions and Drugs
The ionic composition of Krebs' solution was as follows
(mmol/L): Na+ 137.4, K+
5.9, Mg2+ 1.2, Ca2+ 2.5,
HCO3- 15.5,
H2PO4-
1.2, Cl- 134, and glucose 11.5. Drugs used were
(-)-isoproterenol hydrochloride, forskolin, glibenclamide,
acetylcholine chloride, dibutyryl cAMP, propranolol
hydrochloride, phentolamine hydrochloride, butoxamine
hydrochloride, metoprolol, tetrabutylammonium chloride (TBA) (Sigma
Chemical Co), levcromakalim (kindly provided by Smith-Kline Beecham
Pharmaceuticals, Harlow, UK), H-89
(N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide
2HCl) (Biomol), apamin, iberiotoxin, and charybdotoxin (Peptide
Institute). Levcromakalim was dissolved in ethanol. Forskolin,
glibenclamide, dibutyryl cAMP, and H-89 were dissolved in dimethyl
sulfoxide. Other drugs used were dissolved in distilled water. All
drugs were further diluted 1000 times in Krebs' solution to produce
final bath concentrations. The solvents used to dissolve drugs did not
affect membrane potentials in their final bath concentrations.
Statistical Analysis
Data are given as mean±SEM. The number of animals is indicated
by n. The average value of membrane potentials obtained from multiple
impalements was calculated for each animal. These values were then used
for statistical comparison of the membrane potential between the
groups. Statistical analysis was performed by 2-way ANOVA,
followed by Scheffé's test for multiple comparison or by
unpaired Student's t test. Probability values <0.05 were
considered statistically significant.
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Results |
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Body weight was significantly greater in aged (n=17) than in adult (n=37) rats (366.5±18.4 versus 282.8±4.7 g; P<0.001). Systolic blood pressure was also significantly higher in aged than in adult rats (157.9±4.3 versus 143.9±3.0 mm Hg; P<0.05).
Resting membrane potential of the mesenteric resistance arteries was -62.1±0.8 mV (n=37) for adult rats and -61.4±1.6 mV (n=17) for aged rats and did not differ between the 2 groups.
Isoproterenol, a relatively selective ß-agonist, produced hyperpolarization in mesenteric arteries (Figures 1 to 3), which was subsequently abolished by propranolol (10-6 mol/L) (data not shown). Some characteristics of this hyperpolarization were investigated in arteries from adult rats. Isoproterenol-induced hyperpolarization was slightly but significantly inhibited by butoxamine, a relatively selective ß2-adrenoceptor antagonist,23 24 and was markedly inhibited by metoprolol, a selective ß1-adrenoceptor antagonist25 (Figure 1). The combined application of these 2 agents nearly abolished isoproterenol-induced hyperpolarization (Figure 1). Isoproterenol-induced hyperpolarization was still observed in endothelium-rubbed preparations (3x10-6 mol/L; -8.3±0.3 mV; n=4), suggesting that isoproterenol acts directly on smooth muscle cells to elicit hyperpolarization. High-K+ solution (20 mmol/L) and TBA (1 mmol/L), a nonspecific blocker of K+ channels,26 markedly inhibited isoproterenol-induced hyperpolarization (Figure 2). Glibenclamide, an inhibitor of ATP-sensitive K+ channels (KATP),27 also inhibited isoproterenol-induced hyperpolarization (Figure 2). Glibenclamide, at doses of 10-6 and 10-5 mol/L, depolarized the membrane by 3.6±1.7 mV (n=7) and 5.1±1.6 mV (n=6), respectively. Hyperpolarization to forskolin (10-5 mol/L), a direct activator of adenylate cyclase,28 was also inhibited by glibenclamide (-10.8±0.9 and -3.4±0.9 mV in the absence and presence of 10-5 mol/L glibenclamide; n=5; P<0.05). Cholera toxin (10-6 g/mL), a direct activator of Gs, also produced hyperpolarization, which was sensitive to glibenclamide (10-5 mol/L) (-2.8±0.7 and -0.3±0.2 mV in the absence and presence of 10-5 mol/L glibenclamide; n=10 and n=5, respectively; P<0.05). On the other hand, at a concentration of 10-5 mol/L, glibenclamide did not affect hyperpolarization to acetylcholine (10-6 mol/L) (-13.3±1.8 and -12.8±1.6 mV in the absence and presence of 10-5 mol/L glibenclamide; n=5). Apamin (10-6 mol/L),29 iberiotoxin (3x10-8 mol/L),30 and charybdotoxin (10-7 mol/L),31 inhibitors of small-, large-, and intermediate- and large-conductance Ca2+-activated K+ channels, respectively, had no effect on isoproterenol-induced hyperpolarization (Figure 2).
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Isoproterenol (10-6 mol/L)–induced hyperpolarization was markedly inhibited by H-89 (10-5 mol/L), an inhibitor of PKA32 (-9.9±0.3 and -2.7±0.5 mV in the absence and presence of H-89; n=5; P<0.001). In addition, dibutyryl cAMP (10-3 mol/L), a cell-permeable analogue of cAMP,33 produced hyperpolarization by -6.4±1.2 mV (n=5), which was reversed by application of glibenclamide (10-5 mol/L).
Isoproterenol-induced hyperpolarization was markedly less in aged rats than in adult rats (Figure 3). Pretreatment with phentolamine did not affect the hyperpolarization to isoproterenol in aged rats (isoproterenol 3x10-6 mol/L; -1.5±0.3 and -1.3±0.3 mV before and after treatment with 10-6 mol/L phentolamine; n=4; P=NS). Forskolin-induced hyperpolarization also tended to be smaller in aged rats than in adult rats at a concentration of 10-7 mol/L, and the difference was statistically significant at concentrations of 10-5 and 10-4 mol/L (Figure 4). Hyperpolarization to levcromakalim, a direct activator of KATP,34 was comparable between adult and aged rats (Figure 5).
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Hyperpolarization to cholera toxin (10-6 g/mL), a direct activator of Gs, was virtually absent in aged rats (0.7±0.4 mV; n=11) and was significantly smaller in aged rats than in adult rats (-2.8±0.7 mV; n=10) (P=0.01, aged versus adult rats).
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Discussion |
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The present study demonstrated that (1) isoproterenol-induced hyperpolarization in the rat mesenteric resistance artery was inhibited by glibenclamide; (2) isoproterenol-induced hyperpolarization was markedly impaired in aged rats; (3) forskolin-induced hyperpolarization also tended to be reduced in aged rats; and (4) levcromakalim-induced hyperpolarization was comparable between adult and aged rats. These findings suggest that isoproterenol-induced hyperpolarization is mediated by an opening of KATP in the rat mesenteric artery and is attenuated in aged rats mainly because of a defective coupling of ß-adrenoceptor to adenylate cyclase and partly because of an abnormality at the level of adenylate cyclase, but not because of an alteration of KATP per se.
Ionic Mechanisms of Isoproterenol-Induced
Hyperpolarization
The ionic mechanisms underlying smooth muscle
hyperpolarization after ß-adrenoceptor
stimulation have not been fully elucidated. Possible mechanisms include
an increase in K+
conductance7 35 36 37 and stimulation of the electrogenic
Na-K pump.1 Recently, with the use of a patch clamp
technique, Miyoshi et al11 demonstrated that the catalytic
subunit of PKA activated KATP in cultured
porcine coronary smooth muscle cells, whereas Sadoshima et
al10 showed that cAMP and PKA activated
Ca2+-activated K+
channels in cultured rat aortic smooth muscle cells. With a
conventional microelectrode technique, Nakashima and
Vanhoutte12 showed that isoproterenol induced
hyperpolarization through an opening of
KATP in the canine saphenous vein.
In the present study, isoproterenol-induced hyperpolarization was abolished by high-K+ solution and was markedly inhibited by TBA, a nonspecific blocker of K+ channels,26 suggesting that the hyperpolarization was due mostly to an opening of K+ channels. Furthermore, isoproterenol-induced hyperpolarization was nearly abolished by glibenclamide, a selective inhibitor of KATP,27 but not by apamin,29 iberiotoxin,30 or charybdotoxin,31 inhibitors of small-, large-, and intermediate- and large-conductance Ca2+-activated K+ channels, respectively. Nonspecific inhibition of hyperpolarization by glibenclamide seems unlikely because this agent did not inhibit acetylcholine-induced hyperpolarization. These findings suggest that isoproterenol induces hyperpolarization through the opening of KATP in the rat mesenteric artery. In addition, isoproterenol-induced hyperpolarization was mimicked by forskolin, a direct activator of adenylate cyclase,28 ie, forskolin hyperpolarized the membrane, and this hyperpolarization was inhibited by glibenclamide. Cholera toxin, a direct activator of Gs protein, also elicited membrane hyperpolarization in adult rats, which was sensitive to glibenclamide. It thus appears that isoproterenol-induced hyperpolarization in the rat mesenteric resistance artery is achieved primarily through the following signaling cascade: ß-adrenoceptor/Gs protein/adenylate cyclase/KATP. It remains to be determined whether cAMP/PKA is involved in the activation of KATP.11 12 38 39 However, our present findings that dibutyryl cAMP, a cell-permeable analogue of cAMP,33 induced glibenclamide-sensitive hyperpolarization and that isoproterenol-induced hyperpolarization was inhibited by PKA inhibitor H-8932 favor the possibility that the cAMP/PKA cascade is involved in isoproterenol-induced hyperpolarization.
The predominant ß-adrenoceptor subtype that mediates isoproterenol-induced hyperpolarization in the rat mesenteric artery might belong to a ß1 subtype rather than a ß2 subtype because metoprolol, a selective antagonist of ß1-adrenoceptor,25 appeared to inhibit isoproterenol-induced hyperpolarization to a greater extent than butoxamine, a relatively selective ß2 antagonist.23 24 This finding is in agreement with that found in the canine large coronary artery, in which ß1-adrenoceptor played a predominant role in vasodilatation,40 but differs from that found in the canine saphenous vein, in which ß2-adrenoceptor is mainly involved in isoproterenol-induced hyperpolarization.12 Further studies are necessary to fully characterize the receptor subtype involved in ß-adrenergic hyperpolarization.
Impaired Isoproterenol-Induced
Hyperpolarization in Aged Rats
Although several studies have shown that relaxation to
isoproterenol is impaired in isolated blood vessels from aged
animals,15 16 17 18 19 this study is the first to demonstrate that
isoproterenol-induced hyperpolarization is
decreased in arteries from aged rats. Stekiel et al9
demonstrated that in situ hyperpolarization
produced by isoproterenol in cremaster muscle arterioles was markedly
reduced in hypertensive, reduced renal mass rats compared with
normotensive control rats. It appears, therefore, that
isoproterenol-induced hyperpolarization diminishes
with aging as well as in hypertension. This parallels the case of
endothelium-dependent
hyperpolarization, which is also decreased with
aging and in hypertension.21 41 In the present study,
blood pressure was slightly but significantly higher in aged rats than
in adult rats. Thus, the possible effect of high blood pressure on
ß-receptor–mediated hyperpolarization needs to
be considered.9 However, isoproterenol-induced
hyperpolarization was generally reduced in all the
aged rats regardless of individual blood pressure, implying that the
impairment in aged rats could not be ascribed to high blood pressure.
Furthermore, it cannot be generalized from this study alone whether the
loss of ß-adrenoceptor–mediated
hyperpolarization contributed to the elevation of
blood pressure in aged rats.
ß-Adrenoceptors are also present at presynaptic nerve terminals
to facilitate the release of adrenergic
neurotransmitters.42 If the facilitatory action of
isoproterenol on transmitter release is enhanced, the excess
catecholamines released might depolarize the membrane by
acting on postsynaptic 
-adrenoceptors, thereby counteracting
isoproterenol-induced hyperpolarization. However,
such a mechanism is unlikely to explain the present findings,
because isoproterenol-induced hyperpolarization in
aged rats was still impaired under the blockade of -adrenoceptors
with phentolamine. On the same grounds, it is unlikely that
direct stimulation of -adrenoceptors by isoproterenol offset
ß-adrenoceptor–mediated hyperpolarization in
aged rats. Thus, the ability of isoproterenol to produce
hyperpolarization per se may be impaired with
aging.
Mechanisms Underlying Impaired Isoproterenol-Induced
Hyperpolarization in Aged Rats
As mentioned previously, isoproterenol-induced
hyperpolarization may be achieved through the
ß-adrenoceptor/Gs protein/adenylate
cyclase/KATP signaling cascade. In the
present study, the age-related impairment of the maximal
hyperpolarization to isoproterenol appeared to be
more marked than that to forskolin, implying that the major defect
responsible for the impaired ß-adrenergic
hyperpolarization may lie at the level of the
ß-adrenoceptor/Gs protein/adenylate
cyclase coupling step, and the abnormality of adenylate
cyclase may also partially account for the impairment. The lack of
hyperpolarization to chorea toxin in aged rats
might suggest the defective Gs protein.
The aforementioned assumption may be consistent with some of the previous studies in ß-adrenoceptor–mediated relaxations in aged animals. Kazanietz and Enero18 reported that relaxation to isoproterenol, but not to forskolin, was reduced in the aorta of aged rats. In their study, increases in cAMP in response to both isoproterenol and cholera toxin were also reduced in aged rats. On the other hand, Tsujimoto et al15 demonstrated that the sensitivity, but not the maximal response, to forskolin was reduced along with a marked reduction in the maximal relaxation to isoproterenol in the mesenteric artery of aged rats. They also showed the reduced relaxation response to dibutyryl cAMP in vessels from aged rats. Thus, previous studies appear to agree that the coupling step of ß-adrenoceptors to adenylate cyclase is defective in aged animals but differ as to whether adenylate cyclase (and/or a more distal step) is altered.
The present study agrees with that of Tsujimoto et al15 in that the response to forskolin was also altered with aging, but it differs in that the maximal hyperpolarization to forskolin was impaired in this study, whereas only the relaxation sensitivity to forskolin was reduced in their study. The present data alone are not sufficient to evaluate sensitivity to forskolin, and it thus remains to be further determined whether there may also be an age-related alteration in the sensitivity to forskolin regarding hyperpolarization. Differences between this study and previous studies may arise from differences in the vascular bed studied, vessel size, or the type of response examined, ie, hyperpolarization or relaxation. Characteristics of KATP itself, likely a final step of ß-adrenergic hyperpolarization, may not be altered with aging, because hyperpolarization to the direct KATP opener levcromakalim was comparable between adult and aged rats in the present study.
In a previous study on the rat mesenteric artery, the number of ß-adrenoceptors in 5- to 6-week-old rats was the same as in 10- to 12-month-old rats, despite a difference in isoproterenol-induced relaxation between the 2 groups.15 Likewise, in humans the ß-adrenoceptor density in lymphocytes was comparable between young and aged subjects.20 43 These findings might imply that an alteration in ß-adrenoceptor density may not be the major cause of impaired isoproterenol-induced responses in aged rats. Nevertheless, because the present study did not measure ß-adrenoceptor density, the possible alteration in ß-adrenoceptor density in aged rat arteries remains to be determined.
Pathophysiological Implications
ß-Adrenoceptor–mediated hyperpolarization
has been suggested to play an important role in the control of membrane
potential by opposing -adrenoceptor–mediated
depolarization.6 9 In addition, several studies have
demonstrated that the activation of KATP
contributes to the relaxation elicited by
ß-agonists.44 45 46 47 48 It is thus conceivable that an
impairment of ß-adrenoceptor–mediated
hyperpolarization might be detrimental to the
maintenance of peripheral circulation.
In conclusion, isoproterenol-induced hyperpolarization appears to be mediated by KATP in rat mesenteric resistance arteries and is shown to be attenuated in aged rats mostly because of a defective coupling of ß-adrenoceptor to adenylate cyclase and partly because of a defect at the level of adenylate cyclase, but not because of an alteration of KATP per se.
Received August 17, 1998; first decision September 8, 1998; accepted March 26, 1999.
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