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1 Departments of Medical Physics and 2 Pharmacotherapy, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands; and 3 Department of Physiology and Pharmacology, University of Southern Denmark-Odense University, DK-5000 Odense, Denmark
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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T-type calcium channels may be
involved in the maintenance of myogenic tone. We tested their role in
isolated rat cremaster arterioles obtained after CO2
anesthesia and decapitation. Total RNA was analyzed by RT-PCR and
Southern blotting for calcium channel expression. We observed
expression of voltage-operated calcium (CaV) channels
CaV3.1 (T-type), CaV3.2 (T-type), and
CaV1.2 (L-type) in cremaster arterioles (n = 3 rats). Amplification products were observed only in the presence of
reverse transcriptase and cDNA. Concentration-response curves of the
relatively specific L-type blocker verapamil and the relatively
specific T-type blockers mibefradil and nickel were made on cannulated
vessels with either myogenic tone (75 mmHg) or a similar level of
constriction induced by 30 mM K+ at 35 mmHg. Mibefradil and
nickel were, respectively, 162-fold and 300-fold more potent in
inhibiting myogenic tone compared with K+-induced
constriction [log(IC50, M): mibefradil, basal 
7.3 ± 0.2 (n = 9) and K+ 5.1 ± 0.1 (n = 5); nickel, basal 4.1 ± 0.2 (n = 5) and K+ 1.6 ± 0.5 (n = 5); means ± SE]. Verapamil had a 17-fold
more potent effect [log(IC50, M): basal 6.6 ± 0.1 (n = 5); K+ 5.4 ± 0.3 (n = 4); all log(IC50) P < 0.05, basal vs. K+]. These data suggest that T-type
calcium channels are expressed and involved in maintenance of myogenic
tone in rat cremaster muscle arterioles.
arteriole; CaV3.1; CaV3.2; mibefradil; nickel
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IN RESPONSE TO PRESSURE, arterioles and small resistance arteries generally develop vasoconstriction in the absence of any extrinsic agonists. This myogenic tone becomes more dominant in smaller vessels (4) and is thought to play a key role in the local control of tissue perfusion. The mechanisms responsible for myogenic tone have been the subject of ongoing studies. It is now well established that myogenic tone is independent of the endothelium in most vascular beds examined (17), even though endothelial products are the primary modulators of myogenic tone. This tone is associated with a rather modest but necessary smooth muscle cell (SMC) depolarization (28) and rise of intracellular calcium (25, 31) in combination with a pressure-induced increase in calcium sensitivity of the contractile filaments (25).
Pharmacological evidence indicates that L-type voltage-operated
calcium (CaV) channels are significantly involved in
pressure-induced calcium influx and tone in several resistance vessels
(5, 27). However, steady-state open probability of these
channels is quite low at membrane potentials frequently found under
basal conditions [60 to 40 mV at physiological pressures (5,
24)]. The activation range of the smooth muscle L-type channel
CaV1.2 may be shifted by regulation (11), and
only a small calcium influx might be needed to maintain an elevated
intracellular concentration (19). Alternatively,
low-voltage-activated T-type calcium channels may be involved in the
calcium influx associated with myogenic tone. These channels activate
at more negative potentials and may only partially inactivate at
membrane potentials associated with myogenic tone. Two recent studies
have indeed shown that mibefradil, a T-type channel antagonist,
inhibits myogenic tone in rat cerebral and cremaster vessels at
concentrations (IC50 70 and 220 nM) that have been claimed
to be specific for T-type over L-type calcium channels (15,
22).
Expression of recently cloned calcium channels in heterologous cell
systems has established the existence of three pore-forming channel
subunits with T-type current characteristics (activation at low
voltages and rapid inactivation, sensitivity to mibefradil and nickel): CaV3.1, CaV3.2, and
CaV3.3 (previously known as 
1G, 1H, and 1I) (6, 20). mRNA
for CaV3.1 and CaV3.2 and functional involvement in contraction have now been demonstrated in renal afferent
and juxtamedullary efferent arterioles (10). mRNA for T-type calcium channels was also found in rat mesenteric arterioles of
~30 µm in diameter (8), whereas the L-type channel
CaV1.2 was absent, and these arterioles also did not
constrict to high potassium.
The above information supports a widespread distribution of T-type channel expression in vascular resistance segments and a role for T-type calcium channels in arteriolar function. The purpose of this paper was to investigate T-type channel expression in skeletal muscle resistance vessels and to further explore whether T-type channels are involved in the maintenance of myogenic tone. To address these issues, rat cremaster muscle arterioles were cannulated in vitro, and the sensitivity of myogenic tone to pharmacological antagonists of L- and T-type channels was elucidated. Sensitivity to antagonists was compared in two situations with different membrane potentials: at physiological perfusion pressure and at a low perfusion pressure where the same level of tone was achieved by the addition of potassium to depolarize the membrane potential.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Isolation of resistance arteries. Male Wistar rats weighing 250-300 g were briefly anesthetized by CO2 gas and decapitated. The left and right cremaster muscles were carefully isolated, suspended in buffer [containing (in mmol/l) 130 NaCl, 5 KCl, 2 CaCl2, 10 D-glucose, 20 sucrose, and 10 HEPES; pH 7.4] and mounted in dissection chambers for isolation of vessels at 4°C. For molecular biology, first- and second-order vessel segments with a total length of ~1 cm were isolated from each cremaster. For pharmacology on cannulated vessels, unbranched segments of first-order arterioles were isolated of ~3 mm in length.
RNA isolation, RT-PCR, and Southern blotting. First- and second-order arterioles were cut in ~400-µm pieces and directly added to guanidinium-thiocyanate (4 mol/l) as previously described (1, 2). For homogenization, the fragments were repeatedly triturated through syringes with decreasing dimensions ending with 25 gauge. Yeast tRNA (12 µg) was added as a carrier. Total RNA was extracted by phenol-chloroform extraction, precipitated with isopropanol, and repeatedly washed with 70% ethanol (2). RNA pellets were suspended in diethyl pyrocarbonate-treated water and used for cDNA synthesis as previously described in detail (1). RNA corresponding to 1 mm of vessel length was used for cDNA synthesis.
PCRs were performed with 18-mer DNA oligonucleotides (Invitrogen) for rat T- and L-type CaV channels and
-actin as previously described (10). PCR was performed for 32 cycles
(Mastercycler, Eppendorf). For a negative control, reverse
transcription of total RNA was performed in the absence of reverse
transcriptase and then amplified by PCR, and, in separate tubes, water
was added instead of cDNA in PCR. For southern blotting, PCR products
were separated by agarose gel electrophoresis and blotted to Zeta Probe GT membranes (Bio-Rad) using standard capillary blotting procedures as
previously described (1). Hybridization was allowed
overnight to a specific probe in vitro labeled with
[-32P]-dCTP; all procedures were according to Sambrook
et al. (23). Autoradiography was performed for 2-4 h
on Kodak Biomax MS film.
Pharmacological studies.
Isolated cremaster muscle arterioles were cannulated on two glass
micropipettes using previously reported techniques (25). Vessels were pressurized to 75 mmHg at 34°C, the in vivo temperature of the cremaster muscle, and allowed to develop myogenic tone. Cumulative concentration-response curves were then made for the effect
of one of three calcium channel blockers on tone: verapamil, an L-type
calcium channel blocker, the analog mibefradil, which is relatively
selective for T-type channels, and nickel, which also relatively
selectively blocks T-type channels. Only one blocker was used for each
vessel. In separate experiments, the effect of these blockers was
tested on vessels kept at 35 mmHg, resulting in a lack of myogenic
tone, after the induction of preconstriction by 30 mM K+.
On the basis of the potassium equilibrium potential, this concentration was estimated to result in a depolarization to at least 35 mV, where
T-type but not L-type channels are inactivated.
Data analysis and statistics. IC50 values were determined for each individual concentration-response curve using nonlinear curve fitting with variable Hill slope (GraphPad) and subsequently averaged over the group. Unpaired t-tests were used for the comparison of the log(IC50) values on myogenic tone and potassium-induced constriction. P < 0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Expression of 1-units of calcium channels.
RNA was extracted from cremaster muscle arterioles of three rats and
analyzed along with RNA obtained from an aortic cell line (A7r5) and
the rat cerebral cortex, which served as a positive control. As can be
seen in Fig. 1A, amplification
products for T-type channels CaV3.1 and CaV3.2
were detected in all three cremaster vessel preparations by RT-PCR
amplification for 32 cycles. Southern blotting and hybridization
further corroborated the identity of the amplification products as
being CaV3.1 and CaV3.2 cDNAs (Fig. 1B). In contrast, L-type channel CaV1.2 mRNA was
not found in one of the cremaster vessels and was at the limit of
detection by ethidium bromide staining in both other preparations.
However, the increased sensitivity provided by the Southern blot
assured expression and identity of CaV1.2 in these
preparations (Fig. 1B). Expression of all three subunit
mRNAs was also detected in the rat aortic SMC line A7r5 and in RNA
samples isolated from the rat cerebral cortex using 50 ng total RNA as
template for RT-PCR. Amplification products were only obtained in the
presence of reverse transcriptase and cDNA in the RT-PCR, confirming
the mRNA origin of the amplification products. Reverse transcription of
carrier yeast tRNA followed by PCR for each subunit did also not result
in detectable amplification products (Fig. 1, tRNA lane).
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Pharmacological studies.
Nineteen vessels were studied in the myogenic tone group, having an
average passive inner diameter of 145 ± 3 µm at 75 mmHg. When
maintained at this pressure, the vessels developed myogenic tone,
resulting in a reduction of the normalized inner diameter to 0.57 ± 0.03 (mean ± SE, n = 19). Myogenic tone was
sensitive to verapamil, mibefradil, and nickel; concentration-response
curves are indicated in Figs.
2-4.
Log(IC50) values are indicated in Table 1. Fourteen slightly smaller vessels
(passive inner diameter at 75 mmHg: 134 ± 3 µm,
P < 0.05) were kept at 35 mmHg. The vessels remained
passive at this diameter, probably due to myogenic inhibition of tone.
A stable level of preconstriction was induced by 30 mM K+,
resulting in a reduction of the normalized diameter to the same level
as in the previous series: 0.54 ± 0.03 (P = not
significant, basal versus K+). All three calcium channel
blockers were able to inhibit the potassium-induced tone, as indicated
by the concentration-response curves in Figs. 2-4 and the
IC50 values in Table 1. A comparison of the inhibition of
basal versus potassium-induced tone shows marked differences: both
mibefradil and nickel were very potent inhibitors of basal but not of
potassium-induced tone. Thus a 162-fold difference in IC50
was found for mibefradil, whereas the IC50 for nickel was
300-fold lower on myogenic tone compared with potassium-induced
constriction. Verapamil, an L-type calcium channel blocker, 17-fold
more potently blocked myogenic tone compared with potassium-induced
tone (see Table 1).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study shows that T-type calcium channel subunits CaV3.1 and CaV3.2 are expressed in rat cremaster muscle arterioles and that mibefradil and nickel were far more potent inhibitors of myogenic tone compared with potassium-induced tone. While we appreciate that both blockers may also affect L-type calcium channels, the two decades higher potency on myogenic tone compared with potassium-induced constriction suggests specific actions in the current study. Together, these data point at a role for T-type calcium channels in the development and maintenance of myogenic tone.
Care should be taken in relating the expression of CaV3.1
and CaV3.2 at the messenger level to their possible role in
cell function, because the applied RT-PCR was not quantitative and because messenger and protein levels may well diverge. Also, the RT-PCR
was performed on the whole vascular wall. While there is no evidence
for expression of voltage-dependent calcium channels in endothelial
cells, and while it seems highly unlikely that the perivascular nerve
endings contain any mRNA, we cannot fully exclude the possibility that
part of the messenger signal we found for the T-type channels
originated from other cells than SMCs. Immunohistochemical evidence
could further substantiate expression and localization of these
channels, but this awaits the further development of antibodies. We
attempted to obtain electrophysiological evidence for these channels in
SMCs isolated from cremaster arterioles. However, in our hands, the
digestion protocols, which included papain, resulted in cells that had
neither L- nor T-type currents and also did not contract to high
potassium concentrations. The single study we are aware of that did
successfully measure calcium currents in these specific cells
(29) was not aimed at discriminating between both
channels. In that study, using holding potentials of 80 mV, no clear
calcium or barium currents were observed below 50 and 20 mV,
respectively, arguing against functional involvement of T-type channels
under those conditions. Further patch-clamp experiments will be
required here. However, T-type calcium currents have been demonstrated
in vascular smooth muscle cells of other sources (7, 21).
In our study, nickel blocked myogenic tone with a threshold concentration of ~10 µM and an IC50 of 0.1 mM. These values are very similar to the threshold and IC50 reported for inhibition of peak current in expressed CaV3.1 channels, whereas CaV3.2 channels had a higher sensitivity for nickel (16). Nickel also blocks expressed CaV1.2 currents, but at a much higher concentration [<100 µM (30)]. Thus our data indicate that specifically CaV3.1 could be involved in the maintenance of myogenic tone, in accordance with the observed expression of this channel. The role of CaV3.2, which we also found to be expressed, remains to be elucidated.
Mibefradil has been put forward (3, 18) and challenged
(22) as a relatively selective T-type calcium channel
blocker. Mibefradil inhibited Ba2+ current through
expressed CaV3.1 at a holding potential of 60 mV with an
IC50 at 0.12 µM (12), whereas the effects
using calcium as the charge carrier were similar (14). Two
recent studies addressed the effects of mibefradil on myogenic tone.
Lam et al. (15) found mibefradil to inhibit myogenic tone
at 60 mmHg with an IC50 of 70 nM in rat middle cerebral
arteries. Potocnik et al. (22) studied the effects of
mibefradil on rat cremaster arterioles and observed inhibition of
myogenic tone at 70 mmHg with an IC50 of 0.22 µM. The
current study on the same vessel type and perfusion at 75 mmHg found a
similar IC50 for mibefradil at 0.17 µM. Thus these
studies find effects of mibefradil on myogenic tone that are, based on
the electrophysiology of the cloned channel, consistent with an
inhibition of CaV3.1. However, Potocnik et al.
(22) argued that the effects of mibefradil on myogenic
tone may not be carried through T-type calcium channels. In that study (22), mibefradil up to 10 µM did not lower the
intracellular calcium concentration and failed to prevent the rise in
calcium upon pressure steps and application of high potassium, even
though the contractile response was inhibited. The authors suggested that mibefradil could have intracellular effects on calcium sensitivity rather than blockade of T-type calcium channels.
The clear difference in effects of mibefradil and nickel on pressure-induced versus potassium-induced tone could relate to the membrane potential. Alternatively, pressurization might directly affect the opening of the T-type calcium channels. Also, we cannot fully rule out effects of these blockers on the nonselective cation channels recently shown to be involved in pressure-induced depolarization (26). An inhibitory effect of both blockers on nonselective cation conductance has recently been demonstrated on visceral SMCs (13). Whether the difference in potency of verapamil on myogenic versus potassium-induced tone reflects direct modulation of the L-type calcium channels or other effects of this blocker remains to be established.
Whereas in our study the low potency of nickel and mibefradil on K+-induced constriction is in accordance with the involvement of L-type calcium channels, other studies do indicate a higher sensitivity of depolarization-induced arteriolar constriction to mibefradil and/or nickel (10, 22) also in the cremaster arterioles that we studied (22). The protocols, however, were different: we first established a stable potassium-induced contraction and then performed a cumulative concentration-response series of the blockers, whereas others tested the effect of a sudden switch to high potassium in the presence of varying concentrations of the blockers. Comparison of the above studies suggests that potassium-induced contraction could be initiated by calcium influx through T-type channels, whereas its maintenance requires L-type channels. Maintenance of myogenic tone, however, was shown here to depend on T-type calcium channels.
Gustafsson et al. (8) studied the contribution of L- and
T-type calcium channels in local and conducted vasoconstriction of rat
mesenteric arterioles of ~30 µm in diameter. These authors found
the constriction to topical norepinephrine and current stimulation to
be fully insensitive to the L-type channel blockers nifedipine and
nimodipine. Also, the L-type channel CaV1.2 was not
expressed, and the arterioles did not contract to high concentrations
of potassium. In contrast, CaV3.1 and CaV3.2
were expressed, and nickel and mibefradil suppressed the local and
conducted constrictions to norepinephrine and current injection.
Possible side effects of the blockers on L-type currents can be
excluded here because those channels were not expressed. Hansen et al.
(9, 10) found expression of CaV1.2,
CaV3.1, CaV3.2, and the P-/Q-type CaV2.1 in rat afferent arterioles. Each of the calcium
channel blockers calciseptine (specific for L-type channels),
-agatoxin IVA (P-/Q-type blocker), mibefradil, and nickel fully
inhibited contraction of cannulated rabbit afferent arterioles to 100 mM K+ at concentrations believed to reflect specific
actions. Interestingly, T- and L-type calcium channels were not found
in cortical efferent arterioles. Those studies point at a highly
regulated differential distribution of CaV channels along
the renal vasculature and at the significance of T-type calcium
channels. The current study and those of Hansen et al. (9,
10) suggest that a cooperative action of multiple types of
calcium channels is required for the maintenance of constriction. It is
not clear how this correlates with a simple parallel arrangement of the
channels in the cell membrane. Intracellular calcium gradients or
heterogeneity within the SMC population could provide explanations.
In conclusion, T-type calcium channels were expressed at the messenger level in rat cremaster arterioles. Pharmacological evidence supports their contribution to myogenic tone.
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ACKNOWLEDGEMENTS |
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O. Sorop was supported by The Netherlands Heart Foundation Grant 98.180. B. L. Jensen was supported by Danish Heart Foundation Grant 01123022896, The NovoNordisk Foundation, and by the Danish Health Science Research Council.
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FOOTNOTES |
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Address for reprint requests and other correspondence: E. VanBavel, Dept. of Medical Physics, Academic Medical Center, Univ. of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands (E-mail: e.vanbavel{at}amc.uva.nl).
This article belongs to a collection of papers accepted in response to the Editor's special call for papers entitled "Mechanisms of vascular myogenic tone."
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
September 5, 2002;10.1152/ajpheart.00531.2002
Received 28 June 2002; accepted in final form 26 August 2002.
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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 S. M. Charles, L. Zhang, L. D. Longo, J. N. Buchholz, and W. J. Pearce Postnatal maturation attenuates pressure-evoked myogenic tone and stretch-induced increases in Ca2+ in rat cerebral arteries Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2007; 293(2): R737 - R744. [Abstract] [Full Text] [PDF]
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J. Zhang, R. Berra-Romani, M. J. Sinnegger-Brauns, J. Striessnig, M. P. Blaustein, and D. R. Matteson Role of Cav1.2 L-type Ca2+ channels in vascular tone: effects of nifedipine and Mg2+ Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H415 - H425. [Abstract] [Full Text] [PDF]
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 S. Moosmang, N. Haider, B. Bruderl, A. Welling, and F. Hofmann Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Cav1.2 Circ. Res., January 6, 2006; 98(1): 105 - 110. [Abstract] [Full Text] [PDF]
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L. I. Brueggemann, B. L. Martin, J. Barakat, K. L. Byron, and L. L. Cribbs Low voltage-activated calcium channels in vascular smooth muscle: T-type channels and AVP-stimulated calcium spiking Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H923 - H935. [Abstract] [Full Text] [PDF]
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G. Osol and J. Brayden Prologue: vascular myogenic mechanisms Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2157 - H2159. [Full Text] [PDF]
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X174 DNA/HaeIII markers), cDNA amplified from
cremaster muscle arterioles from 3 separate rats (Crem), negative
control [absence of reverse transcriptase (
