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(Hypertension. 1995;26:1060-1064.)
© 1995 American Heart Association, Inc.

Articles

Augmented Calcium Currents in Mesenteric Artery Branches of the Spontaneously Hypertensive Rat

Robert H. Cox; Irina M. Lozinskaya

From Bockus Research Institute, The Graduate Hospital, and the Department of Physiology, University of Pennsylvania, Philadelphia.

	Abstract

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Abstract The greater efficacy of organic channel blockers in lowering peripheral resistance and blood pressure in hypertensive subjects has been suggested to be the result of augmented calcium influx through L-type calcium channels in arterial smooth muscle. These studies were performed to determine whether differences exist in voltage-gated calcium channels of mesenteric artery branches from 20-week-old spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). Single myocytes were acutely isolated by collagenase and elastase treatment and studied at room temperature (20°C) with the use of whole-cell, patch-clamp methods. Maximum values of calcium current measured at 0 mV from a holding potential of -90 mV were larger in SHR myocytes (105±11 versus 149±15 pA). Values of cell capacitance were smaller in SHR (29.5±1.3 pF) compared with WKY (35.0±1.5 pF) myocytes. Cell capacitance measures surface membrane area and, when used to normalize calcium currents, magnified the difference between WKY and SHR to approximately 47%. There was a larger percent reduction of maximum calcium current at holding potentials of -60 and -40 mV in SHR compared with WKY myocytes: for example, at -40 mV calcium current was reduced from values at -90 mV by -73±2% in SHR compared with -58±1% in WKY. When divided by the maximum current for each holding potential, the voltage dependence of normalized calcium currents for the two groups was completely superimposed. Difference currents were calculated by subtracting currents measured from holding potentials of -90 and -40 mV. The voltage dependence of difference currents was identical to that of the calcium currents measured from the two values of holding potential. The results of this study indicate that (1) only L-type calcium currents are present in freshly isolated mesenteric artery myocytes from 20-week-old WKY and SHR, and (2) these currents are larger in SHR. These differences in calcium currents may contribute to augmented contractile responses that have been previously reported.

Key Words: patch-clamp techniques • calcium channels • rats, inbred SHR

	Introduction

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In vascular smooth muscle, force development depends primarily on Ca²⁺ release from intracellular stores with subsequent myosin light chain phosphorylation.^{1 2} In the absence of Ca²⁺ influx, the sustained component of contraction (ie, force maintenance) cannot be maintained.^{3 4 5} Also, the tonic level of contraction has been shown not to depend on the degree to which the intracellular Ca²⁺ stores are filled before activation.⁶ This suggests that Ca²⁺ influx plays an important role in determining force maintenance in smooth muscle,⁷ ie, that Ca²⁺ influx is involved in the determination of peripheral resistance.

There are two pathways for Ca²⁺ influx in vascular smooth muscle: one activated by agonists (receptor-operated channels) and the other activated by membrane potential (voltage-operated channels).⁸ There is also evidence that agonist activation is associated with membrane depolarization.^{7 9} Therefore, both receptor- and voltage-operated channels could contribute to force maintenance associated with agonist activation in smooth muscle.

It is well established that hypertension in human as well as animal models is associated with augmented contractile responses as well as increased sensitivity to agonist activation.^{10 11 12} Also, in smooth muscle it has been shown that force maintenance is closely linked to membrane potential.^{2 7 9} This suggests the possibility that differences in voltage-dependent Ca²⁺ channels may contribute to the increased contractile responsiveness in hypertension.¹³

A number of previous studies have documented differences in the properties of voltage-dependent Ca²⁺ channels between Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR).^{14 15 16 17 18 19} These studies were performed with high concentrations of Ca²⁺ or Ba²⁺ (ie, 10 to 50 mmol/L) as the charge carrier to improve resolution of small Ca²⁺ currents in rat vascular myocytes. However, the use of high concentrations of charge carrier may not provide an accurate representation of differences in the properties of Ca²⁺ channels in hypertension.²⁰

The objective of these experiments was to test the hypothesis that augmented Ca²⁺ currents through voltage-dependent channels occur in hypertension at physiological levels of [Ca²⁺]_o. To test this hypothesis, experiments were performed to determine the properties of voltage-dependent Ca²⁺ channels in myocytes freshly isolated from small mesenteric arteries of 20-week-old male WKY and SHR at 2 mmol/L [Ca²⁺]_o.

	Methods

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Tissue and Solutions
Animals were obtained from an accredited animal supplier (Buckshire Corp, Perkasie, Pa) at an age of 12 weeks and maintained one per cage in our animal facility (accredited by the American Association for Accreditation of Laboratory Animal Care) until used. The methods and procedures regarding the use of experimental animals were approved by the Institutional Animal Care and Use Committee. Myocytes were enzymatically isolated from mesenteric artery branches of 20-week-old male WKY and SHR by a modification of methods previously described by us.²⁰ Briefly, the mesenteric artery and attached branches were removed from the animals after they were killed and cleaned of surrounding fat and matrix.²¹ The tissue was incubated in a Ca²⁺-free solution at 37°C for approximately 40 minutes. The incubation buffer had the following composition (mmol/L): NaCl 140, KCl 5, MgCl₂ 1, HEPES 10, and glucose 10, with pH 7.4 (titrated with NaOH) and an osmolality of 296±2 mOsm. Collagenase (250 U/mL CLS3; Worthington) and elastase (25 U/mL porcine pancreas; ICN) were then added to small pieces of tissue for 30 to 40 minutes at 37°C. Cells were released from the tissue by gentle trituration with a fire-polished Pasteur pipette. An aliquot of cells was transferred to a chamber on the stage of an inverted microscope (Diaphot, Nikon) and allowed to adhere to the chamber's glass bottom before the initiation of perfusion.

Electrophysiological Methods
Membrane currents were recorded with the use of the whole-cell, patch-clamp configuration²² at room temperature (20°C). Micropipettes (2 to 3 M resistance) were made from capillary tubing (WPI Kwik-fil) with a programmable puller (model P-80/PC, Sutter Instruments) and fire polished. The solution used to fill the patch pipettes had the following composition (mmol/L): CsCl 100, tetraethylammonium chloride 20, NaCl 5, Mg-ATP 5, HEPES 10, and BAPTA 10, with pH 7.2 (titrated with CsOH) and an osmolality of 306±3 mOsm. Series resistance and capacitance compensation were adjusted maximally with the use of a patch-clamp amplifier with a 100-M head stage (model 8900, Dagan). Experimental protocols were controlled with the use of a computer (Dell) and PCLAMP software (Axon Instruments). Current signals were converted from analog to digital form at a sampling rate of 2 kHz with the use of a Labmaster A/D board (Axon Instruments) and stored in the computer for analysis. Multiple responses to small (20 mV) hyperpolarizing voltage-clamp steps (n=5) were obtained for each protocol, averaged, and used to provide capacitance and leak compensation of the raw data. Experimental current records were analyzed with the use of PCLAMP software.

Procedures
Cell break-in was accomplished by gentle suction at a holding potential of -60 mV. Membrane potential was stepped at 10-second intervals from -60 to +10 mV for 3 to 5 minutes during cell dialysis with the pipette solution until the inward Ca²⁺ current (I_Ca) stabilized. Current-voltage relations were then determined from a holding potential of -60 mV. Voltage-clamp steps 75 milliseconds long were applied from -60 to +40 mV in 10-mV increments every 10 seconds. Similar current-voltage relations were also determined from holding potentials of -40 and -90 mV in random order. Another current-voltage relation was determined from a holding potential of -60 mV to test for time-dependent changes (ie, run-down). If peak current changed more than 10% between the first and second sets of measurements from the -60 mV holding potential, the cell was discarded.

Statistical Analysis
We performed statistical comparisons of membrane currents with a two-way ANOVA with repeated measures for unpaired data using the STATWORKS application on a Macintosh computer. Values of P<.05 were considered significant. Average values are given as mean±1 SEM.

	Results

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Inward currents recorded with Cs⁺ and TEA⁺ as the predominant cations in the patch pipette solution activated at approximately -40 mV, reached a peak at approximately 0 mV, and exhibited a reversal potential of approximately +60 mV (Fig 1A). On the basis of their voltage dependence as well as their dependence on external [Ca²⁺], independence of external [Na⁺], and alteration by known Ca²⁺ channel modulators, these inward currents were identified as Ca²⁺ currents (I_Ca). Values of peak I_Ca were averaged at each test voltage and are shown for the two groups in Fig 1A. Values for SHR were significantly larger than those for WKY at all voltages between -40 and +40 mV when recorded from a holding potential of -90 mV, where all of the I_Ca were available for activation.

View larger version (18K): [in this window] [in a new window]   Figure 1. Tracings and line graphs show voltage dependence of peak Ca2+ current in mesenteric artery myocytes from Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Currents recorded from representative myocytes from WKY and SHR are shown at the top of the figure. Horizontal and vertical calibration bars below the current records represent 15 milliseconds and 100 pA, respectively. A, Peak current determined by the CLAMPFIT module of PCLAMP and averaged at various voltages. B, Peak values for each cell normalized by dividing by the maximum ICa for each cell before averaging. Symbols represent mean values; vertical bars are ±1 SEM.

Values of peak current measured at the various test voltages in each cell were normalized by dividing by the maximum value of I_Ca for each cell before averaging. As shown in Fig 1B, there was a small but significant shift in the voltage dependence of normalized I_Ca in SHR in the negative voltage direction by approximately 4 mV. Values of cell capacitance were determined from the transient response to a small hyperpolarizing voltage-clamp step that activated no channels.²⁰ Values of cell capacitance were significantly smaller in the SHR compared with the WKY group (WKY, 35.0±1.5 pF; SHR, 29.5±1.3 pF; P>.001). Thus, the larger current in SHR was not the result of a larger cell size (cellular hypertrophy).

To determine whether more than one Ca²⁺ channel type contributed to whole-cell Ca²⁺ current in this study, several experiments were performed. In the first set of experiments, values of I_Ca were measured at the end of a 75-millisecond voltage-clamp step from a holding potential of -90 mV and compared with peak values of I_Ca at the same test voltages. If a low voltage activated, rapidly inactivating Ca²⁺ current (ie, T-type) existed in these cells, the late current would be (relatively) inactivated more at negative compared with positive voltages, and the current-voltage curve would be shifted in the positive voltage direction. Fig 2 shows normalized current-voltage curves for peak and late currents in WKY and SHR myocytes. For both groups of cells, the curves for the late current were shifted in the hyperpolarizing direction (to the left) for voltages negative to the peak I_Ca but were not different for voltages positive to the peak I_Ca. This suggests that the rate of I_Ca inactivation was slower at voltages between -40 and -10 mV compared with that at voltages above 0 mV and not the converse, as would be predicted if T-type channels were present in the former voltage range.

View larger version (17K): [in this window] [in a new window]   Figure 2. Line graphs show comparison of the voltage dependence of peak and late ICa in myocytes from Wistar-Kyoto (WKY) (A) and spontaneously hypertensive (SHR) (B) rats. Late current was determined by averaging over the last 5 milliseconds of a 75-millisecond voltage-clamp step; peak current was determined as in Fig 1. Both currents were normalized by dividing by the maximum value of ICa for each cell before averaging. Symbols represent mean values; vertical bars are ±1 SEM.

In the second set of experiments, I_Ca was measured from three different holding potentials: -40, -60, and -90 mV. If multiple Ca²⁺ channel types were present in these cells, then differences in current-voltage relations would exist because of the known differences in kinetics and gating properties of different Ca²⁺ channel types.²³ Fig 3 summarizes the effects of varying holding potentials on Ca²⁺ current-voltage relations in WKY and SHR. As the holding potential was decreased from -90 mV, values of I_Ca were uniformly decreased in both WKY and SHR at all test voltages. For WKY, values of peak I_Ca averaged 34±4 pA at -40 mV, 95±9 pA at -60 mV, and 109±11 pA at -90 mV. For SHR, values of I_Ca averaged 39±5 pA at -40 mV, 117±12 pA at -60 mV, and 149±15 pA at -90 mV. There was a larger percent reduction in peak I_Ca in SHR when the holding potential was reduced from -90 to -60 mV (WKY, -12±4%; SHR, -17±4%) as well as from -90 to -40 mV (WKY, -58±1%; SHR, -73±2%). Only the differences at -40 mV holding potential were statistically significant, however.

View larger version (18K): [in this window] [in a new window]   Figure 3. Tracings and line graphs show effects of holding potential on peak Ca2+ current-voltage relations in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Representative currents obtained at a test potential of 0 mV from the three values of holding potential in the same cell from a WKY and SHR are shown at the top of the figure. Peak values of ICa were determined at various test potentials from holding potentials of -40, -60, and -90 mV; currents will not normalize; and averaged. Symbols represent mean values; vertical bars are ±1 SEM. Horizontal and vertical calibration bars below the current records represent 20 milliseconds and 100 pA, respectively.

The voltage dependence of I_Ca did not appear to be substantially different for the three values of holding potential. Peak values of I_Ca occurred at 0 mV for all three values of holding potential in the two animal groups (Fig 3). When values of I_Ca were normalized by the peak value of I_Ca at each holding potential, there was no apparent difference in their voltage dependence, as shown in Fig 4. This suggests that both groups of myocytes possess a single type of Ca²⁺ channel and that more positive holding potentials produce inactivation of a portion of the total I_Ca available.

View larger version (14K): [in this window] [in a new window]   Figure 4. Line graphs show voltage dependence of normalized peak ICa for the three holding potentials. Values of ICa were normalized by dividing by the maximum value of ICa for each cell at each holding potential before averaging. Symbols represent mean values; vertical bars are ±1 SEM. WKY indicates Wistar-Kyoto rats; SHR, spontaneously hypertensive rats.

A detailed examination of the Ca²⁺ currents measured at specific values of voltage (Fig 5) revealed relatively monotonic behavior in the effects of holding potential on the inactivation portion of I_Ca. When activated from a hyperpolarized holding potential (-90 mV) at which all Ca²⁺ channels should be available for activation, I_Ca at -20 mV exhibited relatively slow activation followed by slow inactivation kinetics in both WKY and SHR. At 0 mV, where the maximum I_Ca occurred, the rates of activation and inactivation were faster. At +20 mV, where I_Ca was smaller than its peak value (at 0 mV), the rate of inactivation after the peak current remained fast. At progressively more depolarized values of holding potential, the amplitude of the peak I_Ca decreased, as did the rate of inactivation, but the relative differences at the three test voltages were similar. These results do not indicate the presence of a rapidly inactivating I_Ca component activated from a hyperpolarized holding potential, where a T-type I_Ca component might be expected to be found.²³

View larger version (18K): [in this window] [in a new window]   Figure 5. Tracings show effects of holding potential on ICa recorded at several different test potentials. Currents were recorded at test potentials of -20, 0, and +20 mV for each condition. The largest current in each panel occurred at 0 mV and the smallest at -20 mV for all conditions. Holding potentials are indicated in the figure with each set of currents. Horizontal and vertical calibration bars at the bottom of the figure represent 20 milliseconds and 100 pA, respectively. WKY indicates Wistar-Kyoto rats; SHR, spontaneously hypertensive rats.

In some of these experiments, currents were recorded over the same range of test potentials from holding potentials of -40 and -90 mV. Differences between currents (I_Ca) were calculated by point-by-point subtraction of currents recorded at the same value of voltage from the two different holding potentials. Normalized current-voltage relations were determined by dividing by the maximum value of I_Ca for each cell. As shown in Fig 6, the voltage dependence of I_Ca was identical to that of the currents recorded at the two holding potentials. This also suggests the presence of a single channel type in which availability is inhibited by voltage.

View larger version (20K): [in this window] [in a new window]   Figure 6. Tracings and line graphs show voltage dependence of difference currents derived from currents recorded at holding potentials of -40 and -90 mV in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Difference currents were determined by point-by-point subtraction of currents recorded at various test potentials from holding potentials of -40 and -90 mV. Representative currents from a WKY and SHR myocyte are shown in the upper portion of the figure at a test potential of 0 mV. All currents were then normalized by dividing by the maximum value for each cell before averaging. Symbols represent mean values; vertical bars are ±1 SEM.

	Discussion

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At a [Ca²⁺]_o of 2 mmol/L, we found larger Ca²⁺ currents recorded by whole-cell patch-clamp methods in freshly dispersed myocytes from mesenteric artery branches of 20-week-old SHR compared with WKY. This larger I_Ca in SHR myocytes was not the result of a larger cell size (ie, surface area), suggesting that the number and/or open probability of Ca²⁺ channels is larger in SHR. In fact, cell capacitance and by implication cell surface area were smaller in SHR compared with WKY cells in this study group.

Previous studies of Ca²⁺ currents in WKY and SHR myocytes using patch-clamp methods have provided varying results. Rusch and Hermsmeyer,^{14 15} using 20 mmol/L [Ca²⁺]_o, showed similar maximum Ca²⁺ currents in cultured myocytes obtained from the azygous vein of neonatal animals but with a larger ratio of L-type to T-type current components in the SHR. Ohya et al,¹⁷ using 50 mmol/L [Ba²⁺]_o, compared I_Ba in myocytes isolated from mesenteric artery branches of young (4 to 5 weeks) and older (16 to 18 weeks) WKY and SHR. They found larger maximum I_Ba in myocytes from young SHR but no differences in older ones, and they found no differences in cell capacitance or in the voltage dependence of activation or inactivation at either age. Self et al,¹⁸ using 20 mmol/L [Ba²⁺]_o, found larger I_Ba in cultured myocytes from the azygous vein of neonatal stroke-prone SHR. Wilde et al,¹⁹ using 10 mmol/L [Ba²⁺]_o, found larger I_Ba in myocytes from cerebral arteries of 17-week-old stroke-prone SHR compared with WKY.

The present study is the first to show larger I_Ca in SHR myocytes compared with WKY at physiological levels of [Ca²⁺]_o. Also, the maximum values of I_Ca reported in this study are equal to or larger than some of the values reported by others despite the lower concentration of charge carrier. There are obvious differences in these various studies (including this one) that could have contributed to the differences in Ca²⁺ channel currents reported. These include differences in the animal model (SHR or stroke-prone SHR), blood vessels (azygous vein and mesenteric and cerebral arteries), and charge carrier (10 to 50 mmol/L Ca²⁺ or Ba²⁺). Thus, the extent to which the use of larger concentrations of divalent charge carrier may have contributed to the differences in the results is somewhat obscured by the other differences.

Most of the previously cited studies reported the presence of both L- and T-type currents in the whole-cell recordings from depolarized holding potentials. The T- and L-type currents have been identified and separated on the basis of holding potential,¹⁹ test potential,¹⁷ or both.^{14 15 16 18} Most of these previous studies have found smaller ratios of T- to L-type currents in myocytes from hypertensive animals.^{14 15 16 17 19}

We found evidence in this study which suggests that mesenteric myocytes from the SHR possess only one type of Ca²⁺ channel, the L-type. That evidence may be summarized as follows: (1) In comparison with peak I_Ca, current-voltage curves determined after a significant amount of time was allowed for I_Ca inactivation were shifted to the left, suggesting slower rates of inactivation at negative test voltages, rather than shifted to the right, as would be expected if significant T-type currents had been present (faster inactivation). (2) Measurement of the time course of I_Ca at different holding potentials revealed no low-voltage activated, rapidly inactivating currents. (3) While currents were smaller at depolarized holding potentials, when I_Ca was normalized by the maximum I_Ca the resulting current-voltage curves were superimposable. (4) The maximum value of I_Ca at the various holding potentials occurred at the same voltage. (5) Difference currents (I_Ca) determined from I_Ca measured from holding potentials of -90 and -40 mV had the same voltage dependence as the original currents from which they were derived. (6) Nisoldipine (1 µmol/L) completely inhibited the I_Ca recorded from a holding potential of -90 mV (data not shown). The reasons for the differences between the findings of this study and previous ones is not clear, although type of Ca²⁺ channel and detection of increased Ca²⁺ current amplitude may arise from differences in blood vessel source, animal ages, and selection of external solution composition.

There are considerable data in the literature to suggest that augmented Ca²⁺ influx through L-type Ca²⁺ channels contributes to augmented peripheral resistance and contractile responses of vascular smooth muscle in hypertension. Increased peripheral resistance and augmented contractile responses to vasoconstrictors are hallmarks of established hypertension in human as well as animal models.^{24 25} These changes are associated with an increase in basal Ca²⁺ influx as well as augmented Ca²⁺ influx after agonist activation in vascular smooth muscle.^{26 27 28} The effectiveness of organic Ca²⁺ channel blockers in reducing blood pressure, peripheral resistance, and vasoconstrictor responses in smooth muscle is larger in hypertensive subjects.^{29 30 31 32 33} This suggests that altered L-type Ca²⁺ channels play a greater role in agonist-mediated responses in hypertension. The alterations in voltage-gated Ca²⁺ channels in hypertension reported in this study may provide an explanation for these varied observations.

	Acknowledgments

 
This study was supported by research grant HL-28476 from the US Public Health Service.

	Footnotes

 
Reprint requests to Robert H. Cox, PhD, Bockus Research Institute, The Graduate Hospital, One Graduate Plaza, Philadelphia, PA 19146.

Received June 19, 1995; first decision August 18, 1995; accepted September 5, 1995.

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