(Hypertension. 1996;28:888-893.)
© 1996 American Heart Association, Inc.
Articles |
Vascular Gap Junctional Communication Is Increased in Mineralocorticoid-Salt Hypertension
the Department of Pharmacology and Toxicology, Michigan State University, East Lansing (S.W.W.), and Department of Physiology, University of Michigan, Ann Arbor (R.C.W.).
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Abstract |
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Cells rely on gap junctions for intercellular communication, which is important for growth and contractility. For example, gap junctional communication in the uterus increases near parturition, with a concomitant increase in oscillatory contractions. Because arterial responsiveness to contractile agonists is increased in hypertension, we tested the hypothesis that gap junctional communication is increased in hypertension. We examined thoracic aortas from deoxycorticosterone acetate (DOCA)–salt hypertensive and sham normotensive rats using isolated tissue baths and Western blotting techniques. The concentration of 5-hydroxytryptamine necessary to produce a threshold response was significantly lower in aortas from DOCA-salt (4 nmol/L) compared with sham (100 nmol/L) rats; this was also true for norepinephrine and KCl. In these same aortas, the appearance of spontaneous oscillatory contractions, which are sensitive to the gap junctional inhibitor heptanol (0.3 mmol/L), was more frequent in DOCA-salt arteries (93% versus 14% in sham). Heptanol (1 mmol/L) normalized the DOCA-salt aortic contraction to 5-hydroxytryptamine to levels similar to those of the response of the sham aorta in the presence of heptanol. Western analyses revealed that the density of connexin43 immunoreactivity, the connexin being a constituent of gap junctions, was found to be threefold more abundant in aortic homogenates of DOCA-salt rats compared with that of sham rats. This finding supports the hypothesis that gap junctional communication is increased in hypertension, at least at the protein level. We speculate that this increase results in a portion of the increased vascular reactivity and appearance of contractile oscillations in vascular smooth muscle.
Key Words: muscle, smooth, vascular • gap junctions • hypertension, experimental • muscle contraction
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Introduction |
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Vascular reactivity to multiple contractile agonists is increased in hypertension.1 This is observed for agonists as diverse as potassium chloride, 5-hydroxytryptamine (5-HT), and angiotensin II. Although some changes in individual agonist signal transduction pathways may occur, a more global change in signal transduction may occur that can explain the seemingly indiscriminate change in vascular reactivity. We tested the hypothesis that the increase in vascular reactivity may be the result of increased gap junctional communication. Gap junctions (connexons) are integral membrane proteins composed of six connexins.2 3 Each half-connexon combines with a half-connexon in another cell to form a channel that allows passage of substances 1 kD or less in size. Multiple connexins are known to exist (eg, connexin32, connexin30, connexin40), and connexin43 (43-kD protein) is particularly ubiquitous.2 3 Gap junctions or gap junctional activity can be measured with several methods, eg, electrotonic coupling, dye transfer, and measurement of connexin mRNA and protein density. Recent evidence with the use of all these techniques supports the existence of gap junctions in vascular and nonvascular smooth muscle.4 5 6 7 8 9 10 11
We tested the hypothesis that gap junctional communication is increased in hypertension because the general increase in vascular reactivity observed in hypertension may be served by enhanced gap junctional communication. In addition to the increased sensitivity of the vasculature to contractile agonists, the incidence of contractile oscillations in hypertension is increased; this has been observed in both animal and human forms of hypertension.12 13 14 15 These oscillations can be blocked by heptanol16 and resemble those found in the uterus. Contractile oscillatory activity in the uterus, which increases as parturition nears, has been associated with an increase in gap junctional plaque size.17 18 19 Thus, we have applied these findings to the vasculature to test whether gap junctional communication is increased in hypertension.
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Methods |
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Isolated Tissue Bath Protocol
All procedures used were in accordance with guidelines at the University of Michigan and Michigan State University. Adult male Sprague-Dawley rats (300 to 350 g) were used. Rats were anesthetized with pentobarbital (50 mg/kg IP) and their left kidneys removed. A deoxycorticosterone acetate (DOCA, 200 mg/kg)–impregnated implant was placed subcutaneously behind the skull in one half of the rats. After surgery, DOCA-salt rats were given salt water (1% NaCl plus 0.2% KCl), and sham rats received tap water. Systolic pressure in conscious rats was measured by the tail-cuff method (pneumatic transducer). Rats remained on therapy for 4 weeks before experimentation. Rats were anesthetized with pentobarbital (50 mg/kg IP) and exsanguinated, and the thoracic aortas were removed and placed in cold standard physiological salt solution consisting of (mmol/L) NaCl 130, KCl 4.7, KH2PO4 1.18, MgSO4·7H2O 1.17, CaCl2·2H2O 1.6, NaHCO3 14.9, dextrose 5.5, and CaNa2EDTA 0.03, pH 7.2. Vessels were cleaned, cut into helical strips (aorta, 0.1x1.0 cm), and mounted on stainless steel holders in tissue baths for isometric tension recordings on FT03 transducers and polygraphs (Grass Instrument Co). Vessels from sham normotensive and DOCA-salt hypertensive rats were placed in the same tissue bath and put under optimal resting tension (aorta, 1500 mg). Tissues were bathed with warmed (37°C), aerated (95% O2/5% CO2) physiological salt solution. Endothelium was removed and nonfunctional, as the muscarinic agonist acetylcholine (10-6 mol/L) did not relax phenylephrine (10-6 mol/L)-contracted tissues (data not shown).
Tissues equilibrated for 1 hour with frequent washing. Arteries were initially challenged with norepinephrine and washed. At this time, the presence of spontaneous oscillations was analyzed. 5-HT (10-9 to 10-5 mol/L), norepinephrine (10-9 to 10-5 mol/L), or KCl (6 to 100 mmol/L) was then added cumulatively to the aortas. Heptanol (10-6 to 3x10-2 mol/L) or sucrose (100 mmol/L) was used to block gap junctions. In other experiments, aortas were incubated with vehicle (0.15% ethanol) or heptanol (1.0 mmol/L) for 5 minutes. A cumulative concentration-response curve to 5-HT was established.
Western Blot Analyses
Endothelium-denuded aortas from sham and DOCA-salt rats were dissected and the adventitia of the vessels removed. Brains from sham rats were also removed. Aorta and brain were homogenized in a dounce homogenizer in a sucrose/Tris buffer (255 mmol/L sucrose, 10 mmol/L Tris-HCl [pH 7.4], 2 mmol/L EGTA, and 0.5 mmol/L phenylmethylsulfonyl fluoride). Homogenates were sonicated and centrifuged briefly so debris was pelleted. Equal amounts of supernatant protein (20 µg per lane) were loaded and separated on 12.5% sodium dodecyl sulfate–polyacrylamide gels (200 V, 40 minutes). Proteins were transferred electrically (200 mA, 1 hour) onto Immobilon P (Millipore). The blot was blocked overnight with 5% milk, 6% goat serum, and 10 mg/mL bovine serum albumin. Blots were incubated with primary antibody connexin43 (1:1000 in Tween [0.01%] Tris-buffered saline [TTBS], Zymed Laboratories) for 3 hours, after which blots were washed (30 minutes TTBS, 5 minutes TTBS, 5 minutes Tris-buffered saline). Blots were then incubated with horseradish peroxidase–linked goat anti-mouse antibody for 1 hour (1:1000 in Tris-buffered saline, Boehringer Mannheim) and washed again. Connexin43 proteins were visualized with enhanced chemiluminescence (Amersham).
Materials
All compounds were made daily in deionized water; heptanol was diluted in ethanol. Norepinephrine, phenylephrine, acetylcholine chloride, heptanol, Tween 20, goat serum, bovine serum albumin, sodium dodecyl sulfate, Tris, phenylmethylsulfonyl fluoride, EGTA, and sucrose were all purchased from Sigma Chemical Co. All other supplies were purchased through the University of Michigan Stores.
Data Analysis
Data are presented as mean±SE for the number of rats in parentheses. Oscillatory activity was calculated by multiplying the number of oscillations in a 10-minute period with the magnitude of the oscillations. Agonist threshold concentration was defined as the agonist concentration necessary to produce the first measurable arterial contraction. EC50 values (agonist concentrations necessary to produce a half-maximal response) were determined by nonlinear regression analysis with the following equation: Effect=(Maximum)/[1+EC50/(A)], where effect is the contraction response, maximum is the maximal contraction, and A is the agonist concentration. Films of visualized Western blots were scanned and densitized with Image software (version 1.56, National Institutes of Health). A value of P<.05 was considered statistically significant.
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Results |
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After 4 weeks of therapy, systolic pressure of sham rats was 112±3 mm Hg (n=21) and 188±3 (n=21) for DOCA-salt rats. Strips of aorta from sham and DOCA-salt rats were isolated and mounted in tissue baths.
Fig 1
, top, shows the appearance of spontaneous oscillatory contractions in aorta from DOCA-salt but not from sham rats. These oscillations disappeared in calcium-free buffer (zero calcium, 1 mmol/L EGTA) and were blocked by the L-type voltage gated channel antagonist nifedipine (10-6 mol/L). Oscillations were inhibited by the gap junctional inhibitor heptanol (3x10-4 mol/L) and reappeared once heptanol was removed. Fig 1, bottom, shows that heptanol caused a concentration-dependent inhibition of oscillatory activity, suggesting that oscillatory contractions depend on functional gap junctions.
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Fig 2 depicts the effects of the gap junctional inhibitor sucrose on contractile oscillations. Sucrose (100 mmol/L) caused a small contraction in the aorta and also blocked the oscillatory contractions observed in the DOCA-salt aorta. However, the tone of vessels incubated with sucrose decayed to a level nearly equivalent to that before sucrose addition, and oscillations did not reappear. These data support those shown in Fig 1
and further associate contractile oscillations, one form of enhanced vascular reactivity, with gap junctional communication.
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Fig 3, top, shows the concentration-dependent contraction caused by norepinephrine in aorta of sham and DOCA-salt rats. Note that norepinephrine was significantly more potent in the DOCA-salt aorta than the sham aorta. Quantitation of the threshold values of agonist concentration necessary to produce contraction for norepinephrine, 5-HT, and KCl is shown in Fig 3, bottom. All three agonists had a significantly lower threshold for contracting the DOCA-salt aorta when compared with agonist threshold concentrations in the sham aorta. In these same arteries, the EC50 values for agonist-induced contraction were also lower in DOCA-salt aorta (-log EC50 [mol/L] for n=6: norepinephrine: DOCA=7.719±0.120, sham=7.206±0.180; 5-HT: DOCA=7.469±0.210, sham=6.418±0.320; KCl: DOCA=1.807±0.050, sham=1.672±0.030; P<.05 for comparisons between DOCA and sham). Moreover, contractile oscillations were more frequently observed in the DOCA-salt aorta (93% of all tissues); significantly fewer sham aorta displayed any oscillations (13% of all tissues). These data associate the presence of contractile oscillations, which are sensitive to the gap junctional inhibitors heptanol and sucrose, with increased vascular reactivity to contractile agonists.
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Fig 4 presents data that also support the hypothesis that increased gap junctional communication plays a role in the increased vascular reactivity observed in hypertension. Aortas from both DOCA-salt and sham rats were treated with the gap junctional inhibitor heptanol or vehicle (0.1% ethanol). Concentration-response curves to 5-HT were then examined. The threshold concentration of 5-HT was significantly lower in the DOCA-salt tissues (-log threshold [mol/L]=8.13±0.13) than in the sham tissues (7.01±0.20, P<.05). Threshold sensitivity to 5-HT was normalized in the presence of heptanol (DOCA-salt=6.39±0.31, sham=6.76±0.13; P>.05). Moreover, heptanol normalized the DOCA-salt 5-HT concentration-response curve to become statistically similar to that of the sham response in the presence of heptanol (Student's t test, P>.05). Thus, these data suggest that gap junctional activity is probably enhanced in the DOCA-salt aorta because a gap junctional inhibitor normalizes the DOCA-salt supersensitive contraction to at least 5-HT.
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The data in Fig 5 provide molecular evidence for increased vascular gap junctional communication in hypertension. Equivalent amounts of total protein from aorta of DOCA-salt hypertensive and sham normotensive rats as well as the brain of normotensive rats were separated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis and probed with an antibody against connexin43. Per microgram of total protein, brain tissue clearly possessed a higher density of connexin43 immunoreactivity than was seen in the aorta (Fig 5, bar graph). However, a threefold greater density of connexin43 immunoreactivity was observed in aortic protein from DOCA-salt rats compared with that from sham rats. We have also probed these homogenates with antibodies directed against connexin26 and connexin32 and were unable to observe the presence of these proteins in homogenates from either DOCA-salt or sham aorta (data not shown). Thus, these data support the presence of a greater amount of at least one gap junctional protein, connexin43, in aorta from the DOCA-salt hypertensive rat. These data corroborate our functional data and provide one explanation of why gap junctional communication may be increased in hypertension.
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Discussion |
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Recent studies show that in vascular smooth muscle, gap junctional activity is important for contraction to agonists,7 8 20 indicating that gap junctional activity can regulate vascular tone. We provide evidence in the present studies that gap junctions are important for vascular contraction for the appearance of contractile oscillations and that the expression of the functional unit of a ubiquitous gap junction (connexin43) is increased in mineralocorticoid hypertension.
In general, oscillatory contractions were more frequent in aorta from DOCA-salt than from sham rats. In humans, strips of cerebral arteries from hypertensive patients displayed greater contractile oscillatory activity than strips from normotensive subjects.13 This does not mean that contractile oscillations are never found in the vasculature of normotensive subjects, nor does it mean that every artery from a hypertensive individual displays contractile oscillations. A few arteries, such as the cerebral arteries,13 display oscillatory contractions under normal conditions. We have observed that a greater percentage of vessels from hypertensive subjects displays oscillatory contractions and, in instances in which both normotensive and hypertensive arteries have contractile oscillatory activity, this activity is almost always greater in arteries from hypertensive subjects than in those from normotensive subjects.13
The spontaneous oscillatory contractions observed in aorta were completely inhibited by the gap junctional inhibitors heptanol and sucrose, indicating that functional gap junctional communication is crucial for the appearance and/or maintenance of the contractile oscillations. Heptanol and sucrose have different functions in inhibiting gap junctional communication. It is thought that heptanol decreases the probability of the open state of the gap junctional channel21 and may decrease the fluidity of cholesterol-rich domains of the plasma membrane.16 Previously, we demonstrated that heptanol was capable of inhibiting Lucifer yellow dye transfer in cultured mesenteric smooth muscle cells.20 Lucifer yellow dye transfer has classically been used as a measure of cell-to-cell communication via gap junctions, and the reduction of Lucifer yellow dye transfer by heptanol supports the use of heptanol as a gap junctional inhibitor. Sucrose inhibits gap junctional communication by physically uncoupling the gap junction.22 In the present experiments, sucrose caused a small contraction in aorta from both sham and DOCA-salt hypertensive rats. Although it cannot be ruled out that this small contraction may mask the oscillatory contractions by increasing tone, it is unlikely that this is the case. We have observed tissues in which the tone returned to baseline (or near baseline as shown in Fig 2) during the addition of sucrose and the oscillatory contractions were not present. Thus, as both sucrose and heptanol, two distinct gap junctional inhibitors, abolished oscillatory contractions, gap junctional activity is not only necessary for the propagation of oscillatory contractions but may be enhanced in hypertension.
The presence of oscillatory contractions is important because it may predict the threshold sensitivity of a tissue to contractile agonists. In the present studies, we have defined the agonist threshold response as the agonist concentration necessary to produce the first measurable arterial contraction. Those tissues that demonstrated increased contractile oscillations (DOCA-salt aorta) consistently had a lower threshold to the contractile agonists 5-HT, norepinephrine, and KCl. In addition, the threshold supersensitivity of the DOCA-salt aorta to 5-HT could be abolished by the gap junctional inhibitor heptanol, and the DOCA-salt and sham aortic contractions were made equivalent by heptanol. These data support the strong association between oscillatory contractions, responsiveness to contractile agonists, and an increased gap junctional communication; this must remain only an association because we have no evidence to support a direct causal relationship.
However, we have found more direct evidence that supports our hypothesis of increased vascular gap junctional communication in hypertension. Connexin43 is one of a large family of connexins and is found throughout the body.2 3 Using Western blotting techniques, we have demonstrated that connexin43 immunoreactivity is increased in hypertension. An increase in protein levels may well lead to increased gap junctional communication; with more protein present, more connexons would be capable of forming. This statement can be made only for connexin43 because we were unable to identify the presence of connexin26 or connexin32. The mechanism for this increase in connexin43 density is unclear. We speculate that expression of connexin43 may be sensitive to steroids. This possibility is supported by the fact that gap junctional expression in myometrial smooth muscle cells is promoted by estrogen and can be blocked by progesterone.23 24
The question, then, remains as to whether altered gap junctional activity actually results in oscillatory contractions and how important oscillatory contractions are to maintaining the increased total peripheral resistance observed in hypertension. The present studies support the fact that gap junctional communication is important, in general, for vascular reactivity and suggest that it may be enhanced in hypertension. Studies from other laboratories have also documented an increased incidence of oscillatory contractile events in vascular preparations from hypertensive animals and humans.12 13 20 The cellular mechanisms for oscillatory contractile responses are not completely understood, but similarities exist between this pattern of oscillations and that reported previously in portal veins.25 Portal veins exhibit spontaneous rhythmic contractions that depend on extracellular calcium, and the contractile phase of the activity is associated with bursts of action potentials, suggesting that the mechanism of the oscillatory response relates to "pacemaker"-like activity. Experimental evidence indicates that this electrical activity is propagated from cell to cell through low-resistance pathways between cell membranes of adjacent cells.26 In tail arteries from stroke-prone spontaneously hypertensive rats, a burst of spike activity is coordinated with the contractile phase of an oscillation induced by norepinephrine27 ; electrical spikes were absent in artery segments incubated in calcium-free solution. Enhanced cell-to-cell communication via gap junctions provides one mechanism for synchronous electrical activity and coordinated contractile responses in hypertensive arteries. It is possible, however, that other changes in the vasculature result in oscillatory contractions. Ionic movement in vascular smooth muscle cells of hypertensive animals may be such that a greater population of pacemaker cells is present. Thus, in combination with enhanced gap junctional communication and more pacemaker cells, oscillatory contractions may arise. This is supported by the finding that the K+ channel blockers tetraethylammonium and 4-aminopyridine can increase gap junctional plaque size28 29 and induce contractile oscillations in smooth muscle. An alternative explanation for the inhibitory effects of heptanol and sucrose that must be considered is that these compounds may inhibit the promotion of pacemaker-like cells and thereby reduce contractile oscillations, independent of their effect on gap junctional communication. We cannot discriminate between these two possibilities.
Several reports provide evidence for alterations in gap junctions in arteries from hypertensive rats. In aortic samples of media from two-kidney, one clip renal hypertensive rats, gap junctional plaques (a group of individual gap junctions) are larger and more numerous compared with those from normotensive rats.30 Grunwald et al31 and Sosa-Melgarejo et al32 have also reported an increased intracellular communication through gap junctional contacts in vascular preparations from hypertensive animals. Berry and Sosa-Melgarejo30 proposed that these alterations may provide a mechanism for altered intercellular communication or that they may occur as an adaptation to the increase in tangential stress in the vessel wall produced by elevated blood pressure.
The pathophysiological importance of increased oscillatory contractions in hypertensive arteries remains unclear. Meininger et al33 have estimated that 30% of the increased hindquarter vascular resistance in renal hypertensive rats can be attributed to rhythmic arteriolar vasomotor activity. Agonist-induced flow responses in the renal vasculature of hypertensive patients are oscillatory, and like the contractile oscillations we observed in the isolated vasculature, this activity is blocked by calcium channel antagonists.15 34 We have observed that the genetic locus that controls the norepinephrine-induced oscillatory activity in tail arteries may contribute to the observed blood pressure difference between Wistar-Kyoto and stroke-prone spontaneously hypertensive rats,35 suggesting that increased oscillatory activity, which is associated with increased vascular reactivity, may in fact be involved in either the initiation or maintenance of high blood pressure.
Alternatively, it must be considered that increased blood pressure may actually produce some of the vascular changes (supersensitivity and contractile oscillations) observed in hypertension. Moreover, it is also possible that oscillatory contractions result from decreased gap junctional communication; one can view contractile oscillations as an inability to maintain stable tone. Thus, the hypertrophied vasculature in hypertension may take on one characteristic of cancer cells: decreased gap junctional communication.3 The increase in connexin43 protein we observed in aorta from DOCA-salt hypertensive rats could be a compensation in response to decreased communication. To our knowledge, no studies investigating electrotonic coupling or dye transfer have been compared in whole tissue from normotensive and hypertensive subjects. We believe that although possible, it is unlikely that contractile oscillations can be explained through a decrease in gap junctional communication because normal agonist-induced contraction is reduced by gap junctional inhibitors.7 8 20
In summary, vascular smooth muscle from rats depends on gap junctions for cell-to-cell communication and coordination of contractile reactivity, and this communication may be altered in hypertension. Aorta demonstrating an increase in contractile oscillations typically possess a lower threshold for contraction to 5-HT, norepinephrine, and KCl. Contractile oscillations can be blocked by the gap junctional inhibitors sucrose and heptanol, indicating that gap junctions play a role in contractile oscillations. The enhanced contraction to 5-HT in DOCA-salt aorta was normalized by heptanol, suggesting that increased gap junctional communication may result in the observed supersensitivity. Last, the density of connexin43 immunoreactivity was greater in the vasculature of hypertensive rats than in that of normotensive rats. Taken together, these findings support the hypothesis that gap junctional complexes are important for cellular communication and vascular reactivity and raise the possibility that gap junctional activity may be enhanced in hypertension.
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Acknowledgments |
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This work was supported by National Institutes of Health grants HL-18575 and HL-08892 and the Michigan State University Biotechnology Research Center.
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Footnotes |
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Reprints requests to Stephanie W. Watts, PhD, Department of Pharmacology and Toxicology, B445 Life Sciences Bldg, Michigan State University, East Lansing, MI 48824-1317. E-mail wattss@pilot.msu.edu.
Received September 20, 1995; first decision November 14, 1995; accepted June 24, 1996.
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