Bloodvessels 1990;27:246-257

© 1990 S. Karger AG. Basel 0303-6847/90/0275-0246S2.75/0

Mechanoreception by the Endothelium: Mediators and Mechanisms of Pressure- and Flow-Induced Vascular Responses Gabor M. Rubanyia, Ana D. Freayb, Katalin Kauserc, Anthony Johns3, David R. Harderc “Department of Pharmacology, Berlex Laboratories, Cedar Knolls, N.J.; h Department of Pharmacology, University of Miami, Fla., and c Department of Physiology, Medical College of Wisconsin, Milwaukee, Wise., USA

Abstract. Mechanoreception, a widely distributed sensory modality, has been shown to be present in certain blood vessels. Changes in physical forces, like sudden increase of transmu­ ral pressure or flow velocity (shear stress), trigger changes in blood vessel diameter; the former reduces it while the latter increases vessel caliber. These changes in diameter, which are the result of contraction and relaxation of vascular smooth muscle in the blood vessel media, can serve the purpose of physiological regulation of blood flow (autoregulation) and protection of the intima against damages from high shear forces. The precise location of mechanosensor(s) and the mechanism of mechanoreception and signal transduction are poorly understood. Accumulating evidence suggests that the endothelium may be a site of mechanoreception and that changes in the synthesis/release of endothelium-derived relaxing (EDRF, EDHF, PGI2) and contracting factors (EDCF) result in altered vascular smooth muscle tone and vessel caliber. Increased shear stress stimulates the release of EDRF and PGI2 probably via activation of a K+channel (inward rectifier) in endothelial cell membrane. Endothelium-dependent vascular contraction evoked by increased transmural pressure may be the result of (1) reduced release of EDRF (canine carotid artery) and (2) stimulation of the release of a still unidentified EDCF(s) (feline cerebral artery). Thus the endothelium can serve as pressure and flow sensor and is capable of transducing changes in mechanical forces into changes of vascular smooth muscle tone by modulating the release of endotheliumderived vasoactive factors. The physiological importance of the mechanoreception by endo­ thelial cells in the intact circulation remains to be determined.

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Key Words. Pressure • Flow • Shear stress • Endothelium-derived relaxing factor • Endothelium-derived hyperpolarizing factor • Endothelium-derived constrictor factor • Autoregulation of blood flow • K+ channels • Membrane potential • Calcium

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Mechanoreception is the most widely dis­ tributed sensory modality. It contributes to the senses of hearing, orientation to local gravity and touch, and it is required for coor­ dinated movement. It has long been recog­ nized that blood vessels themselves have the ability to sense changes in mechanical forces: rapid elevation of intraluminal pressure trig­ gers vasoconstriction [1], which contributes to the autoregulation of blood flow in certain organs [2], The site of mechanoreception in the vessel wall was thought to be the vascular smooth muscle [2], Recent studies have shown that the endothelium may also be the site of mechanoreception; its presence is es­ sential to observe changes in vascular smooth muscle tone in several blood vessels evoked by increases in flow/shear stress [38] and stretch/pressure [9-12]. This paper attempts to review experimental evidence supporting the role of endothelium in me­ chanoreception by the blood vessel wall.

The Phenomenon: Pressure-Induced Endothelium-Dependent Contraction Canine Carotid Artery Rapid increase of transmural pressure from near zero to 30-40 mm Hg triggers a rapid rise of isometric force in the wall of an isolated perfused canine carotid artery seg­ ment with endothelium (indicative of pas­ sive stretch), which is followed by a second­ ary increase in wall tension [10] (fig. 1). Me­ chanical removal of the endothelium from the perfused carotid artery, prior to mount­ ing (verified by the lack of relaxations in response to acetylcholine), prevents pres­ sure-induced contraction (fig. 1).

Feline Cerebral Artery Elevation of pressure from 40 to 160 mm Hg in isolated segments of cerebral arteries from cats [11] depolarizes the vascular smooth muscle cells and the internal diame­ ter of the vessel is either maintained or reduced (fig. 2, 3). In interlobular arteries obtained from the dog kidney, there was a significant reduction in internal diameter of the vessel in response to an elevation in pres­ sure from 80 to 120 mm Hg [12]. When the endothelial lining of cerebral vessels is disrupted (either by collagenase perfusion or introduction of an air bolus), the vessels dilate as transmural pressure is elevated (fig. 2) and membrane potential does not change (fig. 3) [11].

Bioassay Studies Demonstrating That Pressure-Induced Vasoconstriction Is Mediated by Diffusible Endothelium-Derived Factor(s) Canine Carotid Artery To determine whether increases in pres­ sure trigger the release of diffusable factor(s) from the endothelium of canine carotid ar­ teries, a bioassay technique, developed for the detection of endothelium-derived relax­ ing factor (EDRF) released by vasodilator agents [13] or by increases in flow rate [8], was used with some modifications [10]. These studies revealed that, in parallel with the pressure-induced contraction of the do­ nor carotid artery segment, the bioassay ca­ nine coronary artery ring (not exposed to pressure and supervised by the perfusate from the donor segment) contracted as well (fig. 1). These studies indicated that in­ creases in transmural pressure modulate the

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Introduction

Fig. 1. Changes in isometric force of perfused ca­ rotid artery segments with (a) or without (b) endothe­ lium and bioassay ring without endothelium during endothelial (a) or vascular (b) superfusion caused by rapid increase in intraluminal pressure at constant (2 ml/min) flow rate. Note pressure-induced active contraction (a; A and B) in presence of endothelium and moderate decreases in isometric force (b; A' and B') in absence of endothelium in donor segment. Experiment was carried out in presence of indomethacin (10-5 M). ACh, acetylcholine; PGF 2a, prosta­ glandin F 20. (Reproduced with permission of the American Physiological Society.) Fig. 2. Responses (internal diameter) of cat cere­ bral arteries in the presence (a) and absence (b) of the endothelium. Recovery of vasoconstriction when de­ nuded (recipient) vessel is connected in series with an

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intact donor (c; bioassay conditions). (Adapted with permission of the American Heart Association.) Fig. 3. Summary of membrane potential values obtained in smooth muscle cells of cat middle cere­ bral arteries upon stepwise elevation in transmural pressure, a Control state in which the vascular endo­ thelium is intact and demonstrating progressive membrane depolarization as transmural pressure is elevated, b Data obtained when the endothelium is removed and transmural pressure elevated. After re­ moval of the endothelium, elevation in transmural pressure no longer results in membrane depolariza­ tion. c Recovery of depolarization when the denuded segment is connected in series with an intact donor (bioassay). Each point represents a single impale­ ment. (Reproduced with permission from American Heart Association.)

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release of diffusible and bioassayable va­ soactive factor(s) from the endothelium of carotid arteries. Cat Cerebral Artery To analyze whether pressure-induced en­ dothelium-dependent contraction and mem­ brane depolarization in feline cerebral arter­ ies is mediated by diffusable factor(s), we developed a bioassay system. This system consists of two pressurized cerebral arterial segments connected in series [14]. The up­ stream vessel (donor) has an intact endothe­ lium while the downstream vessel (recipient) is denuded of its endothelial lining by perfu­ sion with collagenase. In this system, the downstream recipient vessel depolarizes and contracts in response to an elevation in pres­ sure when its endothelium is intact, but di­ lates passively after removal of the endothe­ lium. When the denuded recipient vessel is

Fig. 4. Effect of elevated pres­ sure on basal EDRF release from isolated canine carotid arteries. Original experiment (a) and mean ± SEM relaxations of the bioas­ say tissue (b; n = 6). The bioassay tissue was contracted with 50 nM U46619. The release of EDRF (measured as the relaxation of the bioassay ring) during elevated pres­ sure was significantly (* p < 0.05) different from both control I (be­ fore elevation of pressure) and con­ trol II (return to control after eleva­ tion of pressure).

exposed to a perfusate flowing from the in­ tact pressurized donor vessel, it regains its ability to depolarize [11] and contract in response to an elevation in pressure (fig. 2, 3). These studies show that pressure-induced vasoconstriction in cat cerebral arteries is also mediated by diffusible and bioassayable factor(s).

Nature of Endothelium-Derived Vasoactive Factors Mediating Pressure-Induced Contraction Canine Carotid Artery Effect o f Methylene Blue on Pressure-In­ duced Vasoconstriction. Infusion of meth­ ylene blue (10-5 M) downstream of the per­ fused (donor) segment abolished the relax­ ation of the bioassay ring in response to the endothelial effluent [10]. Under these condi-

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Fig. 5. Effect of elevated pres­ sure on the acetylcholine (ACh)induced release of EDRF from iso­ lated canine carotid artery. Original experiment (a) and mean ± SEM relaxations of the bioassay tissue (b; n = 5). The bioassay tissue was con­ tracted with 50 nM U46619. EDRF release was induced with 10-6 A/ ACh. The release of EDRF (mea­ sured as the relaxation of the bioas­ say ring) during elevated pressure was significantly (* p < 0.05) dif­ ferent from both control I (before the elevation of pressure) and con­ trol II (after the elevation of pres­ sure).

tions, an increase of transmural pressure caused contractions of the perfused segment (not exposed to methylene blue), but pre­ vented the contraction of bioassay ring [10]. Although methylene blue could suppress the effect of a contracting factor on bioassay tis­ sue, the data strongly suggest that pressureinduced contraction in carotid arteries is due to inhibition of the release of EDRF(s). Effect o f Pressure on Basal, Acetylcholine-, A23187- and Flow-Induced Release o f EDRF. Increased transmural pressure caused a significant depression in the release of EDRF from the donor tissue under both basal conditions (fig. 4) and when the release of EDRF was stimulated by acetylcholine (fig. 5). In contrast, the release of EDRF by

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the calcium ionophore, A23187, was unaf­ fected by an increase in transmural pressure (fig. 6). These results demonstrate that the decreased relaxing activity of the effluent was not due to technical artifacts (e.g., de­ creased amount and/or biological activity of EDRF) otherwise the relaxation to A23187 would also have been depressed. The inabil­ ity of increased pressure to decrease the re­ lease of EDRF induced by A23187 suggests that pressure interferes with excitation(EDRF)-secretion coupling in endothelial cells at a step that precedes the elevation of cytosolic free calcium. A rapid increase in flow rate from 2 to 4 ml/min induced reversible relaxation of the bioassay tissue with no significant change in

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transmural pressure (fig. 7, left) [8]. An in­ crease in transmural pressure to 35 mm Hg (with no change in flow rate) caused slowly developing increases in isometric force of the bioassay ring reversing the relaxations evoked by the endothelial effluent (fig. 7,

Fig. 6. Effect of elevated pres­ sure on the A23I87 (10-7 A/)-induced release of EDRF from iso­ lated canine carotid artery. Original experiment (a) and mean ± SEM relaxations of the bioassay tissue (b; n « 5). The bioassay tissue was con­ tracted with 50 nAf U46619. Note that elevated pressure had no effect on A23187-induced release of EDRF. Fig. 7. Changes in isometric force of superfused bioassay canine coronary artery ring without endo­ thelium caused by sudden increase in steady flow rate (from 2 to 4 ml/ min) at low (left and right) and high pressure (middle) during superfu­ sion with effluent from carotid ar­ tery segment with endothelium. Basal myogenic tone of bioassay ring was estimated by relaxation in­ duced by sodium nitroprusside (1 0 's M). Note that elevation of pressure in perfused segment caused increase of isometric force and reversibly prevented flow-in­ duced relaxation in bioassay ring. (Reproduced with permission from the American Physiological Soci­ ety.)

middle). Increase in flow rate during highpressure perfusion did not evoke relaxation of the bioassay ring (fig. 7, middle). After return to near zero transmural pressure, iso­ metric force of the bioassay ring decreased and a repeated increase in flow rate pro­

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Feline Cerebral Artery The presence of oxyhemoglobin (10-5 M) in the perfusate and organ bath (to inactivate released EDRF) did not alter pressure-in­ duced endothelium-dependent vasoconstric­ tion in cat cerebral arteries [14]. These re­ sults indicate that in apparent contrast to canine carotid arteries, pressure-induced va­ soconstriction in these blood vessels is me­ diated by the release of a contractile sub­ stance from the endothelium (EDCF), rather than by the suppression of the release of a hemoglobin-sensitive EDRF. However, the possibility exists that elevated pressure re­ duces the synthesis/release of a hemoglobininsensitive hyperpolarizing and relaxing fac­ tor (e.g. EDHF). In further attempts to identify the nature of this factor, we examined the action of endothelin, a recently identified endothelial peptide with vasoconstrictor properties. While endothelin was a potent activator of cerebral arteries, we found that its vasocon­ strictor effects were not reversible [ 15]. We also found that endothelin was much less effective in depolarizing cerebral arterial smooth muscle than elevations in transmu­ ral pressure [15]. Thus, we concluded that endothelin does not fit the pharmacologic profile of an endothelial constrictor sub­ stance released upon rapid elevation of per­ fusion pressure. The pressure-induced endothelium-me­ diated contractile response in either cerebral or renal arteries is not inhibited when the vessel is treated with indomethacin to block cyclooxygenase activity [11, 12]. This dem­ onstrates that cyclooxygenase products of

arachidonic acid metabolism (i.e., prosta­ glandins, prostacyclin, thromboxane and endoperoxides) do not mediate the response. However, preliminary studies suggest that other products of arachidonic acid metabo­ lism may be involved. Nordihydroguaiaretic acid (NDGA), a nonspecific inhibitor of ara­ chidonic acid metabolism via the lipoxygen­ ase, cyclooxygenase and cytochrome P450 pathways, blocks the pressure-mediated acti­ vation of cat cerebral arteries [unpubl., pre­ liminary findings]. Since the metabolism of arachidonic acid by these pathways also produces free radicals which are vasoactive, we examined the effect of the free radical generating system xan­ thine and xanthine-oxidase on cerebral ar­ teries. Our initial findings indicate that oxy­ gen-derived free radicals produced by this system dilate cerebral arteries, suggesting that they probably do not mediate the pres­ sure-induced activation of cerebral arteries.

Proposed Mechanism of Mechanoreception by the Endothelial Cells in Canine Carotid Arteries Since, in contrast to basal, flow- and AChinduced EDRF release, elevated pressure did not affect the release of EDRF by A23187, we postulate that mechanoreception should involve events in the plasma membrane of endothelial cells. Stretch-activated channels have been described in the plasma mem­ brane of erythrocytes [16], skeletal muscle [17], oocytes [18], snail heart cells [19], epi­ thelial cells [20], endothelial cells [21], renal tubule [22], smooth muscle [23] and ventric­ ular myocytes [24], The channels can be acti­ vated by suction within the micropipet, gen­

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duced relaxation (fig. 7, right) not signifi­ cantly different from that observed before elevation of transmural pressure.

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erally in the range of 10-60 mm Hg. Most of the stretch-activated channels thus far de­ scribed are relatively nonselective for mono­ valent cations. Some stretch activated chan­ nels are selective for either K+ [19, 22] or Ca2+ [20]. It is hypothesized that mechanoreception may be mediated through a modu­ lation of these ion channels when the cell membrane is stretched [25], Effect o f High [K+]0 and K* Channel Blockers on Pressure-Induced Depression o f EDRF Release In order to analyze the membrane events affected by pressure, the effects of elevated extracellular potassium concentration ([K+]o which causes membrane depolarization in endothelial cells [26, 27]) on the pressureinduced inhibition of EDRF release were investigated. Elevation of [K+]o to 25 mM had no effect, but 45 mM [K+]o significantly depressed ACh-induced relaxation of the bioassay tissue [28]. In addition, both 25 and 45 mM [K+]o prevented the pressure-in­ duced depression of the release of EDRF by ACh [28]. These data suggest that the effect of pressure on ACh-induced release of EDRF is sensitive to changes in membrane potential. Electrophysiological characterization of cultured endothelial cells has demonstrated that the resting membrane potential is prob­ ably maintained by an inward rectifying po­ tassium channel [27, 29]. To study the possi­ ble involvement of this channel in pressureinduced depression of EDRF release, the ef­ fects of different potassium channel blockers were examined. The effect of pressure on the ACh-induced release of EDRF from the do­ nor tissue was prevented by the potassium channel blocker barium (1CH M ) but not by 4-aminopyridine (10-5 M) [28].

Rubanyi/Freay/Kauser/Johns/Harder

Hypothetical Model o f Mechanoreception by the Endothelium These data suggest that elevated pressure may depress the synthesis/release of EDRF by modulating (blocking) the inward rectify­ ing potassium channel. This hypothesis is supported by the finding that blockade of this potassium channel by cesium and bar­ ium [30] not only had an effect (i.e., depres­ sion of EDRF release) similar to that of ele­ vated pressure, but also prevented the effect of pressure [28]. It has been shown that the response of iso­ lated endothelial cells to shear stress is oppo­ site to that proposed for pressure (see above), since shear stress causes membrane hyperpolarization and activation of the in­ ward rectifying potassium channel of the en­ dothelial cell membrane [31]. Opposing in­ teractions between pressure and shear stress on the release of EDRF from canine carotid arteries was reported recently [ 10] (see also fig. 7). The potential (still hypothetical) mechanisms involved in the mdoulation of EDRF release by pressure and shear stress are illustrated in figure 8. It is proposed that the main driving force on calcium entry into the endothelial cells is the membrane poten­ tial. This hypothesis is supported by experi­ ments that have demonstrated the lack of voltage-operated calcium channels in cul­ tured endothelial cells [26, 30] and that high extracellular potassium concentration de­ creases calcium uptake into cultured endo­ thelial cells [26]. The changes in membrane potential induced by increases in shear stress (i.e., hyperpolarization) and by pressure (i.e., depolarization) would therefore increase or decrease the driving force on calcium entry, respectively. The changes in the driving force would then lead to increased (shear stress) or decreased (pressure) calcium entry.

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Fig. 8. Hypothetical mecha­ nisms that could be involved in the control of EDRF release by pres­ sure and shear stress in endothelial cells. (For details see text.)

Ionic Mechanisms Responsible for Pressure-Induced Endothelium-Mediated Membrane Depolarization in Vascular Smooth Muscle of Cat Cerebral Arteries It appears that the stimulated release of endothelial vasoconstrictor substance(s) (EDCF) or inhibited release of a hyperpolarizing factor (EDHF) by elevations in pres­ sure in cat cerebral arteries act through regu­ lation of ion conductance systems in the vas­ cular smooth muscle membrane as deter­ mined by their ability to depolarize these cells. Both the membrane depolarization and contraction of cerebral arteries in response to pressure depends upon extracellular Ca2+ ([Ca]o). Raising [Ca]o from 2.5 to 4.0 mM

significantly increased the slope of the line relating the change in membrane potential (degree of depolarization) and transmural pressure, while reducing [Ca]o to 0.5 mM abolishes this relationship [11], While extra­ cellular calcium is required for these re­ sponses, ionic mechanisms other than direct activation of Ca2+ conductance may also be responsible for the membrane depolariza­ tion action of the endothelium-derived con­ strictor factor(s). There is a fine balance be­ tween outward K+ current and inward Ca2+ current in vascular muscle and it is possible that an endothelial contractile factor (or the lack of a hyperpolarizing factor) may act to depolarize arterial muscle by regulating K+ conductance.

Conclusions These observations suggest that the endo­ thelium may serve as a unique mechanosensor of flow rate and pressure. Increases in flow rate (shear stress) stimulate the synthe-

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The inward rectifying potassium channel is suggested to be the pressure and shear stress ‘sensor’ in the endothelial cell membrane. However, the mechanisms involved in the alteration of the channel kinetics by these physical forces remain to be elucidated.

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constrictor factor (EDCF), and (3) direct ac­ tion on vascular smooth muscle cells (fig. 9). Thus the endothelium can serve as a pressure transducer and may mediate or contribute to the ‘myogenic’ response, originally thought to be of smooth muscle origin. This recently revealed regulatory mechanism may play a role in the autoregulation of blood flow in the cerebral and renal vascular beds.

Fig. 9. Endothelium-mediated control of vascular smooth muscle tone by flow and pressure. Increases in flow (shear stress) trigger the release of EDRF and evoke vasodilation. Pressure-induced vasoconstric­ tion may be mediated by (1) reduced release of EDRF; (2) facilitated release of EDCF, and (3) direct action on smooth muscle cells. (Reproduced with per­ mission of Perinatology Press.)

sis/release of EDRF in endothelial cells (fig. 9). Although the cellular mechanisms re­ main to be determined, this unique function of the endothelium may contribute to the local adjustment of vascular tone under var­ ious conditions (i.e. negative feedback regula­ tion of shear forces acting on endothelial cells). Several pieces of evidence suggest that active contraction of vascular smooth muscle in response to increases in pressure is me­ diated by the endothelium. Pressure-induced vasoconstriction may be mediated by (1) re­ duced release of EDRF and/or EDHF; (2) facilitated release of endothelium-derived

1 Bayliss, W.M.: On the local reaction of the arterial wall to changes of internal pressure. J. Physiol., Lond. 2S: 220-231 (1902). 2 Johnson, P.C.: The myogenic response; in Bohr, Somlyo, Sparks, Handbook of physiology. Section 2. The cardiovascular system. Vol. 2. Vascular smooth muscle, pp. 409-442 (American Physio­ logical Society, Bethesda 1980). 3 Busse, R.; Pohl, U.; Forstermann, U.: Bassenge, E.: Endothelium-dependent modulation of ar­ terial smooth muscle tone and PGF-relcase: pul­ satile versus steady flow; in Pohl, Forstermann. Busse, Bassenge, Schror, Prostaglandins and other eicosanoids in the cardiovascular system, pp. 553-558 (Karger, Basel 1985). 4 Hintze, T.H.; Vatner, S.F.: Reactive dilation of larger coronary arteries in conscious dogs. Circu­ lation Res. 54: 50-57 (1984). 5 Holtz, F.; Forstermann, U.; Pohl, U.; Geisler, M.; Bassenge, E.: Flow-dependent, endothelium-me­ diated dilation of epicardial coronary arteries in conscious dogs: effects of cyclooxygenase inhibi­ tion. J. cardiovasc. Pharmacol. 6: 1161-1169 (1984). 6 Smiesko, V.; Kozik, J.; Dolezel, S.: Role of endo­ thelium in the control of arterial diameter by blood flow. Blood Vessels 22: 247-251 (1986). 7 Frangos, J.A.; Eskin, G.; Mclntire, L.V.; Ives, C.L.: Flow effects on prostacyclin production by cultured human endothelial cells. Science 227: 1477-1479 (1985). 8 Rubanyi, G.M.; Romero, J.C.; Vanhoutte, P.M.: Flow-induced release of endothelium-derived re­ laxing factor. Am. J. Physiol. 250: HI 145—H 1149 (1986).

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References

Mechanoreception by the Endothelium

21 Lansman, J.B.; Haltam, T.J.; Rink, T.J.: Single stretch-activated ion channels in vascular endo­ thelial cells as mechanotransducers. Nature 325: 811-813 (1987). 22 Sackin, H.: Stretch-activated potassium channels in renal proximal tubule. Am. J. Physiol. 253: F1253-F1262 (1987). 23 Kirber, M.T.; Walsh, J.V., Jr.; Singer, J.J.: Stretchactivated ion channels in smooth muscle a mech­ anism for the initiation of stretch-induced con­ traction. Pflügers Arch. 412: 339-346 (1988). 24 Craelius, W.; Chen, V.; El-Sherif, N.: Stretch acti­ vated ion channels in ventricular myocytes. Biosci. Rep. «. 407-414 (1988). 25 Sachs, F.: Biophysics of mechanoreception. Membr. Bioch. 6: 173-195 (1986). 26 Northover, B.J.: The membrane potential of vas­ cular endothelial cells. Adv. Microcirc., vol. 9, pp. 135-160 (Karger, Basel 1980). 27 Johns, A.; Lategan, T.W.; Lodge, N.J.; Ryan, U.S.; van Breemen, C.; Adams, D.J.: Calcium entry through receptor-operated channels in bovine pul­ monary artery endothelial cells. Tissue Cell 19: 733-745 (1987). 28 Freay, A.D.; Johns, A.; van Breemen, C.; Ruba­ nyi, G.M.: Pressure-induced depression of EDRF release from canine carotid arteries is prevented by K'-channel blockers in vascular endothelial cells. Am. J. Physiol, (submitted). 29 Takeda, K.; Schini, V.; Stoeckel, H.: Voltage-acti­ vated potassium, but not calcium currents in cul­ tured bovine aortic endothelial cells. Pflügers Arch. 410: 385-393 (1987). 30 Hille, B.: Ion channels of excitable membranes (Sinauer, Sunderland 1984). 31 Olesen, S.-P.; Clapham, D.E.; Davies, P.F.: Hae­ modynamic shear stress activates a K ‘ current in vascular endothelial cells. Nature 331: 168-170 (1988).

Gabor M. Rubanyi, MD, PhD Berlex Laboratories, Inc. 110 East Hanover Avenue Cedar Knolls, NJ 07927-2095 (USA)

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9 Katusic, Z.S.; Shepherd, J.T.; Vanhoutte, P.M.: Endothelium-dependent contraction to stretch in canine basilar arteries. Am. J. Physiol. 252: H671-H673 (1987). 10 Rubanyi, G.M.: Endothelium-dependent pres­ sure-induced contraction of isolated canine ca­ rotid arteries. Am. J. Physiol. 255: H783-H788 (1988) . 11 Harder, D.R.: Pressure-induced myogenic activa­ tion of cat cerebral arteries is dependent on intact endothelium. Circulation Res. 60: 102-107 (1987). 12 Harder, D.R.; Gilbert, R.; Lombard, J.H.: Vascu­ lar muscle cell depolarization and activation in renal arteries on elevation of transmural pressure. Am. J. Physiol. 253: F778-F781 (1987). 13 Rubanyi, G.M.; Lorenz, R.R.; Vanhoutte, P.M.: Bioassay of endothelium-derived relaxing fac­ tors). Inactivation by catecholamines. Am. J. Physiol. 249: H95-H101 (1985). 14 Harder, D.R.; Sanchez-Ferrer, C ; Kauser, K.; Stekiel, W.J.; Rubanyi, G.M.: Pressure releases a transferable endothelial contractile factor in cat cerebral arteries. Circulation Res. 65: 193-198 (1989) . 15 Kauser, K.; Rubanyi, G.M.; Harder, D.R.: Endo­ thelium-dependent modulation of endothelin-induced vasoconstriction and membrane depolari­ zation in cat cerebral arteries. J. Pharmac. exp. Ther. 252: 93-97 (1990). 16 Hamill, O.P.: Stretch-channels in erythrocytes; in Sakmann, Neher, Single channel recording, pp. 451-471 (Plenum Press, New York 1983). 17 Brehm, P.; Kuhlberg, R.; Moody-Corbett, F.: Properties of nonjunctional acetyl choline recep­ tor channels on innervated muscle of xenopus-laevis. J. Physiol., Lond. 350: 631-648 (1984). 18 Sakmann, B.; Methfessel, C.; Mishina, M.; Taka­ hashi, T.; Takai, T.; Masaki, K.; Fukoda, K.; Numa, S.: Role of acetylcholine receptor subunits in gating of the channel. Nature 318: 538-540 (1985). 19 Sigurdson, W.J.; Morris, C.E.; Brezden, B.L.; Gardner, D.R.: Stretch activation of a potassium channel in molluscan heart cells. J. exp. Biol. 127: 191-209 (1986). 20 Christensen, O.: Mediation of cell volume regula­ tion by calcium influx through stretch-activated channels. Nature 330: 66-68 (1987).

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Mechanoreception by the endothelium: mediators and mechanisms of pressure- and flow-induced vascular responses.

Mechanoreception, a widely distributed sensory modality, has been shown to be present in certain blood vessels. Changes in physical forces, like sudde...
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