Comprehensive Physiology Wiley Online Library

Neuromuscular transmission in intramural blood vessels

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Organization and Structure of Intramural Blood Vessels
2 Innervation of Intramural Blood Vessels
3 Passive Electrical Properties of Submucosal Arterioles
3.1 Resting Potential
3.2 Electrical Coupling Between Arteriolar Smooth Muscle Cells
3.3 Summary
4 Neuromuscular Transmission in Arterioles
5 Responses of Submucosal Arterioles to Sympathetic Nerve Stimulation
6 Analysis of Excitatory Junction Potentials
6.1 Time Course
6.2 Quantal Content
6.3 Summary
7 Initiation of Contraction in Submucosal Arterioles
7.1 Potential‐Dependent Calcium Entry
7.2 Receptor‐Activated Tension Development
7.3 Summary
8 Integration in Submucosal Arterioles
9 Pharmacology of Excitatory Junction Potentials
9.1 Identity of Transmitter Responsible for Initiation of Excitatory Junction Potentials
10 Summary and Future Directions
Figure 1. Figure 1.

Micrographs of submucosal arteriole of guinea pig ileum viewed with conventional optics showing submucosal arterioles that were dissected from a segment of guinea pig ileum. An arteriole with ∼50‐μm diam runs diagonally across micrographs; finer branch at proximal end is visible in right corner. Arteriole has wall thickness of ∼5 μm, which is less than that of red blood cells remaining in vessel lumen in A. B shows the same vessel during maintained sympathetic nerve stimulation. Calibration bar, 30 μm.

From Hirst
Figure 2. Figure 2.

Micrographs showing sympathetic innervation of submucosal arteriole of guinea pig. Preparation was fixed and viewed with Falck‐Hillarp technique, which demonstrates catecholamine‐containing nerves. Two plates are of same segment of arteriolar tree: one is focused on luminal surface and other on inner surface of arteriole. Bundles of brightly fluorescent axons and single beaded axons can be seen wrapped around arteriole. Calibration bar, μm. 50 μm.

Micrography courtesy of E. M. MacLachlan
Figure 3. Figure 3.

Electron micrograph of sympathetic nerve varicosity. Figure shows varicosity in apposition with 2 submucosal arteriolar smooth muscle cells. Arrow, basal laminae of 1 smooth muscle cell and varicosity are fused. In this section and adjacent ones separation between nerve and muscle was 60 μm. Note abundant small granular vesicles, mitochondria, and occasional large granular vesicle. Calibration bar, 0.5 μm.

Micrograph courtesy of S. Luff.
Figure 4. Figure 4.

Reconstruction of 2 different varicosities. Figure illustrates small (upper) and averaged‐sized (lower) varicosity. Figure prepared by computer superimpositions of successive electron micrographs. Dotted lines, membranes of varicosities seen in sequential sections; crosses, positions of synaptic vesicles; solid shading, areas of fusion of basal laminae, where thickening of these areas reflect undulations in areas of contact rather than variations in cleft width; solid lines, sections of arteriolar muscle membrane. Larger varicosity has a larger area of contact and contains more vesicles. In both, vesicles are concentrated toward regions of apposition with underlying smooth muscle layer. Calibration bar, 1.0 μm. (Micrograph courtesy of S. Luff and E. M. MacLachlan.)

Figure 5. Figure 5.

Drawing of lower varicosity shown in Fig. . For clarity only 1 neuronal membrane has been shown. Open circles, small granular vesicles. Vesicles are connected toward region of fused basal lamellae. Varicosity is en passant; terminal axons can be seen originating on either side of junctional swelling. Calibration bar, 0.5 μm.

Figure 6. Figure 6.

Relationship between membrane potential of submucosal arterioles and external potassium concentration. Closed circles, membrane potentials of submucosal arterioles measured in different extracellular potassium concentrations; solid line, relationship between membrane potential and potassium concentration predicted by Goldman‐Hodgkin‐Katz equation with permeability ratios PK+:PCl‐:PNa+ assumed to be 1:0.09:0.005; dashed line, Nernst prediction for relationship with an intracellular potassium concentration of 120 mM. Fit between Goldman‐Hodgkin‐Katz prediction and experimental data is good for external potassium concentrations in range of 4 to 80 mM. At concentrations <4 mM a marked difference between predicted and observed relationships is apparent.

From Hirst and van Helden
Figure 7. Figure 7.

Relationship between membrane resistance and external potassium concentration. Closed circles, membrane resistances (Rm) of submucosal arterioles [expressed as a ratio of resistance in test potassium to resistance in control potassium (5 mM)], which were determined in different extracellular potassium concentrations. Dashed line, crossing a ratio of unity (solid line), is relationship between membrane resistance and potassium concentration predicted by Goldman‐Hodgkin‐Katz equation. Similar to Fig. there is a marked divergence between predicted and observed curves at extracellular potassium concentrations <4 mM.

From Hirst and van Helden
Figure 8. Figure 8.

Electrical coupling between arteriolar smooth muscle cells. Two independent intracellular recording electrodes were inserted into separate branches of same arteriolar tree with total separation of 580 μm. When current (1 nA) was passed through 1 electrode a membrane potential change was detected at other electrode. Potential change (upper trace) was not detected if same current was passed through current‐passing electrode after just withdrawing it from arteriolar smooth muscle layer.

From Hirst and Neild
Figure 9. Figure 9.

Passive electrical properties of 1.4‐mm segment of arteriole. One electrode, used to inject current, was inserted in center of preparation and second electrode, used for recording membrane potential, was inserted toward one end of arteriole. Short and long current pulses were injected and resultant membrane potential changes, along with excitatory junction potentials evoked by transmural stimulation, were recorded. Data are plotted in the right half of figure. Time course of decay of 3 potential changes is the same, and each can be described by a single exponential. These data can be used to determine passive electrical properties of arteriole (for further details, see ref. .

From Hirst and Neild
Figure 10. Figure 10.

Membrane potential changes recorded from submucosal arteriole in responses to perivascular nerve stimulation. Traces show membrane potential changes produced by 1, 3 (10 Hz), 4 (10 Hz), and 5 stimuli (20 Hz). Excitatory junction potential, initiated by single stimulus, has time to peak of ∼100 ms and total duration of ∼1 s. With large number of stimuli, junctional depolarization exceeded threshold and initiated action potentials with rapid and plateau components. Arteriolar constriction was only detected if an action potential had been first initiated.

From Hirst
Figure 11. Figure 11.

Relationship between amplitude of excitatory junction potentials (EJPs) recorded from 2 different arterioles and stimulus strength applied to perivascular nerves. As strength is increased, amplitude of EJPs increases up to a maximum value. Relationships are not smooth, indicating that each arteriole is innervated by a number of fibers, each of a different threshold. Presumably finer vessel was innervated by 3 fibers and larger by 5 fibers.

From Hirst
Figure 12. Figure 12.

Time course of junctional current (open circles) derived from time course of excitatory junction potential (closed circles) and arteriolar passive electrical properties. Current time was calculated using equation suggested by Curtis and Eccles , which assumes that the segment of arteriole is isopotential during current flow. Current reaches peak after 10 ms and then decays to 0 within a further 200 ms. More prolonged time course of excitatory junction potential reflects long membrane time constant of arteriolar smooth muscle membrane.

From Hirst and Neild
Figure 13. Figure 13.

Comparison between excitatory junctional current (EJC) and excitatory junction potential (EJP) that it produces. EJP was recorded in voltage‐recording mode; EJC was recorded in single‐electrode voltage‐clamp mode. Decay of both can be described by single exponentials: time constant of decay of EJP was 485 ms and that of EJC was 47 ms.

From Hirst et al.
Figure 14. Figure 14.

Effect of membrane potential on excitatory junctional current (EJC) amplitude and time course. A: current records allow comparison between amplitude of EJC recorded at holding potential of −60 mV with those recorded during voltage‐clamp steps to −40 mV and −115 mV. At depolarized potential, current amplitude is reduced, and at hyperpolarized level, amplitude is increased. B: plots of time courses of these 3 junctional currents: time course of decay of each is very similar. Rise time of EJC is slowed because of filtering (100 Hz) to improve signal‐to‐noise ratio.

From Finkel et al.
Figure 15. Figure 15.

Recordings from short segment of arteriole during train of low‐frequency, supramaximal transmural stimuli. Arrows, successive excitatory junction potentials (EJPs) fluctuate in amplitude but not time course. Spontaneous EJPs (SEJPs), with a similar time course, occurred at irregular intervals during recording period. Only a few SEJPs would have to be released synchronously to generate an EJP

From Hirst and Neild
Figure 16. Figure 16.

Voltage‐clamp recording from short segment of arteriole during train of low‐frequency, supramaximal transmural stimuli; 6 successive records of membrane current (holding potential −60 mV) are shown. Closed circles, stimuli were given. Successive excitatory junctional currents (EJCs) fluctuated in amplitude and on one occasion failed to release. Spontaneous EJCs (SEJCs) are also shown as irregularly occurring inward currents; again their amplitudes are only slightly smaller than those evoked currents. SEJCs had peak amplitudes of 0.1–0.2 nA.

From Finkel et al.
Figure 17. Figure 17.

Regenerative membrane potential changes initiated in rat cerebral arterioles. Each record was made from same short segment of arteriole and shows membrane potential changes produced by injecting depolarizing currents. A: control solution; a small regenerative potential change is superimposed on depolarizing potential change. B: after addition of tetraethylammonium chloride (TEA; 10 mM), depolarization now produced larger amplitude regenerative potential changes. C: duration of depolarizing pulse was shortened and 2‐component action potential was readily distinguished. D: action potential had rapid component and slower plateau component each of which persisted in presence of tetrodotoxin (TTX; 1 × 10−6 M). E: control response obtained before addition of manganese ions. F: both components were abolished by substitution of calcium ions by manganese ions.

From Hirst et al.
Figure 18. Figure 18.

Integrals of inward calcium currents in cerebral arterioles. When segments of arteriole were voltage clamped and their potentials stepped to depolarized potentials, 2 distinct inward currents were detected. Small depolarizations resulted in a small‐amplitude, noninactivating current; with larger depolarizations a rapidly inactivating component was superimposed on noninactivating current. Integrals of current flowing through low‐threshold, noninactivating current (open circles) and high‐threshold, inactivating current (closed circles) are plotted as function of membrane potential. Charge increases smoothly as function of depolarization.

From Hirst et al.
Figure 19. Figure 19.

Comparison between membrane potential changes and arteriolar diameter changes produced by repetitive nerve stimulation and superfusion of norepinephrine [noradrenaline (NA)]. A: perivascular nerves were stimulated repetitively to produce maintained depolarization of ∼7 mV; stimulus strength was adjusted so only 1 or 2 nerve fibers were stimulated and to prevent initiation of suprathreshold membrane potential change. This potential change did not lead to constriction. B: in contrast, a threshold concentration of norepinephrine (1 × 10−6 M) caused membrane potential to become “noisy” but produced a constriction. Both responses to norepinephrine unlike responses to sympathetic nerve stimulation, were abolished by phentolamine or prazosin.

Figure 20. Figure 20.

Calculations of membrane potential changes that occur in blood vessels of different sizes during repetitive asynchronous sympathetic nerve activity. A: rabbit ear artery (diam 150 μm); B: arteriole of guinea pig submucosa (diam 50 μm). Sustained but irregular potential changes occur in both vessels and in finer vessel, at a given frequency of stimulation, membrane potential change is larger.

From Neild
Figure 21. Figure 21.

Membrane potential changes produced by ionophoretic application of norepinephrine. A: records were produced by 2 pulses of norepinephrine (duration 10 ms, 40 and 50 nA, respectively); B: records produced by similar pulses after adding phentolamine (3 × 10−5 M) to physiological saline. Both responses persist and a spontaneous excitatory junction potential is also seen.

Figure 22. Figure 22.

Junctional localization of positions where norepinephrine produces receptor activation. Trace A shows membrane potential response produced by ionophoretic application of norepinephrine. Traces B and C show lack of membrane potential changes when electrode position was varied. D: map of distribution of sympathetic nerve fibers. Open circles, positions at which depolarizing responses were detected; closed circles, points where membrane potential changes were not detected. All “hot spots” were subsequently found to be within 10 μm of a fluorescent nerve.

From Hirst and Neild
Figure 23. Figure 23.

Activation of γ‐receptors by bath‐applied norepinephrine [noradrenaline (NA)]. Records were made from a submucosal arteriole in presence of prazosin (1 × 10−6 M). Norepinephrine was applied by superfusion. Note high concentration of norepinephrine required to activate receptors; similar responses were detected in lower concentrations of prazosin, suggesting that responses do not result from activation of receptors.

Figure 24. Figure 24.

Diagram of neural control system in submucosal arteriole. Figure shows sympathetic varicosity containing small granular vesicles (open circles; s.g.v.); vesicles are concentrated toward region of apposition (shaded area) between varicosity and underlying smooth muscle cell. Individual smooth muscle cells are electrically coupled to neighboring cells by low‐resistance electrical contacts (gap junction); resulting syncytium forms neuroeffector target. In junctional cleft, specialized receptors to norepinephrine are located (γ‐receptors), which when activated allow an influx of sodium ions and an efflux of potassium ions. Resulting depolarization causes opening of voltage‐dependent calcium channels (hexagon), leading to calcium entry from extracellular fluid. In contrast, α‐receptors, which have an extrajunctional location, when activated by norepinephrine, lead to increase in internal calcium concentration by discharging a bound store.



Figure 1.

Micrographs of submucosal arteriole of guinea pig ileum viewed with conventional optics showing submucosal arterioles that were dissected from a segment of guinea pig ileum. An arteriole with ∼50‐μm diam runs diagonally across micrographs; finer branch at proximal end is visible in right corner. Arteriole has wall thickness of ∼5 μm, which is less than that of red blood cells remaining in vessel lumen in A. B shows the same vessel during maintained sympathetic nerve stimulation. Calibration bar, 30 μm.

From Hirst


Figure 2.

Micrographs showing sympathetic innervation of submucosal arteriole of guinea pig. Preparation was fixed and viewed with Falck‐Hillarp technique, which demonstrates catecholamine‐containing nerves. Two plates are of same segment of arteriolar tree: one is focused on luminal surface and other on inner surface of arteriole. Bundles of brightly fluorescent axons and single beaded axons can be seen wrapped around arteriole. Calibration bar, μm. 50 μm.

Micrography courtesy of E. M. MacLachlan


Figure 3.

Electron micrograph of sympathetic nerve varicosity. Figure shows varicosity in apposition with 2 submucosal arteriolar smooth muscle cells. Arrow, basal laminae of 1 smooth muscle cell and varicosity are fused. In this section and adjacent ones separation between nerve and muscle was 60 μm. Note abundant small granular vesicles, mitochondria, and occasional large granular vesicle. Calibration bar, 0.5 μm.

Micrograph courtesy of S. Luff.


Figure 4.

Reconstruction of 2 different varicosities. Figure illustrates small (upper) and averaged‐sized (lower) varicosity. Figure prepared by computer superimpositions of successive electron micrographs. Dotted lines, membranes of varicosities seen in sequential sections; crosses, positions of synaptic vesicles; solid shading, areas of fusion of basal laminae, where thickening of these areas reflect undulations in areas of contact rather than variations in cleft width; solid lines, sections of arteriolar muscle membrane. Larger varicosity has a larger area of contact and contains more vesicles. In both, vesicles are concentrated toward regions of apposition with underlying smooth muscle layer. Calibration bar, 1.0 μm. (Micrograph courtesy of S. Luff and E. M. MacLachlan.)



Figure 5.

Drawing of lower varicosity shown in Fig. . For clarity only 1 neuronal membrane has been shown. Open circles, small granular vesicles. Vesicles are connected toward region of fused basal lamellae. Varicosity is en passant; terminal axons can be seen originating on either side of junctional swelling. Calibration bar, 0.5 μm.



Figure 6.

Relationship between membrane potential of submucosal arterioles and external potassium concentration. Closed circles, membrane potentials of submucosal arterioles measured in different extracellular potassium concentrations; solid line, relationship between membrane potential and potassium concentration predicted by Goldman‐Hodgkin‐Katz equation with permeability ratios PK+:PCl‐:PNa+ assumed to be 1:0.09:0.005; dashed line, Nernst prediction for relationship with an intracellular potassium concentration of 120 mM. Fit between Goldman‐Hodgkin‐Katz prediction and experimental data is good for external potassium concentrations in range of 4 to 80 mM. At concentrations <4 mM a marked difference between predicted and observed relationships is apparent.

From Hirst and van Helden


Figure 7.

Relationship between membrane resistance and external potassium concentration. Closed circles, membrane resistances (Rm) of submucosal arterioles [expressed as a ratio of resistance in test potassium to resistance in control potassium (5 mM)], which were determined in different extracellular potassium concentrations. Dashed line, crossing a ratio of unity (solid line), is relationship between membrane resistance and potassium concentration predicted by Goldman‐Hodgkin‐Katz equation. Similar to Fig. there is a marked divergence between predicted and observed curves at extracellular potassium concentrations <4 mM.

From Hirst and van Helden


Figure 8.

Electrical coupling between arteriolar smooth muscle cells. Two independent intracellular recording electrodes were inserted into separate branches of same arteriolar tree with total separation of 580 μm. When current (1 nA) was passed through 1 electrode a membrane potential change was detected at other electrode. Potential change (upper trace) was not detected if same current was passed through current‐passing electrode after just withdrawing it from arteriolar smooth muscle layer.

From Hirst and Neild


Figure 9.

Passive electrical properties of 1.4‐mm segment of arteriole. One electrode, used to inject current, was inserted in center of preparation and second electrode, used for recording membrane potential, was inserted toward one end of arteriole. Short and long current pulses were injected and resultant membrane potential changes, along with excitatory junction potentials evoked by transmural stimulation, were recorded. Data are plotted in the right half of figure. Time course of decay of 3 potential changes is the same, and each can be described by a single exponential. These data can be used to determine passive electrical properties of arteriole (for further details, see ref. .

From Hirst and Neild


Figure 10.

Membrane potential changes recorded from submucosal arteriole in responses to perivascular nerve stimulation. Traces show membrane potential changes produced by 1, 3 (10 Hz), 4 (10 Hz), and 5 stimuli (20 Hz). Excitatory junction potential, initiated by single stimulus, has time to peak of ∼100 ms and total duration of ∼1 s. With large number of stimuli, junctional depolarization exceeded threshold and initiated action potentials with rapid and plateau components. Arteriolar constriction was only detected if an action potential had been first initiated.

From Hirst


Figure 11.

Relationship between amplitude of excitatory junction potentials (EJPs) recorded from 2 different arterioles and stimulus strength applied to perivascular nerves. As strength is increased, amplitude of EJPs increases up to a maximum value. Relationships are not smooth, indicating that each arteriole is innervated by a number of fibers, each of a different threshold. Presumably finer vessel was innervated by 3 fibers and larger by 5 fibers.

From Hirst


Figure 12.

Time course of junctional current (open circles) derived from time course of excitatory junction potential (closed circles) and arteriolar passive electrical properties. Current time was calculated using equation suggested by Curtis and Eccles , which assumes that the segment of arteriole is isopotential during current flow. Current reaches peak after 10 ms and then decays to 0 within a further 200 ms. More prolonged time course of excitatory junction potential reflects long membrane time constant of arteriolar smooth muscle membrane.

From Hirst and Neild


Figure 13.

Comparison between excitatory junctional current (EJC) and excitatory junction potential (EJP) that it produces. EJP was recorded in voltage‐recording mode; EJC was recorded in single‐electrode voltage‐clamp mode. Decay of both can be described by single exponentials: time constant of decay of EJP was 485 ms and that of EJC was 47 ms.

From Hirst et al.


Figure 14.

Effect of membrane potential on excitatory junctional current (EJC) amplitude and time course. A: current records allow comparison between amplitude of EJC recorded at holding potential of −60 mV with those recorded during voltage‐clamp steps to −40 mV and −115 mV. At depolarized potential, current amplitude is reduced, and at hyperpolarized level, amplitude is increased. B: plots of time courses of these 3 junctional currents: time course of decay of each is very similar. Rise time of EJC is slowed because of filtering (100 Hz) to improve signal‐to‐noise ratio.

From Finkel et al.


Figure 15.

Recordings from short segment of arteriole during train of low‐frequency, supramaximal transmural stimuli. Arrows, successive excitatory junction potentials (EJPs) fluctuate in amplitude but not time course. Spontaneous EJPs (SEJPs), with a similar time course, occurred at irregular intervals during recording period. Only a few SEJPs would have to be released synchronously to generate an EJP

From Hirst and Neild


Figure 16.

Voltage‐clamp recording from short segment of arteriole during train of low‐frequency, supramaximal transmural stimuli; 6 successive records of membrane current (holding potential −60 mV) are shown. Closed circles, stimuli were given. Successive excitatory junctional currents (EJCs) fluctuated in amplitude and on one occasion failed to release. Spontaneous EJCs (SEJCs) are also shown as irregularly occurring inward currents; again their amplitudes are only slightly smaller than those evoked currents. SEJCs had peak amplitudes of 0.1–0.2 nA.

From Finkel et al.


Figure 17.

Regenerative membrane potential changes initiated in rat cerebral arterioles. Each record was made from same short segment of arteriole and shows membrane potential changes produced by injecting depolarizing currents. A: control solution; a small regenerative potential change is superimposed on depolarizing potential change. B: after addition of tetraethylammonium chloride (TEA; 10 mM), depolarization now produced larger amplitude regenerative potential changes. C: duration of depolarizing pulse was shortened and 2‐component action potential was readily distinguished. D: action potential had rapid component and slower plateau component each of which persisted in presence of tetrodotoxin (TTX; 1 × 10−6 M). E: control response obtained before addition of manganese ions. F: both components were abolished by substitution of calcium ions by manganese ions.

From Hirst et al.


Figure 18.

Integrals of inward calcium currents in cerebral arterioles. When segments of arteriole were voltage clamped and their potentials stepped to depolarized potentials, 2 distinct inward currents were detected. Small depolarizations resulted in a small‐amplitude, noninactivating current; with larger depolarizations a rapidly inactivating component was superimposed on noninactivating current. Integrals of current flowing through low‐threshold, noninactivating current (open circles) and high‐threshold, inactivating current (closed circles) are plotted as function of membrane potential. Charge increases smoothly as function of depolarization.

From Hirst et al.


Figure 19.

Comparison between membrane potential changes and arteriolar diameter changes produced by repetitive nerve stimulation and superfusion of norepinephrine [noradrenaline (NA)]. A: perivascular nerves were stimulated repetitively to produce maintained depolarization of ∼7 mV; stimulus strength was adjusted so only 1 or 2 nerve fibers were stimulated and to prevent initiation of suprathreshold membrane potential change. This potential change did not lead to constriction. B: in contrast, a threshold concentration of norepinephrine (1 × 10−6 M) caused membrane potential to become “noisy” but produced a constriction. Both responses to norepinephrine unlike responses to sympathetic nerve stimulation, were abolished by phentolamine or prazosin.



Figure 20.

Calculations of membrane potential changes that occur in blood vessels of different sizes during repetitive asynchronous sympathetic nerve activity. A: rabbit ear artery (diam 150 μm); B: arteriole of guinea pig submucosa (diam 50 μm). Sustained but irregular potential changes occur in both vessels and in finer vessel, at a given frequency of stimulation, membrane potential change is larger.

From Neild


Figure 21.

Membrane potential changes produced by ionophoretic application of norepinephrine. A: records were produced by 2 pulses of norepinephrine (duration 10 ms, 40 and 50 nA, respectively); B: records produced by similar pulses after adding phentolamine (3 × 10−5 M) to physiological saline. Both responses persist and a spontaneous excitatory junction potential is also seen.



Figure 22.

Junctional localization of positions where norepinephrine produces receptor activation. Trace A shows membrane potential response produced by ionophoretic application of norepinephrine. Traces B and C show lack of membrane potential changes when electrode position was varied. D: map of distribution of sympathetic nerve fibers. Open circles, positions at which depolarizing responses were detected; closed circles, points where membrane potential changes were not detected. All “hot spots” were subsequently found to be within 10 μm of a fluorescent nerve.

From Hirst and Neild


Figure 23.

Activation of γ‐receptors by bath‐applied norepinephrine [noradrenaline (NA)]. Records were made from a submucosal arteriole in presence of prazosin (1 × 10−6 M). Norepinephrine was applied by superfusion. Note high concentration of norepinephrine required to activate receptors; similar responses were detected in lower concentrations of prazosin, suggesting that responses do not result from activation of receptors.



Figure 24.

Diagram of neural control system in submucosal arteriole. Figure shows sympathetic varicosity containing small granular vesicles (open circles; s.g.v.); vesicles are concentrated toward region of apposition (shaded area) between varicosity and underlying smooth muscle cell. Individual smooth muscle cells are electrically coupled to neighboring cells by low‐resistance electrical contacts (gap junction); resulting syncytium forms neuroeffector target. In junctional cleft, specialized receptors to norepinephrine are located (γ‐receptors), which when activated allow an influx of sodium ions and an efflux of potassium ions. Resulting depolarization causes opening of voltage‐dependent calcium channels (hexagon), leading to calcium entry from extracellular fluid. In contrast, α‐receptors, which have an extrajunctional location, when activated by norepinephrine, lead to increase in internal calcium concentration by discharging a bound store.

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G. D. S. Hirst. Neuromuscular transmission in intramural blood vessels. Compr Physiol 2011, Supplement 16: Handbook of Physiology, The Gastrointestinal System, Motility and Circulation: 1635-1665. First published in print 1989. doi: 10.1002/cphy.cp060145