Endothelium‐dependent hyperpolarizations: Past beliefs and present facts

Figures & data

Figure 1. Endothelium‐dependent relaxation and endothelium‐dependent hyperpolarization. A: Left: The isometric tension developed by an arterial ring is studied in an organ chamber filled with thermostated and oxygenated physiological salt solution. The inset shows recording traces of an experiment reproducing the seminal observation first made by Furchgott and Zawadzki 4. An isolated ring of canine coronary artery with endothelium is contracted with prostaglandin F_2α (PGF_2α). The addition of acetylcholine produces a concentration‐dependent and endothelium‐dependent relaxation. Right: Bradykinin produces a concentration‐dependent and endothelium‐dependent relaxation in canine coronary arterial rings. The cyclooxygenase inhibitor, indomethacin, does not affect the relaxation to bradykinin while the NO synthase inhibitor L‐nitro‐arginine (L‐NA) produces a significant shift to the right of the concentration‐response curves, indicating a contribution of NO in the overall relaxation mechanism. The combination of the two inhibitors produces a further shift, indicating that prostacyclin contributes to the mechanism of bradykinin‐induced endothelium‐dependent relaxation when the NO synthase is inhibited. However, even in the presence of the two inhibitors, bradykinin still evokes the complete relaxation of the isolated arteries (modified from 210). SNP = sodium nitroprusside. B: Left: Changes in tension and in membrane potential are recorded in an isolated canine coronary artery with an intracellular microelectrode. Right: Acetylcholine produces a relaxation and a hyperpolarization of the vascular smooth muscle only when the endothelial cells are present (modified from 211).

Figure 2. Endothelium‐dependent hyperpolarizations in the guinea‐pig carotid artery. A: Acetylcholine (ACh) induces an endothelium‐dependent hyperpolarization. B: In the presence of charybdotoxin (ChTX) plus apamin plus indomethacin plus L‐nitro‐arginine (L‐NA), acetylcholine no longer produces an endothelium‐dependent hyperpolarization but a small depolarization. Depol. = depolarization. C: In the presence of charybdotoxin (ChTX) plus apamin, acetylcholine produces an endothelium‐dependent hyperpolarization attributable to the release of NO and PGI₂. PGI₂ = prostacyclin. D: In the presence of charybdotoxin (ChTX) plus apamin plus indomethacin, acetylcholine produces an endothelium‐dependent hyperpolarization attributable to the release of NO. E: In the presence of charybdotoxin (ChTX) plus apamin plus L‐nitro‐arginine, acetylcholine produces an endothelium‐dependent hyperpolarization attributable to the release of PGI₂. F: In the presence of indomethacin plus L‐nitro‐arginine (L‐NA), acetylcholine produces an EDHF‐mediated response. This response is not affected by the subsequent addition of a second NO synthase inhibitor, L‐monomethyl‐arginine (L‐NMMA) plus a NO scavenger, hemoglobin (middle trace), or another NO scavenger carboxy‐PTIO (lower trace), indicating that residual and stored NO are not involved.

Figure 3. EDHF‐mediated responses. The activation of endothelial receptors (R) and the shear stress exerted by the flowing blood increase endothelial [Ca²⁺]_i through calcium entry (TRP = transient receptor potential channel) and calcium release from internal stores (SR = sarcoplasmic reticulum). This activates endothelial K_Ca channels and produces endothelial hyperpolarization which is conducted through myoendothelial gap junctions to the underlying vascular smooth muscle. Cyclic‐AMP enhances the electrotonic conduction via gap junctions. Additionally, accumulation of potassium ions in the intercellular space can hyperpolarize the smooth muscle cells by activating K_IR and Na⁺/K⁺‐ATPase. The presence of a ‘potassium cloud’ can markedly affect the contribution of K⁺ ions to EDHF‐mediated responses. Contractile agonists that stimulate their receptor on vascular smooth muscle cells increase intracellular calcium (Ca²⁺) concentration and depolarize the cells. The rise in intracellular calcium activates BK_Ca while the depolarization activates K_V as a braking mechanism. Potassium effluxes through these two channels and accumulates in the intercellular space (potassium cloud). Potassium ions activate K_IR and Na⁺/K⁺‐ATPase, preventing the effects of any subsequent rise of potassium during endothelium‐dependent hyperpolarization. The relative proportion of each mechanism depends on numerous parameters, including the state of activation of the vascular smooth muscle, the density of myoendothelial gap junctions, and the level of the expression of the appropriate isoforms of Na⁺/K⁺‐ATPase and/or K_IR. BK = bradykinin; SP = substance P; SLIGRL‐NH2 = peptide agonist of proteinase‐activated recepor‐2; P3 = inositol trisphosphate; TRPV4 = transient receptor potential channel vanilloid 4; AC = adenylyl cyclase; αGA = glycyrrhetinic acid derivatives; CX = connexin; 4‐AP = 4‐aminopyridine; IbTX = iberiotoxin; ChTX = charybdotoxin; SK3 = small conductance calcium‐activated potassium channel formed by SK3 α subunits; IK1 = intermediate conductance calcium‐activated potassium channel formed by IK1 α subunits; Kir2.1 = Inward rectifying potassium channel constituted of Kir2.1 α subunits; K_V = voltage‐gated potassium channels; BK_Ca = large conductance calcium‐activated potassium channels (modified from 58); ACh = acetylcholine.

Figure 4. EDHF‐mediated responses in two strains of mice, wild‐type (C57BL/6), and NOS‐3 knockout mice (eNOS(−/−)). A: NOS‐3 knockout mice are hypertensive. B: Acetylcholine (ACh) produces an endothelium‐dependent relaxation in the isolated aortic rings of wild‐type mice (eNOS(+/+)) but no longer in that of NOS‐3 knockout mice (eNOS(−/−)). However, the NO donor and endothelium‐independent vasodilator sodium nitroprusside (SNP) produces a relaxation in the aorta from both strains. These results confirm the deletion of the NOS‐3 gene and demonstrate that, in a large blood vessel such as the aorta, NO is the preponderant endothelium‐derived relaxing factor released by acetylcholine. C: Acetylcholine induces a vasodilatation in the hindlimb of both wild‐type and NOS‐3 knockout mice. In the wild‐type mice, this vasodilatation is unaffected by a depolarizing solution (KCl) and partially inhibited by the combination of charybdotoxin (CTX) and apamin (apa) but not by charybdotoxin alone, indicating that an EDHF‐mediated response may contribute to the mechanism of vasodilatation but is not the preponderant mechanism. In the NOS‐3 knockout mice, the acetylcholine‐induced vasodilatation is preserved and is blocked by KCl or the combination of charybdotoxin plus apamin, partially inhibited by charybdotoxin alone and unaffected by the combination of iberiotoxin (IbTX), apamin, glibenclamide (Glib) and 4‐aminopyridine (4AP). These results indicate that acetylcholine induces an endothelium‐dependent vasodilatation showing the hallmarks of EDHF‐mediated responses. The EDHF‐mediated response compensates the disruption of the NOS‐3 gene. D: Original recording of arterial blood pressure in an anaesthetized NOS‐3 knockout mouse treated with an inhibitor of cyclooxygenase, diclofenac, and an inhibitor of NO synthase, L‐arginine‐methyl‐ester (L‐NAME). The intravenous administration of the endothelium‐dependent vasodilator bradykinin induces a transient decrease in arterial blood pressure. The summary bar graphs show the concentration‐dependent changes in mean arterial pressure (MAP) evoked by administration of bradykinin in wild‐type and eNOS(−/−) mice under control conditions (top graphs) or after treatment with inhibitors of cyclooxygenases and NO synthases (lower graphs). The amplitude of the hypotensive response induced by bradykinin is similar in NOS‐3 knockout and wild‐type animals. In both strains, the effect of bradykinin is unaffected by the presence of inhibitors of cyclooxygenases and NO synthases. These data strongly suggest that EDHF‐mediated responses play an essential role in the hypotensive effect of bradykinin (modified from 159). CTL = control.

Figure 5. Endothelium‐dependent hyperpolarizations in isolated human coronary arteries (in the presence of inhibitors of cyclooxygenases and NO synthases). A: In coronary arteries taken from a young patient (15 months old, congenital heart disease), bradykinin produces an endothelium‐dependent hyperpolarization. B: In coronary arteries taken from an older patient (64 years old, ischemic heart disease) the endothelium‐dependent hyperpolarization to bradykinin is reduced markedly when compared to that observed in the juvenile patient. C: In coronary arteries taken from a patient (68 years old, ischemic cardiomyopathy) the endothelium‐dependent hyperpolarization to bradykinin is virtually absent. The presence of the angiotensin‐converting enzyme inhibitor, perindoprilat, restores the endothelium‐dependent hyperpolarization (modified from 1).

Table I. Nonexhaustive summary of potential mechanisms underlying endothelium‐dependent hyperpolarizations/relaxations resistant to the combined presence of inhibitors of NO‐synthases and cyclooxygenases.

Species	Artery	Stimulus	NO	MEGJ	K^+ ions	EETs	Lipox.	H2O2	CNP	References
Guinea‐pig	Carotid	ACh		✓						134
	Mesenteric	ACh		✓						122,123
		SP		✓						126
	Coronary	ACh		✓						212
Rat	Hepatic	ACh	✓	✓	✓					55,132,144
	Mesenteric	ACh	✓	✓	✓				✓	55,94,113,130,134,138,144
		Flow						✓		213
	Cerebral	ATP, UTP		✓						214
		SLIGRL			✓					215
	Skelet. M.	Flow				✓				23
		ACh		✓		✓				216
Mouse	Mesenteric	ACh		✓	✓			✓		71,117,217
		SLIGRL		✓	✓					147
	Coronary	BK						✓		218
	Hindlimb	ACh		✓						159
Rabbit	Aorta	ACh					✓			35
	Carotid	ACh	✓			✓				52,219,220
	Ear	ACh		✓						136
	Iliac	ACh		✓						221
	Mesenteric	ACh		✓	✓		✓			133,222
	Cerebral	ACh		✓						223
Pig	Coronary	BK	✓	✓	✓	✓		✓		19,24,53,57,148,224
		SP		✓	✓			✓		24,148,224,225
	Renal	BK			✓					151
Dog	Coronary	ACh				✓		✓		74,226,227
Cow	Coronary	Methachol.				✓				21
		BK		✓	✓	✓				22,149,228
Human	Coronary	Arachid. A.				✓				173
		Flow						✓		68
	Mammary	ACh				✓				176
		BK				✓				176
	Radial	Flow				✓				187
	Mesenteric	BK								72
	Renal	ACh			✓			✓		152
	Resistance	BK		✓						128,177,229
		ACh			✓	✓				126,175,178

This table must be read with a critical mind. Firstly, the authors of the various reported studies very often only suggest a potential mechanism in order to explain these endothelium‐dependent hyperpolarizations/relaxations that are resistant to the combined presence of inhibitors of NO‐synthases and cyclooxygenases. Secondly, specific tools were not necessarily available at the time when some of the above‐mentioned studies were performed, possibly leading to erroneous conclusions. Thirdly, for the sake of clarity, this table has been simplified, and for instance a subheading such as ‘coronary artery’ includes data involving large and small arteries that may exhibit very different behavior.

NO = residual and/or stored nitric oxide; MEGJ = myoendothelial gap junction communication; EETs = cytochrome P450‐derived epoxyeicosatrienoic acids; Lipox = lipoxygenase derivatives; Skelet. M. = skeletal muscle; CNP: C‐type natriuretic peptide; Ach = acetylcholine; BK = bradykinin; SP = substance P; SLIGRL = tethered ligand sequence for proteinase‐activated receptor‐2 (PAR‐2); Arachid. A. = arachidonic acid; Methachol. = methacholine; ATP = adenosine triphosphate; UTP = uridine triphosphate.

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