Endothelium Derived Vasoactive Substances

Endothelium plays a central role in the regulation of vascular smooth muscle tone, including that of coronary artery. Although multiple pathways are involved in en-dothelium-induced relaxation, the major mechanism is via release of NO. L-NAME, an inhibitor of NO synthesis from l-arginine, has been a widely used tool to determine the role of NO. For example, exposure to L-NAME decreases hyperpolarization and relaxation of smooth muscle by acetylcholine demonstrating the participation of NO (69). The release of NO contributes to flow-related vasodilatation, reactive hyperemia, hy-percapnic acidosis, the vasodilatation by adenosine, and the maintenance of flow in the presence of coronary artery stenosis (70).

1. Nitric Oxide

Although there is evidence for direct action of NO on KCa channels (71), the majority of data supports that activation of guanylate cyclase (GC) (72), production of cGMP, and activation of PKG as the main pathway of NO and NO donor-induced smooth muscle dilatation. In native vessels, NO produced in the endothelium diffuses to adjacent coronary smooth muscle cells and triggers the GC-cGMP-PKG pathway and the phosphorylation of various target proteins (Ca2+ handling proteins), including KCa channels (Fig. 5).

KCa channels are also modulated by constitutively active GC, i.e., in the absence of NO or NO donor vasodilators. (73). This property was demonstrated using 1H-[1,2,4]oxadiazolo[4,3,-a] quinoxalin-1-one (ODQ), a selective inhibitor of GC and thus cGMP production. In coronary artery cells, ODQ decreased the basal KCa channel open probability by 60% and, as expected, failed to inhibit the response to a nonhydro-lyzable cGMP analogue, 8-bromo-cGMP. Interestingly, ODQ was more potent in reducing the vasodilation by NO donors than the KCa channel blocker Iberio-toxin, suggesting additional effectors besides KCa channels.

2. Arachidonic Acid and Fatty Acids

Arachidonic and other fatty acids activate KCa channels. The activation by fatty acids seems to be independent of cyclooxygenase or lipoxygenase pathways, as fatty acids, which are not substrates to these enzymes, were also able to activate KCa channels (74). The effect is likely mediated by a direct action on the channel or a closely associated protein rather than via intracellular pathways (74). Ordway et al. (75) were the first to demonstrate that KCa channels from frog stomach could be activated directly by polyunsaturated fatty acids, such as arachidonic acid, and also by monounsaturated (li-noelaidic) and saturated (myristic) free fatty acids. The primary requirement was the solubility of the free fatty acid. Later, a direct action of arachidonic acid (74) and its metabolite 11,12-epoxyeicosatrienoic acid (76) was demonstrated in vascular smooth muscle KCa channels and in smooth muscle-like mesangial cells (77) (important regulators of renal hemodynamics). Although ara-chidonic acid may increase guanylate cyclase activity (78), its effect on KCa channels seems to be direct and not through cGMP pathways (77). In addition to the direct effect of fatty acids on KCa channels, it is also possible that fatty acids may increase membrane fluidity, leading to changes in the Ca2+ sensor as proposed for 2-decanoic acid by Bregestovski et al. (79). It is also possible that fatty acids increase Ca2+ release from intra-

cellular stores (80) in close proximity to plasma membrane KCa channels, leading to their activation.

It has been suggested that arachidonic acid is elevated in the serum and cytosol during cardiac ischemia (81). Thus, activation of KCa channels would increase coronary flow, alleviating ischemia.

3. Endothelium-Derived Hyperpolarizing Factors (EDHF)

Endothelium-derived hyperpolarizing factors appear to play important roles, especially in the microvascula-ture (82). The chemical identity of EDHF has been related to several factors, such as epoxyeicosatrienoic acid (EET) (83), K+ (84), and anandamide (85). There is an emerging consensus that EDHF is unlikely to be a single factor and that considerable tissue and species differences exist for the nature and cellular targets of the hyperpolarizing factors. One of the potential targets is a KCa channel. Randall and Kendall (85) showed that anandamide, an endogenous cannabinoid derived from arachidonic acid, causes vasodilatation via opening of KCa channels. Hayabuchi et al. (86) demonstrated that EET also opens KCa channels via G-protein without changes in cAMP or cGMP. It is of interest that aging and hypercholesterolemia impair EDHF-mediated relaxation; however, the mechanisms of impairment are not clear (82).

G. Other Factors

1. Atrial Natriuretic Peptide (ANP)

ANP dilates mesenteric arteries and increases KCa channel activity likely through the PKG pathway (14, 87).

2. Nonadrenergic Noncholinergic Neurotransmitters: Substance P (SP) and Vasoactive Intestinal Peptide

SP is a potent endothelium-dependent coronary artery vasodilator that appears to hyperpolarize coronary artery endothelial cells by opening KCa channels (88). It is not clear if SP can open KCa channels in vascular smooth muscle cells. VIP is also a potent vasodilator (89) whose action is partially inhibited by the KCa channel blocker Iberiotoxin (17). Thus, KCa channels are partly responsible for the vasorelaxing effects of VIP, possibly via a G-protein.

3. Sexual Hormones

Testosterone and ^-estradiol also have direct vasodi-latory effects on smooth muscle. Testosterone-induced vasodilatation is mediated by opening potassium channels, other than KATP channels (KCa channels?), as their blockade with glibenclamide did not alter the response to testosterone (90). ^-Estradiol is also a potent vasore-laxant of the coronary circulation and its effects appear to be at least in part through a direct activation of KCa channels (91, 92).

4. Oxygen and Carbon Monoxide (CO)

Hypoxia suppresses KCa activity in pulmonary arteries (93, 94), depending on the intracellular redox state. KCa channels are inhibited by NADH, whereas NAD promotes their openings through a mechanism that is not completely understood (93). CO is a direct activator of KCa channels and a potent vasorelaxant whose action does not seem to be mediated by cGMP or G-pro-teins (95).

In summary, KCa channels respond to a variety of stimuli by either increasing or decreasing their open probability and therefore hyperpolarizing or depolarizing the cell membrane and altering blood flow. These stimuli include intracellular calcium concentration, membrane potential, endothelial-derived vasoactive substances (including NO), prostacyclin, PGE2, EDHF, and others. The activity of KCa channels is also modulated by several second messengers, including cGMP, GMP, GDP, GTP, and ATP, as well as hormones such as epinephrine, endothelin, vasopressin, ANP, antidiuretic hormone (ADH), secretin, somatostatin, TRH, and others. The ability of KCa channels to respond to a variety of intracellular local tissue factors and endothelium-derived factors, as well as hormones, makes these channels integrators of multiple stimuli.

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