1. NO Donors
Nitric oxide containing vasodilators such as nitroglyc-erin (NTG) and sodium nitroprusside (SNP) mediate the majority of their vasodilatory effect by releasing NO either spontaneously (SNP) or during enzymatic degradation (NTG). PT10, which neutralizes NO, inhibits the SNP response. In the 1970s, the effect of NO donors (SNP) was thought to be mediated by a decrease in Ca influx (101). However, the doses required to produce this effect were higher than those required for vasodilation, suggesting that a decrease in Ca2+ efflux was not crucial for SNP-induced vasodilation. Later, vasodilation by NTG and SNP was shown to be associated with hyperpolarization of the cell membrane, indicating the involvement of K+ channels (102). This involvement was also supported by the fact that the preconstriction of vascular smooth muscle with KCl (reduced K+ gradient) dramatically reduced vasodila-tion by SNP (103).
The role of KCa channels has now been demonstrated by their blockade with CTX and IBTx, which leads to a drastic reduction of NTG (104) or SNP-induced vasodilatation (105). Moreover, an increase of KCa channel current by SNP has been demonstrated in human coronary arteries (106).
2. "Potassium Channel Openers''
Although frequently thought of as selective KATP channel openers, pinacidil and cromakalim are potent openers of KCa channels. At concentrations less than 1 ^M, these drugs doubled the open probability of the rabbit KCa channel at -40 mV (close to the resting membrane potential). These effects were blocked by glibenclamide, although glibenclamide did not have an effect in the absence of KATP openers. Because of the large effect of pinacidil and cromakalim at clinically relevant concentrations, it is clear that this mechanism significantly contributes to the vasodilatation induced by these drugs (107). Bychkov et al. (108) also demonstrated that pinacidil is a nonselective activator of KATP and KCa channels in human coronary artery. These authors suggested that the conductance of KATP channels and their contribution to vasodilatation by pinacidil is small under physiological conditions and that the majority of the vasodilating effect of pinacidil is due to an increased activation of KCa channels (108).
Iloprost, a prostacyclin analogue, is a potent vasodilator. The role of KCa channels in this vasodilator effect has been proposed for aortic (109) and rat tail (110) arteries. However, in coronary arterial smooth muscle, KCa channels do not seem to play a role (111).
4. Fenamates and Structurally Related Benzimidazole Compounds
Niflumic acid is a potent and readily reversible opener of KCa channels. The effect is dose dependent and involves an increased sensitivity of KCa channels to intracellular calcium and a leftward shift in the voltage-activation curve. The KCa channel-opening property does not appear to be a unique property of niflumic acid and is exhibited by other fenamates. In fact, flufen-amic acid was as potent as niflumic acid, whereas mefe-namic acid was three times less potent. Niflumic acid was more potent (more than four times) from the extracellular than intracellular space, suggesting an extracellular binding site. The fenamate receptor/binding site is different from TEA and CTX binding sites, as fena-mates did not interfere with the KCa channel block by TEA and CTX. Fenamates are helpful tools in the study of functional properties of KCa channels and may be useful therapeutic tools as smooth muscle dilators (112). Several other related compounds have been shown to open KCa channels, including NS004 and its close derivative NS1619 (113-115). NS1619 also inhibited STOC and produced a pronounced dilatation of rat portal vein and aorta (113). Consistent with an activation of KCa channels, NS1619 causes vasodilatation. However, this effect is not prevented by blocking KCa with CTX or by reducing the K+ gradient (80 mEq KCl), suggesting that other or additional mechanisms of action are present. Indeed, in some reports, authors demonstrated that NS1619 is a potent blocker of Ca2+ channels, of voltage-dependent K+ channels, and of KATP channels (113, 116).
5. Nordihydroguaiaretic Acid (NDGA)
NDGA, a lipoxygenase inhibitor and antioxidant, is also a potent opener of KCa channels in porcine coronary artery and is possibly a potential tool for designing more potent vasodilators and/or bronchodilators (117). Interestingly, NDGA was ineffective at low calcium concentrations, indicating that calcium is necessary, possibly as a way to couple a and 0 subunits.
DHS-I is a tripentene glycoside isolated from Desmodium adscedens and is a potent opener of KCa channels (118). In frog oocytes, DHS-I at nanomolar concentrations activated KCa channels only when a and fi subunits were coexpressed (30). However, the presence of the fi subunit is not necessary if micromolar concentrations of DHS-I are used (44). DHS-I binds with 10- to 20-fold higher affinity to the open channel than to the closed. Binding of at least three or four DHS-I molecules is required for maximal activation of the channel (119). DHS-I reversibly activated macroscopic and single cannel activity of human coronary artery KCa channels, indicating that human coronary artery smooth muscle cell KCa channels are composed of q and fi subunits (30).
Volatile anesthetics, especially isoflurane, are potent dilators of coronary arteries. In fact, some authors have suggested that because of the potent vasodilating properties, isoflurane may cause coronary steal and ischemia. The role of KCa channels in coronary vasodilatation by isoflurane is not clear. Kokita et al. (120) suggested that a significant portion of the mesenteric artery smooth muscle hyperpolarization and vasodilatation by isoflur-ane in intact rats is mediated by opening KCa channels. This is contrary to the findings of Buljubasic et al. (121), who demonstrated that isoflurane actually decreased current though KCa channels in isolated coronary artery smooth muscle cells. The major difference between these two studies was that one investigated the effect in vivo (120) whereas the other studied direct effects in isolated cells (121), suggesting a possible role of endo-thelium, circulating factors, or the autonomic system in isoflurane-induced vasodilatation.
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