03-08-2003, 06:31 AM
Okay, here is a very speculative analysis of what may be happening. But, first, I must emphasize that you may not be taking 4-AP since you are in a placebo-controlled trial.
4-AP blocks fast voltage sensitive potassium channels. These channels are present on smooth muscles including those that mediate constriction in blood vessels. 4-AP affects blood flow mechanisms in different organs. I review some of these below. Although none addresses the issue of skin blood flow, I suspect that 4-AP may affect sympathetic and parasympathetic control of skin blood flow that may affect scar.
Pulmonary circulation. When parts of the lung are exposed to hypoxia (i.e. low oxygen), the arteries in those parts of the lung rapidly constrict in order to divert blood flow to better oxygenated parts of the lung. Archer, et al. (2000) report that this response is mediated potassium channels that can be blocked by 4-aminopyridine. A similar vasoconstriction occurs in the placenta (the vascular bed that connects the fetus to the mother) exposed to hypoxia, diverting blood flow to better oxygenated parts of the placenta. Hampl, et al. (2002) found that this response can be reduced by 4-AP.
Coronary circulation. The coronary blood vessels supply blood to the heart. When the heart is exposed to carbon monoxide, the coronary blood vessels (that supply the heart) dilate to increase blood flow to the heart. Barbe, et al. (2002) showed the carbon monoxide selectively increases a population of 4-AP sensitive voltage sensitive potassium channels in coronary myocytes (smooth muscles that constrict coronary blood vessels). Miyashita, et al. (2000) examined the effects of 4-AP on hypoxia induced cardiac arrythmias, finding that the drug prevents ventricular fibrillation (undesirable disorganized activity) but not ventricular tachycardia (increased heart rate). In 1981, Bowman, et al. examined the effects of applied 4-AP on the cardiovascular systems of cats and dogs. 4-AP augments the responses of vagal stimulation. In dogs, 4-AP increased contractions of the heart. These effects were countered by 4-AP facilitation of both sympathetic and parasympathetic systems. These effects of 4-AP were attributed to 4-AP's facilitation of neurotransmitter release.
Cerebral circulation. Edvinsson, et al. (1981) showed that very high concentrations of 4-AP (10 micromolar) slightly increases vasoconstriction of cerebral (brain) arteries but lower therapeutic concentrations significantly increased blood flow in the caudate nucleus (93%), thalamus (74%), and cerebellar (82%) blood flow. More recently, Mihaly, et al. (2000) showed that 4-AP induced seizures in the brain is associated with increased blood flow to the other parts of the brain not undergoing seizures.
Hepatic circulation. 4-AP apparently causes oscillations of blood flow in perfused rat livers. Hill & Ajikobi (1992) proposes that there is an intrinsic oscillator of liver blood flow and that 4-AP exposes sensitivity of liver tissues to the effects of oscillating vasoactive neurotransmitter levels.
Venous circulation. Veins dilate when there is increased blood flow. This dilatory response appears to depend on voltage-sensitive potassium channels. Xie & Bevan (1998) showed that barium (a general potassium channel blocker) and 4-AP inhibit flow-induced relaxation of the facial vein of rabbits.
Intestinal contractions. The intestines constrict and relax as a result of smooth muscles that are influenced by voltage sensitive potassium channels. McDaniel, et al. (2001) showed that 4-AP reduced potassium currents in intestinal smooth muscles and also found that ingestion of 4-AP by rats reduced their weight gain.
Uterine contractions. The uterus of course contains smooth muscles. Fulep, et al. (2001) report that uterine contractions induced by endotherium-derived hyperpolarizing factor (EDHF) is mediated by 4-aminopyridine sensitive potassium channels. Rosenfeld, et al. (2002) reports that 4-AP inhibits uterine blood flow responses to estrogen.
In summary, 4-AP does indeed affect blood flow in many organs. However, it not only directly affects contraction of smooth muscles but also indirectly facilitate the sympathetic and parasympathic systems that regulate smooth muscles. In general, these effects of 4-AP balance each other. Ramping up and down the dose of 4-AP appears to minimize these potential side effects of 4-AP.
• Archer SL, Weir EK, Reeve HL and Michelakis E (2000). Molecular identification of O2 sensors and O2-sensitive potassium channels in the pulmonary circulation. Adv Exp Med Biol 475:219-40. Summary: Small, muscular pulmonary arteries (PAs) constrict within seconds of the onset of alveolar hypoxia, diverting blood flow to better-ventilated lobes, thereby matching ventilation to perfusion and optimizing systemic PO2. This hypoxic pulmonary vasoconstriction (HPV) is enhanced by endothelial derived vasoconstrictors, such as endothelin, and inhibited by endothelial derived nitric oxide. However, the essence of the response is intrinsic to PA smooth muscle cells in resistance arteries (PASMCs). HPV is initiated by inhibition of the Kv channels in PASMCs which set the membrane potential (EM). It is currently uncertain whether this reflects an initial inhibitory effect of hypoxia on the K+ channels or an initial release of intracellular Ca2+, which then inhibits K+ channels. In either scenario, the resulting depolarization activates L-type, voltage gated Ca2+ channels, which raises cytosolic calcium levels [Ca2+]i and causes vasoconstriction. Nine families of Kv channels are recognized from cloning studies (Kv1-Kv9), each with subtypes (i.e. Kv1.1-1.6). The contribution of an individual Kv channel to the whole-cell current (IK) is difficult to determine pharmacologically because Kv channel inhibitors are nonspecific. Furthermore, the PASMC's IK is an ensemble, reflecting activity of several channels. The K+ channels which set EM, and inhibition of which initiates HPV, conduct an outward current which is slowly inactivating, and which is blocked by the Kv inhibitor 4-aminopyridine (4-AP) but not by inhibitors of Ca(2+)- or ATP-sensitive K+ channels. Using anti-Kv antibodies to immunolocalize and inhibit Kv channels, we showed that the PASMC contains numerous types of Kv channels from the Kv1 and Kv2 families., Furthermore Kv1.5 and Kv2.1 may be important in determining the EM and play a role as effectors of HPV in PASMCs. While the Kv channels in PASMCs are the "effectors" of HPV, it is uncertain whether they are intrinsically O2-sensitive or are under the control of an "O2 sensor". Certain Kv channels are rich in cysteine, and respond to the local redox environment, tending to open when oxidized and close when reduced. Candidate sensors vary the PASMC redox potential in proportion to O2. These include Nicotinamide Adenine Dinucleotide Phosphate Oxidase, (NADPH oxidase) and the cytosolic ratio of reduced/oxidized redox couples (i.e. glutathione GSH/GSSG), as controlled by electron flux in the mitochondrial electron transport chain (ETC). Using a mouse that lacks the gp91phox component of NADPH oxidase, we have recently shown that loss of the gp91phox-containing NADPH oxidase as a source of activated oxygen species does not impair HPV. However, inhibition of complex 1 of the mitochondrial electron transport chain mimics hypoxia in that it inhibits IK, reduces the production of activated O2 species and causes vasoconstriction. We hypothesize that a redox O2 sensor, perhaps in the mitochondrion, senses O2 through changes in the accumulation of freely diffusible electron donors. Changes in the ratio of reduced/oxidized redox couples, such as NADH/NAD+ and glutathione (GSH/GSSG) can reduce or oxidize the K+ channels, resulting in alterations of PA tone. Department of Medicine and Physiology, University of Alberta, Canada.
• Barbe C, Dubuis E, Rochetaing A, Kreher P, Bonnet P and Vandier C (2002). A 4-AP-sensitive current is enhanced by chronic carbon monoxide exposure in coronary artery myocytes. Am J Physiol Heart Circ Physiol 282:H2031-8. Summary: A physiological role of carbon monoxide has been suggested for coronary myocytes; however, direct evidence is lacking. The objective of this study was to test the effect of chronic carbon monoxide exposure on the K(+) currents of the coronary myocytes. The effect of 3-wk chronic exposure to carbon monoxide was assessed on K(+) currents in isolated rat left coronary myocytes by the use of the patch-clamp technique in the whole cell configuration. Moreover, membrane potential studies were performed on coronary artery rings using intracellular microelectrodes, and coronary blood flow in isolated heart preparation was recorded. Carbon monoxide did not change the amplitude of global whole cell K(+) current, but it did increase the component sensitive to 1 mM 4-aminopyridine. Carbon monoxide exposure hyperpolarized coronary artery segments by approximately 10 mV and, therefore, increased their sensitivity to 4-aminopyridine. This effect was associated with an enhancement of coronary blood flow. We conclude that chronic carbon monoxide increases a 4-aminopyridine-sensitive current in isolated coronary myocytes. This mechanism could, in part, contribute to hyperpolarization and to increased coronary blood flow observed with carbon monoxide. Unite de Preconditionnement du Myocarde, Unite de Formation et de Recherche Sciences, 49045 Angers Cedex, France.
• Bowman WC, Marshall RJ, Rodger IW and Savage AO (1981). Actions of 4-aminopyridine on the cardiovascular systems of anaesthetized cats and dogs. Br J Anaesth 53:555-65. Summary: The effects of the anti-curare agent 4-aminopyridine on the cardiovascular systems of cats and greyhounds under barbiturate-chloralose anaesthesia have been studied. In both species, 4-amino-pyridine produced a transient atropine-sensitive decrease in arterial pressure followed by a prolonged adrenergically-mediated increase. In the cat, the cardiac responses to vagal stimulation and nictitating membrane responses to sympathetic stimulation were augmented after injection of 4-aminopyridine, and the evidence indicated that these effects were the results of increased release of neurotransmitters. In the greyhound, 4-aminopyridine produced increases in the left ventricular systolic pressure and dP/dt max, right atrial pressure, stroke volume, myocardial blood flow, myocardial oxygen consumption, external cardiac work, arterial oxygen content and blood haemoglobin. These effects were attributable to facilitation of sympathetic transmission to the blood vessels, heart and spleen. Heart rate was not much affected because facilitation of vagal transmission to the S-A node counteracted the increased sympathetic effect. In the greyhound, 4-aminopyridine also produced temporary cardiac arrhythmia which was only partly attributable to facilitated sympathetic transmission. In addition there was evidence of a central stimulant action of 4-aminopyridine and of a stimulant action on visceral activity. It is concluded that, while 4-aminopyridine may be useful in certain relatively rare conditions of neuromuscular transmission failure, its actions are too widespread for routine use as an antagonist to non-depolarizing neuromuscular blocking drugs.
• Edvinsson L, Hardebo JE and Lundh H (1981). Action of 4-aminopyridine on the cerebral circulation. Acta Neurol Scand 63:122-30. Summary: 4-Aminopyridine (4-AP) facilitates both inhibitory and excitatory synaptic activity in the central nervous system, and may, therefore, be a drug of potential therapeutic use in brain diseases with a disturbed synaptic transmission. In the present study the vasomotor effects upon isolated feline brain vessels, and regional cerebral blood flow and brain cortical metabolism in rats were examined. At high concentrations (above 10-6 M) a minor vasoconstriction was obtained of isolated pial vessels. Measurements of regional cerebral blood flow using the 14C-ethanol technique resulted in a significant increase in blood flow of caudate nucleus (93%), thalamus (74%) and cerebellum (82%). The arteriovenous oxygen difference of cortical tissue was reduced from 3.20 mmol O2/ml to 1.69 mmol O2/ml by 4-AP. This was not associated with an increase in cortical blood flow. Calculation of the cortical metabolic rate of oxygen, however, failed to demonstrate any significant change.
• Fulep EE, Vedernikov YP, Saade GR and Garfield RE (2001). The role of endothelium-derived hyperpolarizing factor in the regulation of the uterine circulation in pregnant rats. Am J Obstet Gynecol 185:638-42. Summary: OBJECTIVE: The purpose of this study was to determine whether endothelium-derived hyperpolarizing factor regulates rat uterine circulation in pregnant rats. STUDY DESIGN: Intact isolated uterine vascular beds from late pregnant rats were perfused in situ with Krebs buffer that contained dextran, indomethacin, N-nitro-L-arginine methyl ester, and phenylephrine. Endothelium-derived hyperpolarizing factor-induced decreases in perfusion pressure in response to acetylcholine were analyzed. RESULTS: The decrease in perfusion pressure induced by endothelium-derived hyperpolarizing factor was significantly attenuated by 4-aminopyridine and was abolished by a combination of 4-aminopyridine and tetraethylammonium. Endothelium-derived hyperpolarizing factor-induced decrease in perfusion pressure was abolished by potassium chloride and attenuated by miconazole, but not linoleyl hydroxamic acid. Endothelium-derived hyperpolarizing factor-induced decrease in perfusion pressure persisted after perfusion with solutions that contained 2 inhibitors of nitric oxide synthase and a scavenger of nitric oxide. Nitric oxide exerted negative feedback on the endothelium-derived hyperpolarizing factor effects. CONCLUSION: In the pregnant rat uterine vascular beds, endothelium-derived hyperpolarizing factor release is activated by a delayed rectifier type of voltage-sensitive potassium channel. Endothelium-derived hyperpolarizing factor does not seem to be related to nitric oxide or to products of lipoxygenase or cytochrome p450 mono-oxygenase pathways of arachidonic acid metabolism. Department of Obstetrics and Gynecology, Reproductive Sciences, University of Texas Medical Branch, Galveston, USA.
• Hampl V, Bibova J, Stranak Z, Wu X, Michelakis ED, Hashimoto K and Archer SL (2002). Hypoxic fetoplacental vasoconstriction in humans is mediated by potassium channel inhibition. Am J Physiol Heart Circ Physiol 283:H2440-9. Summary: Fetal to maternal blood flow matching in the placenta, necessary for optimal fetal blood oxygenation, may occur via hypoxic fetoplacental vasoconstriction (HFPV). We hypothesized that HFPV is mediated by K(+) channel inhibition in fetoplacental vascular smooth muscle, as occurs in several other O(2)-sensitive tissues. With the use of an isolated human placental cotyledon perfused at a constant flow rate, we found that hypoxia reversibly increased perfusion pressure by >20%. HFPV was unaffected by cyclooxygenase or nitric oxide synthase inhibition. HFPV and 4-aminopyridine, an inhibitor of voltage-dependent K(+) (K(v)) channels, increased pressure in a nonadditive manner, suggesting they act via a common mechanism. Iberiotoxin, a large conductance Ca(2+)-sensitive K(+) (BK(Ca)) channel inhibitor, had little effect on normoxic pressure. Immunoblotting and RT-PCR showed expression of several putative O(2)-sensitive K(+) channels in peripheral fetoplacental vessels. In patch-clamp experiments with smooth muscle cells isolated from peripheral fetoplacental arteries, hypoxia reversibly inhibited K(v) but not BK(Ca) or ATP-dependent currents. We conclude that human fetoplacental vessels constrict in response to hypoxia. This response is largely mediated by hypoxic inhibition of K(v) channels in the smooth muscle of small fetoplacental arteries. Department of Physiology, Charles University Second Medical School, 15000 Prague 5, Czech Republic. email@example.com
• Hill CE and Ajikobi DO (1992). Induction of haemodynamic oscillations in the perfused rat liver by K+ channel blockers. J Physiol 453:33-44. Summary: 1. Exposure of the isolated perfused (constant flow) rat liver to the K+ channel blockers 4-aminopyridine (4-AP) or Cs+ causes the appearance of oscillations in portal pressure and oxygen uptake. The oscillations have a mean frequency of 0.035 Hz (2.1 cycles/min) and are fully reversible upon perfusion with blocker-free saline. Tetraethylammonium (0.17-24.7 mM) does not induce oscillatory behaviour. 2. Reversible block of the 4-AP-induced oscillations is caused by 2 mM-EGTA, or verapamil, chlorpheniramine, phentolamine or propranolol with IC50 values of 0.42, 13.5, 15 or 11.5 microM respectively. The oscillations are transiently blocked by atropine (IC50 = 8.3 microM at peak inhibition) and are not affected by 2.7 microM-tetrodotoxin. 3. Endothelium-dependent vasorelaxants, Kupffer cell activity modifiers, retrograde perfusion, or removal of the portal vein from the circuit do not modify the oscillation parameters. 4. Oscillations are also caused by infusion of physiological concentrations of adrenaline or phenylephrine, but not isoprenaline. 5. The results provide new evidence for the existence of intrahepatic voltage-sensitive Ca2+, and 4-AP- and Cs(+)-sensitive K+ channels. We propose that the K+ channel blockers reveal an intrinsic oscillator in the liver, and that phasic vasoactivity may involve a minor contribution from neurotransmitter and/or hormonal substances. Department of Biology, Concordia University, Montreal, Quebec, Canada.
• McDaniel SS, Platoshyn O, Yu Y, Sweeney M, Miriel VA, Golovina VA, Krick S, Lapp BR, Wang JY and Yuan JX (2001). Anorexic effect of K+ channel blockade in mesenteric arterial smooth muscle and intestinal epithelial cells. J Appl Physiol 91:2322-33. Summary: Activity of voltage-gated K+ (Kv) channels controls membrane potential (E(m)). Membrane depolarization due to blockade of K+ channels in mesenteric artery smooth muscle cells (MASMC) should increase cytoplasmic free Ca2+ concentration ([Ca2+]cyt) and cause vasoconstriction, which may subsequently reduce the mesenteric blood flow and inhibit the transportation of absorbed nutrients to the liver and adipose tissue. In this study, we characterized and compared the electrophysiological properties and molecular identities of Kv channels and examined the role of Kv channel function in regulating E(m) in MASMC and intestinal epithelial cells (IEC). MASMC and IEC functionally expressed multiple Kv channel alpha- and beta-subunits (Kv1.1, Kv1.2, Kv1.3, Kv1.4, Kv1.5, Kv2.1, Kv4.3, and Kv9.3, as well as Kvbeta1.1, Kvbeta2.1, and Kvbeta3), but only MASMC expressed voltage-dependent Ca2+ channels. The current density and the activation and inactivation kinetics of whole cell Kv currents were similar in MASMC and IEC. Extracellular application of 4-aminopyridine (4-AP), a Kv-channel blocker, reduced whole cell Kv currents and caused E(m) depolarization in both MASMC and IEC. The 4-AP-induced E(m) depolarization increased [Ca2+]cyt in MASMC and caused mesenteric vasoconstriction. Furthermore, ingestion of 4-AP significantly reduced the weight gain in rats. These results suggest that MASMC and IEC express multiple Kv channel alpha- and beta-subunits. The function of these Kv channels plays an important role in controlling E(m). The membrane depolarization-mediated increase in [Ca2+]cyt in MASMC and mesenteric vasoconstriction may inhibit transportation of absorbed nutrients via mesenteric circulation and limit weight gain. Department of Medicine, University of California School of Medicine, San Diego, California 92103, USA.
• Mihaly A, Shihab-Eldeen A, Owunwanne A, Gopinath S, Ayesha A and Mathew M (2000). Acute 4-aminopyridine seizures increase the regional cerebral blood flow in the thalamus and neocortex, but not in the entire allocortex of the mouse brain. Acta Physiol Hung 87:43-52. Summary: Systemic injections of 4-aminopyridine precipitate epileptiform generalized seizures characterized mainly by shivering of the body, tail movements and tonic-clonic convulsions in rats and mice. However, only few details are known as concerns which brain regions are possibly affected and stimulated by the compound. The aim of the present study was to investigate the changes in regional cerebral blood flow in mice by using the lipophilic compound technetium-99m-hexamethyl-propyleneamineoxime (99mTc-HMPAO). Whilst the uptake of 99mTc-HMPAO was increased significantly in the neocortex and thalamus following the induction of acute 4-aminopyridine seizures, no such changes were observed in the allocortex of the mice. The increases in uptake in the neocortex and thalamus were completely prevented by carbamazepine (which abolished the symptoms of the seizure, too). The primary involvement of the neocortex and thalamus points to the importance of thalamocortical circuits in the precipitation and maintenance of experimental 4-aminopyridine convulsions. Department of Anatomy, Faculty of Medicine, Albert Szent-Gyorgyi Health Science Center, University of Szeged, Hungary. firstname.lastname@example.org
• Miyashita T, Kubota I, Yamaki M, Watanabe T, Yamauchi S and Tomoike H (2000). 4-aminopyridine inhibits the occurrence of ventricular fibrillation but not ventricular tachycardia in the reperfused, P6olated rat heart. Jpn Circ J 64:602-5. Summary: The 4-aminopyridine (4-AP)-sensitive transient outward current (Ito) has been reported to play an important role in the ischemia- or high [Ca2+]o-induced reentrant ventricular arrhythmias. However, the role of 4-AP sensitive Ito in reperfusion arrhythmia remains unknown. Rat hearts were perfused with Tyrode solution (control), and treated with 0.5 micromol/L verapamil, 1 micromol/L glibenclamide, 10 micromol/L E-4031 or 2 mmol/L 4-AP. After a 10-min perfusion, hearts were subjected to 30-min global ischemia followed by 10-min reperfusion. The effects of the ion-channel blockers on the incidence of ventricular tachycardia (VT), torsades de pointes (Tdp) and ventricular fibrillation (VF) during the reperfusion period were investigated. Verapamil and 4-AP abolished VF and Tdp. The incidence of VT was also attenuated by verapamil, but not by 4-AP. Glibenclamide and E-4031 (a blocker of a rapidly activating component of delayed rectifier K+ current) did not affect the incidence of those tachyarrhythmias. Accordingly, (1) the underlying mechanism of VF or Tdp is different from that of VT, and (2) 4-AP sensitive Ito is required for the occurrence of reperfusion Tdp or VF in the present model. First Department of Internal Medicine, Yamagata University School of Medicine, Japan.
• Rosenfeld CR, Roy T and Cox BE (2002). Mechanisms modulating estrogen-induced uterine vasodilation. Vascul Pharmacol 38:115-25. Summary: Estrogen, a potent vasodilator, has its greatest effects in reproductive tissues, e.g., increasing uterine blood flow (UBF) 5- to 10-fold within 90 min after a bolus dose. High-conductance potassium channels and nitric oxide (NO) contribute to the uterine responses, but other factors may be involved. We examined the role of ATP-dependent (ATP-sensitive) and voltage-gated (Kv) potassium channels and new protein synthesis in ovariectomized ewes with uterine artery flow probes, infusing intraarterial inhibitors glibenclamide (GLB; KATP), 4-aminopyridine (4-AP; Kv) or cycloheximide, respectively, into one uterine horn before and/or after systemic estradiol-17 beta (E2 beta, 1 microgram/kg i.v.). E2 beta alone increased UBF > 5-fold and heart rate by 10-25% (P < .01) within 90 min; mean arterial pressure [MAP) was unaffected. GLB did not alter basal hemodynamic parameters or responses to E2 beta. Basal UBF and heart rate were unaffected by 4-AP, but MAP increased by 10% and 25% at 30 and 120 min of infusion [P < .01), respectively. Although E2 beta-induced rises in UBF were unaffected in the control uterine horn, 4-AP dose-dependently inhibited UBF responses in the infused horn [R = .83, P = .003, n = 10). Cycloheximide not only dose-dependently inhibited UBF responses [R = .57, P = .01, n = 18) and increases in uterine cGMP secretion, 23.4 +/- 10.7 versus 340 +/- 60 pmol/min [P < .001), but also decreased UBF by 50% and cGMP by approximately 90% at the time of maximum UBF. Mechanisms modulating estrogen-induced uterine vasodilation involve signaling pathways that include NO, smooth muscle cGMP, smooth muscle potassium channels and new protein synthesis. Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9063, USA. email@example.com
• Xie H and Bevan JA (1998). Barium and 4-aminopyridine inhibit flow-initiated endothelium-independent relaxation. J Vasc Res 35:428-36. Summary: Although much is known about the underlying mechanism of endothelium-dependent flow-induced vasorelaxation, the cellular processes responsible for the endothelium-independent flow-induced relaxation observed in some vessels is unknown. As there is evidence for the participation of K+ channels in the endothelium-dependent response, the present study was designed to determine whether such channels are involved in the endothelium-independent response and if so, which ones. We examined the effects of various selective K+ channel blockers on endothelium-independent relaxation initiated by intraluminal flow (10-80 microl/min), and by an endothelium-independent vasodilator sodium nitroprusside (SNP, 1 nmol/l to 3 micromol/l) in segments of the rabbit facial vein under isometric conditions. Flow-initiated relaxation was abolished by 25 and 40 mmol/l K+ as well as 10 mmol/l tetraethylammonium (TEA), significantly inhibited by 100 micromol/l Ba2+, 5 mmol/l Cs+ and 7.5 mmol/l 4-aminopyridine (4-AP), but unaffected by 5 micromol/l glibenclamide and 50 nmol/l charybdotoxin. Relaxation induced by SNP was reduced by 7.5 mmol/l 4-AP, but not by any of the above drugs in their listed concentrations. The inhibitory effect of 100 micromol/l Ba2+ on the relaxation caused by low concentrations of K+ (15-20 mmol/l) supports the presence of inward rectifier K+ channels in the vascular smooth muscle cells of this tissue. We speculate that endothelium-independent flow-initiated relaxation of the rabbit facial vein may be associated with activation of inward rectifier and voltage-dependent K+ channels. The latter may also contribute to the vasorelaxation initiated by SNP. Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vt. 05405-0068, USA.