PubMed Health⌕ Search

Biomedical subjects

S L Archer

Publications and source records attributed to S L Archer.

At least 37 records · Page 2Linked to original sources
PubMed1998

Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes.

Hypoxia initiates pulmonary vasoconstriction (HPV) by inhibiting one or more voltage-gated potassium channels (Kv) in the pulmonary artery smooth muscle cells (PASMCs) of resistance arteries. The resulting membrane depolarization increases opening of voltage-gated calcium channels, raising cytosolic Ca2+ and initiating HPV. There are presently nine families of Kv channels known and pharmacological inhibitors lack the specificity to distinguish those involved in control of resting membrane potential (Em) or HPV. However, the Kv channels involved in Em and HPV have characteristic electrophysiological and pharmacological properties which suggest their molecular identity. They are slowly inactivating, delayed rectifier currents, inhibited by 4-aminopyridine (4-AP) but insensitive to charybdotoxin. Candidate Kv channels with these traits (Kv1.5 and Kv2.1) were studied. Antibodies were used to immunolocalize and functionally characterize the contribution of Kv1. 5 and Kv2.1 to PASMC electrophysiology and vascular tone. Immunoblotting confirmed the presence of Kv1.1, 1.2, 1.3, 1.5, 1.6, and 2.1, but not Kv1.4, in PASMCs. Intracellular administration of anti-Kv2.1 inhibited whole cell K+ current (IK) and depolarized Em. Anti-Kv2.1 also elevated resting tension and diminished 4-AP-induced vasoconstriction in membrane-permeabilized pulmonary artery rings. Anti-Kv1.5 inhibited IK and selectively reduced the rise in [Ca2+]i and constriction caused by hypoxia and 4-AP. However, anti-Kv1.5 neither caused depolarization nor elevated basal pulmonary artery tone. This study demonstrates that antibodies can be used to dissect the whole cell K+ currents in mammalian cells. We conclude that Kv2. 1 is an important determinant of resting Em in PASMCs from resistance arteries. Both Kv2.1 and Kv1.5 contribute to the initiation of HPV.

Animals↗
PubMed1998

Utility of a nitric oxide electrode for monitoring the administration of nitric oxide in biologic systems.

Amperometric techniques for the detection of nitric oxide (NO) are commercially available, but their sensitivity and specificity are not well described. We evaluated the sensitivity and specificity of a Clark-style, platinum NO electrode. The electrode has a lower limit of detection for NO of <25 pmol/ml in vitro and is linear over the range from 25 pmol/ml to 4 nmol/ml. The electrode is specific for NO so long as the protective membrane that covers the electrode is intact. Any defect in this membrane results in the detection of other redox agents such as hydrogen peroxide. Because of its ease of handling, specificity, and sensitivity, the NO electrode is a useful tool for quantification of administered NO in vitro and in various biologic systems.

Animals↗
PubMed1998

Relationship between changes in dietary sucrose and high density lipoprotein cholesterol: the CARDIA study. Coronary Artery Risk Development in Young Adults.

PURPOSE: Cross-sectional data from several observational studies have suggested that dietary sucrose may be inversely associated with high density lipoprotein cholesterol (HDL-C). This study examined associations between energy from dietary sucrose and HDL-C at baseline, year 7 and longitudinally (year 7 minus baseline) in a cohort of young black and white men and women from the Coronary Artery Risk Development in Young Adults (CARDIA) study. METHODS: The sample included 4734 black men, black women, white men and white women, ages 18-30 years, in 1985-86 (baseline); 3513 at year 7; and 3335 for longitudinal analyses. Multivariate analyses was used with adjustment for age, BMI, cigarettes smoked per day, physical activity score, and alcohol intake. RESULTS: Multivariate analyses indicated that energy intake from sucrose was inversely associated with HDL-C for each race-gender group at baseline, year 7, and longitudinally from baseline to year 7. This association was significant at baseline for black men, and white men and women (p < 0.01); at year 7 for white men and black women (p < 0.01), and longitudinally for white men, white women, and black women (p < 0.05). CONCLUSIONS: The consistent inverse associations between energy from dietary sucrose and HDL-C observed in both cross-sectional and longitudinal analyses, and in different race and gender groups in CARDIA suggest that lowering dietary sucrose intake may be beneficial for those who may have low HDL-C.

Adolescent↗
PubMed1998

A maturational shift in pulmonary K+ channels, from Ca2+ sensitive to voltage dependent.

The mechanism responsible for the abrupt decrease in resistance of the pulmonary circulation at birth may include changes in the activity of O2-sensitive K+ channels. We characterized the electrophysiological properties of fetal and adult ovine pulmonary arterial (PA) smooth muscle cells (SMCs) using conventional and amphotericin B-perforated patch-clamp techniques. Whole cell K+ currents of fetal PASMCs in hypoxia were small and characteristic of spontaneously transient outward currents. The average resting membrane potential (RMP) was -36 +/- 3 mV and could be depolarized by charybdotoxin (100 nM) or tetraethylammonium chloride (5 mM; both blockers of Ca2+-dependent K+ channels) but not by 4-aminopyridine (4-AP; 1 mM; blocker of voltage-gated K+ channels) or glibenclamide (10 microM; blocker of ATP-dependent K+ channels). In hypoxia, chelation of intracellular Ca2+ by 5 mM 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid further reduced the amplitude of the whole cell K+ current and prevented spontaneously transient outward current activity. Under these conditions, the remaining current was partially inhibited by 1 mM 4-AP. K+ currents of fetal PASMCs maintained in normoxia were not significantly reduced by acute hypoxia. In normoxic adult PASMCs, whole cell K+ currents were large and RMP was -49 +/- 3 mV. These 4-AP-sensitive K+ currents were partially inhibited by exposure to acute hypoxia. We conclude that the K+ channel regulating RMP in the ovine pulmonary circulation changes after birth from a Ca2+-dependent K+ channel to a voltage-dependent K+ channel. The maturational-dependent differences in the mechanism of the response to acute hypoxia may be due to this difference in K+ channels.

Aging↗
PubMed1998

Association of dietary fish and n-3 fatty acid intake with hemostatic factors in the coronary artery risk development in young adults (CARDIA) study.

Hemostatic factors play an important role in the complications of ischemic heart and vessel disease. Dietary fats such as n-3 fatty acids have been shown to possibly influence hemostatic factors. However, most studies reporting an inverse association between cardiovascular disease and fish and n-3 fatty acid consumption used supplemental doses of fish oil or intakes exceeding the typical amount consumed by the US population. This report examined the associations of usual intakes of fish, linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid with fibrinogen, factor VII, factor VIII, and von Willebrand factor in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The analyses reported here included 1672 black and white men and women aged 24 to 42 years in 1992 to 1993. After adjustment for age, body mass index, diabetes, number of cigarettes smoked per day, race, and energy and alcohol consumption, no significant associations were observed between those who consumed no fish versus those who consumed the highest level of dietary fish with respect to fibrinogen, factor VIII, or von Willebrand factor for any race-sex group. Comparisons of tertile 1 versus tertile 3 for dietary linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid were also not significantly associated with fibrinogen, factor VII, factor VIII, or von Willebrand factor for any race-sex group. These data suggest that customary intakes of fish and n-3 fatty acids in populations that generally do not consume large amounts of these food items are not associated with these hemostatic factors.

Adult↗
PubMed1998

Nitric oxide deficiency in fenfluramine- and dexfenfluramine-induced pulmonary hypertension.

Dexfenfluramine and fenfluramine greatly increase the risk of developing pulmonary hypertension (PHT). The mechanism of anorexigen-associated PHT (AA-PHT) and the reason PHT occurs in a minority of people exposed are unknown. Anorexigens are weak pulmonary vasoconstrictors, but they become potent when synthesis of the endogenous vasodilator nitric oxide (NO) is suppressed. We hypothesized NO deficiency predisposes affected individuals to develop AA-PHT. A prospective, case-control, study was performed on consecutive patients with AA-PHT (n = 9). Two sex-matched control groups were selected: patients with primary PHT (P-PHT, n = 8) and normal volunteers (n = 12). Lung NO production (VNO) and systemic plasma oxidation products of NO (NOx) were measured at rest and during exercise. AA-PHT developed 17 +/- 6 mo after a short course of anorexigen (6 +/- 2 mo) and was irreversible. VNO was lower in AA-PHT than in P-PHT and correlated inversely with PVR (p < 0.05). The apparent VNO deficiency may have resulted from increased oxidative inactivation of NO in patients with AA-PHT, as their NOx levels were elevated (p < 0.05) in inverse proportion to VNO (r2 = 0. 55; p < 0.02). In susceptible persons, anorexigens can cause an irreversible syndrome of PHT, hypoxemia, and systemic vascular complications after brief exposures. These patients have a relative NO deficiency years after discontinuing the anorexigen, perhaps explaining their original susceptibility.

Adult↗
PubMed1998

A role for potassium channels in smooth muscle cells and platelets in the etiology of primary pulmonary hypertension.

Plasma serotonin levels are markedly elevated in patients with primary pulmonary hypertension (PPH) and platelet levels of serotonin are low. Furthermore, plasma serotonin levels remain elevated after bilateral lung transplantation, in the absence of any pulmonary hypertension. Dexfenfluramine can cause the anorexigen-induced form of PPH that is clinically and histologically indistinguishable from PPH. We find that dexfenfluramine releases serotonin from platelets and inhibits its reuptake. These observations suggest that serotonin might be involved in, or be a marker for, the mechanism responsible for both forms of PPH. Dexfenfluramine causes inhibition of voltage-sensitive potassium (Kv) channels, membrane depolarization, and calcium entry in pulmonary artery smooth muscle cells and vasoconstriction in isolated perfused rat lungs. We have recently found that dexfenfluramine also inhibits Kv channels in megakaryocytes, the stem cell for platelets. In smooth muscle cells, taken from the pulmonary arteries of PPH patients, Kv channels appear to be dysfunctional. The underlying defect in PPH is likely to be an abnormality of one or more Kv channels in both pulmonary artery smooth muscle cells and platelets. Relatively few patients exposed to dexfenfluramine develop PPH. The factors responsible for susceptibility might be a difference in expression of potassium channels and/or a decrease in the endogenous production of nitric oxide.

Animals↗
PubMed1997

Diversity of response in vascular smooth muscle cells to changes in oxygen tension.

Hypoxia causes pulmonary vasoconstriction (HPV), but also dilation of systemic vessels and the ductus arteriosus. In the adult animal. HPV is initiated by inhibition of potassium current (IK) in the smooth muscle cells of small resistance arteries, which results in membrane depolarization and calcium entry through voltage-gated calcium channels. The oxygen-sensitive channels that initiate HPV are 4-aminopyridine (4-AP)-sensitive delayed rectifier channels (KDR), the most prominent of which has a conductance of 37 pS. In the fetus, hypoxia causes pulmonary vasoconstriction through inhibition of a calcium-sensitive potassium channel (KCa). In smooth muscle cells from the rabbit ductus arteriosus, which dilates in response to hypoxia, whole-cell potassium current is reversibly enhanced, rather than inhibited, by hypoxia. The principal oxygen-sensitive channel is inhibited by 4-AP and has a conductance of about 58 pS. There are morphological and electrophysiological differences between individual pulmonary artery smooth muscle cells, for example, in some cells IK is predominantly carried by KDR channels and in others by KCa channels. KDR cells are more common in the resistance pulmonary arteries and KCa in the conduit arteries. Responses of specific vessels (conduit, resistance; pulmonary, systemic, ductus) at different stages of development (fetal, neonatal and adult) to changes in oxygen tension may be determined by the distribution of a variety of ion channels in the smooth muscle cells.

Animals↗
PubMed1997

Potassium channel diversity in vascular smooth muscle cells.

Several recent observations suggest that the vascular medium is a mosaic of functionally and morphologically unique cell types. This diversity includes differences in cell phenotype and expression of cytoskeletal and contractile proteins as well as heterogeneity of the number and activity of potassium (K+) channel types. K+ channels play a role in the regulation of arterial tone and in the control of cell proliferation. There is evidence for cell to cell, segment to segment, and vascular bed to bed diversity of K+ channels that could explain the varying responses of arterial segments or different arteries to stimuli such as hypoxia, vasoactive drugs, or arterial wall injury. Pulmonary artery vascular smooth muscle cells contain several types of K+ channels, including calcium sensitive (KCa), delayed rectifier (KDR), and ATP gated (KATP). Hypoxic pulmonary vasoconstriction (HPV) is more prominent in the resistance than in the conduit arteries. HPV is initiated by the inhibition of a KDR channel, resulting in membrane depolarization, increase in the intracellular calcium, and contraction. We have shown that some pulmonary artery smooth muscle cells are enriched in KDR channels whereas others have more KCa channels. These cells can be differentiated by their morphology (using light microscopy and electron microscopy) and their electrical properties (using patch-clamp techniques). Although present throughout the pulmonary artery, KDR-enriched cells are more prominent in the distal-resistance segments whereas KCa-enriched cells are more prominent in the proximal-conduit segments. Nitric oxide (NO) causes relaxation in part by activating a KCa channel, causing membrane hyperpolarization and inactivation of the voltage-gated calcium channels. NO is a slightly more potent vasodilator in the conduit than in the resistance pulmonary artery. In summary, the pulmonary artery may be thought of as a mosaic of cells that have different proportions of key proteins, such as K+ channel subtypes, which confer upon the cell an ability to respond to a stimulus (hypoxia or NO) differently than an adjacent cell exposed to the same stimulus. The prevalence of these cells differs from conduit to resistance arteries. Diversity of cell function may be important in physiology and pathophysiology, allowing responses to vasodilators, vasoconstrictors, and proliferative stimuli to vary within or between vascular beds.

Animals↗
PubMed1996

Anorexic agents aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction.

BACKGROUND: The appetite suppressant aminorex fumarate is thought to have caused an epidemic of pulmonary hypertension in Europe in the 1960s. More recently, pulmonary hypertension has been described in some patients taking other amphetamine-like, anorexic agents: fenfluramine and its d-isomer, dexfenfluramine. No mechanism has been demonstrated that might account for the association between anorexic drugs and pulmonary hypertension. METHODS AND RESULTS: Using the whole-cell, patch-clamp technique, we found that aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in smooth muscle cells taken from the small resistance pulmonary arteries of the rat lung. Dexfenfluramine causes reversible membrane depolarization in these cells. These actions are similar to those of hypoxia, which initiates pulmonary vasoconstriction by inhibiting a potassium current in pulmonary vascular smooth muscle. In the isolated, perfused rat lung, aminorex, fenfluramine, and dexfenfluramine induce a dose-related increase in perfusion pressure. When the production of endogenous NO is inhibited by N-nitro-L-arginine methyl ester, the pressor response to dexfenfluramine is greatly enhanced. CONCLUSIONS: These observations indicate that anorexic agents, like hypoxia, can inhibit potassium current, cause membrane depolarization, and stimulate pulmonary vasoconstriction. They suggest one mechanism that could be responsible for initiating pulmonary hypertension in susceptible individuals. It is possible that susceptibility is the result of the reduced production of an endogenous vasodilator, such as NO, but this remains speculative.

Aminorex↗
PubMed1996

Oxygen-induced constriction of rabbit ductus arteriosus occurs via inhibition of a 4-aminopyridine-, voltage-sensitive potassium channel.

The ductus arteriosus is a vital fetal structure allowing blood ejected from the right ventricle to bypass the pulmonary circulation in utero. Closure of the ductus arteriosus at birth, essential for postnatal adaptation, is initiated by an increase in oxygen (O2) tension. We recently demonstrated the presence of O2-sensitive potassium channels in the fetal and adult pulmonary circulation which regulate vascular tone in response to changes in O2 tension. In this study, we assessed the cellular mechanisms underlying O2-induced constriction of the ductus arteriosus in late-gestation fetal rabbits. We report that O2 reversibly inhibits a 58-pS voltage- and 4-aminopyridine-sensitive potassium channel, causing membrane depolarization, an increase in intracellular calcium through L-type voltage-gated calcium channels, and constriction of the ductus arteriosus. We conclude that the effector mechanism for O2 sensing in the ductus arteriosus involves the coordinated action of delayed rectifier potassium channels and voltage-gated calcium channels.

4-Aminopyridine↗
PubMed1996

Diversity of phenotype and function of vascular smooth muscle cells.

Recent observations indicate that cell-to-cell and segment-to-segment variation occur in the morphology and function of vascular smooth muscle (VSM) cells in pulmonary and systemic arteries. This diversity includes differences in cell phenotype and in expression of cytoskeletal proteins as well as heterogeneity of the number and activity of potassium (K) channel types. The concept of cell diversity indicates that the arterial media is a mosaic of cell populations that differ from each other in phenotype and function. The prevalence of various VSM populations varies from segment to segment within a single artery and also may contrast among vascular trees of different organs. The composition of the arterial media is plastic, changing with normal development from fetus to adult and in response to vascular injury. Diversity of cell function is important in physiology and pathophysiology, allowing localized responses to vasodilators, vasoconstrictors, and proliferative stimuli within a vascular segment. Diversity may also explain the divergent responses of vascular beds to a common stimulus, such as hypoxia.

Animals↗
PubMed1996

Ventilation-induced pulmonary vasodilation at birth is modulated by potassium channel activity.

At birth, pulmonary blood flow rapidly increases 8- to 10-fold, and pulmonary arterial pressure falls by 50% within 24 h. The postnatal adaptation of the pulmonary circulation is mediated, in part, by endothelium-derived nitric oxide (EDNO). Recent studies suggest that EDNO may reduce vascular resistance, in part, by activating K+ channels. We hypothesized that K+ channels modulate the changes in pulmonary hemodynamics associated with birth. To test this hypothesis, we studied the effect of K+ channel inhibition on two separate, but interdependent stimuli: 1) mechanical ventilation with low inspired O2 concentrations (designed to maintain normal fetal blood gas tensions) and 2) mechanical ventilation with high inspired O2 concentrations. Tetraethyl-ammonium (TEA, 1 mg/min for 100 min; n = 5), a nonspecific K+ channel blocker, glibenclamide (Gli, 1 mg/min for 30 min; n = 6), an ATP-sensitive K+ channel blocker, or saline (n = 7) was infused into the left pulmonary artery (LPA) of acutely instrumented fetal lambs. The umbilical-placental circulation remained intact, and lambs were ventilated with 0.10 inspired O2 concentration (FIO2) for 60 min, followed by 1.0 FIO2 for 20 min. Neither TEA nor Gli had an effect on basal pulmonary tone. TEA attenuated the increase in LPA flow and decrease in pulmonary vascular resistance in response to mechanical ventilation with 0.10 and 1.0 FIO2; Gli had no effect. These results support the hypothesis that non-ATP-sensitive K+ channels modulate the transition from fetal to neonatal pulmonary circulation.

Adenosine Triphosphate↗