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Biomedical subjects

S L Archer

Publications and source records attributed to S L Archer.

At least 19 recordsLinked to original sources
PubMed2006

Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment.

The demonstration that angiogenic growth factors can stimulate new blood vessel growth and restore perfusion in animal models of myocardial ischemia has led to the development of strategies designed for the local production of angiogenic growth factors in patients who are not candidates for conventional revascularization. The results of recent clinical trials of proangiogenesis gene therapy have been disappointing; however, significant limitations in experimental design, in particular in gene transfer strategies, preclude drawing definitive conclusions. In the REVASC study cardiac gene transfer was optimized by direct intramyocardial delivery of a replication-deficient adenovirus-containing vascular endothelial growth factor (AdVEGF121, 4 x 10(10) particle units (p.u.)). Sixty-seven patients with severe angina due to coronary artery disease and no conventional options for revascularization were randomized to AdVEGF121 gene transfer via mini-thoracotomy or continuation of maximal medical treatment. Exercise time to 1 mm ST-segment depression, the predefined primary end-point analysis, was significantly increased in the AdVEGF121 group compared to control at 26 weeks (P=0.026), but not at 12 weeks. As well, total exercise duration and time to moderate angina at weeks 12 and 26, and in angina symptoms as measured by the Canadian Cardiovascular Society Angina Class and Seattle Angina Questionnaire were all improved by VEGF gene transfer (all P-values at 12 and 26 weeks < or =0.001). However, if anything the results of nuclear perfusion imaging favored the control group, although the AdVEGF121 group achieved higher workloads. Overall there was no significant difference in adverse events between the two groups, despite the fact that procedure-related events were seen only in the thoracotomy group. Therefore, administration of AdVEGF121 by direct intramyocardial injections resulted in objective improvement in exercise-induced ischemia in patients with refractory ischemic heart disease.

Adenoviridae↗
PubMed2004

Differences in food habits and cardiovascular disease risk factors among Native Americans with and without diabetes: the Inter-Tribal Heart Project.

OBJECTIVE: To examine differences in food habits among Native Americans with and without diabetes. DESIGN: A cross-sectional epidemiological study in which participants underwent a physical examination and answered an extensive interviewer-administered questionnaire to assess differences in food servings, preparation and eating habits. SETTING/PARTICIPANTS: Participants aged >/=25 years were randomly selected from three reservations in Minnesota and Wisconsin. There were 990 persons without diabetes, 294 with a prior diagnosis of diabetes, and 80 with fasting glucose >125 mg dl(-1) but no prior diabetes diagnosis. RESULTS: Persons with prior diabetes diagnosis were less likely than those without diabetes to report eating fast-food meals two or more times per week, eat visible fat on meat or the skin on poultry, eat fried chicken or fried fish, to add fat to cooked vegetables and drink whole milk. Persons with previously undiagnosed diabetes were more likely than previously diagnosed persons to report eating fast-food meals two or more times per week, eat visible fat on meat and the skin on poultry, drink whole milk and eat fried fish, but were less likely to drink low-fat milk. Previously undiagnosed persons were more likely than either diagnosed persons or persons without diabetes to consume lard from cooked foods and use it when cooking. CONCLUSION: Persons with diagnosed diabetes showed healthier eating patterns than those without diabetes, while undiagnosed persons showed some less favourable patterns. Because virtually all persons with diabetes in these communities receive nutrition education, the results suggest that nutrition education programmes for diabetics may be associated with healthier eating patterns.

Adult↗
PubMed2003

Association of education with dietary intake among young adults in the bi-ethnic Coronary Artery Risk Development in Young Adults (CARDIA) cohort.

OBJECTIVE: To examine associations of changes in dietary intake with education in young black and white men and women. DESIGN: The Coronary Artery Risk Development in Young Adults (CARDIA) study, a multi-centre population-based prospective study. Dietary intake data at baseline and year 7 were obtained from an extensive nutritionist-administered diet history questionnaire with 700 items developed for CARDIA. SETTING: Participants were recruited in 1985-1986 from four sites: Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California. SUBJECTS: Participants were from a general community sample of 703 black men (BM), 1006 black women (BW), 963 white men (WM) and 1054 white women (WW) who were aged 18-30 years at baseline. Analyses here include data for baseline (1985-1986) and year 7 (1992-1993). RESULTS: Most changes in dietary intake were observed among those with high education (>or=12 years) at both examinations. There was a significant decrease in intake of energy from saturated fat and cholesterol and a significant increase in energy from starch for each race-gender group (P<0.001). Regardless of education, taste was considered an important influence on food choice. CONCLUSION: The inverse relationship of education with changes in saturated fat and cholesterol intakes suggests that national public health campaigns may have a greater impact among those with more education.

Adolescent↗
PubMed2001

Gene transfer and metabolic modulators as new therapies for pulmonary hypertension. Increasing expression and activity of potassium channels in rat and human models.

UNLABELLED: Chronic Hypoxic Pulmonary Hypertension (CH-PHT) is characterized by pulmonary artery (PA) vasoconstriction and cell proliferation/hypertrophy. PA smooth muscle cell (PASMC) contractility and proliferation are controlled by cytosolic Ca++ levels, which are largely determined by membrane potential (E(M)). E(M) is depolarized in CH-PHT due to decreased expression and functional inhibition of several redox-regulated, 4-aminopyridine (4-AP) sensitive, voltage-gated K+ channels (Kv1.5 and Kv2.1). Humans with Pulmonary Arterial Hypertension (PAH) also have decreased PASMC expression of Kv1.5 and Kv2.1. We speculate this "K+-channelopathy" contributes to PASMC depolarization and Ca++ overload thus promoting vasoconstriction and PASMC proliferation. We hypothesized that restoration of Kv channel expression in PHT and might eventually be beneficial. METHODS: Two strategies were used to increase Kv channel expression in PASMCs: oral administration of a metabolic modulator drug (Dichloroacetate, DCA) and direct Kv gene transfer using an adenovirus (Ad5-Kv2.1). DCA a pyruvate dehydrogenase kinase inhibitor, promotes a more oxidized redox state mimicking normoxia and previously has been noted to increase K+ current in myocytes. Rats were given DCA in the drinking water after the development of CH-PHT and hemodynamics were measured approximately 5 days later. We also tested the ability of Ad5-Kv2.1 to increase Kv2.1 channel expression and function in human PAs ex vivo. RESULTS: The DCA-treated rats had decreased PVR, RVH and PA remodeling compared to the control CH-PHT rats (n=5/group, p<0.05). DCA restored Kv2.1 expression and PASMC Kv current density to near normoxic levels. Adenoviral gene transfer increased expression of Kv2.1 channels and enhanced 4-AP constriction in human PAs. CONCLUSION: Increasing Kv channel function in PAs is feasible and might be beneficial.

Animals↗
PubMed2001

Triple-bonded unsaturated fatty acids are redox active compounds.

Unsaturated fatty acids with triple bonds are used as inhibitors of unsaturated fatty acid metabolism or cytochrome P450 reactions because they are believed to be chemically inert. In this paper we use in vitro cytochrome C reduction to show that two commonly used triple-bonded unsaturated fatty acids are in fact potent electron transfer agents and could affect the multiple cellular systems that are redox-modulated.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed2001

Potassium channels regulate tone in rat pulmonary veins.

Intrapulmonary veins (PVs) contribute to pulmonary vascular resistance, but the mechanisms controlling PV tone are poorly understood. Although smooth muscle cell (SMC) K(+) channels regulate tone in most vascular beds, their role in PV tone is unknown. We show that voltage-gated (K(V)) and inward rectifier (K(ir)) K(+) channels control resting PV tone in the rat. PVs have a coaxial structure, with layers of cardiomyocytes (CMs) arrayed externally around a subendothelial layer of typical SMCs, thus forming spinchterlike structures. PVCMs have both an inward current, inhibited by low-dose Ba(2+), and an outward current, inhibited by 4-aminopyridine. In contrast, PVSMCs lack inward currents, and their outward current is inhibited by tetraethylammonium (5 mM) and 4-aminopyridine. Several K(V), K(ir), and large-conductance Ca(2+)-sensitive K(+) channels are present in PVs. Immunohistochemistry showed that K(ir) channels are present in PVCMs and PV endothelial cells but not in PVSMCs. We conclude that K(+) channels are present and functionally important in rat PVs. PVCMs form sphincters rich in K(ir) channels, which may modulate venous return both physiologically and in disease states including pulmonary edema.

4-Aminopyridine↗
PubMed2001

Alterations in a redox oxygen sensing mechanism in chronic hypoxia.

The mechanism of acute hypoxic pulmonary vasoconstriction (HPV) may involve the inhibition of several voltage-gated K+ channels in pulmonary artery smooth muscle cells. Changes in PO2 can either be sensed directly by the channel(s) or be transmitted to the channel via a redox-based effector mechanism. In control lungs, hypoxia and rotenone acutely decrease production of activated oxygen species, inhibit K+ channels, and cause constriction. Two-day and 3-wk chronic hypoxia (CH) resulted in a decrease in basal activated oxygen species levels, an increase in reduced glutathione, and loss of HPV and rotenone-induced constriction. In contrast, 4-aminopyridine- and KCl-mediated constrictions were preserved. After 3-wk CH, pulmonary arterial smooth muscle cell membrane potential was depolarized, K+ channel density was reduced, and acute hypoxic inhibition of whole cell K+ current was lost. In addition, Kv1.5 and Kv2.1 channel protein was decreased. These data suggest that chronic reduction of the cytosol occurs before changes in K+ channel expression. HPV may be attenuated in CH because of an impaired redox sensor.

Animals↗
PubMed2000

Coronary nitric oxide production in response to exercise and endothelium-dependent agonists.

BACKGROUND: Endothelium-derived nitric oxide (NO) contributes to epicardial coronary artery vasodilation during exercise. However, blockade of NO production does not impair the increase in coronary blood flow (CBF) during exercise, suggesting that NO is not obligatory for exercise-induced coronary resistance vessel dilation. In contrast, the increases in CBF produced by endothelium-dependent agonists are decreased after NO blockade. Consequently, this study was performed to determine whether the increase in coronary NO production in response to agonists is greater than that which occurs during exercise. METHODS AND RESULTS: We measured the oxidation products of NO (nitrate+nitrite=NO(x)) in aortic and coronary sinus plasma using chemiluminescence to assess NO(x) production across the coronary circulation in chronically instrumented dogs during a 3-stage treadmill exercise protocol and in response to intracoronary administration of the endothelium-dependent agonists acetylcholine (37.5 microg/min) and bradykinin (3.0 microg/min). No coronary NO(x) production could be detected at rest or during the first 2 stages of exercise; only at the highest level of exercise was a small increase in coronary NO(x) production measured. In contrast, coronary production of NO(x) was significantly increased in response to endothelium-dependent agonists. CONCLUSIONS: Coronary NO production in response to endothelium-dependent agonists is greater than in response to the increase in shear stress associated with exercise. These findings support previous studies suggesting that NO is not required for the coronary vasodilation that occurs in the normal heart during exercise.

Acetylcholine↗
PubMed2000

Molecular identification of O2 sensors and O2-sensitive potassium channels in the pulmonary circulation.

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.

Animals↗
PubMed1999

O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase.

The rapid response to hypoxia in the pulmonary artery (PA), carotid body, and ductus arteriosus is partially mediated by O2-responsive K+ channels. K+ channels in PA smooth muscle cells (SMCs) are inhibited by hypoxia, causing membrane depolarization, increased cytosolic calcium, and hypoxic pulmonary vasoconstriction. We hypothesize that the K+ channels are not themselves "O2 sensors" but rather respond to the reduced redox state created by hypoxic inhibition of candidate O2 sensors (NADPH oxidase or the mitochondrial electron transport chain). Both pathways shuttle electrons from donors, down a redox gradient, to O2. Hypoxia inhibits these pathways, decreasing radical production and causing cytosolic accumulation of unused, reduced, freely diffusible electron donors. PASMC K+ channels are redox responsive, opening when oxidized and closing when reduced. Inhibitors of NADPH oxidase (diphenyleneiodonium) and mitochondrial complex 1 (rotenone) both inhibit PASMC whole-cell K+ current but lack the specificity to identify the O2-sensor pathway. We used mice lacking the gp91 subunit of NADPH oxidase [chronic granulomatous disease (CGD) mice] to assess the hypothesis that NADPH oxidase is a PA O2-sensor. In wild-type lungs, gp91 phox and p22 phox subunits are present (relative expression: macrophages > airways and veins > PASMCs). Deletion of gp91 phox did not alter p22 phox expression but severely inhibited activated O2 species production. Nonetheless, hypoxia caused identical inhibition of whole-cell K+ current (in PASMCs) and hypoxic pulmonary vasoconstriction (in isolated lungs) from CGD vs. wild-type mice. Rotenone vasoconstriction was preserved in CGD mice, consistent with a role for the mitochondrial electron transport chain in O2 sensing. NADPH oxidase, though a major source of lung radical production, is not the pulmonary vascular O2 sensor in mice.

Animals↗
PubMed1999

Aerosol delivery of diethylenetriamine/nitric oxide, a nitric oxide adduct, causes selective pulmonary vasodilation in perinatal lambs.

Postnatal adaptation of the pulmonary circulation is mediated partly by endothelium-derived nitric oxide (NO). Recent studies have demonstrated that inhaled NO causes selective and sustained vasodilation in infants with persistent pulmonary hypertension of the newborn. Because the short half-life of NO limits its clinical application, we hypothesized that aerosol delivery of an NO-adduct, diethylenetriamine (DETANO), can cause sustained and selective pulmonary vasodilation. To test the acute effects of DETANO, we studied the pulmonary vascular response of late-gestation fetal lambs (n = 8; age = 138 days; term = 147) to aerosolized DETANO in the presence of an endothelium-derived NO inhibitor, nitro-L-arginine. To determine whether DETANO has a sustained effect, fetal lambs were ventilated with FiO2 0.10 before and 15 minutes after they were treated with aerosolized DETANO. Fetal lambs were acutely prepared. Nitro-L-arginine (1 mg/min x 30 minutes) was infused into the left pulmonary artery before ventilation with FiO2 1.00 for 30 minutes, followed by continued ventilation with FiO2 0.10 for 10 minutes. This represented the control period. Ventilation was continued with FiO2 1.00, and aerosolized DETANO was given in doses of 0.1, 0.4, and 1.0 mg. Fifteen minutes after the last dose of DETANO was administered, animals were ventilated with FiO2 0.10. In the control period, during ventilation with FiO2 0.10, left pulmonary artery flow was 122+/-33 mL/min and decreased to 104+/-22 mL/min. Aerosol delivery of DETANO increased left pulmonary artery flow to 176+/-26 mL/min (P<.05) and had no effect on aortic pressure or heart rate. After DETANO was administered, ventilation with FiO2 0.10 did not cause any change in left pulmonary artery flow. We conclude that DETANO can cause selective fetal pulmonary vasodilation. Aerosol delivery of DETANO may increase the clinical applications of NO.

Aerosols↗
PubMed1999

GTP (gammaS) and GDP (betaS) as electron donors: new wine in old bottles.

G proteins are membrane-bound regulatory proteins which modulate the activity of ion channels and other effector systems. The GTP and GDP analogs GTP (gammaS) and GDP (betaS) have been used to study the role of G proteins in numerous physiologic systems. The prolonged effects of these analogs have been thought to be due to the fact that they are nonhydrolyzable. However, in this paper we show that the GTP (gammaS) and GDP (betaS) analogs are potent reducing agents at physiologic pH. This observation suggests that previous data obtained using these compounds may need to be reinterpreted.

Cytochrome c Group↗
PubMed1999

Effects of fluoxetine, phentermine, and venlafaxine on pulmonary arterial pressure and electrophysiology.

The anorexic agents dexfenfluramine and fenfluramine plus phentermine have been associated with outbreaks of pulmonary hypertension. The fenfluramines release serotonin and reduce serotonin reuptake in neurons. They also inhibit potassium current (IK), causing membrane potential depolarization in pulmonary arterial smooth muscle cells. The recent withdrawal of the fenfluramines has led to the use of fluoxetine and phentermine as an alternative anorexic combination. Because fluoxetine and venlafaxine reduce serotonin reuptake, we compared the effects of these agents with those of phentermine and dexfenfluramine on pulmonary arterial pressure, IK, and membrane potential. Fluoxetine, venlafaxine, and phentermine caused minimal increases in pulmonary arterial pressure at concentrations < 100 microM but did cause a dose-dependent inhibition of IK. The order of potency for inhibition of IK at +50 mV was fluoxetine > dexfenfluramine = venlafaxine > phentermine. Despite the inhibitory effect on IK at more positive membrane potentials, fluoxetine, venlafaxine, and phentermine, in contrast to dexfenfluramine, had minimal effects on the cell resting membrane potential (all at a concentration of 100 microM). However, application of 100 microM fluoxetine to cells that had been depolarized to -30 mV by current injection elicited a further depolarization of >18 mV. These results suggest that fluoxetine, venlafaxine, and phentermine do not inhibit IK at the resting membrane potential. Consequently, they may present less risk of inducing pulmonary hypertension than the fenfluramines, at least by mechanisms involving membrane depolarization.

Animals↗
PubMed1999

Vitamin A decreases the incidence and severity of nitrofen-induced congenital diaphragmatic hernia in rats.

Congenital diaphragmatic hernia (CDH) is a major cause of refractory respiratory failure in the newborn. Pulmonary hypoplasia often limits survival. Vitamin A (Vit A) is an important signal for lung growth. We hypothesized that antenatal treatment with Vit A would stimulate lung growth and decrease mortality in experimental CDH induced in rats by ingestion of the herbicide nitrofen (2, 4-dichlorophenyl-p-nitrophenyl ether). Nitrofen was administered to pregnant rats on day 12 of gestation (term 22 days). Rats were assigned to five groups: three groups received one dose of oral antenatal Vit A (15,000 IU) before (day 10), concomitant with (day 12), or after (day 14) nitrofen administration; one group received only nitrofen; and a control group received vehicle (olive oil). The incidence of CDH was markedly lower in all groups receiving Vit A (day 10, 44%; day 12, 20%; and day 14, 40%) compared with the nitrofen-treated group (84%; P < 0.05). The 72-h survival was higher in all 3 Vit A-treated groups (day 10, 40%; day 12, 58%; and day 14, 70%) compared with the nitrofen-treated group (16%; P < 0.05). Lung-to-body weight ratio and radial saccular count were significantly increased by Vit A. Antenatal treatment with Vit A lowers the incidence and severity of experimental CDH and increases lung growth and maturation.

Animals↗
PubMed1999

Dexfenfluramine increases pulmonary artery smooth muscle intracellular Ca2+, independent of membrane potential.

The anorexic agent dexfenfluramine causes the development of primary pulmonary hypertension in susceptible patients by an unknown mechanism that may include changes in K+-channel activity and intracellular Ca2+ concentration ([Ca2+]i). We investigated the dose-dependent effects of dexfenfluramine on [Ca2+]i, K+ current, and membrane potential in freshly dispersed rat pulmonary artery smooth muscle cells. Dexfenfluramine caused a dose-dependent (1-1,000 microM) increase in [Ca2+]i, even at concentrations lower than those necessary to inhibit K+ currents (10 microM) and cause membrane depolarization (100 microM). The [Ca2+]i response to 1 and 10 microM dexfenfluramine was completely abolished by pretreatment of the cells with 0.1 microM thapsigargin, whereas the response to 100 microM dexfenfluramine was reduced. CoCl2 (1 mM), removal of extracellular Ca2+, and pretreatment with caffeine (1 mM) reduced but did not abolish the response to 100 microM dexfenfluramine. We conclude that dexfenfluramine increases [Ca2+]i in rat pulmonary artery smooth muscle cells by both release of Ca2+ from the sarcoplasmic reticulum and influx of extracellular Ca2+.

Animals↗
PubMed1999

Dexfenfluramine elevates systemic blood pressure by inhibiting potassium currents in vascular smooth muscle cells.

Appetite suppressants, such as dexfenfluramine (dex), are associated with primary pulmonary hypertension, valvular heart disease, and systemic vascular complications, such as coronary, cerebral, or mesenteric ischemia. These drugs suppress appetite by enhancing release and inhibiting reuptake of serotonin in the central nervous system. The effects of dex on the systemic circulation have not been studied. K(+) channels regulate vascular tone in most vascular beds. We hypothesized that dex is a systemic vasoconstrictor acting primarily by inhibiting K(+) channels, independent of effects on serotonin. The effects of clinically relevant concentrations of dex (10(-6) to 10(-4) M) on outward K(+) current and membrane potential were studied with whole-cell patch clamping in freshly isolated smooth muscle cells from rat renal, carotid, and basilar arteries. Tone was measured in tissue baths. Blood pressure, cardiac output, and left ventricular end diastolic pressure were assessed in open- and closed-chest anesthetized rats. At 10(-4) M, dex inhibits outward K(+) current (50%) and increases membrane potential (by >35 mV), an effect comparable with 4-aminopyridine (5 mM). Furthermore, dex constricts rings and acutely elevates systemic pressure (+17 +/- 3 mm Hg) and systemic vascular resistance in the presence of ketanserin. Dex vasoconstriction is dose-dependent (threshold dose 10(-6) M; 156 microg/ml) and enhanced in L-NAME-fed rats. We conclude that dex causes acute systemic vasoconstriction, at least in part by inhibition of voltage-gated K(+) channels, independent of effects on serotonin. To our knowledge, this is the first time that a commonly prescribed drug with voltage-gated K(+) channel-blocking properties is shown to have significant hemodynamic effects in vivo.

4-Aminopyridine↗