Expression of Group I metabotropic glutamate receptors on phenotypically different cells within the nucleus of the solitary tract in the rat.

Group I metabotropic glutamate receptors (mGluRs) are G-coupled receptors that modulate synaptic activity. Previous studies have shown that Group I mGluRs are present in the nucleus of the solitary tract (NTS), in which many visceral afferents terminate. Microinjection of selective Group I mGluR agonists into the NTS results in a depressor response and decrease in sympathetic nerve activity. There is, however, little evidence detailing which phenotypes of neurons within the NTS express Group I mGluRs. In brainstem slices, we performed immunohistochemical localization of Group I mGluRs and either glutamic acid decarboxylase 67 kDa isoform (GAD67), neuronal nitric oxide synthase (nNOS) or tyrosine hydroxylase (TH). Fluoro-Gold (FG, 2%; 15 nl) was microinjected in the caudal ventrolateral medulla (CVLM) of the rat to retrogradely label NTS neurons that project to CVLM. Group I mGluRs were distributed throughout the rostral-caudal extent of the NTS and were found within most NTS subregions. The relative percentages of Group I mGluR expressing neurons colabeled with the different markers were FG (6.9+/-0.7) nNOS (5.6+/-0.9), TH (3.9+/-1.0), and GAD67 (3.1+/-1.4). The percentage of FG containing cells colabeled with Group I mGluR (13.6+/-2.0) was greater than the percent colabeled with GAD67 (3.1+/-0.5), nNOS (4.7+/-0.5), and TH (0.1+/-0.08). Cells triple labeled for FG, nNOS, and Group I mGluRs were identified in the NTS. Thus, these data provide an anatomical substrate by which Group I mGluRs could modulate activity of CVLM projecting neurons in the NTS.

Predictors of systolic and diastolic improvement in patients with dilated cardiomyopathy treated with metoprolol.

OBJECTIVES: The aim of this study was to determine which patients will have systolic and diastolic improvement after beta-blockade with metoprolol. BACKGROUND: Beta-adrenergic blocking agents improve systolic and diastolic function in patients with heart failure. However, it is unclear which patients will respond best to therapy. METHODS: We retrospectively examined baseline characteristics of 24 patients who underwent double-blind then open-label treatment with metoprolol to determine which characteristic predicted improvement in systolic and diastolic function. Degree of improvement in systolic function (22 patients) was defined by the change in left ventricular ejection fraction after 3 months of therapy. Degree of improvement in diastolic function (15 patients) was defined as the change in left ventricular end-diastolic pressure and change in the slope of the isovolumetric relaxation rate-end-systolic pressure relation. RESULTS: Both systolic blood pressure at baseline (r = 0.54, p = 0.009) and the maximal positive value of the first derivative of left ventricular pressure with respect to time (peak +dP/dt) at baseline (r = 0.39, p = 0.07) correlated with improvement in ejection fraction after metoprolol treatment. Stepwise logistic regression demonstrated that only peak systolic pressure was an independent predictor of systolic improvement. Baseline heart rate, ventricular volumes, ejection fraction and adrenergic activation, as reflected by coronary sinus norepinephrine, did not predict response. Patients with the most diastolic impairment at baseline had the most favorable diastolic improvement. Those with the lowest myocardial respiratory quotient (most fatty acid utilization) at baseline also had the most marked reduction in left ventricular end-diastolic pressure. CONCLUSIONS: These data suggest that those patients with the highest peak systolic pressure, highest left ventricular end-diastolic pressure and most prolonged isovolumetric relaxation at baseline will respond best to therapy with metoprolol. However, other patients without these characteristics may also benefit.

Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: This study examined the effects of metoprolol on left ventricular performance, efficiency, neurohormonal activation and myocardial respiratory quotient in patients with dilated cardiomyopathy. BACKGROUND: The mechanism by which beta-adrenergic blockade improves ejection fraction in patients with dilated cardiomyopathy remains an enigma. Thus, we undertook an extensive hemodynamic evaluation of this mechanism. In addition, because animal models have shown that catecholamine exposure may increase relative fatty acid utilization, we hypothesized that antagonism of sympathetic stimulation may result in increased carbohydrate utilization. METHODS: This was a randomized, double-blind, prospective trial in which 24 men with nonischemic dilated cardiomyopathy underwent cardiac catheterization before and after 3 months of therapy with metoprolol (n = 15) or placebo (n = 9) in addition to standard therapy. Pressure-volume relations were examined using a micromanometer catheter and digital ventriculography. RESULTS: At baseline, the placebo-treated patients had somewhat more advanced left ventricular dysfunction. Ejection fraction and left ventricular performance improved only in the metoprolol-treated patients. Stroke and minute work increased without an increase in myocardial oxygen consumption, suggesting increased myocardial efficiency. Further increases in ejection fraction were seen between 3 and 6 months in the metoprolol group. The placebo group had a significant increase in ejection fraction only after crossover to metoprolol. A significant relation between the change in coronary sinus norepinephrine and myocardial respiratory quotient was seen, suggesting a possible effect of adrenergic deactivation on substrate utilization. CONCLUSIONS: These data demonstrate that in patients with cardiomyopathy, metoprolol treatment improves myocardial performance and energetics, and favorably alters substrate utilization. Beta-adrenergic blocking agents, such as metoprolol, are hemodynamically and energetically beneficial in the treatment of myocardial failure.

Pregnancy restores the renal vasodilator response to glycine in Dahl salt-sensitive rats.

To determine if pregnancy alters the impaired renal vasodilator responses in hypertensive Dahl salt-sensitive (Dahl S) rats, we measured glomerular filtration rate and effective renal plasma flow and calculated renal vascular resistance before, during, and after renal vasodilation with glycine (0.17 mmol/kg per minute IV). Conscious, midterm (day 11 to 14) pregnant and age-matched virgin Dahl S and Dahl salt-resistant (Dahl R) rats were fed an 8% NaCl diet for 4 weeks (n = 6 per group). Mean arterial pressure was elevated (P < .05) in Dahl S compared with Dahl R rats, with no significant difference between pregnant and virgin animals in either group. Pregnancy resulted in significant increases in plasma volume, baseline glomerular filtration rate, and renal plasma flow and a significant decrease in renal vascular resistance. The glycine-induced increase in filtration rate in virgin Dahl S rats (27 +/- 4%) was less (P < or = .01) than pregnant Dahl S (60 +/- 4%) and either group of Dahl R (virgin, 43 +/- 3%; pregnant, 45 +/- 5%) rats. Similarly, the 21 +/- 4% increase in renal plasma flow in virgin Dahl S rats was less (P < or = .01) than the pregnant Dahl S (45 +/- 4%) and either pregnant (45 +/- 5%) or virgin (45 +/- 5%) Dahl R rats. Glycine decreased renal vascular resistance only 12 +/- 2% in the virgin Dahl S compared with 31 +/- 3% in the pregnant Dahl S rats and 30 +/- 4% and 28 +/- 3% in pregnant and virgin Dahl R rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention or attenuation of baroreceptor resetting by pulsatility during elevated pressure.

Acute static elevation of arterial pressure increases the pressure threshold for activation of baroreceptors (acute resetting). The purpose of this study was to test the hypothesis that pulsatility during acute elevation of pressure modifies this acute resetting. Activity was recorded in 21 single baroreceptor units from the isolated carotid sinuses of dogs anesthetized with chloralose. Single-unit pressure thresholds were determined with a slow ramp increase in pressure. After a control period of static pressure at 25 to 50 mm Hg, the pressure threshold averaged 69 +/- 4 (SE) mm Hg. Three graded levels of static pressure were held for 5 to 15 minutes. The levels averaged 76 +/- 4, 115 +/- 6, and 170 +/- 5 mm Hg. The corresponding nerve activity during these periods was 0, 44 +/- 6, and 63 +/- 6 spikes per second, and the resulting increases in pressure threshold averaged 10 +/- 1, 17 +/- 2, and 26 +/- 3 mm Hg, respectively. In contrast, during equivalent elevations of pulsatile pressure, nerve activity averaged 20 +/- 3, 37 +/- 4, and 61 +/- 5 spikes per second, and the increases in pressure threshold averaged 0 +/- 4, 14 +/- 2, and 24 +/- 2 mm Hg, respectively. In some units, the pressure threshold decreased following elevation of pulsatile pressure. The results indicate that: pulsatility during elevation in pressure prevents or attenuates the acute baroreceptor resetting except at maximal pressure; upward resetting occurs with elevation of static pressure even when there is no nerve activity during the period of elevated pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic and energetic comparison of bucindolol and metoprolol for the treatment of congestive heart failure.

Although beta blockers have demonstrated a salutary effect on ventricular function in patients with heart failure, it is unclear whether a nonselective third-generation beta blocker produces different hemodynamic and energetic effects than a second-generation beta 1 selective agent. In 30 male patients with heart failure, we retrospectively analyzed hemodynamic data from 2 protocols examining the effects of a nonselective beta antagonist bucindolol (n = 15), and a highly selective beta 1 antagonist metoprolol (n = 15). Both studies were conducted in a similar fashion with patients undergoing cardiac catheterization before and after receiving 3 months of beta blockade. Both groups were matched at baseline in terms of ventricular function. beta blockade resulted in similar reductions in heart rate and similar improvements in ejection fraction, ventricular volumes, stroke and minute work, peak +dP/dt, and isovolumic relaxation in both groups. Only patients taking bucindolol had a significant within-group decrease in resting left ventricular end-diastolic pressure. The metoprolol group had a greater decrease in coronary sinus blood flow and myocardial oxygen consumption. Bucindolol increased cardiac index more than metoprolol, but did not increase stroke volume index more than metoprolol. The bucindolol group had an increase in systolic elastance, whereas the metoprolol group had a parallel left shift in this relation. Thus, metoprolol reduces coronary blood flow and myocardial oxygen consumption more than bucindolol, whereas bucindolol produces slightly more favorable improvements in resting cardiac index and end-diastolic pressure. Otherwise, these 2 agents produced similar hemodynamic changes.

Effects of in vivo cocaine administration on human platelet aggregation.

To evaluate whether cocaine administration to human volunteers in vivo increases platelet aggregation, 12 healthy male volunteers were studied twice in a prospective, double-blinded fashion. There was a decrease in aggregation following cocaine exposure compared to placebo, which was most prominent at high doses of adenosine diphosphate.

CNS effects of ovarian hormones and metabolites on neural control of circulation.

Pregnant women often experience orthostatic hypotension, and pregnancy is associated with increased susceptibility to hemorrhagic hypotension. Experiments evaluating arterial baroreflex control of efferent sympathetic nerve activity in virgin and term-pregnant rats revealed that arterial baroreflex sympathoexcitation is attenuated, while sympathoinhibitory responses are well-maintained or potentiated. Following a hypotensive challenge, pregnant animals exhibit attenuated Fos expression in the rostral ventrolateral medulla (RVLM), suggesting that unloading of arterial baroreceptors results in less excitation of presympathetic neurons in the brain stem. Other experiments, in which afferent baroreceptor discharge was recorded, suggest that this was not due to differences in afferent baoreceptor function. GABAergic mechanisms are responsible for tonic inhibition of sympathoexcitatory neurons in the RVLM and the major metabolite of progesterone, 3 alpha-OH-dihydro-progesterone (3 alpha-OH-DHP), which is elevated in pregnancy, is the most potent endogenous positive modulator of CNS GABAA receptor function. Additional experiments revealed that acutely administered 3 alpha-OH-DHP, either intravenously or directly into the RVLM, mimicked the effects of pregnancy on baroreflex control of efferent sympathetic nerve activity and potentiated pressure sensitivity of spinally projecting RVLM neurons. Preliminary experiments using semiquantitative RT-PCR, evaluated the relative expression of three subunits (alpha 1-3) of the GABAA receptor, and suggest that chronic exposure to elevated levels of ovarian hormones can result to changes in GABAA receptor subunit composition. It is likely that changes in control of sympathetic outflow in pregnancy are related to complex interactions between genomic and nongenomic actions of ovarian hormones and metabolites.

Neurosteroid modulation of [3H]flunitrazepam binding in the medulla: an autoradiographic study.

Neurosteroids bind to unique sites on the GABA(A) receptor complex and modulate receptor function. The effects of neurosteroids on GABA(A) receptors have been well characterized in forebrain regions. However, little is known about their effects on GABA(A) receptors in the medulla, especially those areas involved in autonomic reflex pathways. Stimulation of [3H]flunitrazepam binding to the GABA(A) receptor by two progesterone metabolites, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-OH-DHP) and 3beta-hydroxy-5alpha-pregnan-20-one (3beta-OH-DHP), was studied using autoradiographic methods in the medulla and cerebellum of female rats at estrus. [3H]Flunitrazepam binding was enhanced by 3alpha-OH-DHP in every nucleus examined in the medulla and cerebellum. This effect was stereoselective since 3beta-OH-DHP had no effect on binding in any region. No differences were observed in the degree of stimulation of [3H]flunitrazepam binding by 3alpha-OH-DHP among medullary brain regions. However, in the cerebellum, the stimulation of binding was significantly greater in the granular layer than in the molecular layer. Stimulation of [3H]flunitrazepam binding by 3alpha-OH-DHP in nuclei involved in the baroreflex pathways supports previous studies which report that neurosteroids modulate autonomic regulation of blood pressure. These actions may also underlie alterations in autonomic function during pregnancy.

Effects of chronic smoke exposure on the cardiovascular responses to acute nicotine infusion in the rat.

Rats were exposed daily to cigarette smoke for 17-22 weeks in order to characterize mean arterial pressure and regional hemodynamic effects of chronic smoke exposure and to determine if cardiovascular reactivity to acute nicotine infusions is altered by chronic smoke exposure. Urethane-anesthetized animals were instrumented with miniaturized pulsed-Doppler flow probes on the iliac and mesenteric vascular beds. Under resting conditions sham-smoked and smoke-exposed animals had similar levels of mean arterial pressure and mesenteric blood flow; however, resting heart rate was lower in the smoke-exposed group, while iliac blood flow was elevated in the smoke-exposed group. Acute nicotine infusion (6.25, 12.5 and 25 micrograms/kg per min) produced equivalent, dose-dependent pressor effects as well as increases in iliac and mesenteric resistance in sham and smoke-exposed groups. Thus, chronic cigarette smoke-exposure in rats may exert significant cardiovascular effects other than on arterial pressure such as lowered heart rate and elevated blood flow to skeletal muscle beds, while cardiovascular responses to nicotine are not altered by chronic smoke-exposure.

Effects of cocaine on cortisol secretion in humans.

The effects of acute cocaine administration on the pituitary adrenal axis in humans without a history of drug abuse are unknown. The authors studied 12 male volunteers twice in a double-blinded, placebo-controlled, randomized fashion. After intranasal administration of 2 mg/kg cocaine, cortisol levels were significantly higher than after placebo administration. The authors concluded that acute administration of cocaine to humans increases cortisol secretion.

H2O2 induces delayed hyperexcitability in nucleus tractus solitarii neurons.

Hydrogen peroxide (H2O2) is a stable reactive oxygen species and potent neuromodulator of cellular and synaptic activity. Centrally, endogenous H2O2 is elevated during bouts of hypoxia-reoxygenation, a variety of disease states, and aging. The nucleus tractus solitarii (nTS) is the central termination site of visceral afferents for homeostatic reflexes and contributes to reflex alterations during these conditions. We determined the extent to which H2O2 modulates synaptic and membrane properties in nTS neurons in rat brainstem slices. Stimulation of the tractus solitarii (which contains the sensory afferent fibers) evoked synaptic currents that were not altered by 10-500 µM H2O2. However, 500 µM H2O2 modulated several intrinsic membrane properties of nTS neurons, including a decrease in input resistance (R(i)), hyperpolarization of resting membrane potential (RMP) and action potential (AP) threshold (THR), and an initial reduction in AP discharge to depolarizing current. H2O2 increased conductance of barium-sensitive potassium currents, and block of these currents ablated H2O2-induced changes in RMP, Ri and AP discharge. Following washout of H2O2 AP discharge was enhanced due to depolarization of RMP and a partially maintained hyperpolarization of THR. Hyperexcitability persisted with repeated H2O2 exposure. H2O2 effects on RMP and THR were ablated by intracellular administration of the antioxidant catalase, which was immunohistochemically identified in neurons throughout the nTS. Thus, H2O2 initially reduces excitability of nTS neurons that is followed by sustained hyperexcitability, which may play a profound role in cardiorespiratory reflexes.

Sensory afferent and hypoxia-mediated activation of nucleus tractus solitarius neurons that project to the rostral ventrolateral medulla.

The nucleus tractus solitarius (nTS) of the brainstem receives sensory afferent inputs, processes that information, and sends projections to a variety of brain regions responsible for influencing autonomic and respiratory output. The nTS sends direct projections to the rostral ventrolateral medulla (RVLM), an area important for cardiorespiratory reflexes and homeostasis. Since the net reflex effect of nTS processing ultimately depends on the properties of output neurons, we determined the characteristics of these RVLM-projecting nTS neurons using electrophysiological and immunohistochemical techniques. RVLM-projecting nTS neurons were identified by retrograde tracers. Patch clamp analysis in the horizontal brainstem nTS slice demonstrated that RVLM-projecting nTS cells exhibit constant latency solitary tract evoked excitatory postsynaptic currents (EPSCs), suggesting they receive strong monosynaptic contacts from visceral afferents. Three distinct patterns of action potential firing, associated with different underlying potassium currents, were observed in RVLM-projecting cells. Following activation of the chemoreflex in conscious animals by 3 h of acute hypoxia, 11.2+/-1.9% of the RVLM-projecting nTS neurons were activated, as indicated by positive Fos-immunoreactivity. Very few RVLM-projecting nTS cells were catecholaminergic. Taken together, these data suggest that RVLM projecting nTS neurons receive strong monosynaptic inputs from sensory afferents and a subpopulation participates in the chemoreflex pathway.

Polarized light out-coupling from lightguides for LCDs.

New designs of lightguide systems, which emit linear polarized light with a high efficiency for transmissive and transflective LCD applications, are presented. These systems are equipped with nano- and/or micro-structured films or coatings, which emit highly collimated or diffuse linearly polarized light with a high efficiency. The films are based on polarization-selective scattering, reflection, or diffraction of light and their properties can be tuned to a large extent dependent on their envisioned application. For instance, edge-lit lightguide systems are discussed, which combine a range of desirable features such as a high transparency in direct view, a direct emission of light at normal angles to the plane of the lightguide, and a purely unidirectional out-coupling of light towards the LCD-side.

Effects of pregnancy and progesterone metabolites on regulation of sympathetic outflow.

1. Pregnancy is characterized by a 40% increase in blood volume and cardiac output, a decrease in arterial blood pressure and thus a substantial decrease in total peripheral resistance. The aims of the experiments described in this manuscript were: (i) to determine if pregnancy resulted in alterations in baroreflex control of sympathetic outflow; and (ii) to evaluate possible mechanisms for pregnancy-induced changes in control of sympathetic outflow. 2. Arterial baroreflex control of efferent renal sympathetic nerve activity was examined in female pregnant and non-pregnant normotensive Sprague-Dawley and Wistar-Kyoto rats. In both rat strains, pregnancy was associated with a decrease in baseline arterial pressure, a shift in the baroreflex function curve to a lower operating pressure range and an attenuated ability to reflexly increase sympathetic outflow above baseline levels during a hypotensive challenge. Pregnant Sprague-Dawley rats retained their ability to respond to a hypertensive challenge, whereas pregnant Wistar-Kyoto rats exhibited a decreased sensitivity to hypertensive as well as hypotensive challenges. 3. The inhibitory amino acid transmitter, GABA, mediates baroreflex sympatho-inhibition within the rostral ventral lateral medulla (RVLM) of the brainstem. Since 3 alpha-OH dihydroprogesterone (3 alpha-OH-DHP), a major metabolite of progesterone, is elevated in pregnancy and has been reported to potentiate central nervous system GABAA inhibitory responses, experiments were performed to determine if effects of this metabolite of progesterone could contribute to the pregnancy associated changes in control of sympathetic outflow.(ABSTRACT TRUNCATED AT 250 WORDS)

Magnesium in acute myocardial infarction.

Clinical studies on the use of magnesium in acute myocardial infarction have yielded contradictory results. While the exact reasons for these discrepancies are unclear, it appears that the timing of magnesium administration is crucial to the success or failure of therapy. Although some studies have shown a significant reduction in the odds of death with this agent, the exact reasons underlying this possible benefit are not yet fully understood. A reduction in arrhythmias, inhibition of thrombus generation, changes in coronary and peripheral hemodynamics, and the limitation of ischemic damage and reperfusion injury have been inferred as possible mechanisms. IV magnesium is inexpensive and easy to administer, and has minimal side effects. While further research on magnesium therapy in ischemic states is warranted, the early use of IV magnesium should be considered in selected patients with suspected acute myocardial infarction.

Cardiovascular effects of posterior hypothalamic stimulation in baroreflex-denervated rats.

The overall purpose of this study was to examine the effect of sinoaortic baroreceptor denervation (SAD) on the cardiovascular and sympathetic outflow responses to electrical stimulation of the posterior hypothalamus. In anesthetized rats that had undergone SAD 7-10 days before experimentation, electrical stimulation of the posterior hypothalamus elicited greater increases in mean arterial pressure, iliac vascular resistance, mesenteric vascular resistance, and lumbar sympathetic nerve activity than in sham-operated baroreceptor-intact animals. Similarly, the pressor effects of intravenous norepinephrine were also augmented in the baroreceptor-denervated group compared with the baroreceptor-intact group. When posterior hypothalamic and intravenous norepinephrine pressor stimuli, which produced equivalent pressor responses in sham-operated baroreceptor-intact animals, were compared in baroreceptor-denervated animals, the pressor effects of the central hypothalamic stimulus were enhanced to a greater degree than the norepinephrine pressor effects. These data provide evidence that arterial baroreceptor reflexes exert greater buffering of pressor stimuli initiated from the central nervous system compared with pressor responses due to peripheral vascular vasoconstrictor agents.

Effects of pregnancy and progesterone metabolites on arterial baroreflex in conscious rats.

Previous experiments in anesthetized rats suggested that sympathoexcitatory responses were attenuated in pregnant (P) rats. The major progesterone metabolite, 3alpha-hydroxy-dihydroprogesterone (3alpha-OH-DHP), is elevated in pregnancy and reportedly potentiates central gamma-aminobutyric acidergic mechanisms, whereas the 3beta-isomer (3beta-OH-DHP) is inactive. This study obtained baroreflex curves in conscious rats by recording reflex changes in renal sympathetic nerve activity (RSNA) and heart rate (HR) due to perturbations in mean arterial pressure (MAP) [i.v. phenylephrine (PE) and nitroprusside (NTP)] in P rats and in virgin (V) rats before (control) and 15 min after infusion (i.v.) of 3alpha-OH-DHP or 3beta-OH-DHP. Baseline MAP was lower in P rats (P = 102 +/- 2 vs. V = 124 +/- 3 mmHg). Compared with V rats, P rats exhibited less "sympathetic reserve" to respond to a hypotensive challenge, as evidenced by decreased maximum NA and decreased slope of RSNA baroreflex responses to NTP. However, HR baroreflex curves were similar in P and V rats. Acute intravenous administration of 3alpha-OH-DHP to conscious V rats mimicked the effects of pregnancy. Baroreflex sympathoexcitatory responses were decreased, whereas baroreflex control of HR was unaffected. The 3beta-isomer of DHP had no effect on NA or HR baroreflex responses. These results suggest that pregnancy may have differential effects on baroreflex control of sympathetic outflow and HR, and the major metabolite of progesterone, 3alpha-OH-DHP, may contribute to this adaptation of pregnancy.