Baseline clinical and angiographic data in the Quinapril Ischemic Event (QUIET) Trial.

The QUinapril Ischemic Event Trial (QUIET) is the first prospective, double-blind, placebo-controlled trial to investigate the long-term antiatherosclerotic effects of angiotensin-converting enzyme inhibition. Normotensive, nonhyperlipidemic subjects (1,750) with normal left ventricular systolic function were randomly assigned to treatment or placebo at percutaneous transluminal coronary angioplasty (PTCA). The primary end point is time to first cardiac ischemic event. Baseline clinical characteristics are (mean +/- SD): age 58 +/- 9 years; blood pressure 123 +/- 15/74 +/- 10 mm Hg; low density lipoprotein cholesterol 124 +/- 27 mg/dL; high density lipoprotein cholesterol 37 +/- 10 mg/dL; and triglycerides 167 +/- 91 mg/dL. In addition, 81% are men; 22% are current smokers; 49% give a history of myocardial infarction. Baseline angiographic characteristics are (mean +/- SD): left ventricular ejection fraction 59% +/- 11%; per patient diameter stenosis (excluding the PTCA segment) 49% +/- 31%; 8.9 +/- 3.5 analyzable segments per patient (excluding the PTCA segment), 3.8 +/- 2.3 of which have visible stenosis. Including the PTCA segment, 52% have single vessel disease and 48% have multivessel disease. Baseline angiographic data for non-PTCA segments will be correlated with cardiac ischemic events which occur after 6 months. Up to 500 subjects will undergo follow-up angiography with quantitative coronary angiographic analysis (QCA) of baseline and follow-up films. The primary QCA end point will be per-patient categorical designation as progressor or nonprogressor based on the presence or absence of > or = 400 microns narrowing in > or = 1 vessels that did not undergo PTCA.

Aging changes in voltage-gated calcium currents in hippocampal CA1 neurons.

Previous current-clamp studies in rat hippocampal slice CA1 neurons have found aging-related increases in long-lasting calcium (Ca)-dependent and Ca-mediated potentials. These changes could reflect an increase in Ca influx through voltage-gated Ca channels but also could reflect a change in potassium currents. Moreover, if altered Ca influx is involved, it is nuclear whether it arises from generally increased Ca channel activity, lower threshold, or reduced inactivation. To analyze the basis for altered Ca potentials, whole-cell voltage-clamp studies of CA1 hippocampal neurons were performed in nondissociated hippocampal slices of adult (3- to 5-month-old) and aged (25- to 26-month-old) rats. An aging-related increase was found in high-threshold Ca and barium (Ba) currents, particularly in the less variable, slowly inactivating (late) current at the end of a depolarization step. Input resistance of neurons did not differ between age groups. In steady-state inactivation and repetitive-pulse protocols, inactivation of Ca and Ba currents was not reduced and, in some cases, was slightly greater in aged neurons, apparently because of larger inward current. The current blocked by nimodipine was greater in aged neurons, indicating that some of the aging increase was in L-type currents. These results indicate that whole-cell Ca currents are increased with aging in CA1 neurons, apparently attributable to greater channel activity rather than to reduced inactivation. The elevated Ca influx seems likely to play a role in impaired function and enhanced susceptibility to neurotoxic influences.

Associative EPSP--spike potentiation induced by pairing orthodromic and antidromic stimulation in rat hippocampal slices.

1. Pairing low-frequency orthodromic stimulation with high-frequency antidromic conditioning of pyramidal cells in area CA1 of the rat hippocampus resulted in long-lasting potentiation of the extracellular population spike of the cells, without an accompanying increase in the extracellular excitatory postsynaptic potential (EPSP), indicating an increase in EPSP-spike (E-S) coupling, also called E-S potentiation. 2. The amplitude of the antidromically conditioned E-S potentiation took up to 60 min to reach its peak, much longer than synaptic long-term potentiation (LTP) induced by orthodromic tetanic stimulation. 3. The population spike amplitude of a control orthodromic input, which stimulated a separate set of fibres and which was inactive during the pairing, was also increased in over half the slices tested. That it can affect a silent pathway suggests that antidromically conditioned E-S potentiation is not generated locally at tetanized synapses. 4. Bath application of 50 microM D,L-2-amino-5-phosphonovaleric acid (AP5) blocked induction of antidromically conditioned E-S potentiation. After washing out the AP5, the same stimulation resulted in population spike increases. This suggests that activation of the NMDA subtype of glutamate receptor is necessary for the induction of this form of E-S potentiation. 5. Application of 10 microM picrotoxin and/or 10 microM bicuculline, which block inhibition mediated by gamma-aminobutyric acid A (GABAA) receptors, did not reduce antidromically conditioned E-S potentiation. Thus, plasticity in GABAA-mediated inhibition cannot account for the increased population spike amplitude. 6. E-S potentiation did not increase the amplitude of either extracellular or intracellular EPSPs recorded at the cell body.

Contractile-based model interpretation of pressure-volume dynamics in the constantly activated (Ba2+) isolated heart.

A contractile-based model was constructed to represent responses to changes in left ventricular (LV) volume in a heart with constantly activated myocardium. Hearts were isolated from rabbits, the myocardium was put into a state of constant activation by perfusion with Krebs Henseleit solution containing 0.5 mM Ba2+, and recordings were taken of LV pressure responses to step and sinusoidal changes in LV volume. Pressure responses to volume steps were divided into five characteristic phases. An elastance frequency spectrum was calculated from pressure responses to sinusoidal volume changes. Values of features of the elastance frequency spectrum were in accord with values of corresponding features of the step response. Using an explicit homology between elements responsible for LV pressure development (pressure generators) and elements responsible for muscle force development (myofilament cross-bridges), mathematical models were constructed to re-create the data. Basic assumptions were that (1) pressure was the summed effect of pressure generators undergoing volumetric distortion; (2) changes in volume brought about changes in both generator numbers (recruitment) and generator distortion; (3) pressure generators cycle through states that variously do and do not generate pressure. An initial two-step model included a cycle with one attachment step and one detachment step between non-pressure-bearing and pressure-bearing states. Predictions by the two-step model had many similarities with the experimental observations, but were lacking in some important respects. The two-step model was upgraded to a multiple-step model. In addition to multiple attachment and detachment steps within the cycle, the multiple-step model incorporated distortion-dependent detachment steps. The multiple-step model re-created all aspects of the experimentally observed step and frequency responses. Furthermore, this model was consistent with current theories of contractile processes.

Hippocampal glucocorticoid receptor activation enhances voltage-dependent Ca2+ conductances: relevance to brain aging.

Glucocorticoids (GCs) activate several biochemical/molecular processes in the hippocampus through two receptor types. In addition, GCs influence cognitive behaviors and hippocampal neural activity and can also increase the rate of aging-dependent cell loss in the hippocampus. However, the ionic mechanisms through which GCs modulate hippocampal neuronal function are not well understood. We report here direct evidence that activation of cytosolic steroid receptors, specifically of the type II GC receptor, can enhance voltage-dependent Ca2+ conductances in brain neurons. Ca2+ current was assessed by current-clamp measures of Ca2+ action potentials and by sharp electrode voltage-clamp analyses of voltage-sensitive currents in cesium-, tetrodotoxin-, and tetraethylammonium-treated CA1 neurons in hippocampal slices. Both Ca2+ action potentials and voltage-activated Ca2+ currents (N- and L-like) were increased by 2-hr exposure to the synthetic GC receptor agonist, RU 28362. This effect of RU 28362 was blocked by coincubation with cycloheximide, indicating that the GC receptor-Ca2+ channel interaction depends on de novo protein synthesis. Dysregulated calcium homeostasis is also viewed as a candidate mechanism in brain aging. Thus, present results are consistent with the hypothesis that excessive GC-receptor activation and resultant increased Ca2+ influx may be two sequential phases of a brain-aging process that results initially in impairment of function and eventually in neuronal loss.

Chronic stress-induced acceleration of electrophysiologic and morphometric biomarkers of hippocampal aging.

There is increasing evidence that experimental interventions that alter adrenal corticosteroid plasma concentrations can modulate aging changes in the rodent hippocampus. However, there still is very little evidence that elevation of endogenous corticosteroid levels within physiological ranges, such as occurs during chronic stress, can accelerate hippocampal aging-like changes. In addition, almost all prior intervention studies of corticosteroid effects on brain biomarkers of aging have utilized morphologic measures of aging, and it is not yet clear whether electrophysiologic biomarkers of hippocampal aging can also be accelerated by conditions that elevate corticosteroids. In the present studies, specific pathogen-free rats of three ages (4, 12, and 18 months at the start) were trained for 6 months (4 hr/d, 5 d/week) in a two-way shuttle escape task, using low intensity foot shock. This task induces "anxiety" stress, because animals receive little actual shock, but chronic training in the task has been shown to elevate plasma corticosteroids and to downregulate hippocampal corticosteroid receptors. At the end of 6 months, animals were allowed to recover for 3 weeks and were then assessed in acute, anesthetized preparations on a battery of hippocampal neurophysiological markers known to separate young from aged animals (frequency potentiation, synaptic excitability thresholds, EPSP amplitude). The brains were then fixed and sectioned for quantification of neuronal density in field CA1 (a highly consistent anatomic marker of hippocampal aging). The pattern of stress effects differed considerably across age groups. The two younger stress groups exhibited increased evidence of aging-like neurophysiologic change, but exhibited no indications of accelerated neuronal loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Corticosteroid modulation of hippocampal potentials: increased effect with aging.

Adrenal steroids bind specifically to hippocampal neurons under normal conditions and may contribute to hippocampal cell loss during aging, but little is known about the neurophysiological mechanisms by which they may change hippocampal cell functions. In the present studies, adrenal steroids have been shown to modulate a well-defined membrane conductance in hippocampal pyramidal cells. The calcium-dependent slow afterhyperpolarization is reduced in hippocampal slices from adrenalectomized rats, and it is increased after in vivo or in vitro administration of the adrenal steroid, corticosterone. Calcium action potentials are also reduced in adrenalectomized animals, indicating that the primary effect of corticosteroids may be on calcium conductance. The afterhyperpolarization component reduced by adrenalectomy is greater in aged rats than in young rats, suggesting that, with aging, there is an increased effect of corticosteroids on some calcium-mediated brain processes. Because elevated concentrations of intracellular calcium can be cytotoxic, these observations may increase the understanding of glucocorticoid involvement in brain aging as well as of the normal functions of these steroids in the brain.