Calcium influx is believed to play a critical role in the cascade of biochemical events leading to neuronal cell death in a variety of pathological settings, including cerebral ischemia. The synthetic t-conotoxin peptide , which selectively blocks depolarization-induced calcium fluxes through neuronal N-type voltage-sensitive calcium channels, protected the pyramidal neurons in the CAl subfield of the hippocampus from damage caused by transient forebrain ischemia in the rat model of four-vessel occlusion. SNX-111 provided neuroprotection when a single bolus inj,ection was administered intravenously up to 24 hr after the ischemic insult. These results suggest that the window of opportunity for therapeutic intervention after cerebral ischemia may be much longer than previously thought and point to the potential use of t-conopeptides and their derivatives in the prevention or reduction of neuronal damage resulting from ischemic episodes due to cardiac arrest, head trauma, or stroke. Microdialysis studies showed that SNX-1ll was 3 orders of magnitude less potent in blocking potassium-induced glutamate release in the hippocampus than the conopeptide SNX-230, which, in contrast to SNX-11l, failed to show any efficacy in the four-vessel occlusion model of ischemia. These results imply that the ability of a conopeptide to block excitatory amino acid release does not correlate with its neuroprotective efficacy.Transient global ischemia of the forebrain, experimentally induced in rats by occlusion of the four major blood vessels supplying the brain, results in degeneration of a majority of the pyramidal neurons in the CAl region of the hippocampus (1). Neuronal damage following global forebrain ischemia has been attributed to increases in extracellular concentration of excitatory neurotransmitters such as glutamate and the resultant influx of calcium into neurons, which initiates a cascade of calcium-dependent intracellular degradative processes (2-4). However, selective antagonists of excitatory amino acid receptors-in particular, N-methyl-D-aspartate (NMDA) antagonists-have not been effective in protecting the vulnerable CAl neurons in the four-vessel occlusion model of transient forebrain ischemia in rats (5-7). Similarly, classical calcium channel antagonists such as the dihydropyridines, which block L-type calcium channels, have also failed to protect neurons from the consequences of ischemia when administered after the ischemic episode (8, 9). To develop therapies for preventing the brain damage caused by ischemia, we have investigated the utility of selectively blocking N-type calcium channels.Numerous studies suggest that the N-type calcium channels at presynaptic nerve terminals mediate a substantial portion of the calcium-dependent transmitter release in the The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.brain (10-12). The N-type channel has bee...
Steroid hormones modulate physiological processes by a number of mechanisms including regulation of gene expression. We wondered if glucocorticoids might induce expression of al adrenergic receptors, which could contribute to the increased sensitivity of vascular smooth muscle to catecholamines that may occur with glucocorticoid excess. We examined the effects of dexamethasone on the expression of the alB adrenergic receptor gene in DDT1 MF-2 smooth muscle cells. Dexamethasone (10' M) produced a 1.8±0.2-fold increase in expression of alB receptors determined with VI-Hprazosin. Steady-state values of aiB adrenergic receptor mRNA, analyzed by Northern blotting, increased 2.8±0.7-fold after 48 h exposure to dexamethasone. This effect of dexamethasone occurred in the presence of the protein synthesis inhibitor cycloheximide. alB receptor mRNA abundance was also increased by testosterone and aldosterone, whereas f estradiol and progesterone had no effect. The a1B receptor gene transcription rate, determined in nuclear run-off assays, increased 2.6±0.6-fold in cells treated with dexamethasone for 24 h. The half-life of the alB receptor mRNA was unchanged by dexamethasone. These data indicate that glucocorticoids regulate expression of aiB receptors by increasing the rate oftranscription ofthis gene. (J. Clin. Invest.
Both nicotinic acid (NA) and the adenosine receptor agonist phenylisopropyladenosine (PIA) are potent antilipolytic agents. We have evaluated the ability of these compounds to lower plasma glucose concentration in 450-g male diabetic rats. Diabetes was induced by intravenous streptozotocin, and the rats were studied 7-10 days later. Mean (+/- SE) fasting glucose decreased 4 h after subcutaneous injections of PIA at 0 and 2 h. A similar change in plasma glucose level was also seen in rats injected with NA. The decrease in the concentration of plasma glucose in both instances was preceded by marked sustained reductions in plasma free fatty acid (FFA) concentrations; FFA decreased in PIA-injected rats and in response to NA. With injection of normal saline, neither plasma glucose nor FFA concentrations decreased in diabetic rats. There was no change in the plasma insulin concentration of rats that had hypoglycemic responses to PIA or NA. In vitro glucose uptake was determined in isolated adipocytes, and both PIA and NA were shown to increase basal and maximal insulin-stimulated glucose uptake. The stimulating effect of the two compounds was similar, and the magnitude of the effect was comparable in adipocytes from either normal or diabetic rats. As a result, neither NA nor PIA could restore the defects in glucose transport to normal in adipocytes from diabetic rats. Insulin-stimulated glucose uptake was assessed in vivo by determining the steady-state glucose response of diabetic rats to a continuous infusion of insulin and glucose and was found to be significantly enhanced in response to NA compared with NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)
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