Pressor responses to ephedrine are not impaired in dopamine beta-hydroxylase knockout mice.

BACKGROUND AND PURPOSE: Ephedrine and amphetamine can cause substantial increases in systemic arterial pressure. However, the role of endogenous noradrenaline release in mediating the pressor response to ephedrine is controversial. Studies using pharmacologic agents to decrease the synthesis, storage, and release of catecholamines have supported both a direct and an indirect mechanism of action for ephedrine. The purpose of the present study was to determine if endogenous noradrenaline release is required for cardiovascular responses to ephedrine and amphetamine using a genetic mouse model. EXPERIMENTAL APPROACH: Increases in systemic arterial pressure and heart rate in response to ephedrine and amphetamine were investigated and compared in dopamine beta-hydroxylase knockout (Dbh -/-) mice that cannot synthesize noradrenaline. Dbh +/- littermates have normal noradrenaline and adrenaline tissue levels, and served as controls in all experiments. KEY RESULTS: In Dbh -/- mice the increases in systemic arterial pressure and heart rate in response to i.v. injections of ephedrine were not impaired whereas responses to amphetamine were markedly reduced, when compared with responses in Dbh +/- mice. The pressor response to tyramine was abolished whereas pressor responses to noradrenaline, phenylephrine, dopamine, and angiotensin II were similar in Dbh -/- and Dbh +/- mice. CONCLUSIONS AND IMPLICATIONS: The present results in Dbh -/- mice provide support for the hypothesis that pressor responses to ephedrine are directly mediated whereas responses to amphetamine are dependent on the release of noradrenaline and suggest that Dbh +/- and Dbh -/- mice are useful for the study of direct and indirect mechanisms.

Effects of MDMA administration on scopolamine-induced disruptions of learning and performance in rats.

Functional deficits following short-course high-dose administration of 3,4-methylenedioxymethamphetamine (MDMA) have been difficult to characterize despite evidence indicating that MDMA is neurotoxic in several species. Therefore, the present research used rats trained to respond under a complex behavioral procedure (i.e., a multiple schedule of repeated acquisition and performance of response chains), pharmacological challenge with scopolamine and neurotransmitter assays to examine the effects of MDMA neurotoxicity on learning. Prior to MDMA administration, 0.032-0.32 mg/kg of scopolamine produced dose-dependent rate-decreasing and error-increasing effects in both components of the multiple schedule. Administration of 10 mg/kg of MDMA twice per day for 4 days also produced rate-decreasing and error-increasing effects on these days, but responding returned to baseline levels several days after the final injection. In contrast to the recovery of responding, this regimen of MDMA in untrained rats significantly reduced levels of both serotonin and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), for 13-14 days. Furthermore, the rate-decreasing and error-increasing effects of scopolamine were significantly attenuated after MDMA treatment. These results indicate that certain complex operant behaviors rapidly recover from the effects of short-course high-dose MDMA administration, despite the reduced levels of serotonin in the central nervous system (CNS), and that this MDMA-induced loss of serotonin may affect cholinergic transmission.

The metabolic clearance rate of corticosterone in lean and obese male Zucker rats.

The obese Zucker rat is an animal model of human juvenile-onset obesity. These rats exhibit numerous endocrine and metabolic abnormalities. Adrenalectomy of obese rats has been shown to reduce or reverse several of these abnormalities, thereby implying that corticosterone may contribute to the expression of obesity in this animal. Furthermore, it has been shown that the circadian rhythm of plasma corticosterone is disturbed in obese Zucker rats resulting in elevated morning plasma corticosterone concentrations in obese rats as compared to lean rats. In a effort to better elucidate the mechanism of the elevated morning levels of plasma corticosterone, the metabolic clearance rate of corticosterone was determined in the morning for lean and obese male Zucker rats (12 to 20 weeks). Additionally, the biliary and urinary excretion of labeled corticosterone and/or its metabolites were determined. The metabolic clearance rate of corticosterone was significantly greater in obese rats than in their lean counterparts. Both the metabolic clearance rate and the volume of compartments significantly correlated with body weight. No correlation was found between body weight and the elimination rate constant. The increased metabolic clearance rate of obese rats appeared to be due to an increase in the physiologic distribution of corticosterone and not to an alteration in the enzymes responsible for corticosterone metabolism. It appears that the metabolic clearance rate of corticosterone in obese Zucker rats does not contribute to elevated morning concentrations of plasma corticosterone previously observed in these animals. It suggests that the adrenal corticosterone secretion rate must actually be greater than one would expect from the plasma corticosterone concentrations alone.

Comparison of lipoprotein lipase activity in heart myocytes and perfused hearts.

This study was initiated to compare lipoprotein lipase activity in isolated heart myocytes and the heparin residual compartment of perfused hearts from adult rats. Heart lipoprotein lipase activity was divided into two fractions by 1 min of heparin perfusion. Heparin-residual and myocyte lipoprotein lipase activity were lower in hearts obtained from fasted compared to fed rats. In each case, the myocyte enzyme activity was 55 to 60% of heparin-residual levels. The difference between myocyte and heparin-residual activity may be a consequence of the time and treatment required to isolate cells in that long-term in vitro exposure of heart tissue to heparin also reduces residual activity. In vivo treatment with endotoxin decreased both heparin-residual and myocyte lipoprotein lipase activities; whereas, colchicine administration increased both activities compared to saline injected rats. In this latter experiment heart heparin-residual and myocyte lipoprotein lipase activities were positively correlated (r = 0.90). The results indicate that in the mature heart intracellular lipoprotein lipase activity is primarily associated with myocytes.

Triacylglycerol kinetics in endotoxic rats with suppressed lipoprotein lipase activity.

Hypertriglyceridemia observed in animals after bacterial endotoxin administration and some forms of sepsis can result from increased hepatic triacylglycerol (TG) output or decreased TG clearance by extrahepatic tissues. To differentiate between these two possibilities, TG and free fatty acid (FFA) kinetics were determined in control and endotoxin-injected (0.1-0.5 mg/100 g) rats 18 h after treatment. Plasma TG and FFA kinetics were assessed by a constant intravenous infusion with [9,10-3H]palmitate-labeled very low-density lipoprotein and [1-14C]palmitate bound to albumin, respectively. In addition, lipoprotein lipase (LPL) activity was determined in heart, skeletal muscle, and adipose tissue as well as in postheparin plasma of functionally hepatectomized, adrenalectomized, and gonadectomized rats. Plasma FFA acid concentrations were slightly increased in endotoxin-treated rats but their turnover did not differ from control. Endotoxin-treated rats had a threefold increase in plasma TG concentrations and decreased heart, skeletal muscle, and post-heparin plasma LPL activity. Plasma TG turnover was decreased, indicating that hypertriglyceridemia was not due to an increased TG output by the liver. Instead, the endotoxin-induced increase in plasma TG concentration was a consequence of the 80% reduction in TG metabolic clearance rate. Thus, suppression of LPL activity in endotoxic animals impairs TG clearance resulting in hypertriglyceridemia. Furthermore, endotoxin administration reduced the delivery of TG-FFA to extrahepatic tissues because hepatic synthesis and secretion of TG from plasma FFA was decreased and LPL activity was suppressed.

Lipoprotein lipase-suppressing mediator in serum of endotoxin-treated rats.

The conditions under which lipoprotein lipase-suppressing mediator is present in serum of endotoxin-treated rats was determined in this study. The suppression of lipoprotein lipase activity in 3T3-L1 cells was used as a bioassay for mediator in serum. Endotoxin (0.1-10 micrograms/ml) and serum from control rats did not suppress lipoprotein lipase activity. Maximum suppression of cell lipoprotein lipase activity (70%) by serum from endotoxic rats required a cell exposure time of 5 h. At the highest dose of endotoxin used (1 mg/100 g), significant suppression was achieved when cells were incubated with 0.5% serum from endotoxic rats (P less than 0.05). Serum obtained 2-3 h after endotoxin injection possessed the maximal ability to suppress lipase activity, but suppressing activity was not present in serum collected 8 h after endotoxin. Rats rendered tolerant to endotoxin by 5 daily injections (0.1 mg/100 g) did not contain detectable levels of mediator in serum after endotoxin injection. The results demonstrate that the presence of lipoprotein lipase activity-suppressing mediator is transitory after in vivo exposure of naive rats to endotoxin, but does not appear in serum of endotoxin tolerant rats.