Renal hemodynamic effects of chronic ketorolac tromethamine treatment in aged lean and obese Zucker rats.

Ketorolac tromethamine is a relatively new non-steroidal anti-inflammatory drug (NSAID), with potent analgesic activity. Similar to other NSAIDs, ketorolac has the potential to impair renal function. To assess the renal hemodynamic impact of the ketorolac in aged lean and obese rats, ketorolac was orally administered to 46-week-old lean and obese Zucker rats for two weeks. Ketorolac was mixed with rat chow in a manner to provide a dose equivalent to 15 mg/kg body weight/day. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured under anesthesia by standard inulin and p-aminohippuric acid clearance method, respectively. Urinary prostaglandin (PG) E2 excretion was measured before and after ketorolac treatment. Ketorolac treatment significantly reduced obese rat GFR (0.47 +/- 0.08 vs 0.78 +/- 0.03 ml/min/g, p < 0.002) and ERPF (1.12 +/- 0.14 vs 2.36 +/- 0.26 ml/min/g, p < 0.001) relative to obese control rats. In comparison, ketorolac did not significantly alter lean rats GFR (0.77 +/- 0.04 vs 0.91 +/- 0.06 ml/min/g) or ERPF (1.92 +/- 0.20 vs 2.48 +/- 0.15 ml/min/g) relative to lean control rats. Chronic ketorolac treatment significantly reduced hematocrit by 20 and 30 percent in lean and obese rats relative to controls, respectively. The renal vascular resistance was significantly increased with ketorolac treatment in obese rats (36 +/- 4 vs 79 +/- 14 mmHg/ml/min, p < 0.001) but not lean rats (28 +/- 3 vs 38 +/- 5 mmHg/ml/min, NS) relative to corresponding controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism and metabolite pharmacokinetics of BRB-I-28, a class Ib antiarrhythmic agent.

The metabolism of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane), a novel class Ib antiarrhythmic agent, was characterized in vivo in dogs and rats and in vitro with rat liver microsomal preparations containing a NADPH-generating system. In dogs, rats and the in vitro hepatic microsomal oxidation system, BRB-I-28 was extensively metabolized to form 7-benzyl-3-thia-7-azabicyclo [3.3.1]nonane-3-oxide (I), a major metabolite. The metabolite I was produced via S-oxidation, presumably by the hepatic P-450 system. Formation of minor metabolite, 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane (II) via the oxidation of the benzylic site was also identified in rats. Following intravenous and oral administration of BRB-I-28 to dogs, the plasma concentration of major metabolite I could be test described by a 1-compartmental model. The plasma AUC of metabolite I was 20% (i.v.) and 179.4% (oral) of that of the parent BRB-I-28, respectively, suggesting that BRB-I-28 was metabolized significantly by the first pass effect following oral administration. Extensive metabolism of BRB-I-28 to form metabolites I and II, which have demonstrated much lower antiarrhythmic activities, further supports previously observed pharmacodynamic and pharmacokinetic findings.

Renal hemodynamic and histological consequences of diets high in unsaturated fat, protein or sucrose in obese Zucker rats.

The objective of this study was to determine the long-term effect of different dietary macronutrients on renal hemodynamics in obese Zucker rats. Female obese (fa/fa) Zucker rats were allowed to eat control chow (ObCL) or diets high in unsaturated fat (ObHF), protein (ObHP) or sucrose (ObHS) for a period of 24 weeks. Lean chow fed (LnCL) Zucker rats served as lean controls. After 24 weeks of dietary treatments, glomerular filtration rate (GFR, ml/mg/g, mean +/- SE) of ObHP and ObHS (0.38 +/- 0.06 and 0.27 +/- 0.05) rats were significantly (p < 0.005) lower than ObCL (0.74 +/- 0.05) and ObHF (0.88 +/- 0.1) rats. In a similar manner, the effective renal plasma flow (ERPF, ml/min/g) was significantly (p < 0.005) lower in ObHP and ObHS (1.28 +/- 0.16 and 1.04 +/- 0.2) than ObCL (2.46 +/- 0.31) or ObHF (2.85 +/- 0.25) rats. The ObHF rats appeared "protected" since they had similr GFR and ERPF but less proteinuria and glucosuria than ObCL rats. Histological examination of renal tissue from ObHP and ObHS fed rats revealed significant (p < 0.005) increase in sclerosis relative to ObCL rats. The sclerosis of renal tissue in ObHF was minimized and was found to be similar to ObCL rats. The mean arterial pressure and heart rates were similar in all dietary treated obese Zucker rats. When comparing obese and lean controls, ObCL rats had significantly (p < 0.03) lower GFR (0.74 +/- 0.05 vs 0.92 +/- 0.05) but similar ERPF (2.46 +/- 0.3 vs 2.82 +/- 0.12) than LnCL rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of ketorolac tromethamine on erythropoietin levels in Sprague Dawley rats.

Ketorolac tromethamine (KT) is a potent analgesic, most often used in its injectable form postoperatively. Similar to other nonsteroidal antiinflammatory drugs (NSAIDs), it inhibits prostaglandin (PG) synthesis. Prostaglandins have been shown to be involved in the regulation of renal function as well as erythropoietin (Ep) production. The intent of this study was to determine the effect of KT on plasma Ep levels in Sprague Dawley (SD) rats. Twenty rats received either 15 mg/kg/d or the KT vehicle IM for 5d. Blood samples (1 ml) were collected via tail vein each day of treatment. Plasma Ep levels were significantly higher in the KT rats than normal controls with the greatest difference occurring on d4 of treatment (70.1 +/- 10.8 vs 30.9 +/- 10.84 mU/ml, p < 0.01). This change in Ep corresponded with a significant reduction in hematocrit (KT, 29.5 +/- 2.2 vs C, 40.8 +/- 2.2%, p < 0.01). Presence of fecal blood was noted in the KT treated rats. A similar second experiment was designed to determine if blood loss was the cause of altered Ep production. In this experiment controls (HC) were bled via tail vein, to match the hematocrits of KT treated animals. Repeated administration of KT led to a steady reduction in hematocrit. When compared, hematocrit matched animals showed no difference in plasma Ep levels on all days of treatment (KT, 48.0 +/- 4.9 vs HC, 44.6 +/- 3.1 mU/ml, N.S.). In conclusion, repeated administration of KT showed no impairment of Ep production and release in response to reduced hematocrit, suggesting that in this instance, prostaglandin inhibition plays a minimal role in Ep production or release.

Effect of dietary obesity on naloxone disposition in sheep.

Naloxone is an opioid antagonist used frequently in studies of appetite regulation in lean and obese animals and humans. Body condition may affect plasma and tissue distribution of injected naloxone and thus confound interpretation of responses to naloxone in lean compared with obese subjects. The objective of this experiment was to determine the effect of dietary obesity per se on the pharmacokinetic behavior of iv-injected naloxone (3 mg/kg) in lean (46 kg body weight) and dietary obese (77 kg body weight) sheep that were maintained at equilibrium weight. To this end, an HPLC procedure combined with electrochemical detection was developed for measuring naloxone in sheep plasma. Naloxone disappearance from plasma followed an apparent first-order process, the kinetics of which were described best using a two-compartment open model. Components of the biexponential equations describing the plasma concentration (C)-time (t) curves for naloxone disappearance in lean (Ct = 1814e(-0.190t) + 413e(-0.017t)) and obese (Ct = 2282e(-0.282t) + 573e(-0.018t)) sheep were similar (p > 0.05). Mean (+/- SE) elimination half-lives for naloxone in lean (42.7 +/- 4.6 min) and obese (44.3 +/- 10.2 min) sheep were similar (p > 0.05). Volume of distribution of naloxone (Vd) was extensive but also similar (p > 0.05) in lean (5.6 +/- 0.9 L/kg) and obese (4.1 +/- 0.6 L/kg) sheep. Naloxone was distributed extensively throughout the body fluids and trapped or stored in significant amount in extravascular tissues because the naloxone Vd greatly exceeded 100% of body weight in both lean (557 +/- 86 mL/100 g) and obese (413 +/- 58 mL/100 g) sheep.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic factors and renal hemodynamic effects of high-protein meal versus low-protein meal in conscious dogs.

The effects of a high-protein (HP) and low-protein (LP) meal on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and renal vascular resistance (RVR) were examined in conscious dogs. Ingestion of the HP and LP meal produced a temporary increase in systemic hemodynamic parameters due in part to a 'cephalic phase' of sympathetic excitement. However only the HP significantly altered renal hemodynamics, i.e. GFR, ERPF and RVR. Plasma renin activity (PRA), serum aldosterone and plasma atrial natriuretic peptide (ANP) concentrations were not significantly altered by either a HP or LP meal. Of all the serum electrolytes measured, serum Ca2+ concentrations were significantly lower after a HP meal. It would appear that protein-meal-induced changes in renal hemodynamics are independent of changes in systemic hemodynamics. The exact mechanism of action of a HP meal on renal hemodynamics is not clear, but it appears that one mechanism by which a HP meal may alter renal hemodynamics is by altered calcium homeostasis.

Feeding behavior and its responsiveness to naloxone differ in lean and obese sheep.

Feeding and its regulation by opioids were studied in lean sheep and sheep in the static phase of dietary obesity. Sheep were fasted 16 h and on separate days were injected IV with 0 (saline), 0.01, 0.1, 1, or 3 mg/kg naloxone 5 min before they were allowed ad lib intake for the ensuing 32 h. All sheep were in chronic zero energy balance when not fed ad lib during naloxone treatment. After 0 mg/kg naloxone, intake rate was at least twice as fast (p < 0.05) in lean than obese sheep through the first 4 h of ad lib feeding, but was similar (approximately 0.5 g/min) in both groups of sheep after 8 h of ad lib feeding. Dose-dependent inhibitory effects of naloxone on intake were observed in lean and obese sheep through the first 4 h of ad lib feeding with maximum inhibition at +2 h. Dose-response curve for naloxone inhibition of intake was shifted leftward in obese compared with lean sheep. Dose of naloxone needed to inhibit intake by 25% was less (p < 0.05) in obese (0.13 mg/kg) than lean (0.57 mg/kg) sheep when both groups experienced similar plasma concentrations of injected naloxone. Basal concentrations of immunoreactive beta-endorphin in fasted plasma were similar in lean (33 +/- 4 pg/ml) and obese (48 +/- 9 pg/ml) sheep. Dietary obesity in sheep was associated with reduced appetite and with enhanced responsiveness to the intake-inhibitory effects of naloxone.

Effects of naloxone on ad libitum intake and plasma insulin, glucose, and free fatty acids in maintenance-fed sheep.

The dose-dependent effects of naloxone on feed intake, and plasma chemicals (insulin, glucose, FFA) purportedly involved in feed intake regulation, were determined in 16-hr fasted sheep that were lean and chronically fed maintenance. Dorset ewes (n = 5) were treated with 0 (saline), 0.3, 1 or 3 mg/kg of naloxone in a generalized randomized block experiment with at least 7 d between successive doses. Feed intakes and plasma insulin, glucose and FFA were determined frequently during 24 hr of ad libitum intake after each naloxone treatment. The 0.3, 1 and 3 mg/kg doses of naloxone reduced (P less than 0.01) the 4-hr feed intake by 30, 40, and 60% respectively, whereas the initial feed intake (10 min) was decreased (P less than 0.05) 45% only by 3 mg/kg naloxone. However, total 24-hr intakes were similar across all doses because intakes between 4 and 24 hr of feeding in sheep treated with 0.3 (839 g), 1.0 (802 g) and 3.0 (1330 g) mg/kg naloxone exceeded (P less than 0.01) that in saline-treated sheep (391 g). Feeding-induced changes in plasma insulin, glucose and FFA concentrations were independent of naloxone treatment, suggesting that endorphinergic control of feed intake may not involve coincidental changes in plasma insulin, glucose and FFA levels which are thought to play a role in systemic regulation of appetite in animals. The endorphinergic regulation of appetite in sheep may involve the central nervous system, rather than peripheral opiate mechanisms that utilize blood-borne signals. Further, the ability of naloxone to suppress appetite in sheep appears inversely related to the duration of fasting or severity of negative energy balance.

Failure of naloxone to attenuate fasting induced hyperphagia in broiler chicks.

Subcutaneous administration of naloxone at 1 to 10 mg/kg produced a dose-related decrease in feed intake of broiler chicks. Food deprivation for 3, 6, 12, and 24 hours produced a significant increase in feed intake compared to non-food deprived birds. Subcutaneous administration of naloxone at 1 to 10 mg/kg failed to attenuate hyperphagia of broiler chicks, deprived of food for 12 hrs. These data suggest that opiate receptors are involved in the regulation of spontaneous feeding behavior in broiler chicks. However, in contrast to other mammals and pigeons, a mechanism, other than endorphinergic system, not sensitive to naloxone blockade, might be involved in food deprivation induced hyperphagia in broiler chicks.