VASOCONSTRICTOR RESPONSES TO COMPONENTS OF THE RENIN-ANGIOTENSIN SYSTEM IN CYCLOSPORIN-INDUCED HYPERTENSION IN THE RAT

1. Since plasma renin activity is increased in cyclosporin A (CsA)-induced hypertension in the rat, the role of the vascular renin-angiotensin system (RAS) in CsA-induced hypertension was investigated in rat mesenteric resistance vessels. 2. Female Wistar rats received CsA (10 mg/kg per day, s.c.) or vehicle for 30 days. CsA treatment increased tail-cuff systolic blood pressure (CsA treated 135 ± 3 mmHg vs control 125 ± 1 mmHg, P<0.0001). 3. Mesenteric resistance arteries (200–300 μm) were isolated and mounted in a microvessel myograph. Concentration-response curves to tetradecapeptide renin substrate (10-¹¹-10^?6 mol/L), angiotensin I (10-^l1-10^?6 mol/L) and angiotensin II (10-¹²-10^?6 mol/L) showed no differences between CsA-treated and control groups. 4. Mesenteric vascular angiotensin-converting enzyme (ACE) characteristics were determined by radioligand binding. There were no differences in the content or affinity of ACE between CsA-treated and control rats. 5. These results suggest that the mesenteric vascular RAS does not play a major role in CsA-induced hypertension in the rat.     

INTERACTION BETWEEN EPIDERMAL GROWTH FACTOR AND ARGININE VASOPRESSIN IN RENAL MEDULLARY MEMBRANES

1. Epidermal growth factor is a potent mitogen that causes natriuresis, diuresis and inhibition of arginine vasopressin-induced water reabsorption. 2. The aim of this study was to determine any interaction between epidermal growth factor and the V1 (vascular) and/or V2 (antidiuretic) arginine vasopressin receptor subtypes. 3. Radioligand binding displacement assays demonstrated that although arginine vasopressin related peptides displaced both radioligands from renal medullary membranes at low concentrations epidermal growth factor displaced neither. 4. Arginine vasopressin V2 receptor second messenger cyclic adenosine monophosphate (CAMP) production was inhibited by epidermal growth factor (IC₅₀ 2 ± 10^?7 mol/L) as was sodium fluoride cAMP production but only at much higher concentrations. 5. Therefore the diuretic effect of epidermal growth factor is not via direct antagonism of arginine vasopressin receptors but seems mediated via inhibition of the V2 second messenger system.     

Effects of mifepristone on rabbit intraocular pressure in the presence and absence of dexamethasone

Topical dexamethasone was used to elevate rabbit intraocular pressure in order to study the interaction with a steroid antagonist, mifepristone. Dexamethasone did not cause a consistently significant increase in intraocular pressure. Animals treated with mifepristone followed by dexamethasone showed no apparent increase in intraocular pressure after dexamethasone, indeed mifepristone caused a lower intraocular pressure than seen in other groups whether in the presence or absence of dexamethasone. Reductions of intraocular pressure when mifepristone was given after 14 days of dexamethasone administration were not found. No conclusion can be reached regarding any dexamethasone antagonism by mifepristone, except that intraocular pressure tended to be lower even in the presence of dexamethasone.     

The value of CT in determining potential instability of simple wedge-compression fractures of the lumbar spine.

PURPOSETo determine whether plain films alone are sufficient in the evaluation of stability of simple wedge-compression fractures of the lumbar spine.METHODSPlain films and CT scans of 53 consecutive patients seen during a 2-year period with lumbar spine fractures were retrospectively reviewed. Six readers blinded to the CT diagnosis independently read each patient''s plain films. Plain-film findings were scored on a five-point graded response scale using criteria proposed by Gehweiler and Daffner. In addition, a fracture was considered to be possibly unstable if there was involvement of more than one vertebral level or greater than 50% loss of anterior vertebral body height. CT findings represented the standard for comparison. CT scans were independently evaluated by three additional readers. Two-column involvement, middle-column involvement alone but with retropulsion, multiple-level involvement, or greater than 50% loss of vertebral height indicated potential instability.RESULTSFor 14 stable and 39 potentially unstable lumbar spine fractures, the pooled (mean) plain-film negative predictive value for detection of potentially unstable fractures was 0.62 (95% confidence interval, 0.53 to 0.70), with a sensitivity of 0.83 (95%, confidence interval; 0.78 to 0.87), and specificity of 0.80 (95% confidence interval, 0.70 to 0.87).CONCLUSIONPlain films are not adequate for determining stability of lumbar spine fractures.     

Factors involved in the anti-cancer activity of the investigational agents LM985 (flavone acetic acid ester) and LM975 (flavone acetic acid)

LM985 has been shown previously to hydrolyse to flavone acetic acid (LM975) in mouse plasma and to produce significant anti-tumour effects in transplantable mouse colon tumours (MAC). It has undergone Phase I clinical trials and dose limiting toxicity was acute reversible hypotension. Substantially higher doses of LM975 can be given clinically without dose limiting toxicity. We have investigated the activity of LM975 against a panel of MAC tumours and also the in vitro cytotoxicity of both LM985 and LM975 in two cell lines derived from MAC tumours. LM985 is considerably more cytotoxic than LM975 in vitro but increased length of exposure to LM975 results in improved activity. Single in vivo injection of LM975 showed no activity against the ascitic tumour MAC 15A, moderate activity against the s.c. poorly differentiated tumour MAC 13 and produced a significant growth delay in the well differentiated MAC 26. These latter responses were considerably enhanced by repeated injection 7 days later. Pharmacokinetic studies in mice following i.p. injection of LM985 demonstrated rapid degradation of LM985 to LM975 in the peritoneum. Length of exposure as well as drug concentration appear important factors in determining anti-tumour responses.     

Alpha 2U-globulin: measurement in rat kidney and relationship to hyaline droplets

The concentration of renal alpha 2U-globulin increased in a dose-dependent manner in adult male but not female rats which received a single dose of 2,2,4-trimethylpentane (TMP). After administration of a single dose of 12 mmol TMP/kg to adult male rats, the renal concentration of alpha 2U-globulin reached a peak at 48 hours and returned to near background level after 7 days. These changes in renal alpha 2U-globulin concentration were closely paralleled by changes in renal hyaline droplet formation. Renal alpha 2U-globulin and hyaline droplets were absent in normal pre-puberty male rats, and neither could be stimulated by a single dose of TMP. alpha 2U-Globulin was localised in the renal cortex of adult male rats, in particular the S2 segment of the proximal tubule. A greater staining intensity due to alpha 2U-globulin was seen in the S2 and adjacent segments after a single dose of TMP. A strong association is suggested between the presence of renal hyaline droplets and the occurrence of alpha 2U-globulin.     

Reduced blood clearance and increased urinary excretion of N-nitrosodimethylamine in patas monkeys exposed to ethanol or isopropyl alcohol.

Low concentrations of N-nitrosodimethylamine are metabolized in rodent and human liver by cytochrome P450IIE1, an activity competitively inhibitable by ethanol. In rodents coadministration of ethanol with N-nitrosodimethylamine results in increased tumorigenicity in extrahepatic organs, probably as a result of reduced hepatic clearance. To test this concept in a primate, the effects of ethanol cotreatment on the pharmacokinetics of N-nitrosodimethylamine were measured in male patas monkeys. Ethanol, 1.2 g/kg given p.o. before i.v. N-nitrosodimethylamine (1 mg/kg) or concurrently with an intragastric dose resulted in a 10-50-fold increase in the area under the blood concentration versus time curves and a 4-13-fold increase in mean residence times for N-nitrosodimethylamine. Isopropyl alcohol, 3.2 g/kg 24 h before N-nitrosodimethylamine, also increased these parameters 7-10-fold; this effect was associated with persistence of isopropyl alcohol and its metabolic product acetone, both IIE1 inhibitors, in the blood. While no N-nitrosodimethylamine was detected in expired air, trace amounts were found in urine. Ethanol and isopropyl alcohol pretreatment increased the maximum urinary N-nitrosodimethylamine concentration 15-50-fold and the percentage of the dose excreted in the urine by 100-800-fold. Thus ethanol and isopropyl alcohol greatly increase systemic exposure of extrahepatic organs to N-nitrosodimethylamine in a primate.