Oxidative DNA damage induced by dioxetanes, photosensitizing ketones, and photo-fenton reagents.
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Animals↗
Biomedical subjects
S Emmert
Publications and source records attributed to S Emmert.
Assessment of genotoxicity and mutagenicity of 1,2-dioxetanes in human cells using a plasmid shuttle vector.
1,2-Dioxetanes are efficient sources of triplet excited carbonyl compounds on thermal decomposition. They cause photochemical and photobiological transformations in the dark. In order to study the genotoxicity and mutagenicity of 1,2-dioxetanes, the replicating shuttle vector pZ189 was damaged with 3,3,4-trimethyl-1,2-dioxetane (TrMD) or 3-hydroxymethyl-3,4,4-trimethyl-1,2-dioxetane (HTMD) in vitro and subsequently transfected into normal human lymphoblasts. We found a dose-dependent increase of genotoxicity (decrease of plasmid survival) and increase of mutation frequency with both dioxetanes. However, TrMD was less mutagenic than HTMD at similar genotoxicity. Sequence analysis of the supF gene revealed more point mutations with TrMD and 100% with HTMD were G:C to T:A and G:C to C:G transversions. These are the typical mutations following 7,8-dihydro-8-oxoguanine (8-oxo-G) formation, the main DNA lesion induced by TrMD and HTMD. Only with TrMD we found 5.4% G:C to A:T transitions, probably reflecting the more pronounced ability of TrMD to form some pyrimidine dimers. Our results indicate that 8-oxo-G is also the most relevant modification in in vivo mutagenesis.
Base Sequence↗
Enalapril in experimental hypertension and acute heart failure: comparison with calcium channel blockers.
The hemodynamic effects of enalaprilat (MK-422) and lisinopril (MK-521) were compared with the calcium channel blocker felodipine in dogs with ischemic left ventricular (LV) failure. The combination of nitrendipine plus enalapril was also examined in ischemic failure and in rats with spontaneous hypertension. In anesthetized dogs coronary embolization with 50 micron plastic microspheres reduced cardiac output and LV dP/dt max by approximately 40%, and LV end-diastolic pressure increased to greater than 13 mm Hg. Enalaprilat and lisinopril reduced mean arterial pressure by a maximum of 20 mm Hg and total peripheral resistance by approximately 30%. Left ventricular dP/dt:LVP, which was substantially decreased by embolization, was slightly increased by both angiotensin converting enzyme (ACE) inhibitors. The calcium entry blockers felodipine and nitrendipine qualitatively produced many of the same hemodynamic effects as the ACE inhibitors, but, in addition, they markedly reduced coronary resistance, increased myocardial blood flow, and did not alter cardiac contractility (LV dP/dt max). In spontaneously hypertensive rats single doses of nitrendipine (1.25 to 5.0 mg/kg per os) and enalapril (0.3 and 3.0 mg/kg per os) reduced mean arterial pressure, but differences were observed in the onset (enalapril 2 h versus nitrendipine 0.5 h), the duration of action, and magnitude of effect. In terms of blood pressure lowering, nitrendipine, 5.0 mg/kg per os, was clearly additive to 3.0 mg/kg per os of enalapril, but other combinations (enalapril, 3 mg/kg per os plus 0.625 mg/kg of nitrendipine or enalapril, 0.3 mg/kg per os plus 0.625 mg/kg nitrendipine) were not.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Effects of dehydration and renin on vasopressin concentration in the subfornical organ area.
The subfornical organ (SFO), one of the brain circumventricular organs, contains immuno-reactive arginine-vasopressin (AVP). AVP in the SFO area may originate in neurons of the hypothalamo-neurohypophysial system. If AVP in the SFO area is part of the magnocellular neuroendocrine system and is important in the regulation of hydration, then its concentration [(]) should change during prolonged dehydration. The SFO is also a target for angiotensin II when the peptide stimulates drinking and releases AVP from the hypothalamo-neurohypophysial system. For these reasons, it was reasoned that hormones of the renin-angiotensin system may also influence [AVP] in the SFO area. To test these hypotheses [AVP] was measured in the SFO area, hippocampal commissure-fornix (HC-F), neural lobe and plasma of rats after 24, 48 and 72 h of water deprivation and at various times after intracerebroventricular (i.v.t.) administration of 5 milli -Goldblatt Units of renin. Before examining the responsiveness of [AVP] in these brain regions to stimulation, we characterized the extraction and recovery of AVP from brain tissue and determined the variance of [AVP] in the SFO area and HC-F among different groups of animals. AVP was extracted from pooled brain tissue into 0.1 N HCl. The homogenate was centrifuged and AVP in the supernatant was quantified by radioimmunoassay either directly or after bentonite extraction. AVP extracted from the SFO area and HC-F displaced labelled antigen bound to antisera in a manner similar to that displaced by standard AVP. The recovery of AVP, added to the 0.1 N HCl extract and assayed directly, averaged 78-108%, whereas 51% was recovered after bentonite extraction. [AVP] in the SFO area from 47 or more groups of 2-6 organs each, averaged 16 +/- 5 pg/organ, 16 +/- 4 pg/mg wet wt, 153 +/- 31 pg/mg protein, and was not significantly different from that contained in the HC-F, 10 +/- 1 pg/mg wet wt and 111 +/- 16 pg/mg protein. A frequency histogram of these data revealed a normal (HC-F) and skewed distribution (SFO). Water deprivation for 24, 48 and 72 h stimulated drinking and increased plasma [AVP]. The elevation in plasma [AVP] plateaued after 48 and 72 h of water deprivation, whereas [AVP] in the neural lobe was reduced (P less than 0.05). Water deprivation increased [AVP] in the HC-F (control vs 72 h water deprivation), but did not alter hormone in the SFO area when expressed as pg/mg protein or pg/mg wet wt.(ABSTRACT TRUNCATED AT 400 WORDS)
Angiotensin I↗
Enkephalin inhibition of angiotensin-stimulated release of oxytocin and vasopressin.
The effect of leucine5 -enkephalin on angiotensin II (AII)-stimulated release of oxytocin and vasopressin (VP) was investigated in the conscious male rat. Changes in the plasma concentration ([]) of both oxytocin and VP were measured in animals: (1) 60 s after intracerebroventricular (i.v.t.) administration of either artificial cerebrospinal fluid (CSF) or CSF with AII (10, 50, 100 ng/5 microliter); (2) 30, 60, 90 and 300 s after single injection of AII (50 ng/5 microliter; i.v.t.) or CSF and (3) 60 s after AII (50 ng/5 microliter) or CSF in animals pretreated with leucine5 -enkephalin (100 ng/5 microliter; i.v.t.) or CSF (5 microliter). Oxytocin and VP were quantified by radioimmunoassay and values corrected for 100% recovery. The development of a sensitive radioimmunoassay for oxytocin is described. The antiserum for oxytocin enabled detection of greater than or equal to 0.8 pg/ml oxytocin with cross-reactivity of 0.01% with arginine vasopressin and 0.10% with arginine vasotocin. The inter- and intra-assay coefficients of variation were 3-9% and 3.2%, respectively. The hypotheses being tested were that i.v.t. injection of AII stimulates release of both neurohypophysial hormones non-selectively and that leucine5 -enkephalin inhibits both AII-stimulated oxytocin and VP release. Angiotensin II at doses ranging from 10 to 100 ng/5 microliter, i.v.t. increased the plasma concentration of both oxytocin and VP. Plasma levels of both neurohypophysial hormones were elevated 30 s after AII administration i.v.t. and remained elevated 300 sec later.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Effects of pinealectomy on neurohypophysial hormones in the SFO and plasma of dehydrated rats exposed to 12 hours of light.
Magnocellular neurons in the supraoptic and paraventricular nuclei synthesize and release vasopressin and oxytocin in response to dehydration. Pinealectomy has been observed to decrease the distribution in the supraoptic nuclei of thiamine diphosphate-phosphohydrolase, an enzyme specific for the Golgi apparatus that correlates positively with neurosecretory activity. Based upon these studies we postulated that pinealectomy would alter the concentration of neurohypohysial hormones in plasma elevated by 48 hr of water deprivation. In addition, we investigated the possibility that pinealectomy would affect vasopressin concentration in another circumventricular organ, the subfornical organ (SFO) and in a adjacent fiber tract of the limbic system, the hippocampal commissure-fornix (HC-F). Adult, male, Sprague-Dawley rats exposed to a 12 hr light/dark cycle were either unoperated (controls; C), sham-operated (Sham; S) or pinealectomized (PX) three weeks prior to testing. Food and water consumption and urinary excretion of Na and K were measured for 7 days. On the fifth day, half of the animals in each treatment group (C, S, PX) were deprived of water for 48 hr. Animals were decapitated on day 8. Vasopressin and oxytocin in plasma were extracted using bentonite and acetone-ether, respectively, then quantified by radioimmunoassay. The SFO and HC-F were microdissected from each brain. Like tissues from 4 rats were pooled, homogenized in 0.1 N HCl, and centrifuged. The supernatant was neutralized and vasopressin was quantified by radioimmunoassay. Dehydration resulted in antidiuresis, increased urine concentrations of Na and K, a decreased ratio of Na:K in urine, and reduced food consumption of similar magnitudes in all groups (C, S, PX; p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗