Veratridine-evoked release of dopamine from guinea pig isolated cochlea

Dopamine released from the lateral olivocochlear efferent system is thought to inhibit the toxic effect of the extreme glutamate outflow from the inner hair cells during ischemia or acoustic trauma. Using in vitro microvolume superfusion, we have studied the release of [(3)H]dopamine from the lateral olivocochlear efferent bundle of guinea pig in response to accumulation of [Na(+)](i), under condition characteristics of ischemia. Veratridine, that acts only on excitable membranes as a specific activator of voltage-sensitive sodium channels, significantly increased the electrically evoked release of [(3)H]dopamine, which was completely inhibited by tetrodotoxin. Dizocilpine (MK-801), a non-competitive NMDA-receptor antagonist, and GYKI-52466, a selective non-NMDA-receptor antagonist, had no effect on veratridine-induced [(3)H]dopamine release. Our data provide further evidence that the cochlear release of dopamine is of neural origin and possibly independent on a local effect of glutamate. The veratridine-induced transmitter release in the cochlea will be a very useful method in studying the effect of drugs on ischemic injury.     

Pentoxifylline ameliorates cerulein-induced pancreatitis in rats: role of glutathione and nitric oxide

Reactive oxygen radicals, nitric oxide, and cytokines have been implicated in the initiation of pancreatic tissue damage and impairment of the pancreatic microcirculation in acute pancreatitis. Pentoxifylline is a methylxanthine derivative with rheologic and marked anti-inflammatory properties and inhibits the production of proinflammatory cytokines. We have examined whether pentoxifylline ameliorates interstitial edema, inflammatory infiltrate, and glutathione depletion associated with cerulein-induced pancreatitis. Cotreatment of animals with pentoxifylline significantly reduced cerulein-induced pancreatic inflammation and edema and attenuated the depletion of pancreatic glutathione and the increase in serum lipase activity, nitrate, and tumor necrosis factor-alpha levels. Pentoxifylline also prevented both mitochondrial swelling and damage to mitochondrial cristae caused by cerulein. Our findings provide an experimental basis for using pentoxifylline to attenuate inflammatory responses within the pancreas in acute pancreatitis and as an adjuvant in the treatment of acute pancreatitis.     

Photodynamic therapy with hypericin in a mouse P388 tumor model: vascular effects determine the efficacy

Hypericin, a polycyclic quinone obtained from plants of the Hypericum genus, exhibits strong photodynamic antitumor effects. In the present study, PDT efficacy of hypericin under different conditions was compared in a P388 mouse tumor model. Plasma and tumor drug measurements and assessment of vascular damage by fluorescein dye exclusion were performed to determine the relative contributions of vascular effects and direct tumor cytotoxicity. Furthermore, the influence of modifying tumor oxygenation on PDT effect was also evaluated. Study of PDT efficacy and tissue distribution revealed that PDT efficacy was more dependent on plasma concentration than tumor drug level. Fluorescein dye exclusion indicated the complete microvascular occlusion in the tumor and surrounding skin immediately after effective PDT treatments, while only a limited vascular occulation was observed after non-effective PDT treatment. It was found that neither tumor hypoxia induced by hydralazine nor increasing tumor oxygenation achieved by nicotinamide could significantly affect the effectiveness of various PDT protocols. These results suggest that tumor vasculature damage might be the primary mechanism of hypericin-mediated PDT effect. The existence of this potent secondary vascular effect is likely to account for the inability of tumor oxygenation modifiers to affect tumor response after PDT with hypericin.     

The Hungarian translation of the "Dental Fear Survey" based on the Hungarian population

Authors translated the "Dental Fear Survey" (DFS) into Hungarian. 196 persons have been investigated and the DFS values have been compared to DAS, STAI-S, STAI-T values. Mean values were: DFS: 46.27; DAS: 12.24; STAI-S: 41.58; STAI-T: 42.68. Authors found all values higher in the case of women comparing to men. Positive correlation has been found between DAS and DFS, but STAI-S and STAI-T increased only moderately comparing to the DAS and DFS values.     

J-shaped relation between blood pressure and stroke in treated hypertensives

The objective of this study was to investigate the relationship between hypertension and risk of stroke in the elderly. The study was performed within the framework of the Rotterdam Study, a prospective population-based cohort study. The risk of first-ever stroke was associated with hypertension (relative risk, 1.6; 95% CI, 1.2 to 2.0) and with isolated systolic hypertension (relative risk, 1.7; 95% CI, 1.1 to 2.6). We found a continuous increase in stroke incidence with increasing blood pressure in nontreated subjects. In treated subjects, we found a J-shaped relation between blood pressure and the risk of stroke. In the lowest category of diastolic blood pressure, the increase of stroke risk was statistically significant compared with the reference category. Hypertension and isolated systolic hypertension are strong risk factors for stroke in the elderly. The increased stroke risk in the lowest stratum of blood pressure in treated hypertensive patients may indicate that the therapeutic goal of "the lower the better" is not the optimal strategy in the elderly.     

Evidence for the involvement of ATP, but not of VIP/PACAP or nitric oxide, in the excitatory effect of capsaicin in the small intestine

The contractile effect of capsaicin in the guinea-pig small intestine involves an activation of enteric cholinergic neurons. Our present data show that the P(2) purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 30 microM) significantly reduces the contractile response to capsaicin (2 microM) in the presence, but not in the absence, of the tachykinin receptor antagonists [O-Pro(9), (Spiro-gamma-lactam)Leu(10), Trp(11)]physalaemin (1-11) (GR 82334; 3 microM) and (S)-(N)-(1-(3-(1-benzoyl-3-(3, 4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenylpiperidine-4-yl)-N -methylacetamide (SR 142804: 100 nM) (for blocking tachykinin NK1 and NK3 receptors, respectively). PPADS (30 microM) fails to influence submaximal cholinergic contractions evoked by cholecystokinin octapeptide (CCK-8; 2-3 nM) or senktide (1 nM), or the direct smooth muscle-contracting effect of histamine (100-200 nM). A higher concentration (300 microM) of PPADS is also without effect against the stimulatory action of cholecystokinin octapeptide. This means that PPADS can probably be safely used as a purinoceptor antagonist in intestinal preparations. The putative pituitary adenylate cyclase activating peptide (PACAP) receptor antagonist PACAP-(6-38) (3 microM) significantly reduces the contractile effect of PACAP-(1-38) (10 nM) and abolishes that of vasoactive intestinal polypeptide (VIP; 10 nM). PACAP-(6-38) (3 microM) fails to influence the effect of capsaicin (2 microM) both in the absence and in the presence of tachykinin receptor antagonists. The nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine (L-NOARG; 100 microM) also fails to inhibit the capsaicin-induced motor response. We conclude that an endogenous ligand of PPADS-sensitive P(2) purinoceptors (possibly ATP), but not a VIP/PACAP-like peptide or NO, is involved in the nontachykininergic activation of cholinergic neurons in the course of the capsaicin-induced contraction.