Converting enzyme inhibition in isolated porcine resistance artery potentiates bradykinin relaxation

The purpose of this study was to determine the effects of converting enzyme inhibition on the contractile reactivity of porcine femoral and intramuscular resistance arteries. The arteries were dissected free of hind limb skeletal muscle from anaesthetized pigs (Micro-pig Yucatan, Charles River), and were mounted in organ chambers and in a myograph system for tension recording. Bradykinin induced an endothelium-dependent relaxation in both vessels which was potentiated by S 10211, a converting enzyme inhibitor, only in resistance arteries. Under basal conditions angiotensin II and angiotensin I did not contract resistance arteries although contraction could be obtained with other agents such as KCl, noradrenaline or vasopressin. If the tone was increased with noradrenaline, angiotensin II and angiotensin I produced an increase in tension. S 10211 inhibited the increase in tension induced by angiotensin I but not by angiotensin II in vessels with and without endothelium. These results suggest that (1) converting enzyme is present in the vascular wall of porcine resistance arteries, (2) this enzyme is not necessarily located on the endothelial cells and, (3) converting enzyme could influence the responsiveness to angiotensin I and bradykinin.     

Involvement of prolactin in the REM sleep-promoting activity of systemic vasoactive intestinal peptide (VIP)

The involvement of pituitary prolactin (PRL) in systemic vasoactive intestinal peptide (VIP)-induced sleep was studied. Male rats were implanted with electrodes for EEG-recording, with brain thermistors to record cortical temperature (T_crt) and with chronic intracardial catheters to obtain blood samples and to deliver substances. One group of rats (n = 8) received normal rabbit serum (NS) + physiological saline (SAL) on the baseline day and was injected with NS + VIP on the experimental day. In the other group of rats (n = 6), the baseline day was followed by administration of PRL-antiserum (PRL-AS) + VIP on the experimental day. The sera and VIP or SAL were injected 30 min before and at light onset, respectively. Sleep-wake activity was then recorded for the next 12-h light period. Systemic VIP-stimulated PRL secretion as measured by RIA in serial samples obtained hour 1 postinjection. VIP also elicited selective increases in REM sleep (REMS) in the rats pretreated with NS. T_crt was not affected by VIP. Administration of PRL-AS blocked the increase in circulating levels of free (non-IgG-bound) PRL and prevented VIP-enhanced REMS. Comparisons of the sleep effects of PRL-AS + VIP with the previously reported changes in sleep after PRL-AS alone indicate that PRL has a major role in the mediation of the REMS-promoting activity of systemic VIP. The results suggest that an increased release of endogenous pituitary PRL modulates REMS.     

Increase of prolactin mRNA in the rat hypothalamus after intracerebroventricular injection of VIP or PACAP

Vasoactive intestinal peptide (VIP), the structurally homologous pituitary adenylate cyclase-activating peptide (PACAP) and the pituitary hormone, prolactin (PRL) enhance rapid eye movement sleep (REMS). VIP and PACAP are both inducers of PRL gene expression and release in the pituitary gland. Little is known about PRL regulation in the brain although it is hypothesized that the REMS-promoting activity of i.c.v. administered VIP may be mediated via the activation of cerebral PRL. To test whether VIP or PACAP in fact increase intracerebral mRNA, the peptides (VIP: 30 or 300 pmol; PACAP: 220 pmol) were injected i.c.v. into rats at dark onset. 1 h later, cDNA was synthesized from purified hypothalamic mRNA. Standardized amounts were analysed for PRL using the polymerase chain reaction followed by Southern blotting and hybridization. Compared with β-actin mRNA levels, both VIP and PACAP increased PRL mRNA levels in a dose-dependent fashion though VIP was more effective on a molar basis. The previously reported alternatively spliced PRL mRNA (lacking exon 4) was not detected. The data support the hypothesis that the REMS-promoting activity of central VIP and PACAP might be mediated by cerebral PRL.     

Caffeic acid phenethyl ester (CAPE) supplemented St. Thomas' hospital cardioplegic solution improves the antioxidant defense system of rat myocardium during ischemia-reperfusion injury.

BACKGROUND AND AIM OF STUDY: Cardioplegic arrest remains the method of choice for myocardial protection in cardiac surgery. Caffeic acid phenethyl ester (CAPE) prevents lipid peroxidation induced by ischemia-reperfusion injury and has a potent antioxidant property. We investigated the advantages of CAPE supplemented cardioplegic solution (St. Thomas' Hospital cardioplegic solution No.: 2) on the antioxidant defense system of myocardium against ischemia-reperfusion injury. MATERIAL AND METHODS: Isolated rat hearts were mounted on a nonrecirculating type of Langendorff apparatus. The hearts were arrested for 60 min with cardioplegic solution given at 20-min intervals and then reperfused for 15 min. The hearts were divided into three groups. Cold saline (0.9%, 4 degrees C) in group 1, St. Thomas' Hospital solution in group 2 and CAPE added St. Thomas' Hospital solution in group 3 were used as the cardioplegic solution. Krebs-Henseleit buffer solution was used for reperfusion. The tissues were examined biochemically for oxidative stress. RESULTS: Significant differences among the three groups existed in tissue myeloperoxidase (MPO), catalase (CAT), Na+-K+ ATPase activity and in the concentrations of malonydealdehyde (MDA) and 3-nitrotyrosine (3-NT). Group 2 showed significant changes in MPO (P = 0.04), Na+-K+ ATPase enzyme activity (P = 0.02) and the levels of MDA (P = 0.004) and 3-NT (P = 0.01) in comparison with group 1. Group 3 efficiently reduced MDA levels (P = 0.004) and also led to significant decrease in levels of MPO (P = 0.006), 3-NT (P = 0.01) and Na+-K+ ATPase activity (P = 0.01) and increase in the level of CAT (P = 0.004) in comparison with group 1. Significant changes were also found in the levels of MDA (P = 0.03), MPO (P = 0.04) and CAT (P = 0.009) in comparison between groups 2 and 3. CONCLUSIONS: We demonstrated that the administration of CAPE into cardioplegic solutions improves the antioxidant defense system of rat heart during the ischemia-reperfusion injury.     

Dronabinol reduces signs and symptoms of idiopathic intracranial hypertension: a case report.

A case is presented in which a woman diagnosed with a longstanding history of idiopathic intracranial hypertension reported improvement of frontal headaches, photophobia, transient blindness, enlarged blind spots, and tinnitus after smoking marijuana. All these symptoms and signs were associated with increased intracranial pressure (220-425 mm of water). Treatment with dronabinol at a dose of 10 mg twice a day, then reduced to 5 mg twice a day, relieved all of her symptoms. Previously noted papilledema and enlargement of blind spots also resolved, and this, in the absence of psychoactive effect or weight gain.     

Anthracycline-induced cardiotoxicity: Overview of studies examining the roles of oxidative stress and free cellular iron

The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance. Anthracyclines may promote the formation of ROS through redox cycling of their aglycones as well as their anthracycline-iron complexes. This proposed mechanism has become particularly popular in light of the high cardioprotective efficacy of dexrazoxane (ICRF-187). The mechanism of action of this drug has been attributed to its hydrolytic transformation into the iron-chelating metabolite ADR-925, which may act by displacing iron from anthracycline-iron complexes or by chelating free or loosely bound cellular iron, thus preventing site-specific iron-catalyzed ROS damage. However, during the last decade, calls for the critical reassessment of this “ROS and iron” hypothesis have emerged. Numerous antioxidants, although efficient in cellular or acute animal experiments, have failed to alleviate anthracycline cardiotoxicity in clinically relevant chronic animal models or clinical trials. In addition, studies with chelators that are stronger and more selective for iron than ADR-925 have also yielded negative or, at best, mixed outcomes. Hence, several lines of evidence suggest that mechanisms other than the traditionally emphasized “ROS and iron” hypothesis are involved in anthracycline-induced cardiotoxicity and that these alternative mechanisms may be better bases for designing approaches to achieve efficient and safe cardioprotection.     

Late side-effects with cosmetic relevance following soft X-ray therapy of cutaneous neoplasias

Background Cosmetic changes are to be expected after radiotherapy for skin tumours. Objectives This study aimed to answer the questions: How frequent are cosmetic changes after soft X‐ray therapy? Do treatment parameters, tumour thickness, localization and size of the irradiated field have a major influence? Were patients irritated by the visual appearance of the irradiated field? Methods In total, 2474 examinations of 1149 irradiated fields were performed. Results Hypopigmentation was found in 64.7% of examinations more than 90 days after therapy, teleangiectases in 43.1%, erythema in 24.8%, and hyperpigmentation in 16.8%. The frequency of hypopigmentation, teleangiectases and hyperpigmentation increased with time from X‐ray exposure; more than 4 years after therapy hypopigmentation was diagnosed in 91.8% and teleangiectases in 82.2% of examinations. Total dose, the time–dose–fractionation factor (TDF), field size and dose per fraction were significantly related to the frequency of cosmetic changes. Incidence rates of cosmetic changes differed by less than 15% if different treatment conditions were compared: thicker vs. thinner tumours, larger vs. smaller fields, higher vs. lower total doses, doses per fraction, and TDF. Frequencies of hypopigmentation, teleangiectases, erythema and hyperpigmentation differed by more than 15% between some localizations on the head. Women reported irritation by the visual appearance of the irradiated field in 12.6% of 1116 interviews, and men in 4.4% of 1284 interviews. Conclusions Cosmetic changes after soft X‐ray therapy are relatively frequent. Treatment parameters, tumour thickness and field size have only a minor influence. Few patients, but more women than men, were irritated by the visual appearance of the irradiated field.