Elevation of intraluminal pressure increases vasomotor tone, which thought to have a substantial role in regulation of cerebral blood flow (CBF). Interestingly, responses of cerebral vessels to increases in flow varied and have not been studied in human cerebral arteries. We hypothesized that increases in flow elicit constrictions of isolated human and rat cerebral arteries and aimed to elucidate the underlying mechanisms. Human cerebral arteries and rat middle cerebral arteries constricted to increases in flow (P < 0.05). Simultaneous increase in intraluminal flow + pressure further reduced the diameter compared with pressure-induced changes (P < 0.05), leading to constant estimated CBF. Flow-induced constrictions were abolished by HET0016 (inhibitor of synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) or inhibition of COXs or blocking TP (thromboxane A 2 /prostaglandin H 2 , receptors and attenuated by scavenging reactive oxygen species (ROS). Flow-enhanced ROS formation was significantly reduced by HET0016. In conclusion, in human and rat cerebral arteries (1) increases in flow elicit constrictions, (2) signaling mechanism of flow-induced constriction of cerebral arteries involves enhanced production of ROS, COX activity, and mediated by 20-HETE via TP receptors, and (3) we propose that simultaneous operation of pressure-and flow-induced constrictions is necessary to provide an effective autoregulation of CBF.
A high incidence of LHRH receptors in BPH supports the use of LHRH antagonists such as cetrorelix, for treatment of patients with lower urinary tract symptoms from BPH.
Uveal melanoma is the most common primary intraocular malignancy in adults, with a very high mortality rate due to frequent liver metastases. Consequently, the therapy of uveal melanoma remains a major clinical challenge and new treatment approaches are needed. For improving diagnosis and designing a rational and effective therapy, it is essential to elucidate molecular characteristics of this malignancy. The aim of this study therefore was to evaluate as a potential therapeutic target the expression of luteinizing hormone-releasing hormone (LHRH) receptor in human uveal melanoma. The expression of LHRH ligand and LHRH receptor transcript forms was studied in 39 human uveal melanoma specimens by RT-PCR using gene specific primers. The binding charachteristics of receptors for LHRH on 10 samples were determined by ligand competition assays. The presence of LHRH receptor protein was further evaluated by immunohistochemistry. The expression of mRNA for type I LHRH receptor was detected in 18 of 39 (46%) of tissue specimens. mRNA for LHRH-I ligand could be detected in 27 of 39 (69%) of the samples. Seven of 10 samples investigated showed high affinity LHRH-I receptors. The specific presence of full length LHRH receptor protein was further confirmed by immunohistochemistry. A high percentage of uveal melanomas express mRNA and protein for type-I LHRH receptors. Our results support the merit of further investigation of LHRH receptors in human ophthalmological tumors. Since diverse analogs of LHRH are in clinical trials or are already used for the treatment of various cancers, these analogs could be considered for the LHRH receptor-based treatment of uveal melanoma.
Abstract. The presence of four different isoforms of luteinizing hormone-releasing hormones (LHRH) and one LHRH receptor (LHRH-R) has been reported in vertebrates. In the human genome only LHRH-I and LHRH-II genes have been identified. The human LHRH-I gene is composed of four exons separated by three introns. Three LHRH receptor or receptor-like genes have been demonstrated. The wellestablished type-I LHRH receptor (LHRH-R-I) gene is composed of three exons separated by two introns. In this study we investigated the expression of transcript forms of LHRH-R-I in human benign prostatic hyperplasia (BPH) with reverse transcriptase-polymerase chain reaction (RT-PCR) using gene specific primers. Thirty-five human BPH specimens were obtained at surgery. Normal human pituitaries collected at autopsy served as control. RNA extraction and RT-PCR with gene-specific primers for LHRH-R-I forward (F1)/reverse (R1), LHRH-R-I F2/R3, LHRH-R-I F1'/R2' were carried out to determine the mRNA expression for LHRH-R-I transcript forms. The expected PCR products amplified with gene specific primers were LHRH-R-I F1/R1 with 319 bp, LHRH-R-I F2/R3 with 309 bp and LHRH-R-I F1'/R2' with 219 bp. PCR products for LHRH-R-I F1/R1 were detected in 21 (60%) and for LHRH-R-I F2/R3 in 5 of 35 (14%) BPH samples. No PCR products for LHRH-R-I F1'/R2' were found. In conclusion, we detected mRNA for LHRH-R-I in human BPH specimens. Our results suggest that LHRH-R-I gene may have more than two splice variants or uncharacterised transcript forms of LHRH-R-I. Our findings support the merit of further investigation of the expression of LHRH-R-I and its transcript forms in human BPH.
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