Emerging roles of urotensin-II in cardiovascular disease

Urotensin-II (UII) is a highly potent endogenous peptide within the cardiovascular system. Through stimulation of Galphaq-coupled UT receptors, UII mediates contraction of vascular smooth muscle and endothelial-dependent vasorelaxation, and positive inotropy in human right atrium and ventricle. A pathogenic role of the UT receptor system is emerging in cardiovascular disease states, with evidence for upregulation of the UT receptor system in patients with congestive heart failure (CHF), pulmonary hypertension, cirrhosis and portal hypertension, and chronic renal failure. In vitro and in vivo studies show that under pathophysiological conditions, UII might contribute to cardiomyocyte hypertrophy, extracellular matrix production, enhanced vasoconstriction, vascular smooth muscle cell hyperplasia, and endothelial cell hyper-permeability. Single nucleotide polymorphisms of the UII gene may also impart a genetic predisposition of patients to diabetes. Therefore, the UT receptor system is a potential therapeutic target in the treatment of cardiac, pulmonary, and renal diseases. UT receptor antagonists are currently being developed to prevent and/or reverse the effects of over-activated UT receptors by the endogenous ligand. This review describes UII peptide and converting enzymes, and UT receptors in the cardiovascular system, focusing on pathophysiological roles of UII in the heart and blood vessels. (C) 2004 Elsevier Inc. All rights reserved,

Factors affecting the formation of a skin reservoir for topically applied solutes

The reservoir function of the skin is an important determinant of the duration of action of a topical solute. The reservoir can exist in the stratum corneum, in the viable avascular tissue (viable epidermis and supracapillary dermis) and in the dermis. A steroid reservoir in the stratum corneum has been demonstrated by the reactivation of a vasoconstrictor effect by occlusion or application of a placebo cream to the skin some time after the original topical application of steroid. Other solutes have also been reported to show a reservoir effect in the skin after topical application. A simple compartmental model is used to understand why reactivation of vasoconstriction some time after a topical steroid application shows dependency on time, topical solute concentration and the product used to cause reactivation. The model is also used to show which solutes are likely to show a reservoir effect and could be potentially affected by desquamation, especially when the turnover of the skin is abnormally rapid. A similar form of the model can be used to understand the promotion of reservoir function in the viable tissue and in the dermis in terms of effective removal by blood perfusing the tissues. Copyright (C) 2004 S. Karger AG, Basel.

Differential involvement of N-type calcium channels in transmitter release from vasoconstrictor and vasodilator neurons

1 The effects of calcium channel blockers on co-transmission from different populations of autonomic vasomotor neurons were studied on isolated segments of uterine artery and vena cava from guinea-pigs. 2 Sympathetic, noradrenergic contractions of the uterine artery (produced by 200 pulses at 1 or 10 Hz; 600 pulses at 20 Hz) were abolished by the N-type calcium channel blocker omega-conotoxin (CTX) GVIA at 1-10 nM. 3 Biphasic sympathetic contractions of the vena cava (600 pulses at 20 Hz) mediated by noradrenaline and neuropeptide Y were abolished by 10 nM CTX GVIA. 4 Neurogenic relaxations of the uterine artery (200 pulses at 10 Hz) mediated by neuronal nitric oxide and neuropeptides were reduced < 50% by CTX GVIA 10-100 nM. 5 Capsaicin (3 muM) did not affect the CTX GVIA-sensitive or CTX GVIA-resistant neurogenic relaxations of the uterine artery. 6 The novel N-type blocker CTX CVID (100-300 nM), P/Q-type blockers agatoxin IVA (10-100 nM) or CTX CVIB (100 nM), the L-type blocker nifedipine (10 muM) or the 'R-type' blocker SNX-482 (100 nM), all failed to reduce CTX GVIA-resistant relaxations. The T-type channel blocker NiCl2 (100-300 muM) reduced but did not abolish the remaining neurogenic dilations. 7 Release of different neurotransmitters from the same autonomic vasomotor axon depends on similar subtypes of calcium channels. N-type channels are responsible for transmitter release from vasoconstrictor neurons innervating a muscular artery and capacitance vein, but only partly mediate release of nitric oxide and neuropeptides from pelvic vasodilator neurons.

Nitric oxide synthase inhibition in sepsis? Lessons learned from large-animal studies

Nitric Oxide (NO) plays a controversial role in the pathophysiology of sepsis and septic shock. Its vasodilatory effects are well known, but it also has pro- and antiinflammatory properties, assumes crucial importance in antimicrobial host defense, may act as an oxidant as well as an antioxidant, and is said to be a vital poison for the immune and inflammatory network. Large amounts of NO and peroxynitrite are responsible for hypotension, vasoplegia, cellular suffocation, apoptosis, lactic acidosis, and ultimately multiorgan failure. Therefore, NO synthase (NOS) inhibitors were developed to reverse the deleterious effects of NO. Studies using these compounds have not met with uniform success however, and a trial using the nonselective NOS inhibitor N-G-methyl-L-arginine hydrochloride was terminated prematurely because of increased mortality in the treatment arm despite improved shock resolution. Thus, the issue of NOS inhibition in sepsis remains a matter of debate. Several publications have emphasized the differences concerning clinical applicability of data obtained from unresuscitated, hypodynamic rodent models using a pretreatment approach versus resuscitated, hyperdynamic models in high-order species using posttreatment approaches. Therefore, the present review focuses on clinically relevant large-animal studies of endotoxin or living bacteria-induced, hyperdynamic models of sepsis that integrate standard day-today care resuscitative measures.

Physical and psychological factors maintain long-term predictive capacity post-whiplash injury

Higher initial levels of pain and disability, older age, cold hyperalgesia, impaired sympathetic vasoconstriction and moderate post-traumatic stress symptoms have been shown to be associated with poor outcome 6 months following whiplash injury. This study prospectively investigated the predictive capacity of these variables at a long-term follow-up. Sixty-five of an initial cohort of 76 acutely injured whiplash participants were followed to 2-3 years post-accident. Motor function (ROM; kinaesthetic sense; activity of the superficial neck flexors (EMG) during cranio-cervical flexion), quantitative sensory testing (pressure, thermal pain thresholds and brachial plexus provocation test), sympathetic vasoconstrictor responses and psychological distress (GHQ-28, TSK and IES) were measured. The outcome measure was Neck Disability Index (NDI) scores. Participants with ongoing moderate/severe symptoms at 2-3 years continued to manifest decreased ROM, increased EMG during cranio-cervical flexion, sensory hypersensitivity and elevated levels of psychological distress when compared to recovered participants and those with milder symptoms. The latter two groups showed only persistent deficits in cervical muscle recruitment patterns. Higher initial NDI scores (OR 1.00-1.1), older age (OR 1.00-1.13), cold hyperalgesia (OR 1.1-1.13) and post-traumatic stress symptoms (OR 1.03-1.2) remained significant predictors of poor outcome at long-term follow-up (r(2) = 0.56). The robustness of these physical and psychological factors suggests that their assessment in the acute stage following whiplash injury will be important. (c) 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Combined external-endonasal approach for complete excision of the lacrimal drainage apparatus

Purpose: The purpose of this study was to describe a new surgical technique for the complete excision of the lacrimal drainage apparatus (LDA) that combines external and endoscopic approaches. Methods: This study involved a noncomparative, retrospective chart review of the clinical and pathological findings of four patients presenting with LDA papillomas who underwent a combined open and endonasal excision of the lacrimal system. Results. Of the four patients, three were male. The mean age at referral was 41 years, and all cases were unilateral. Histopathology revealed two transitional cell papillomas, one squamous cell papilloma, and one combined transitional/squamous papilloma. Epiphora and an external lesion were the main complaints at presentation. Nasolacrimal duct obstruction was present in all four patients. Papilloma virus infection was suggested in two cases and was confirmed in the only patient who had recurrence. CT identified a solid enhancing mass in two cases. The surgical approach in all cases was performed with the patient under general anesthetic supplemented with infiltration of local anesthesia with vasoconstriction. The lacrimal sac was exposed as per an external dacryocystorhinostomy with biopsy collection from the lacrimal sac lumen to confirm the diagnosis prior LDA excision. The superior aspect of the LDA was isolated by using lacrimal probes in each canaliculus to stabilized parallel incisions and careful dissection toward the common canaliculus until they met the medial aspect of the lacrimal sac. The sac was then separated from the periosteum from the medial orbital wall, using sharp dissection. Finally, an endoscopic dissection of the lower end of the nasolacrimal duct released the most inferior aspect of the LDA, allowing the surgeon to pull and excise the complete system from the external wound. Conclusions: Extensive LDA papillomas required complete excision of the drainage system to prevent recurrence and/or malignant transformation. The use of a combined approach through an open excision of the superior part of the LDA in conjunction with the direct manipulation of the nasolacrimal duct guided by the nasal endoscope facilitates the complete excision of the system for extensive benign lesions.

Perindopril, an angiotensin converting enzyme inhibitor, in pulmonary hypertensive rats: comparative effects on pulmonary vascular structure and function

1 Hypoxic pulmonary hypertension in rats (10% O-2, 4 weeks) is characterized by changes in pulmonary vascular structure and function. The effects of the angiotensin converting enzyme inhibitor perindopril (oral gavage, once daily for the 4 weeks of hypoxia) on these changes were examined. 2 Perindopril (30 mg kg(-1) d(-1)) caused an 18% reduction in pulmonary artery pressure in hypoxic rats. 3 Structural changes (remodelling) in hypoxic rats included increases in (i) critical closing pressure in isolated perfused lungs (remodelling of arteries (50 mu m 0.d.) and (ii) medial wall thickness of intralobar pulmonary arteries, assessed histologically (vessels 30-100 and 101-500 mu m o.d.). Perindopril 10 and 30 mg kg(-1) d(-1) attenuated remodelling in vessels less than or equal to 100 mu m (lungs and histology), 30 mg kg(-1) d(-1) was effective in vessels 101-500 mu m but neither dose prevented hypertrophy of main pulmonary artery. 3 mg kg(-1) d(-1) was without effect. 4 Perindopril (30 mg kg(-1) d(-1)) prevented the exaggerated hypoxic pulmonary vasoconstrictor response seen in perfused lungs from hypoxic rats but did not prevent any of the functional changes (i.e. the increased contractions to 5-HT, U46619 (thromboxane-mimetic) and K+ and diminished contractions to angiotensins I and II) seen in isolated intralobar or main pulmonary arteries. Acetylcholine responses were unaltered in hypoxic rats. 5 We conclude that, in hypoxic rats, altered pulmonary vascular function is largely independent of remodelling. Hence any drug that affects only remodelling is unlikely to restore pulmonary vascular function to normal and, like perindopril, may have only a modest effect on pulmonary artery pressure.