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We propose a method of constriction of the renal artery consisting in pulling of a loop of isolated artery into a thin plastic tube with calibrated inner diameter. This method can be used in experiments with constriction of other small blood vessels to diminish the local blood flow.
Infusion of radiocontrast agents in vivo results in renal artery constriction and subsequent renal hypoperfusion. To examine the role of endothelin and of prostaglandins in radiocontrast-mediated renal vasoconstriction, rats were treated with an endothelin receptor antagonist, CP170687, and with indomethacin. The dose of CP170687 utilized was sufficient to reverse endothelin1-mediated constriction of isolated aortic rings and of renal blood flow in intact rats. In normal rats there was a transient drop in renal blood flow to 80% of baseline following sodium iothalamate injection, an effect which was not prevented by CP170687. In rats first given indomethacin, the drop in renal blood flow was more pronounced (to 63% of baseline) and was sustained. In this instance, CP170687 fully reversed the sustained decrease of renal perfusion. CP170687 also diminished the rise in systemic blood pressure seen following iothalamate injection. In the absence of indomethacin, iothalamate increased urinary prostaglandin E2 to a maximum of sevenfold above baseline values. In summary, injection of radiocontrast results in an immediate decrease in renal blood flow that is counteracted by an increase in renal prostaglandin formation. When prostaglandin synthesis is inhibited, prolonged endothelin-mediated renal vasoconstriction is observed that is reversed by an endothelin receptor antagonist.
Sexual dysfunction is a frequent result of traumatic and non traumatic neurological disorders, including spinal cord injury, stroke, traumatic brain injury and autonomic neuropathy (for example, as may be seen in patients with diabetes mellitus). Although many methods have been suggested for the treatment of some of these problems in male patients, most are invasive and have a substantial morbidity. This is the report of a pilot trial of vacuum tumescence constriction therapy for 30 patients with chronic neurological impotence. Seventeen of these patients, following sexual counselling and training, decided to purchase such a device. At follow up, a mean of 21 months, over 50% of those who had purchased the device were still actively using it. The frequency of coitus increased from 0.3/wk to 1.5/wk (t = -5.7; p less than 0.0001). No significant morbidity was reported by patients. Vacuum tumescence constriction therapy shows promise as a noninvasive method for the treatment of neurological impotence.
1. It has previously been shown that the antimigraine drug sumatriptan constricts porcine carotid arteriovenous anastomoses via 5-HT1-like receptors, identical to 5-H1B/1D receptors. The recent availability of silent antagonists selective for the 5-HT1B (SB224289) and 5-HT1D (BRL15572) receptor led us to further analyse the nature of receptors involved. 2. In pentobarbitone-anaesthetized, bilaterally vagosympathectomized pigs, sumatriptan (30, 100 and 300 microg kg(-1), i.v.) dose-dependently decreased carotid arteriovenous anastomotic conductance by up to 70+/-5%. 3. The dose-related decreases in carotid arteriovenous anastomotic conductance by sumatriptan (30, 100 and 300 microg kg(-1), i.v.) remained unchanged in animals treated (i.v.) with 1 mg kg(-1) of BRL15572 (maximum decrease: 72+/-3%), but were significantly attenuated by 1 mg kg(-1) (maximum decrease: 30+/-11%) and abolished by 3 mg kg(-1) (maximum decrease: 3+/-7%) of SB224289. The highest dose of SB224289 did not attenuate the hypertension, tachycardia or increases in carotid blood flow induced by bolus injections of noradrenaline (0.1-3 microg kg(-1), i.v.). 4. The results indicate that sumatriptan constricts porcine carotid arteriovenous anastomoses primarily via 5-HT1B, but not via 5-HT1D receptors.
We examined the mechanisms underlying leukotriene D4- (LTD4) induced constriction of human small (300 - 500 micron i.d.) bronchioles, and the effect of LTD4 on ion currents and Ca2+ transients in smooth muscle cells (SMC) isolated from these bronchioles. LTD4 caused a concentration-dependent bronchoconstriction with an EC50=0.58+/-0.05 nM (n=7) which was not easily reversible upon washout. This bronchoconstriction was entirely dependent on extracellular Ca2+. Blockade of L-type Ca2+ channels with nifedipine (10 microM) reduced LTD4 response by 39+/-2% (n=8), whilst La3+, Gd3+ and SK&F 96,365 abolished LTD4-induced bronchoconstriction completely and reversibly, suggesting the majority of Ca2+ entry was via non-selective cation channels. Antagonists of PI-PLC (U73,122 and ET-18-OCH3), PLD (propranolol) and PKC (cheleretrine and Ro31-8220) were without any effect on LTD4-induced bronchoconstriction, whilst the PC-PLC inhibitor D609 caused complete relaxation. Inhibition of protein tyrosine kinase with tyrphostin A23 (100 microM) caused about 50% relaxation, although the inactive analogue tyrphostin A1 was without effect. In freshly isolated SMC from human small bronchioles LTD4 caused a slow increase of intracellular Ca2+ concentration, with a consequent rise of the activity of large conductance Ca2+-dependent K+ channels and the amplitude of depolarization-induced outward whole-cell current. Again, no effect of LTD4 could be observed in the absence of extracellular Ca2+. We conclude that LTD4 causes constriction of these small bronchioles primarily by activating Ca2+ entry via non-voltage gated channels, possibly by a PC-PLC mediated pathway.
We previously reported that intrathecal pro-opiomelanocortin gene electroporation could reduce pain sensitivity induced by chronic constriction injury (CCI) of the sciatic nerve. For optimal use of antinociceptive gene therapy, it might be important to control the expression of the transfected gene extrinsically. For this purpose, a doxycycline-controlled transrepressor system composed of two plasmids coding, respectively, for pro-opiomelanocortin gene (pTRE2-POMC) and the silencer (pTel-off) was employed. The regulation of beta-endorphin expression was first assessed in spinal neuronal culture, then we electrotranfected this plasmid into the spinal cord of mononeuropathic rats and evaluated the analgesic potential of this therapy in vivo by thermal and mechanical withdrawal latency. Intraperitoneal injections of various doses of doxycycline were made to elucidate the possible exogenous downregulation of transfected beta-endorphin gene expression in vivo. The levels of beta-endorphin were analyzed by intrathecal microdialysis and radioimmunoassay. Intrathecal pTRE2-POMC/pTel-off electroporation elevated spinal beta-endorphin levels, as manifested in a significantly elevated pain threshold for chronic constriction injury limbs. Intraperitoneal doxycycline decreased the antinociceptive effect and spinal beta-endorphin levels in a dose-dependent manner. We concluded that intrathecal pTRE2-POMC/pTel-off electroporation alleviates CCI-induced limb pain, and can be controlled by intraperitoneal doxycycline administration.
To assess the efficacy of vacuum constriction devices (VCD) following radical prostatectomy (RP) and determine whether early use of VCD facilitates early sexual activity and potentially earlier return of erectile function. This prospective study consisted of 109 patients who underwent nerve-sparing (NS) or non-nerve-sparing (NNS) RP between August 1999 and October 2001 and developed erectile dysfunction following surgery. The patients were randomized to VCD use daily for 9 months (Group 1, N=74) or observation without any erectogenic treatment (Group 2, N=35). Treatment efficacy was analyzed by responses to the Sexual Health Inventory of Men (SHIM) (abridged 5-item International Index of Erectile Function (IIEF-5)), which were stratified by the NS status. Patient outcome regarding compliance, change in penile length, return of natural erection, and ability for vaginal intercourse were also assessed. The mean patient age was 58.2 years, and the minimum follow-up was 9 months. Use of VCD began at an average of 3.9 weeks after RP. In Group 1, 80% (60/74) successfully used their VCD with a constriction ring for vaginal intercourse at a frequency of twice/week with an overall spousal satisfaction rate of 55% (33/60). In all, 19 of these 60 patients (32%) reported return of natural erections at 9 months, with 10/60 (17%) having erections sufficient for vaginal intercourse. The abridged IIEF-5 score significantly increased after VCD use in both the NS and NNS groups. After a mean use of 3 months, 14/74 (18%) discontinued treatment. In Group 2, 37% (13/35) of patients regained spontaneous erections at a minimum follow-up of 9 months after surgery. However, only four of these patients (29%) had erections sufficient for successful vaginal intercourse and rest of patients (71%) sought adjuvant treatment. Of the 60 successful users, 14 (23%) reported a decrease in penile length and circumference at 9 months (range, 4-8 months) compared to 12/14 (85%) among the nonresponders. However, in control group 22/35 reported decrease in penile length and circumference. Early use of VCD following RP facilitates early sexual intercourse, early patient/spousal sexual satisfaction, and potentially an earlier return of natural erections sufficient for vaginal penetration.
OBJECTIVE: To determine whether two structurally and mechanistically different inhibitors of cytochrome P-450 omega-hydroxylase would alter the enhanced vasoconstrictor response to elevated PO2 in arterioles of spontaneously hypertensive rats (SHR). Cytochrome P-450 omega-hydroxylases, which catalyze the formation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid from arachidonic acid, have been proposed to serve as microvascular O2 sensors. METHODS: Arteriolar diameters were measured in the in situ cremaster muscle of 4- to 6- and 12- to 16-week-old SHR and normotensive Wistar-Kyoto (WKY) controls during superfusion with physiological salt solution (PSS) equilibrated with 0% O2 and 21% O2 before and after P-450 enzyme inhibition. RESULTS: The P-450 omega-hydroxylase inhibitors 17-octadecynoic acid (17-ODYA) and N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS) significantly reduced O2-induced constriction of arterioles of 12- to 16-week-old SHR and WKY and eliminated the difference in the response between the two groups. In contrast, both enzyme inhibitors attenuated the O2-induced constriction of arterioles in the younger WKY, but not in the 4- to 6-week-old SHR. CONCLUSIONS: These results support the hypothesis that cytochrome P-450 4A may act as an O2 sensor in the skeletal muscle microcirculation and suggest that 20-hydroxyeicosatetraenoic acid plays an important role in the enhanced response to elevated PO2 in the SHR with established hypertension. Other mechanisms seem to contribute to the enhanced sensitivity of arterioles to elevated PO2 in young SHR during the early development of hypertension.
Laryngeal functioning during the production of whispered speech is not well understood. The efficacy of whispering as a means of voice rest is a common clinical concern that is unresolved. This investigation examined vocal-fold configuration, glottal size, and airway constriction by supraglottal structures during whispering. Ten normally speaking adults produced consonant-vowel syllables with three different vowels while whispering in low-effort and high-effort manners. The larynx was visualized through fiberoptic endonasolaryngoscopy, and the views were recorded on videotape. Analysis and descriptions of the data revealed that low-effort and high-effort whispering were differentiated to a small extent by vocal-fold adjustments and to a somewhat larger degree by supraglottal constriction. However, for each dependent variable, individual subject differences tended to be considerably larger than any systematic effects due to whisper type or vowel.
Partial nerve injury is a potential cause of distressing chronic pain for which conventional analgesic treatment with opiates or anti-inflammatory agents is not very effective. Constriction nerve injury, widely used to study neuropathic pain, was shown here to induce interleukin-6 (IL-6) mRNA in a subset of rat primary sensory neurons. When we inflicted chronic nerve constriction on mice with null mutation of the IL-6 gene, the hypersensitivity to cutaneous heat and pressure that is induced in wild-type mice was not evident, the loss of substance P in sensory neurons was excessive and the induction of galanin in central sensory projections was reduced. In additional experiments, intrathecal infusion of IL-6 in rats was shown to stimulate synthesis of galanin in approximately one-third of lumbar dorsal root ganglion neurons. The results of these experiments indicate that endogenous IL-6 mediates some of the hypersensitive responses that characterize peripheral neuropathic pain, and influences two neuropeptides that have been implicated in pain transmission.
Chronic constriction of the sciatic nerve, leading to a hyperalgesic state, results in a partial lesion wherein some axons are injured and others remain intact. Here we sought to characterize reactive changes which occur in DRG cell bodies of injured and uninjured axons projecting to skin and muscle. Using immunohistochemistry combined with flurorogold and fluororuby retrograde labelling to define DRG cell bodies associated with injured and uninjured axons, we analysed the DRG immunoreactivity (IR) for tumour necrosis factor-alpha (TNF), interleukin-10 (IL-10), the sensory neuron-specific channel vanilloid receptor 1 (VR1), isolectin B4 (IB4) and calcitonin-gene-related peptide (CGRP) 4 days after a unilateral chronic constriction injury (CCI) of the rat sciatic nerve. TNF IR was predominantly localized in neuronal DRG cells. In DRG with an intact nerve, TNF IR was present in 45%, IL-10 IR in 46%, VR1 IR in 44%, IB4 IR in 51% and CGRP IR in 40% of all neuronal profiles. Four days after CCI, TNF IR was increased in medium-sized neurons, whereas IR for IL-10, VR1 and IB4, predominantly present in small neurons, was reduced. Importantly, not only injured but also adjacent spared neurons contributed markedly to increased TNF IR. Neurons projecting to both muscle and skin displayed upregulated TNF IR after CCI. TNF in medium-sized neurons colocalized with neurofilament and trkB, but not with IB4, trkA or RET, suggesting a selective phenotypic switch in presumably low-threshold myelinated primary afferents. Spared myelinated fibres with intact sensory functions but upregulated TNF expression may contribute to behavioural changes observed after nerve injury.
Previous investigations from our laboratory have shown that ergotamine causes a selective vasoconstriction in the carotid vascular bed of the dog and that the drug constricts arteriovenous anastomoses (AVAs) in cats and pigs. Since ergotamine can act via alpha-adrenergic or D-serotonergic receptors in certain vascular and non-vascular tissues, we have attempted to ascertain here if these receptors mediate the constriction of AVAs. Using radioactive microspheres of 15 microns diameter we found in the dog that about 40% of the carotid arterial blood is shunted to the venous side via AVAs. Ergotamine (2-20 micrograms X kg-1, i.v.) reduced total carotid blood flow to a larger extent in the AVA part than in the extracerebral part (muscles, ears, skin and fat). The cerebral component of carotid blood did not change. These results, confirming that ergotamine decreases arteriovenous shunting, show that the drug has a more selective action on the AVAs than on the arterioles. Pretreatment with phentolamine (0.5 mg X kg-1), pizotifen (0.5 mg X kg-1) or their combination did not effectively modify the responses to ergotamine. It is concluded that the vasoconstriction of cranial AVAs (and arterioles) by ergotamine does not appear to be primarily mediated by either alpha-adrenergic or D-serotonergic receptors. However, the role of atypical serotonin receptors has yet to be determined.
Some of the sensory abnormalities that follow peripheral nerve injury may result from the development of ectopic discharge from the damaged axons. Previous studies in our laboratory have shown that, following tight ligation of the inferior alveolar nerve (IAN), there is a close association between the time-course of this neural activity and the accumulation of neuropeptides at the injury site. In this study we investigated whether the type of injury has any effect on the time-course or level of neuropeptide expression. In 36 adult ferrets, the IAN was either loosely constricted or sectioned, and the animals left to recover for 3 days, 3 weeks, or 3 months. The tissue was processed using indirect immunofluorescence and image analysis was used to quantify levels of substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide, enkephalin, galanin, and neuropeptide Y. Immunoreactivity to all of the neuropeptides was present within the injured nerve 3 days after both types of injury, and decreased to lower levels by 3 weeks and 3 months. Comparisons between the levels of neuropeptide immunoreactivity in each group revealed that the pattern of accumulation was similar following loose constriction or section, and also similar to that found in our previous study on tight ligation. For each injury the time-course of neuropeptide expression was similar to that of the spontaneous activity we had previously recorded. These data support the suggestion that neuropeptide accumulation may be linked to the development of ectopic neural activity but indicate that the type of injury has little effect on the extent of expression.
Epilepsy patients treated with vigabatrin may develop symptomatic or asymptomatic concentric visual field constriction due to GABA-associated retinal dysfunction. The prevalence and course of this side effect are not established yet; in previously reported adult patients the visual disturbances seem to be irreversible. We present two patients with a significant improvement of visual field constriction and retinal function after the discontinuation of vigabatrin. These findings suggest that vigabatrin-associated retinal changes are at least partly reversible in some patients, and that these patients may benefit significantly from a withdrawal of vigabatrin. Larger scale clinical studies are needed to identify predictive factors both for the occurrence and reversibility of vigabatrin-associated visual field defects.
While vigabatrin-associated visual field constrictions have been generally considered irreversible, some case reports have raised the hope of partial improvement after drug withdrawal in occasional patients. Here we describe seven children with epilepsy, whose visual field constrictions, as demonstrated by the kinetic perimetry (Goldmann), attenuated or recovered after discontinuation of vigabatrin therapy. While this improvement may be largely due to better performance in later test sessions, we want to raise the possibility that some visual field recovery may be possible at least in young patients.
A case of congenital annular constricting band syndrome with an open pseudarthrosis of the tibia and fibula is reported. Ischemia, neurological defect and major lymphoedema were present. The child had an emergency treatment combining an external fixator and a one-stage resection of the constricting band. Bone union was obtained within 4 weeks and complete neurological recovery at 6 months. Long-term result, with realignment and normal function, is satisfactory. A review of the literature is undertaken. Amputations are frequent, however pseudarthroses are rare. One-step treatment of the band has been proposed by certain authors. Neurological recovery is usual. The risk of ischemia favors an early surgical treatment.
OBJECTIVE: This study was undertaken to determine whether adrenomedullin, a hypotensive peptide, decreases vasomotor tone in fetoplacental vasculature that has been constricted with the thromboxane sympathomimetic U46619. STUDY DESIGN: The fetoplacental vascular beds of 20 perfused human placental cotyledons were vasoconstricted with a continuous infusion of U46619 (10(-8) mol/L). The vasculature was then sequentially injected with deionized water, 30 ng adrenomedullin, 300 ng adrenomedullin, and 3000 ng adrenomedullin. Any change in perfusion pressure was noted after each dose. In a separate experiment the fetoplacental vasculature in 2 perfused cotyledons from each of 10 placentas was vasoconstricted with U46619 (10(-8) mol/L). Adrenomedullin was infused continuously at either 200 ng/min (n = 5) or 2000 ng/min (n = 5) for 40 minutes. A corresponding control cotyledon from each placenta had isotonic sodium chloride solution added to its perfusion. Perfusion pressures were recorded every minute during the infusion and for 40 minutes afterward. Analysis of variance was used to compare pressure changes in the cotyledons that received bolus doses of adrenomedullin. Paired t tests of mean percentage pressure changes were used to compare the study and control groups that received the continuous infusions. RESULTS: In the cotyledons that received bolus doses of adrenomedullin, the mean (+/-SEM) percentage perfusion pressure changes from the baseline were -6.7 +/- 0.5 for 30 ng adrenomedullin (P =.0039), -8.5+/- 0.7 for 300 ng adrenomedullin (P <.0001), and -13.1 +/- 1.0 for 3000 ng adrenomedullin (P <.0001). With the continuous adrenomedullin infusion of 200 ng/min, there was no significant difference in the mean percentage pressure change from baseline between the study and control groups (-0.57%). At 2000 ng/min there was a significant difference (-15.34%; P <.0001). CONCLUSION: Adrenomedullin caused vasodilatation of fetoplacental vasculature previously constricted with the thromboxane sympathomimetic U46619 in the isolated perfused placental cotyledon. This vasodilatation occurred in a dose-dependent manner.
In the homotrimeric OmpF porin from Escherichia coli, each channel is constricted by a loop protruding into the beta-barrel of the monomer about halfway through the membrane. The water-filled channels exist in open or closed states, depending on the transmembrane potential. For the transition between these conformations, two fundamentally different mechanisms may be envisaged: a bulk movement of the constriction loop L3 or a redistribution of charges in the channel lumen. To distinguish between these hypotheses, nine mutant proteins were constructed on the basis of the high-resolution x-ray structure of the wild-type protein. Functional changes were monitored by measuring single-channel conductance and critical voltage of channel closing. Structural alterations were determined by x-ray analysis to resolutions between 3.1 and 2.1 A. Tethering the tip of L3 to the barrel wall by a disulfide bridge (E117C/A333C), mobilizing L3 by perturbing its interaction with the barrel wall (D312N, S272A, E296L), or deleting residues at the tip of the loop (Delta116-120) did not alter appreciably the sensitivity of the channels to an external potential. A physical occlusion, due to a gross movement of L3, which would cause the channels to assume a closed conformation, can therefore be excluded.