Biomedical subjects

J W Wright

Publications and source records attributed to J W Wright.

At least 19 recordsLinked to original sources

PubMed1992

Discovery of a distinct binding site for angiotensin II (3-8), a putative angiotensin IV receptor.

We report here the discovery of a unique and novel angiotensin binding site and peptide system based upon the C-terminal 3-8 hexapeptide fragment of angiotensin II (NH3(+)-Val-Tyr-Ile-His-Pro-Phe-COO-) (AII(3-8) (AIV)). This fragment binds saturably, reversibly, specifically, and with high affinity to membrane-binding sites in a variety of tissues and from many species. The binding site is pharmacologically distinct from the classic angiotensin receptors (AT1 or AT2) displaying low affinity for the known agonists (AII and AIII) and antagonist (Sar1,Ile8-AII). Although a definitive function has not been assigned to this system in many of the tissues in which it resides, AIV's interaction with endothelial cells may involve a role in endothelial cell-dependent vasodilation. Consequent to this action, AIV is a potent stimulator of renal cortical blood flow.

Adrenal Cortex↗

PubMed1992

Calpain II induced insolubilization of lens beta-crystallin polypeptides may induce cataract.

Addition of calpain II (EC 3.4.22.17) to soluble proteins from 10-day-old rat lens caused an increase in turbidity and production of water-insoluble protein. The insolubilization increased with higher concentrations of both lens protein and calpain II, it could be prevented by the cysteine protease inhibitor E-64; it required at least 0.5 mM Ca2+, it was limited to 6% of the soluble protein present and resulted from precipitation of proteolyzed beta-crystallin polypeptides. When compared by two-dimensional electrophoresis, the insoluble beta-crystallin polypeptides produced by calpain II were similar to insoluble beta-crystallin polypeptides found in cataractous lenses. Trypsin also caused insolubilization of beta-crystallin polypeptides, but these polypeptides were unlike polypeptides produced during cataract formation. These data suggested that the loss of solubility was due to a specific removal of N/or C-terminal extensions from beta-crystallin polypeptides by calpain II, and that a similar process may occur in vivo during cataract formation. It is hypothesized that the insoluble protein produced by calpain II causes cataract by increasing light scatter in the lens.

Animals↗

PubMed1992

Identification of an AII(3-8) [AIV] binding site in guinea pig hippocampus.

A unique angiotensin binding site specific for the hexapeptide, AII(3-8), has been identified in guinea pig hippocampus. This binding site, which is present in the pyramidal cell layer of CA1, CA2, CA3 of the hippocampus and dentate gyrus, binds AII(3-8) with high affinity (KD = 1.29 +/- 0.18 nM) in a saturable manner (Bmax = 449 +/- 62 fmol/mg protein). The N-terminal structure of the binding ligand is paramount in determining the binding affinity. The C-terminal requirements seem less stringent as evidenced by the binding affinity of AII(3-7) (KD = 20.9 +/- 2.1 nM). Neither AII, AIII,Sar1, Ile8-AII, Dup 753 nor CGP42112A appear to bind, indicating that this binding site is neither the AT1 nor AT2 sites described for AII/AIII. Autoradiographic analysis of hippocampus binding confirms the inability of Sar1,Ile8-AII to compete for [125I]AII(3-8) binding. Conversely AII(3-8) was unable to displace [125I]Sar1,Ile8-AII binding.

Angiotensin II↗

PubMed1992

Stereotaxic atlas of the brain of Octodon degus.

We present a stereotaxic atlas of the brain of the trumpet-tailed rat or degu (Octodon degus), an hystricomorph rodent native to Chile and one which has become increasingly popular as a research animal, among other things because of its use as a model for diabetic cataracts and its tendency to become hyperglycemic. The atlas contains 38 transverse and two sagittal sections of the brain covering pros-, mes-, and rhombencephalon, as well as diagrams of the brain's surface anatomy. It was constructed from brains of young adult male degus but can be used readily in studies of adult females, since there is no apparent sexual dimorphism in the brain size of this rodent. Ninety percent of 40 experimental lesions used to check the accuracy of the atlas were correctly placed. The fore- and midbrain of the degu are generally more compact than corresponding regions of the brain in the laboratory rat (suborder Myomorpha) and the guinea pig (another hystricomorph). The amygdaloid complex extends further forward in the telencephalon. Major mesencephalic nuclei and fiber tracts are more rostral in position. However, superior and inferior colliculi are much longer in degus than rats. The basic organization of the rhombencephalon is similar in degus and rats, although there are clearcut differences in the length or size of some hindbrain nuclei.

Anatomy, Artistic↗

PubMed1992

Release of angiotensins in paraventricular nucleus of rat in response to physiological and chemical stimuli.

The brain angiotensin (ANG II and III) system is known to play an important role in the central control of cardiovascular function and body water homeostasis. A number of components of the angiotensin system including active peptides, precursors, synthetic enzymes, and receptors have been localized to specific brain nuclei including the paraventricular nucleus (PVN) of the hypothalamus. We and others have hypothesized that the PVN is a major integrative hub of the central angiotensin system receiving angiotensinergic input from central detectors (circumventricular organs) and sending efferents to higher brain and spinal cord centers. Implicit in this idea is that angiotensins, like all neurotransmitters, should be releasable with appropriate chemical and physiological stimuli. Therefore we examined the ability of water deprivation or direct infusion of either 65 mM K+ or 80 microM veratridine to stimulate the release of angiotensins from the PVN of the rat. Using push-pull cannulas to perfuse the PVN and radioimmunoassay (RIA) to analyze the superfusate for immunoreactive angiotensins, we established that 24 h of water deprivation resulted in an approximate 5-fold increase in the angiotensin release rate, whereas 48-h deprivation produced a dramatic 492-fold increase in release. Direct infusion of 65 mM K+ into the PVN was unable to stimulate angiotensin release, but 80 microM veratridine elicited a sevenfold increase in the angiotensin release rate. High-performance liquid chromatographic separation and RIA analysis of veratridine- and water deprivation-stimulated angiotensin release demonstrated that 93.4% of the releasable angiotensin coeluted with ANG III, whereas only 6.8% eluted with authentic ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1992

Role of paraventricular nucleus in control of blood pressure and drinking in rats.

The present investigation examined the abilities of angiotensin (ANG) II and III to produce increases in blood pressure and drinking when microinfused into the paraventricular nucleus (PVN) of the hypothalamus of the Sprague-Dawley rat. Dose-dependent elevations in systemic blood pressure and heart rate were measured to both ANG II and III in the anesthetized rat, with ANG II more potent than ANG III at the two highest doses examined. Pretreatment with the specific ANG receptor antagonist [Sar1,Thr8]ANG II (sarthran), blocked subsequent ANG II- and III-induced elevations in blood pressure, suggesting that these responses were dependent on the activation of ANG receptors. A similar analysis in awake rats yielded nearly equivalent results. A final experiment demonstrated that microinfusions of ANG II and III into the PVN produced drinking in a dose-dependent manner, with greater consumption to ANG II than ANG III. Again, sarthran was found to block the dipsogenic response. Histological examination revealed that the location of the injection site was linked to the character of the ANG-dependent response. These data suggest that the PVN may play a critical role in mediating central ANG effects on body water homeostasis and blood pressure regulation. Furthermore, it appears that subnuclei of the PVN may participate differentially in ANG-mediated actions.

Angiotensin II↗

PubMed1991

Hypotensive effects of sarthran in normotensive and spontaneously hypertensive rat strains.

The specific angiotensin receptor antagonist [Sar1, Thr8]AII (sarthran) was intracerebroventricularly (ICV) infused in anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) normotensive controls. The results extend earlier findings by determining that: 1) the hypotensive effect of ICV-infused sarthran could be enhanced in anesthetized as compared with alert animals; 2) SHRs revealed a greater hypotensive response as compared with WKY rats; and 3) no sarthran-induced agonistic effects were observed in contrast with previous results using alert SHRs. These findings support the use of sarthran as a potent angiotensin receptor antagonist to investigate the role of the brain angiotensin system in the control of normal and dysfunctional blood pressure.

Angiotensin II↗

PubMed1991

Use of aminopeptidase M as a hypotensive agent in spontaneously hypertensive rats.

The present investigation determined that a commercially available aminopeptidase M (AmM, Sigma Chemical) can be utilized to lower blood pressure in normotensive and hypertensive rats. In vitro analyses indicated that the predominant peptidase present in this preparation was AmM; however, it also contained some aminopeptidase A (AmA) and less DAP IV. Although no DAP IV-mediated metabolism of angiotensin II (AII) or angiotensin III (AIII) was measured, both AmM and AmA metabolized AII and AIII. Upon further examination, it appeared that AII could be converted to AIII by either AmM or AmA; however, Arg was cleaved from the N-Terminal of AIII predominantly by AmM. The aminopeptidase inhibitors actinonin (AC), amastatin (AM), and bestatin (BE) effectively blocked the AmM-induced hydrolysis of the Asp-Arg bond of AII, and the Arg-Val bond of AIII. The activity of AmA was inhibited by AM but was relatively resistant to inhibition by AC and BE. Next, exogenous aminopeptidase replacement was employed in the anesthetized spontaneously hypertensive rat (SHR) in an attempt to temporarily correct a hypothesized brain deficiency of receptor-associated peptidases and lower blood pressure. Third-ventricle infusion of AmM produced significant drops in blood pressure and heart rate in both SHRs and Wistar-Kyoto normotensive controls. Pretreatment with AC or BE was particularly effective at interfering with the subsequent AmM-induced hypotensive effect, while AM was less effective. The central mechanisms underlying these effects are in need of further investigation; however, they are at least partially dependent upon the brain angiotensin system.

Aminopeptidases↗

PubMed1991

The influence of intra-arterial infusion of arginine vasopressin on cochlear blood flow in the rat.

Intra-arterially infused arginine vasopressin (AVP) elevated systemic blood pressure (BP) in the Sprague-Dawley rat according to a dose-response pattern while cochlear blood flow (CoBF), as measured by laser Doppler flowmetry, was elevated only at the highest dose. Skin blood flow (SBF) decreased significantly with AVP infusion. The local infusion of AVP into the anterior inferior cerebellar artery (AICA), which supplies the common cochlear artery, produced significant dose-dependent reductions in CoBF with no changes in systemic blood pressure. Pretreatment of the local cochlear supplying vessels with an AVP-specific V1 receptor antagonist attenuated subsequent AVP-induced decreases in CoBF, thereby demonstrating specificity of the response. These results suggest that CoBF is reasonably stable in response to systemic AVP infusion until blood pressure exceeds an elevation from base level of approximately +60 mm Hg. One of the mechanisms responsible for this autoregulatory response may be vasoconstriction mediated by the interaction of vasoactive peptides such as AVP and its receptors located in the vasculature of the inner ear or in the more peripheral vessels directly supplying the cochlea.

Animals↗

PubMed1991

Alcohol and the laboratory in the United Kingdom.

Reliable and rapid assays for the measurement of ethanol in breath and body fluids are now widely available. In view of the importance of alcohol abuse as a cause of a wide variety of both acute and chronic clinical conditions, hospital laboratories should be prepared to perform these assays for clinical purposes, although many will choose not to become involved in the assay of medico-legal samples.

Alcohol Drinking↗

PubMed1991

Effects of hydroxyethyl starch, nimodipine, and propylene glycol on cochlear blood flow.

A primary goal of pharmacologic treatment for otopathologies of vascular origin is to elevate cochlear blood flow (CoBF), thus facilitating the transport of oxygen and nutrients without compromising perfusion pressure in other tissues. In the present investigation, significant increases in CoBF were measured during intra-arterial infusion of the plasma expanding agent, hydroxyethyline starch (HES), and the vasodilator nimodipine, in anesthetized adult male guinea pigs. There were no changes in systemic blood pressure during the infusion of HES or nimodipine. Intra-arterial infusion of propylene glycol (PG), which is used as a nonaqueous solvent, produced inconsistent CoBF effects accompanied by initial decreases in systemic blood pressure with subsequent increases. It is concluded that nimodipine and HES are very promising agents for inducing increases in CoBF, whereas PG produced inconsistent effects on CoBF while elevating blood pressure, thus compromising its potential usefulness in the treatment of otopathologies.

Animals↗

PubMed1991

Effects of perilymph volume adjustments on cochlear blood flow in the guinea pig.

Previous research suggests a potential relationship between perilymphatic pressure (Pp) and cochlear blood flow (CBF); however, the alterations in Pp necessary to produce changes in CBF have not been adequately described or quantified. The effects of perilymph volume changes on systemic blood pressure (BP) and CBF were presently investigated in the guinea pig cochlea. Five microliters of perilymph were displaced in each of three conditions: viz. evacuation of 5 microliters from the cochlea; replacement of these 5 microliters; and finally the addition of 5 microliters of artificial perilymph into the cochlea. All perilymph volume adjustments were completed in 1-microliter increments during which changes in CBG and BP were recorded. Significant alterations in CBF were observed during 1-microliter perilymph volume adjustments in each condition with no significant changes in systemic BP. The results from this study support our hypothesis that an inverse relationship exists between CBF and Pp in that decreases in perilymph volume yielded elevations in CBF while increases in perilymph volume yielded reductions in CBF.

Animals↗

PubMed1991

Endothelin binding in brain of normotensive and spontaneously hypertensive rats.

The endothelins (ETs) are a recently discovered family of peptides which appear to be involved in hemodynamic regulation; they have potent vasoconstrictor properties and dose-related effects on blood pressure when administered peripherally. Little is known about the role of ET in the brain. The purpose of this study was to characterize the binding properties of various ETs in the brain of normotensive (Wistar-Kyoto) and hypertensive (spontaneously hypertensive) rats. [125I]ET 1 was prepared using the enzymobead lactoperoxidase method and purified by high-pressure liquid chromatography. Membrane fractions were prepared from homogenates of various brain regions. A differential distribution of ET binding was found among the 14 brain regions studied. The cerebellum, brainstem and area postrema/nucleus tractus solitarius had the highest binding, whereas the cortex, pituitary and septum had the least binding. Competition experiments performed with hypothalamus, brainstem and cerebellum demonstrated different Ki values for the ET studied. ET 2 had the highest affinity with a Ki of 4 x 10(-1) M, whereas the ET analog, Ala3,11-ET 1, had the lowest affinity with a Ki of 3 x 10(-10) M. Saturation experiments indicated a single class of high-affinity receptors in cerebellar (Kd = 2.5 x 10(-11) M, maximal binding Bmax = 1.25 x 10(-12) mol/mg) and hypothalamic membranes (Kd = 1.9 x 10(-11) M, Bmax = 0.93 x 10(-12) mol/mg). No differences in Kd or Bmax were detected between Wistar-Kyoto and spontaneously hypertensive rats hypothalamic and cerebellar tissues. The results of this study suggest a role for ET in the brain, but revealed no differences between normotensive and hypertensive strains.

Angiotensin II↗

PubMed1991

Treatment of sensorineural hearing loss.

Of the 25 million people who are hearing impaired, 85% suffer from sensorineural hearing loss (SNL). In the past decade, the identification and treatment of SNL have evolved from futile efforts to active intervention. This paper identifies nine forms of inner ear disorders causing SNL for which medical/surgical treatment is available. Physicians must realize that, with appropriate diagnosis and treatment, hearing nerve loss can have a satisfactory outcome.

Autoimmune Diseases↗

PubMed1991

Surgical glove perforation in obstetrics.

Perforation of surgical gloves places the obstetrician at risk for blood-borne infectious diseases. Seven hundred fifty-four surgical gloves used in vaginal and cesarean deliveries and postpartum tubal ligations were examined for evidence of perforation by the air inflation-water submersion technique. The overall glove perforation rate was 13.3%, with 62% of the perforations remaining unrecognized during the surgical procedure. The majority of perforations occurred on the fingers of the nondominant hand. Multivariate analysis with logistic regression indicated that cesarean delivery (odds ratio 3.52), any vaginal laceration or episiotomy (odds ratio 4.95), and chief resident status (odds ratio 3.00) were the major risk factors for surgical glove perforation. Surgical technique by assistants, especially in complex cases, is as important as that of the primary surgeon in regard to glove perforations.

Equipment Failure↗

PubMed1990

Intracerebroventricularly applied peptidase inhibitors increase endogenous angiotensin levels.

Rats received the aminopeptidase inhibitors amastatin (AM) and bestatin (BE), and carboxypeptidase inhibitor Plummer's (PL) via intracerebroventricular infusion in various combinations, i.e. PL alone, AM + BE, and a cocktail consisting of AM + BE + PL. Blood pressure responses were recorded and a postinfusion sample of cerebrospinal fluid (CSF) was radioimmunoassayed for endogenous angiotensin levels. Results indicate that CSF angiotensin was increased approximately 1.5x over control levels when PL was infused; a 2.5x increase accompanied AM + BE administration; and a 10.3x elevation was measured when all 3 inhibitors were infused as a cocktail. Concomitant elevations in blood pressure accompanied increased concentrations of angiotensin. We conclude that endogenous levels of angiotensin can be significantly increased in the ventricular space when a combination of these inhibitors is utilized to protect both the amino and carboxyl terminals of the angiotensin molecule from enzymatic degradation.

3-Mercaptopropionic Acid↗

PubMed1990

Comparison of angiotensin metabolism by brain membranes from SHR and WKY rats.

The ability of membrane-associated peptidases from the brains of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats to metabolize iodinated angiotensin (125I-Ang II) and 125I-Ang III was compared. 125I-Ang II was metabolized to 125I-Ang III and other fragments exclusively by membrane-associated peptidases. In contrast to 125I-Ang III which was effectively degraded by both membrane-associated and residual cytosolic peptidases, 125I-Ang II was unaltered by contaminating cytosolic enzymes. The ability of SHR-derived membranes to metabolize 125I-Ang II and produce 125I-Ang III was enhanced when compared to membranes from WKY rats. No difference was observed in the ability of membrane or cytosolic enzymes from SHR and WKY rats to degrade 125I-Ang III. These data are consistent with an increased availability of Ang III in the brains of SHRs.

Angiotensin II↗

PubMed1990

Pentoxifylline increases cochlear blood flow while decreasing blood pressure in guinea pigs.

The effects of pentoxifylline on cochlear blood flow (CoBF) were investigated in anesthetized guinea pigs by laser Doppler flowmetry and intravital microscopy red blood cell velocity measurement. Intra-arterial infusion of pentoxifylline (3, 4, and 5 mg/kg/min) produced dose-dependent reductions in blood pressure, accompanied by significant elevations in CoBF that were not dose-dependent. These results are in general agreement with previous findings from our laboratory utilizing normotensive and spontaneously hypertensive rats, however, in contrast with rats, guinea pigs revealed an initial decrease in CoBF followed by an increase. Also, pentoxifylline produced relatively smaller elevations in CoBF in guinea pigs as compared with those previously reported in rats. Taken together these results support the hypothesis that pentoxifylline increases vascular perfusion by decreasing blood viscosity and increasing the plasticity of red blood cells.

Animals↗