Biomedical subjects

J W Wright

Publications and source records attributed to J W Wright.

At least 73 records · Page 4Linked to original sources

PubMed1994

The use of urine protein 1 as an indicator of renal tubular function in type I (insulin-dependent) diabetes.

One hundred male insulin-dependent diabetic patients, aged 16 to 85 (mean 51.9) years, with albumin excretion ranging from normal to gross excess were examined for glomerular and tubular functional alterations by estimating urinary levels of albumin and indicator proteins of tubular damage. Urine protein 1 (UP1), a newly-discovered low-molecular weight alpha-2 glycomicroglobulin, together with alpha 1-microglobulin was used to assess tubular function. 19% of the patients showed increased albumin excretion with normal levels of tubular proteins (glomerular proteinuria), 11% excreted only tubular proteins in excess (tubular proteinuria), while 40% had a mixed pattern of both increased albumin and tubular proteins (glomerulotubular or mixed proteinuria). 30% had normal albumin and tubular protein excretion in urine. UP1 was found to be a more sensitive indicator of tubular abnormality than alpha 1-microglobulin. It is concluded that, although glomerular changes may be responsible for the proteinuria seen in most diabetics (mixed proteinuria), in a small but significant proportion of diabetics, tubular functional alteration may occur before, or in the absence of, glomerular dysfunction, and may warn of subclinical tubular abnormality. This finding may have a direct bearing on the development and course of progression of diabetic nephropathy, and may question the reliability of the present prognostic interpretation of microalbuminuria.

Adolescent↗

PubMed1993

Motion-induced aversions during and after recovery from olfactory nerve section in mice.

Bilaterally nerve-sectioned male albino mice were given access to a novel food (almond) and then body rotated for 50 min. Two days later the mice were given a second access to almond. The procedures were repeated after recovery of olfactory function. Mice formed a presumably taste-mediated aversion while anosmic and a second flavor-mediated aversion (to the same food) after the return of olfactory function. Rotation control subjects formed only the standard flavor aversion subsequent to the first pairing of novel food and motion. It appears that olfaction is required for recognition of a food as novel.

Animals↗

PubMed1993

Hypothalamic angiotensin release in response to AII or glutamic acid stimulation of the SFO in rats.

Recent evidence from our laboratory suggests that angiotensin II (AII) is synthesized, stored within cells in the paraventricular nucleus (PVN) of the hypothalamus, and upon appropriate stimulation, released and rapidly converted to angiotensin III (AIII). The present investigation extends these observations by first employing a retrograde tracer to confirm a direct connection from the subfornical organ (SFO) to the PVN, and then showing that microinfusion of AII or glutamic acid into the SFO provokes release of endogenous angiotensin within the PVN. Potentially it is this release that contributes to the elevations in blood pressure and drinking that have been reported to occur with electrical and chemical stimulation of the SFO. These results represent the first evidence of releasable angiotensin provoked by the chemical activation of a neural pathway that has been histochemically demonstrated to link the SFO with the PVN and brain stem structures concerned with cardiovascular functioning.

Angiotensin II↗

PubMed1993

Angiotensin II(3-8) (ANG IV) hippocampal binding: potential role in the facilitation of memory.

The present research characterizes a newly discovered ANG II(3-8) (ANG IV) binding site localized in structures associated with memory function (hippocampus, neocortex, cerebellum), as well as other brain stem structures (thalamus, inferior olivary nucleus). This site is not the AT1 or AT2 site that binds angiotensins II (ANG II) and III (ANG III) nor does it bind the nonpeptide AT1 or AT2 receptor antagonists DuP753 and PD123177, respectively. The intracerebroventricular (ICV) infusion of ANG IV was ineffective at inducing drinking in rats as compared with equivalent doses of ANG II and III. Although not as effective as ANG II or ANG III, ICV infusion of ANG IV did provoke a pressor response at the highest dose (100 pmol/min), which appeared to be mediated by ANG II (AT1)-type receptors and not the specific AIV binding site described here. By contrast, the ICV infusion of ANG IV resulted in greater effects upon retention and retrieval of a passive avoidance task as compared with ANG II. Specifically, ANG II was not different from the ICV infusion of artificial cerebrospinal fluid, while ANG IV improved retention and retrieval of this task.

Angiotensin II↗

PubMed1993

Substance P increases cochlear blood flow without changing cochlear electrophysiology in rats.

Carotid artery infusions of substance P yielded reductions in systemic blood pressure and elevations in cochlear blood flow (CoBF), measured via laser Doppler flowmeter, with no alterations in cochlear action potentials or cochlear microphonics in Wistar-Kyoto rats. Additionally, direct micro-infusions of substance P into the anterior inferior cerebellar artery, which contributes to the local vascular perfusion of the cochlea, yielded elevations in CoBF with no changes in systemic blood pressure. Pretreatment with a specific substance P receptor antagonist, ([D-Pro2,D-Trp7,9]SP) via the carotid artery or the anterior inferior cerebellar artery, diminished subsequent substance P-induced vascular responses. These results suggest that endogenous substance P, like other vasoactive peptides, may interact with a substance P-specific receptor population in the cochlea and may therefore participate in the ongoing regulation of CoBF. These findings also support the premise that vasodilatory hormones, along with vasoconstrictive agents, may be involved in the autoregulation of CoBF.

Action Potentials↗

PubMed1993

GABA and bicuculline-induced blood pressure changes in spontaneously hypertensive rats.

The brain GABAergic system was previously shown to influence blood pressure (BP) maintenance in rats which may in part be accomplished by disruption of the central renin-angiotensin system (RAS). We examined the potential role of GABA in sustaining the high BP exhibited by the spontaneously hypertensive rat (SHR) model of human essential hypertension. Intracerebroventricular (i.c.v.) infusion of GABA produced decreases in BP in members of three rat strains, including Wistar-Kyoto (WKY) and Sprague-Dawley normotensive controls and SHR. The SHR were significantly more sensitive to GABA than the normotensive strains. Next, the GABA receptor antagonist bicuculline (BMI) was infused i.c.v. and produced increases in BP in members of each strain. Finally, i.c.v. pretreatment with the specific angiotensin receptor antagonist [Sar1, Thr8]AII (sarthran), blocked subsequent GABA-induced decreases in BP in members of all three strains, and there was a trend toward sarthran attenuation of BMI-induced increases in BP. These results encourage the hypothesis that the hypotensive effects produced by central application of GABA are mediated by the brain angiotensin system.

Analysis of Variance↗

PubMed1993

Central angiotensin IV binding sites: distribution and specificity in guinea pig brain.

Our laboratory has reported previously that a unique binding site specific for the hexapeptide angiotensin (A)II(3-8), now referred to as AIV, is present in a number of tissues including bovine adrenal gland, rabbit and guinea pig heart and guinea pig kidney, liver, lung, uterus and brain. The present results extend previous findings in the guinea pig brain and identify binding sites for AIV in the neocortex, paleocortex, hippocampus, medial habenula, superior and inferior colliculi, caudate putamen, thalamus, dorsal tegmentum, central gray, red nucleus, inferior olivary, oculomotor and hypoglossal nuclei and cerebellum. Binding of [125I]AIV in selected regions was shown to be of high affinity (Kd = 0.60-1.47 nM), saturable (maximal number of binding sites = 181-449 fmol/mg of protein) and specific. This binding site was shown to be distinct from the AT1 and AT2 sites with Ki values > 10(-4) M for DuP 753, CGP42112A and PD123177. Changes at the N-terminal of the peptide, either by removal of the valine or by extension of the peptide, resulted in a large decrease in binding affinity. In contrast, C-terminal extensions resulted in little change in affinity for the binding site. Guanosine 5'-0-(3-thiotriphosphate) was shown to have no effect on binding, suggesting that the guinea pig brain binding site is not G-protein-linked. Potential functions associated with this newly discovered A binding site are discussed.

Amino Acid Sequence↗

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↗