Biomedical subjects

C S Wilcox

Publications and source records attributed to C S Wilcox.

At least 19 recordsLinked to original sources

PubMed1998

Structure and transcriptional function of the 5'-flanking region of rat thromboxane receptor gene.

We cloned a cDNA for rat TX receptor, and observed its expression in the kidney, including vascular smooth muscle. The aim of the present study was to clone the 5'-flanking region (5'-FL) of rat TX receptor gene, and to examine its transcriptional gene expression regulation. The 5'-FL was cloned by a PCR method, and the nucleic acid structure of 5'-FL (approximately 1 Kb) was disclosed. The transcription initiation site was shown to be 63 bases upstream of the 5' end of the cDNA by the primer extension. In the 5'-FL, putative AP-1 binding sites, glucocorticoid-responsive elements, NF-kappa B binding sites, GATA box, and shear stress-responsive elements were identified. The 5'-FL was then fused upstream of firefly luciferase cDNA in an expression vector, and we examined its transcriptional activity in transiently transfected cultured vascular smooth muscle cells (VSMC). Luciferase expression was dependent on the length of 5'-FL, and it was significantly stimulated by phorbol 12-myristate 13-acetate (PMA), dexamethasone (Dex), tumor necrosis factor-alpha, and interleukin (IL). By a semi-quantitative RT-PCR method, TX receptor mRNA was shown to be induced by Dex, IL-6, and PMA in cultured VSMC. In conclusion, we have revealed the structure of transcription regulatory region of TX receptor. Expression of TX receptor gene is possibly up-regulated by activation of protein kinase C, glucocorticoid excess, and IL-6, in vascular smooth muscle.

Animals↗

PubMed1998

Divalproate augmentation in lithium-resistant rapid cycling mania in four geriatric patients.

This report describes four geriatric patients, with rapid cycling bipolar disorder, who were treated successfully with divalproex sodium in combination with lithium carbonate, noting that both drugs were necessary for clinical remission of symptoms. Divalproex sodium may actually enhance the sensitivity to lithium carbonate in this population, potentially leading to treatment with lower lithium concentrations. This strategy has an advantage in enabling a greater safety range in the use of lithium carbonate in elderly patients. This report further raises questions as to the nature of rapid cycling illness in the "old-old" population.

Age Factors↗

PubMed1998

Mild metabolic alkalosis impairs the natriuretic response to bumetanide in normal human subjects.

1. This study was designed to test the hypothesis that acid-base status affects the response to a loop diuretic in human subjects. The renal responses to bumetanide (1 mg intravenously) were studied in eight normal subjects consuming a constant diet supplemented for 3 days on three separate occasions with equivalent quantities of NaCl, NaHCO3 (metabolic alkalosis) or NH4Cl (metabolic acidosis). 2. A significant (P < 0.025) reduction in bumetanide-induced diuresis (-40%), natriuresis (-21%), and chloruresis (-25%) was observed during NaHCO3 compared with NaCl. The renal response was unaltered during NH4Cl. 3. The creatinine and para-aminohippurate clearances were unchanged during NaHCO3, as were the blood pressure and plasma levels of renin activity, aldosterone and noradrenaline, and the plasma volume. 4. Bumetanide excretion was increased during NaHCO3 compared with NaCl (2.13 +/- 0.18 versus 1.76 +/- 0.17 micrograms/min, P < 0.025) but was not changed during NH4Cl (1.68 +/- 0.26 micrograms/min; not significant). 5. Plasma aldosterone concentration was increased 3-fold during acidosis and the kaliuretic response to bumetanide was enhanced significantly. 6. In conclusion, compared with NaCl, NaHCO3 reduces the diuretic, natriuretic and chloruretic response to bumetanide without significant changes in renal haemodynamics, plasma volume, the renin-angiotensin-aldosterone axis or the sympathetic nervous system, and despite increasing renal bumetanide excretion. NH4Cl enhances aldosterone secretion and diuretic-induced kaliuresis.

Acidosis↗

PubMed1998

Salt intake determines the renal response to L-arginine infusion in normal human subjects.

Studies in experimental animals have shown that nitric oxide (NO) generation in the kidney from L-arginine participates in adapting renal function to changes in salt intake, but similar studies in human subjects are lacking. Therefore, we compared the infusion of 30 g of L-arginine to 30 g of branched chain amino acids (control), in eight normal human subjects after 5 to 7 days of equilibration to a low salt (LS; 20 mumol.24 hr-1) or high salt (HS; 200 mumol.24 hr-1) intake. Lithium clearance was used as a marker of proximal tubular reabsorption. Compared to the control infusion, L-arginine did not significantly alter blood pressure, inulin or paraaminohippurate clearance, but significantly increased (P < 0.05) the excretion of NO2 + NO3 (NOx) (LS, 157 +/- 46 to 210 +/- 48 mumol.min-1; HS, 138 +/- 30 to 182 +/- 70) and cGMP (LS, 253 +/- 63 to 337 +/- 76 pmol.min-1; HS, 311 +/- 68 to 563 +/- 52). Renal sodium excretion was decreased by L-arginine infusion during the low salt intake (45 +/- 5 to 21 +/- 3 mumol.min-1; P < 0.05) but was increased by L-arginine during the high salt intake (298 +/- 56 to 537 +/- 84 mumol.min-1; P < 0.05). The calculated fractional reabsorption of sodium in the proximal and distal nephrons, as assessed from lithium and sodium clearances, was increased by L-arginine during the low salt intake but was decreased by L-arginine during the high salt intake. L-arginine increased plasma insulin concentration significantly (P < 0.05). This effect was independent of salt intake (LS, 67 +/- 7 to 92 +/- 13 ng.ml-1; HS, 66 +/- 7 to 76 +/- 9 ng.ml-1). L-arginine did not significantly after plasma renin activity. In conclusion, L-arginine increases the excretion of NOx and cGMP and increases plasma insulin, but the effect on sodium excretion depends upon salt intake. L-arginine enhances Na reabsorption in the proximal and distal nephrons during the low salt intake, but inhibits it during the high salt intake. Effects of L-arginine on NO and cGMP may contribute to its effects on Na reabsorption.

Adult↗

PubMed1998

Macula densa nitric oxide synthase: expression, regulation, and function.

The type 1 brain nitric oxide synthase (bNOS) isoform occurs in macula densa (MD) cells where it functions to vasodilate the afferent arteriole and blunt expression of tubuloglomerular feedback (TGF). Dietary salt restriction enhances bNOS expression, yet microperfusion studies with NOS inhibitors imply that it is functionally inactive. We thus assessed the hypothesis that reduced L-arginine (L-Arg) availability during low salt (LS) intake limits MD NO generation. Maximal TGF responses were recorded during Henle's loop perfusion with artificial tubular fluid (ATF). Microperfusion of L-Arg into the MD of LS, but not normal or high-salt (HS) rats blunted maximal TGF responses (8.0 +/- 0.4 to 6.0 +/- 0.5 mm Hg; N = 23; P < 0.01). Response to L-Arg was stereospecific, inhibited by coperfusion with monomethyL-L-arginine (L-NMA), and dependent on system y+ transport, because it was blocked by coperfusion with the competitors L-lysine or L-homoarginine. Absorption of [3H]-L-Arg from the perfused loop, via an L-Arg- or L-homoarginine-inhibitable process, was enhanced during HS. Salt restriction thus diminishes TGF attenuation by NO in the MD despite enhanced bNOS expression because of limited delivery and/or uptake of L-Arg via system y+. This defines a novel mechanism of renal microcirculatory adaptation to salt restriction via L-Arg-dependent changes in TGF.

Animals↗

PubMed1998

Role of macula densa NOS in tubuloglomerular feedback.

Recent studies have amply confirmed the robust expression of neuronal nitric oxide synthase (nNOS) in macula densa cells and its function in blunting tubuloglomerular feedback responses. Regulation of nNOS may occur at many levels: (1) transcriptional and translational regulation, which is enhanced by salt restriction and angiotensin II; (2) functional enhancement by L-arginine delivery and uptake via system Y+, which is enhanced during salt loading; (3) structural activation and feedback inhibition provided by postsynaptic density proteins co-expressed with nNOS in the macula densa; (4) competitive inhibition by dimethylarginines, which can be metabolized via NG, NG dimethylarginine dimethylaminohydrolase co-expressed with nNOS in the macula densa; and (5) intracellular activation linked to changes in [Ca++] or pH during luminal Na+ reabsorption. Nitric oxide, once formed, can be degraded by O2- produced principally in the interstitium between the macula densa and afferent arteriole and in the wall of the arteriole. In genetic hypertension, tubuloglomerular feedback responses are enhanced, in part at least because of diminished buffering by macula densa NO and enhanced O2- generation in the juxtaglomerular apparatus. These recent studies highlight the importance of the macula densa nitric oxide-tubuloglomerular feedback system in adapting glomerular hemodynamics and renal function to changes in salt intake, and define potentially important defects in models of genetic hypertension.

Animals↗

PubMed1998

NO generation and action during changes in salt intake: roles of nNOS and macula densa.

Micropuncture studies of single nephrons have shown that macula densa solute reabsorption via a furosemide-sensitive pathway activates nitric oxide (NO) generation via neuronal NO synthase (nNOS). This pathway is enhanced during salt loading. We investigated the hypothesis that changes in NO generation via nNOS in the macula densa contribute to changes in whole kidney NO generation and action during alterations in salt intake. Groups of rats (n = 6-10) were equilibrated to high-salt (HS) or low-salt (LS) diets and were administered a vehicle (Veh), 7-nitroindazole (7-NI; a relatively selective inhibitor of nNOS), or furosemide (F; an inhibitor of macula densa solute reabsorption) with volume replacement. Compared with LS, excretion of the NO metabolites, NO2 plus NO3 (NOX) was increased during HS (LS: 9.0 +/- 0.5 vs. HS: 15.7 +/- 0.8 micromol/24 h; P < 0.001), but this difference was prevented by 7-NI (LS: 7.4 +/- 1.3 vs. HS: 9.4 +/- 1.6 micromol/24 h; NS). During nonselective blockade of NOS with NG-nitro-L-arginine methyl ester (L-NAME), renal vascular resistance (RVR) increased more in HS than LS (HS: +160 +/- 17 vs. LS: +83 +/- 10%; P < 0.001). This difference in response to nonselective NOS inhibition was prevented by pretreatment with 7-NI (HS: +28 +/- 6 vs. LS: +34 +/- 8%; NS) or F with volume replacement (HS: +79 +/- 11 vs. LS: +62 +/- 4%; NS). In conclusion, compared with salt restriction, HS intake increases NO generation and renal action that depend on nNOS and macula densa solute reabsorption.

Absorption↗

PubMed1998

Normalization of blood pressure and renal vascular resistance in SHR with a membrane-permeable superoxide dismutase mimetic: role of nitric oxide.

Superoxide radical (O2-) is increased in the vessel wall of spontaneously hypertensive rats (SHR) where its blockade potentiates endothelium-dependent vasodilation. The purpose of this study was to determine the role of O2- in the hypertension and renal vasoconstriction of SHR and its interaction with nitric oxide (NO). Baseline mean arterial pressure (MAP) and renal vascular resistance were markedly elevated in SHR (n=6) compared with Wistar-Kyoto rats (WKY; n=6) (145+/-4 versus 118+/-4 mmHg, P<0.05, and 24+/-3 versus 17+/-1 mmHg x mL(-1) x min(-1), respectively; P<0.05). The stable membrane-permeable superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (tempol; 72 micromol/kg i.v.) normalized MAP (103+/-9 versus 96+/-6 mm Hg for SHR and WKY, respectively) and RVR (17+/-2 versus 15+/-1 mm Hg x mL(-1) x min(-1)) of SHR. The MAP of SHR was more sensitive and responsive to graded infusions of tempol (0, 1.8, 18, 180, and 1800 micromol x kg(-1) x h(-1) i.v.) than that of WKY. To determine whether O2- increases MAP by inactivation of NO, its synthesis was blocked in SHR with NW-nitro-L-arginine methyl ester (L-NAME, 11 micromol x kg(-1) x min(-1) i.v., n=6). Whereas tempol alone significantly reduced MAP by 32% (184+/-12 to 121 +/- 18 mm Hg, P<0.05, n=6), L-NAME infusion abolished the MAP response to tempol (187+/-8 to 186+/-4 mm Hg, n=5). In contrast, tempol did reduce MAP of SHR (188+/-7 to 161+/-7 mm Hg, P<0.05) where MAP was elevated by norepinephrine (31 nmol x kg(-1) x min(-1) i.v., n=6). Finally, to determine the longer-term effect of O2-, tempol (1.5 mmol x kg(-1) x d(-1) i.p.) was given for 7 days. Tempol had no effect on MAP in WKY (96+/-1 to 97+/-1 mmHg, n=7) but significantly decreased MAP in SHR (133+/-2 to 120+/-3 mm Hg, P<0.05, n=7). These data implicate O2- in the hypertension of SHR in vivo. The antihypertensive action of tempol depends on NO synthesis presumably because O2- inactivates NO and thus diminishes its vasodilatory actions.

Animals↗

PubMed1997

Macula densa arginine delivery and uptake in the rat regulates glomerular capillary pressure. Effects of salt intake.

These studies tested the hypothesis that delivery and/or cellular uptake of L-arginine limits macula densa nitric oxide generation and actions on tubuloglomerular feedback (TGF) during salt restriction. Maximal TGF responses were assessed from reductions in proximal stop flow pressure during loop of Henle (LH) perfusion at 40 nl/min with artificial tubular fluid containing vehicles or drugs. Orthograde LH perfusion of L-arginine (10[-3] M) reduced maximal TGF significantly in rats adapted to low salt (LS: 7.9+/-0.4-6.3+/-0.4 mmHg; P < 0.05), but not high salt (HS: 5.8+/-0.3-5.9+/-0.3; NS). The effects were stereospecific and prevented by coperfusion with NG-methyl-L-arginine. Microperfusion of L-arginine (10[-3] M) into the peritubular capillaries reduced the maximum TGF response more in nephrons of LS than HS rats (deltaTGF: LS, 32+/-6 vs. HS, 13+/-4%; P < 0.05) and restored a TGF response to luminal perfusion of NG-methyl-L-arginine in LS rats. Coperfusion of nephrons with excess L-lysine or L-homoarginine, which compete with L-arginine for system y+ transport, blocked the fall in proximal stopflow pressure produced by orthograde LH perfusion of L-arginine in LS rats. Reabsorption of [3H]arginine by the perfused loop segment was similar in LS (93+/-2%) and HS (94+/-1%) rats. Coperfusion with excess L-arginine, L-lysine, or L-homoarginine, however, reduced [3H]arginine reabsorption significantly (P < 0.05) more in HS rats than in LS rats. In conclusion, blunting of maximal TGF responses in salt-restricted rats by nephron-derived NO is limited by L-arginine availability and cellular uptake via system y+.

Animals↗

PubMed1997

Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney.

NG-monomethylarginine (L-NMA) and asymmetric NG, NG-dimethylarginines (ADMA) are endogenous inhibitors of cellular L-arginine uptake and/or nitric oxide (NO) synthesis that are implicated in renal parenchymal and Dahl salt-sensitive hypertension. Since the L-arginine:(L-NMA + ADMA) ratio determines NO synthase (NOS) activity, we compared the immunohistochemical distribution of NOS with NG, NG-dimethylarginine dimethylaminohydrolase (DDAH), which inactivates dimethylarginines (DMA) and L-NMA by hydrolysis to L-citrulline. Neuronal NOS (nNOS) was expressed predominantly in tubular epithelial cells of macula densa (MD), endothelial NOS (eNOS) in vascular endothelial cells (EC), and inducible NOS (iNOS) quite widely in tubular epithelium, including proximal tubules (PT), thick ascending limbs of Henle (TAL), distal convoluted tubule and intercalated cells (IC) of the collecting duct. Immunostaining for DDAH was present in PT, TAL, MD, and IC, and was also present in the glomerulus, Bowman's capsule, and endothelium of blood vessels. DDAH was detected in small vesicles of TAL and PT by electron microscopic (EM) immunocytochemistry. To study the effects of methylarginines on tubuloglomerular feedback (TGF) response, vehicle or methylarginines (10(-3) M) were added to artificial tubular fluid (ATF) perfused orthogradely from the late PT at 40 nl. min-1 while assessing changes in glomerular capillary pressure from proximal stop flow pressure (PSF). Whereas the maximal TGF responses were unchanged by vehicle (delta TGF 0 +/- 0%) or symmetric DMA (SDMA; +1 +/- 2%, NS), they were enhanced by L-NMA (+22 +/- 4%, P < 0.001) and asymmetric DMA (ADMA; +28 +/- 3%, P < 0.001). Since L-arginine transport can regulate renal epithelial NO generation, methylarginines (10(-3) M) or vehicle were co-perfused orthogradely with [3H]-L-arginine from the late PT and collected at the early distal tubule to study arginine uptake from the perfused loop of Henle. All methylarginines reduced fractional loop [3H] absorption significantly (P < 0.001; vehicle, 84 +/- 6; ADMA, 49 +/- 6; SDMA, 56 +/- 6; L-NMA, 41 +/- 6%). In conclusion, sites of DDAH expression in the vasculature or nephron are all sites of expression of an isoform of NOS. L-NMA, ADMA, and SDMA all inhibit renal tubular L-arginine uptake, whereas L-NMA and ADMA, but not SDMA, enhance TGF responses. Therefore, DDAH may regulate the cellular L-arginine: methylarginine levels in specific renal cells, thereby governing cell-specific L-arginine uptake and NO generation in renal tubular epithelium.

Amidohydrolases↗

PubMed1997

Vasopressin V2-receptor antagonists: panaceas for hyponatremia?

The current treatment of hyponatremia is unsatisfactory and can be associated with significant morbidity. Vasopressin is inappropriately elevated in the majority of patients with hyponatremia and causes free water retention by stimulating V2-receptors in the collecting ducts. Recently, orally active, nonpeptide, selective vasopressin V2-receptor antagonists have been characterized and offer an exciting prospect for the treatment for hyponatremia. V2-receptor antagonists are effective aquaretic agents, that are capable of increasing free water clearance and plasma sodium and might be useful in the treatment of hyponatremia caused by syndrome of inappropriate secretion of antidiuretic hormone, heart failure, cirrhosis, and nephrotic syndrome. The rationale for their use and evidence from animal and human studies are discussed.

Animals↗

PubMed1997

Role of nitric oxide in tubuloglomerular feedback: effects of dietary salt.

1. The tubuloglomerular feedback (TGF) response operates primarily by vasoconstriction of the afferent arteriole and a fall in glomerular capillary pressure (PGC) and single-nephron glomerular filtration rate (SNGFR) during increased NaCl reabsorption in the macula densa (MD). Numerous studies have suggested that nitric oxide (NO) is synthesized by the MD and acts to suppress TGF. As a high-salt (HS) diet has been found to blunt TGF, we tested the effects of salt intake on NO-dependent changes in TGF. 2. In the first series of experiments, values of SNGFR were contrasted from samples of tubular fluid taken from the proximal tubule (PT; MD delivery interrupted) and the distal tubule DT; MD delivery intact). Compared with HS rats, the difference between PT and DT values of SNGFR was increased in low-salt (LS) diet rats (4.3 +/- 0.4 vs 10.3 +/- 1.2 nL/min, respectively; P < 0.001). Intravenous infusion of NG-monomethyl-L-arginine (L-NMMA), in pressor doses increased the difference between PT and DT values of SNGFR of HS rats (4.3 +/- 0.4 vs 9.5 +/- 1.2 nL/min before and during L-NMMA, respectively; P < 0.001) without significantly affecting values in LS rats (10.3 +/- 1.2 vs 12.3 +/- 1.4 nL/min before and during L-NMMA, respectively; NS). 3. A second series of experiments assessed TGF responses directly. Changes in stop-flow pressure (PSF; an index of PGC) were measured in response to graded perfusion of the loop of Henle (LH) with artificial tubular fluid. Loop perfusion with 10(-3) mol/L L-NMMA did not affect the PSF responses of LS rats but did reduce (P < 0.01) the PSF of HS rats during perfusion at 20 nL/min (-1.5 +/- 0.4 mmHg; P < 0.01), 30 nL/min (-1.8 +/- 0.5 mmHg; P < 0.01) and 40 nL/min (-2.2 +/- 0.5 mmHg; P < 0.001). 4. We conclude that the TGF response is increased by suppression of NOS activity during HS but not LS intake.

Animals↗

PubMed1997

Sympathetic nervous system and hypertension during prolonged TxA2/PGH2 receptor activation in rats.

The thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptor mimetic U-46619 (0.6 microgram.kg-1.min-1) was infused into conscious rats receiving a high-salt diet. U-46619 increased the mean arterial pressure (MAP) over 13 days by 25 +/- 2 mmHg, whereas the MAP of vehicle-infused controls did not change (-2 +/- 2 mmHg). In subgroups infused with U-46619, cardiac output was unchanged, whereas renal blood flow was reduced (before: 8.5 +/- 0.8; day 4: 5.7 +/- 0.7 ml/min; P < 0.01). Ifetroban (a specific TxA2/PGH2 receptor antagonist) reduced MAP to basal levels in the group receiving U-46619 when infused intravenously (1-100 micrograms/kg) but not intracerebroventricularly (1-100 ng/kg). Hexamethonium (10 mg/kg i.v., a ganglionic blocking agent) and prazosin (0.1 mg/kg, an alpha-adrenergic antagonist) decreased MAP significantly (P < 0.05) more in the experimental group (hexamethonium, U-46619: -55 +/- 3 vs. vehicle: -43 +/- 4 mmHg; and prazosin, U-46619: 28 +/- 3 vs. vehicle: 17 +/- 2 mmHg). In conclusion, hypertension during prolonged infusions of U-46619 into conscious, salt-loaded rats is accompanied by an increase in total and renal vascular resistance and is dependent on peripheral but not central TxA2/PGH2 receptors and on the autonomic and alpha 1-adrenergic peripheral sympathetic nervous systems.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1997

Role of AVP in pressor responses during activation of central TxA2/PGH2 receptors.

Administration of thromboxane A2/prostaglandin H2 (TxA2/PGH2)-receptor agonist U-46619 (2.86 nmol/kg i.v.) to conscious rats increased mean arterial pressure (MAP) by 17 +/- 2 mmHg (n = 6; P < 0.001) and plasma arginine vasopressin (AVP) by 3.5 +/- 1.1 IU/ml (n = 6; P < 0.001). Ifetroban (TxA2/PGH2 antagonist; intracerebroventricularly) prevented both responses. Intracerebroventricular U-46619 increased MAP in Long-Evans rats (n = 6) more than in AVP-deficient Brattleboro rats. AVP V1-receptor antagonist d(CH2)5Tyr(Me)AVP (3 microg/kg i.v.) blocked 67 +/- 5% and 69 +/- 7% of pressor response to intravenous AVP and intracerebroventricular U-46619, respectively. AVP (10 ng/kg i.v.) increased AVP by 4.7 +/- 0.5 pg/ml, comparable to the increase of 3.5 +/- 1.2 pg/ml with intracerebroventricular U-46619 (2.86 nmol/kg), but the rise in MAP was only one-half as great (+8 +/- 3 mmHg for AVP vs. +17 +/- 2 mmHg for U-46619; P < 0.05). In conclusion, U-46619 raises blood pressure and releases AVP by activating brain receptors. AVP explains approximately one-half of the pressor response.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1997

Central thromboxane receptors: mRNA expression and mediation of pressor responses.

These studies tested whether activation of central thromboxane (Tx)A2/prostaglandin (PG) H2 receptors raises blood pressure (BP). Messenger RNA for TxA2/PGH2 receptors was detected in normal Sprague-Dawley rat brain and in rat neuronal and astroglial brain cells in culture. The mean arterial blood pressure (MAP) was recorded in conscious rats during graded administration of the TxA2/PGH2 receptor agonist U-46,619 given intracerebroventricularly or intravenously. Because the pressor responses to intracerebroventricular (but not intravenous) U-46,619 were significantly greater in-high-salt compared with low-salt rats, high-salt rats were used for subsequent studies. The rise in MAP with intracerebroventricular administration of U-46,619 was greater than with intravenous administration and was more sustained. A comparison of plasma radioactivity after intracerebroventricular or intravenous injection of [3H]U-46,619 demonstrated that approximately 35% of the drug reached the systemic circulation by 5-15 min after intracerebroventricular administration. Coadministration of a TxA2/PGH2 antagonist, ifetroban, by intravenous or intracerebroventricular routes blocked the pressor responses induced by U-46,619. The half-maximal inhibition for blockade of responses was substantially lower for intracerebroventricular than for intravenous responses (intracerebroventricular: 0.03 +/- 0.01 vs. intravenous: 3.1 +/- 0.6 micrograms/kg; P < 0.001). The intravenous administration of ifetroban (10 micrograms/kg) caused a greater (P < 0.02) inhibition of pressor responses to U-46,619 (1 microgram/kg) given intravenously (81 +/- 3%) compared with U-46,619 given intracerebroventricularly (40 +/- 13%). In conclusion, TxA2/PGH2 receptor mRNA is expressed in neurons, glial, and brain stem of normal rats. The central administration of a TxA2/PGH2 mimetic raises blood pressure by interaction with specific central and peripheral receptors. This response is augmented in rats fed a high-salt compared with a low-salt diet.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1997

Salt loading enhances rat renal TxA2/PGH2 receptor expression and TGF response to U-46,619.

The tubuloglomerular feedback (TGF) response is potentiated by thromboxane A2 (TxA2) and/or prostaglandin endoperoxide (PGH2) acting on specific receptors. Infusion of the TxA2/PGH2 mimetic, U-46,619, into conscious rats leads to hypertension that is potentiated by a high-salt intake. Therefore, we tested the hypothesis that a high-salt intake enhances the expression of transcripts for TxA2/PGH2 receptors in the kidney and glomeruli and enhances the response of TGF to TxA2/PGH2 receptor stimulation. Groups of rats were accommodated to a low-salt (LS), normal salt (NS), or high-salt (HS) diet for 8-10 days. TxA2/PGH2 receptor mRNA was detected by reverse transcription-polymerase chain reaction in kidney cortex, isolated glomeruli, and abdominal aorta. TxA2/PGH2 mRNA abundance was significantly (P < 0.001) increased during intake of high-salt compared with low-salt diets in the kidney cortex (1.34 +/- 0.10 vs. 0.84 +/- 0.04 arbitrary units) and isolated outer cortical glomeruli (0.68 +/- 0.04 vs. 0.32 +/- 0.03 arbitrary units), but there was no effect of salt on TxA2/PGH2 receptor mRNA expression in the aorta. Maximal TGF responses were assessed from the increase in proximal stop flow pressure (an index of glomerular capillary pressure) during increases in loop of Henle perfusion with artificial tubular fluid from 0 to 40 nl/min. Compared with vehicle, the enhancement of maximal TGF with U-46,619 (10(-6) M) added to the perfusate was greater in rats adapted to high-salt than normal salt (HS: +9.6 +/- 1.1 vs. NS: +5.1 +/- 0.4 mmHg; P < 0.001) or low-salt (LS: +3.8 +/- 1.3 mmHg; P < 0.001) intakes. Responses to U-46,619 at each level of salt intake were blocked by > 70% by the TxA2/PGH2 receptor antagonist ifetroban. In contrast, enhancement of TGF by peritubular capillary perfusion of arginine vasopressin (AVP; 10(-7) M) was similar in high-salt and low-salt rats (HS: +1.5 +/- 0.6 vs. LS: +1.6 +/- 0.5 mmHg; not significant). We conclude that salt loading increases selectively the abundance of TxA2/PGH2 receptor transcripts in the kidney cortex and glomerulus, relative to the aorta, and enhances selectively TGF responses to TxA2/PGH2 receptor activation but not to AVP.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1996

Breakdown of blood pressure and body fluid homeostasis in heart transplant recipients.

OBJECTIVES: This study was designed to investigate disturbances in arterial blood pressure and body fluid homeostasis in stable heart transplant recipients. BACKGROUND: Hypertension and fluid retention frequently complicate heart transplantation. METHODS: Blood pressure, renal and endocrine responses to acute volume expansion were compared in 10 heart transplant recipients (57 +/- 9 years old [mean +/- SD]) 20 +/- 5 months after transplantation, 6 liver transplant recipients receiving similar doses of cyclosporine (cyclosporine control group) and 7 normal volunteers (normal control subjects). After 3 days of a constant diet containing 87 mEq/24 h of sodium, 0.154 mol/liter saline was infused at 8 ml/kg per h for 4 h. Blood pressure and plasma vasopressin, angiotensin II, aldosterone, atrial natiuretic peptide and renin activity levels were determined before and at 30, 60, 120 and 240 min during the infusion. Urine was collected at 2 and 4 h. Blood pressure, fluid balance hormones and renal function were monitored for 48 h after the infusion. RESULTS: Blood pressure did not change in the two control groups but increased in the heart transplant recipients (+15 +/- 8/8 +/- 5 mm Hg) and remained elevated for 48 h (p < or = 0.05). Urine flow and urinary sodium excretion increased abruptly in the control groups sufficient to account for elimination of 86 +/- 9% of the sodium load by 48 h; the increases were blunted (p < or = 0.05) and delayed in the heart transplant recipients, resulting in elimination of only 51 +/- 13% of the sodium load. Saline infusion suppressed vasopressin, renin activity, angiotensin II and aldosterone in the two control groups (p < or = 0.05) but not in the heart transplant recipients. Heart transplant recipients had elevated atrial natriuretic peptide levels at baseline (p < or = 0.05), but relative increases during the infusion were similar to those in both control groups. CONCLUSIONS: Blood pressure in heart transplant recipients is salt sensitive. These patients have a blunted diuretic and natriuretic response to volume expansion that may be mediated by a failure to reflexly suppress fluid regulatory hormones. These defects in blood pressure and fluid homeostasis were not seen in liver transplant recipients receiving cyclosporine and therefore cannot be attributed to cyclosporine alone. Abnormal cardiorenal neuroendocrine reflexes, secondary to cardiac denervation, may contribute to salt-sensitive hypertension and fluid retention in heart transplant recipients.

Angiotensin II↗

PubMed1996

Predictors of cure of hypertension in fibromuscular renovascular disease.

Patients with fibromuscular dysplasia (FMD) and hypertension are frequently treated with percutaneous transluminal renal angioplasty (PTRA). Because the goal of this procedure is the cure of hypertension, we reviewed the outcomes of 23 consecutive patients undergoing this procedure to determine factors associated with cure. Twelve (52.2%) of the patients were taking no antihypertensive medications at 6 months and were classified as cured. Using logistic regression, we found three variables to be independently associated with cure: level of systolic blood pressure before intervention (P = 0.02), duration of hypertension (P = 0.03), and age (P = 0.03). Younger patients with milder hypertension of a shorter duration were most likely to be cured. Analysis of the regression equation predicts that some patients with an extremely low chance of cure might be managed with a trial of medical therapy, because FMD is unlikely to progress to renal failure.

Adult↗