Joshua S Speed

University of Mississippi Medical Center, Jackson, MS, United States

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Publications (10)27.48 Total impact

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    ABSTRACT: The inner medullary collecting duct (IMCD) is the nephron segment with the highest production of endothelin-1 (ET-1) and the greatest expression of ET-1 receptors that function to adjust Na+ and water balance. We have reported that male rats have reduced natriuresis in response to direct intramedullary infusion of ET-1 compared to females. Our aim was to determine whether alterations of ET-1 receptor expression and downstream intracellular Ca(2+) signaling within the IMCD could account for these sex differences. IMCDs from male and female rats were isolated for radioligand binding or microdissected for intracellular Ca(2+) ([Ca(2+)]i) measurement by fluorescence imaging of fura 2-AM. IMCD from male and female rats had similar ETB expression (655±201 vs. 567±39 fmol/mg protein, respectively) while male rats had significantly higher ETA expression (436±162 vs. 47±29 fmol/mg protein respectively; p<0.05). The [Ca(2+)]i response to ET-1 was significantly greater in IMCDs from male compared to female rats (288±52 vs. 118±32 AUC, nM x 3 min, respectively; p<0.05). In IMCDs from males, the [Ca(2+)]i response to ET-1 was significantly blunted by the ETA antagonist BQ-123, but not the ETB antagonist BQ-788 (control: 137±27, BQ-123: 53±11, and BQ-788: 84±25 AUC, nM x 3 min, respectively; p<0.05), consistent with greater ETA receptor function in males. These data demonstrate a sex difference in ETA receptor expression that results in differences in ET-1 Ca(2+) signaling in IMCD. As activation of ETA receptors is thought to oppose ETB receptor activation, enhanced ETA function in males could limit the natriuretic effects of ETB receptor activation.
    AJP Renal Physiology 08/2013; · 4.42 Impact Factor
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    ABSTRACT: Nitric oxide (NO) and NO synthase 1 (NOS1) maintains sodium and water homeostasis. NOS1α and NOS1β splice variants are expressed in the rat inner medulla, but only NOS1β expressed in the mouse. Collecting duct NOS1 is necessary for blood pressure control. We hypothesized that NOS1 splice variant expression and NO production in the inner medullary collecting duct (IMCD) are regulated distinctly in mice and rats by high dietary sodium. Male C57blk/J6 mice and Sprague-Dawley rats were fed a 0.4% (normal salt, NS), or 4% (high salt, HS) NaCl diet for 2 or 7 days. Mean arterial pressure was not altered with HS, while urinary sodium excretion in mice and rats was significantly increased. Urinary NOx excretion and IMCD nitrite production was significantly greater in mice on HS compared to rats. Western blotting indicated that only NOS1β and NOS3 were expressed in the mouse IMCD and that expression was unaffected by HS diet at either time point. NOS1α and β, as well as NOS3 were detected in the IMCD of the rat. Two-day HS diet increased NOS1α and NOS1β IMCD expression in the rat, and 7-day HS further increased NOS1β expression. While NOS3 expression was unchanged by HS diet at either time point. In conclusion, IMCD NO production in mice and rats is distinctly regulated under both NS and HS conditions including expression of NOS1 splice variants. © 2013 The Authors Clinical and Experimental Pharmacology and Physiology © 2013 Wiley Publishing Asia Pty Ltd.
    Clinical and Experimental Pharmacology and Physiology 01/2013; · 2.16 Impact Factor
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    ABSTRACT: Despite major advances in understanding the pathophysiology of hypertension and availability of effective and safe antihypertensive drugs, suboptimal blood pressure (BP) control is still the most important risk factor for cardiovascular mortality and is globally responsible for more than 7 million deaths annually. Short-term and long-term BP regulation involve the integrated actions of multiple cardiovascular, renal, neural, endocrine, and local tissue control systems. Clinical and experimental observations strongly support a central role for the kidneys in the long-term regulation of BP, and abnormal renal-pressure natriuresis is present in all forms of chronic hypertension. Impaired renal-pressure natriuresis and chronic hypertension can be caused by intrarenal or extrarenal factors that reduce glomerular filtration rate or increase renal tubular reabsorption of salt and water; these factors include excessive activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, increased formation of reactive oxygen species, endothelin, and inflammatory cytokines, or decreased synthesis of nitric oxide and various natriuretic factors. In human primary (essential) hypertension, the precise causes of impaired renal function are not completely understood, although excessive weight gain and dietary factors appear to play a major role since hypertension is rare in nonobese hunter-gathers living in nonindustrialized societies. Recent advances in genetics offer opportunities to discover gene-environment interactions that may also contribute to hypertension, although success thus far has been limited mainly to identification of rare monogenic forms of hypertension. © 2012 American Physiological Society. Compr Physiol 2:2393-2442, 2012.
    Comprehensive Physiology. 10/2012; 2(4):2393-2442.
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    ABSTRACT: Although it is well established that the renal endothelin (ET-1) system plays an important role in regulating sodium excretion and blood pressure through activation of renal medullary ET(B) receptors, the role of this system in Dahl salt-sensitive (DS) hypertension is unclear. The purpose of this study was to determine whether the DS rat has abnormalities in the renal medullary endothelin system when maintained on a high sodium intake. The data indicate that Dahl salt-resistant rats (DR) on a high-salt diet had a six-fold higher urinary endothelin excretion than in the DR rats with low Na(+) intake (17.8 ± 4 pg/day vs. 112 ± 44 pg/day). In sharp contrast, urinary endothelin levels increased only twofold in DS rats in response to a high Na(+) intake (13 ± 2 pg/day vs. 29.8 ± 5.5 pg/day). Medullary endothelin concentration in DS rats on a high-Na(+) diet was also significantly lower than DR rats on a high-Na(+) diet (31 ± 2.8 pg/mg vs. 70.9 ± 5 pg/mg). Furthermore, DS rats had a significant reduction in medullary ET(B) receptor expression compared with DR rats while on a high-Na(+) diet. Finally, chronic infusion of ET-1 directly into the renal medulla blunted Dahl salt-sensitive hypertension. These data indicate that a decrease in medullary production of ET-1 in the DS rat could play an important role in the development of salt-sensitive hypertension observed in the DS rat.
    AJP Regulatory Integrative and Comparative Physiology 05/2011; 301(2):R519-23. · 3.28 Impact Factor
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    ABSTRACT: We sought to determine the effect of an endothelin type A receptor antagonist (ETA) on uterine artery resistive index (UARI) and mean arterial pressure (MAP) in a placental ischemia rat model of preeclampsia produced by reduction in uterine perfusion pressure (RUPP). UARI was assessed by Doppler velocimetry in RUPP and normal pregnant controls (NP) on gestational days (GD) 12, 15, and 18. UARI was also determined on GD 18 in NP and RUPP pregnant dams after pretreatment with ETA. MAP was recorded on GD 19. The RUPP group had a higher MAP and UARI on GD 15 and 18 than the NP group. Pretreatment with ETA attenuated both the MAP and GD-18 UARI in the RUPP group without affecting these parameters in the NP group. The improvement in UARI could be one potential mechanism for the reduction in MAP in response to ETA in pregnant dams with ischemic placentas.
    American journal of obstetrics and gynecology 04/2011; 204(4):330.e1-4. · 3.28 Impact Factor
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    ABSTRACT: The renal medullary endothelin (ET-1) system plays an important role in the control of sodium excretion and arterial pressure (AP) through the activation of renal medullary ET-B receptors. We have previously shown that blockade of endothelin type B receptors (ET-B) leads to salt-sensitive hypertension through mechanisms that are not fully understood. One possible mechanism is through a reduction in renal medullary production of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a metabolite of arachidonic acid, has natriuretic properties similar to ET-B activation. While these findings suggest a possible interaction between ET-B receptor activation and 20-HETE production, it is unknown whether blockade of medullary ET-B receptors in rats maintained on a high sodium intake leads to reductions in 20-HETE production. The effect of increasing sodium intake from low (NS = .8%) to high (HS = 8%) on renal medullary production of 20-HETE in the presence and absence of renal medullary ET-B receptor antagonism was examined. Renal medullary blockade of ET-B receptors resulted in salt sensitive hypertension. In control rats, blood pressure rose from 112.8±2.4 mmHg (NS) to 120.7±9.3 mmHg (HS). In contrast, when treated with an ET-B receptor blocker, blood pressure was significantly elevated from 123.7±3.2 (NS) to 164.2±7.1 (HS). Furthermore, increasing sodium intake was associated with elevated medullary 20-HETE (5.6±.8 in NS vs. 14.3±3.7 pg/mg in HS), an effect that was completely abolished by renal medullary ET-B receptor blockade (4.9±.8 for NS and 4.5±.6 pg/mg for HS). Finally, the hypertensive response to intramedullary ET-B receptor blockade was blunted in rats pretreated with a specific 20-HETE synthesis inhibitor. These data suggest that increases in renal medullary production of 20-HETE associated with elevating salt intake may be, in part, due to ET-B receptor activation within the renal medulla.
    PLoS ONE 01/2011; 6(10):e26063. · 3.73 Impact Factor
  • American Journal of Obstetrics and Gynecology - AMER J OBSTET GYNECOL. 01/2011; 204(1).
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    ABSTRACT: Induction of heme oxygenase-1 (HO-1) in the renal medulla increases carbon monoxide and bilirubin production and decreases ANG II-mediated superoxide production. The goal of this study was to determine the importance of increases in bilirubin to the antioxidant effects of HO-1 induction in cultured mouse thick ascending loop of Henle (TALH) and inner medullary collecting duct (IMCD3) cells. Bilirubin levels were decreased by using small interfering RNAs (siRNAs) targeted to biliverdin reductase (BVR), which is the cellular enzyme responsible for the conversion of biliverdin to bilirubin. Treatment of cultured TALH or IMCD-3 cells with BVR siRNA (50 or 100 nM) resulted in an 80% decrease in the level of BVR protein and decreased cellular bilirubin levels from 46 +/- 5 to 23 +/- 4 nM (n = 4). We then determined the effects of inhibition of BVR on ANG II-mediated superoxide production. Superoxide production induced by ANG II (10(-9) M) significantly increased in both TALH and IMCD-3 cells. Treatment of TALH cells with BVR siRNA resulted in a significant increase in ouabain-sensitive rubidium uptake from 95 +/- 6 to 122 +/- 5% control (n = 4, P < 0.05). Lastly, inhibition of BVR with siRNA did not prevent the decrease in superoxide levels observed in cells pretreated with the HO-1 inducer, hemin. We conclude that decreased levels of cellular bilirubin increase ANG II-mediated superoxide production and sodium transport; however, increases in bilirubin are not necessary for HO-1 induction to attenuate ANG II-mediated superoxide production.
    AJP Regulatory Integrative and Comparative Physiology 09/2009; 297(5):R1546-53. · 3.28 Impact Factor
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    ABSTRACT: An elevated plasma level of homocysteine (hyperhomocysteinemia) is thought to be an important risk factor for a variety of cardiovascular diseases including preeclampsia. Although clinical studies have reported a two- to threefold elevation in plasma levels of homocysteine in women who developed preeclampsia, the importance of hyperhomocysteinemia in causing endothelial dysfunction and increases in arterial pressure during pregnancy is unknown. Therefore, the purpose of this study was to determine the effects of a two- to threefold elevation in plasma homocysteine levels on arterial pressure, chronic pressure-natriuresis relationship, and endothelial factors during pregnancy in the rat. Homocysteine treatment for 4 weeks increased plasma homocysteine levels in pregnant rats from 7.1 +/- 1.9 to 16.7 +/- 2.3 micromol/l. Homocysteine treatment decreased urinary nitrate/nitrite levels from 53 +/- 7 vs. 39 +/- 5 (micromol/24 h/kg body weight) in pregnant rats whereas having no effect on urinary excretion of endothelin. Homocysteine treatment had no effect on mean arterial pressure (MAP) in pregnant rats (104 +/- 2 vs. 107 +/- 3 mm Hg) nor on the chronic pressure-natriuresis relationship. These results suggest that although hyperhomocysteinemia decreases nitric oxide (NO) production in pregnant rats, hyperhomocysteinemia does not affect MAP, the chronic pressure-natriuresis relationship, or urinary excretion of endothelin in pregnant rats. Moreover, the reported two- to threefold elevation in plasma level of homocysteine in women with preeclampsia is unlikely to contribute to the hypertension of preeclampsia.
    American Journal of Hypertension 08/2009; 22(10):1115-9. · 3.67 Impact Factor
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    ABSTRACT: The importance of beta and gamma epithelial Na(+) channel (ENaC) proteins in vascular smooth muscle cell (VSMC)-mediated pressure-induced constriction in renal interlobar arteries has been demonstrated recently. In renal epithelial tissue, ENaC expression is regulated by angiotensin II (Ang II). However, whether Ang II regulates vascular ENaC expression has never been determined. Therefore, the goal of the current investigation was to determine whether Ang II affects vascular ENaC expression and its contribution to pressure-induced constriction. To address this goal, Sprague-Dawley rats were infused with Ang II (50 ng/kg/min) via osmotic minipump for 1 week. Mean arterial pressure (MAP) was measured using radiotelemetry. Interlobar arteries were isolated from these animals to assess VSMC ENaC protein expression, pressure-induced constriction, and agonist induced vascular reactivity. MAP was not different in control (113 +/- 2 mm Hg) and Ang II- (114 +/- 2 mm Hg) infused mice. We found that Ang II infusion decreased renal VSMC beta and gammaENaC immunolabeling by 18%. Consistent with this finding, we also found that ENaC-dependent peak pressure-induced constriction was inhibited from 38 +/- 3% to 25 +/- 1% at 125 mm Hg. Vasoreactivity to KCl, phenylephrine (PE), and acetylcholine (ACh) was unchanged. Ang II suppression of pressure-induced constrictor responses in renal interlobar arteries may be mediated, at least in part, by inhibition of beta and gammaENaC protein expression.
    American Journal of Hypertension 04/2009; 22(6):593-7. · 3.67 Impact Factor