Jacqueline Novak
Walsh University
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Featured researches published by Jacqueline Novak.
Circulation Research | 2003
Arundhathi Jeyabalan; Jacqueline Novak; Lee A. Danielson; Laurie J. Kerchner; Shannon L. Opett; Kirk P. Conrad
Abstract— During pregnancy, relaxin stimulates nitric oxide (NO)–dependent renal vasodilation, hyperfiltration and reduced myogenic reactivity of small renal arteries via the endothelial ETB receptor subtype. Our objective in this study was to elucidate the mechanisms by which relaxin stimulates the endothelial ETB receptor/NO vasodilatory pathway. Using chronically instrumented conscious rats, we demonstrated that a specific peptide inhibitor of the gelatinases MMP-2 and −9, cyclic CTTHWGFTLC (cyclic CTT), but not the control peptide, STTHWGFTLS (STT), completely reversed renal vasodilation and hyperfiltration in relaxin-treated rats. Comparable findings were observed with a structurally different and well-established, general antagonist of MMPs, GM6001. In contrast, phosphoramidon, an inhibitor of endothelin-converting enzyme, did not significantly change the renal vasodilatory response to relaxin administration. When small renal arteries were incubated with either of the general MMP inhibitors, GM6001 or TIMP-2 (tissue inhibitor of MMP), or with the specific gelatinase inhibitor, cyclic CTT, the reduced myogenic reactivity of these blood vessels from relaxin-treated nonpregnant and midterm pregnant rats was totally abolished. Moreover, a neutralizing antibody specific for MMP-2 completely abrogated the reduced myogenic reactivity of small renal arteries from relaxin-treated nonpregnant and midterm pregnant rats. In contrast, phosphoramidon did not significantly affect the reduction in myogenic reactivity. Using gelatin zymography, we showed increased pro and active MMP-2 activity in small renal arteries from relaxin-treated nonpregnant and midterm pregnant rats relative to the control animals. Thus, inhibitors of MMPs in general and of gelatinases in particular reverse the renal vascular changes induced by pregnancy or relaxin administration to nonpregnant rats. Finally, the typical reduction in myogenic reactivity of small renal arteries from relaxin-treated nonpregnant rats was absent in ETB receptor–deficient rats, despite an increase in vascular MMP-2 activity. These results indicate an essential role for vascular gelatinase, which is in series with, and upstream of, the endothelial ETB receptor/NO signaling pathway in the renal vasodilatory response to relaxin and pregnancy.
Hypertension | 1998
Salah Kassab; M. Todd Miller; Jacqueline Novak; Jane F. Reckelhoff; Ben R. Clower; Joey P. Granger
The aim of this study was to examine the role of endothelin-A (ET(A)) receptors in mediating the hypertension and renal injury associated with high salt intake in Dahl salt-sensitive (DS) rats. To achieve this goal, we examined the effects of chronic selective ET(A) antagonist (A-127722) treatment at a dose of 10 mg/kg/d on arterial pressure, renal function, and morphology in DS and Dahl salt-resistant (DR) rats placed on a high sodium (8% NaCl) diet (HSD) for 3 weeks. Placement of DS rats (n=13) on HSD for 3 weeks caused a progressive increase in systolic pressure (from 118+/-3 to 186+/-15 mm Hg). The increase in systolic pressure was significantly attenuated (from 125+/-4 to 167+/-12 mm Hg) in DS rats treated with A-127722 (n=13). Mean arterial pressure (MAP) measured directly at the end of the study was also significantly lower by 18 mm Hg (P<.02) in the DS rats treated with A-127722. The slope of the chronic pressure-natriuresis curve was shifted to the right in DS rats and to the left by chronic ET(A) receptor blockade in DS rats. The hypertension in DS rats was associated with marked proteinuria (from 4.1+/-1.1 to 74.3+/-5.3 mg/24 h/100 g body weight) that was significantly attenuated (from 5.7+/-1.2 to 55.2+/-6.5 mg/24 h/100 g body weight) in DS rats treated with A-127722. The percentage of glomeruli displaying fibrosis, hypercellularity, and hyalinization was also significantly reduced after treatment with A-127722 in DS rats. Arterial pressure, protein excretion, renal hemodynamics, and morphologic structure were not significantly changed in response to ET(A) receptor blockade in DR rats placed on HSD. These data indicate that endothelin-A receptor activation may play a role in the exacerbation of hypertension and development of renal injury in DS rats.
Hypertension | 1998
Raouf A. Khalil; Janice K. Crews; Jacqueline Novak; Salah Kassab; Joey P. Granger
Pregnancy-induced hypertension has been suggested to be mediated by several mechanisms, including reduced nitric oxide (NO) synthesis. In this study, the effects of chronic treatment with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on blood pressure and the underlying changes in vascular reactivity were investigated in virgin and late-pregnancy Sprague-Dawley rats. The systolic blood pressure was 120+/-2, 124+/-5, 116+/-4, and 171+/-5 mm Hg in untreated virgin, virgin treated with L-NAME, untreated pregnant, and pregnant treated with L-NAME rats, respectively. The rats were killed, and the thoracic aorta was cut into strips for measurement of active stress in response to alpha1-adrenergic stimulation with phenylephrine and membrane depolarization by high KCl. In pregnant rats, the maximal active stress to phenylephrine (0.31+/-0.03 x 10(4) N/m2) and the high-KCl-induced active stress (0.55+/-0.09 x 10(4) N/m2) were smaller than those in virgin rats. By contrast, in the L-NAME-treated pregnant rats, the maximal phenylephrine-induced active stress (0.76+/-0.1 x 10(4) N/m2) was greater than that in virgin rats (0.52+/-0.1 x 10(4) N/m2), whereas the high-KCl-induced active stress (1.08+/-0.14 x 10(4) N/m2) was indistinguishable from that in virgin rats (1.03+/-0.14 x 10(4) N/m2). Treatment with L-NAME did not affect the phenylephrine-releasable Ca2+ stores in pregnant rats and had minimal effect on active stress in virgin rats. Thus, reduction of NO synthesis during late pregnancy is associated with a significant increase in blood pressure and vascular responsiveness to alpha-adrenergic stimulation, which can possibly be explained in part by enhanced Ca2+ entry from extracellular space. However, other mechanisms such as increased myofilament force sensitivity to Ca2+ and/or activation of a completely Ca2+-independent mechanism cannot be excluded.
The FASEB Journal | 2006
Jacqueline Novak; Laura J. Parry; Julianna Matthews; Laurie J. Kerchner; Kimberly Indovina; Karen Hanley-Yanez; Ketah D. Doty; Dan O. Debrah; Sanjeev G. Shroff; Kirk P. Conrad
Relaxin is a 6 kDa protein hormone produced by the corpus luteum and secreted into the blood during pregnancy in rodents and humans. Growing evidence indicates that circulating relaxin causes vasodilatation and increases in arterial compliance, which may be among its most important actions during pregnancy. Here we investigated whether there is local expression and function of relaxin and relaxin receptor in arteries of nonpregnant females and males. Relaxin‐1 and its major receptor, Lgr7, mRNA are expressed in thoracic aortas, small renal and mesenteric arteries from mice and rats of both sexes, as well as in small renal arteries from female tammar wallabies (an Australian marsupial). Using available antibodies for rat and mouse Lgr7 receptor and rat relaxin, we also identified protein expression in arteries. Small renal arteries isolated from relaxin‐1 gene‐deficient mice demonstrate enhanced myogenic reactivity and decreased passive compliance relative to wild‐type (WT) and heterozygous mice. Taken together, these findings reveal an arterial‐derived, relaxin ligand‐receptor system that acts locally to regulate arterial function.—Novak, J., Parry, L. J., Matthews, J. E., Kerchner, L. J., Indovina, K., Hanley‐Yanez, K., Doty, K. D., Debrah, D. O., Shroff, S. G., Conrad, K. P. Evidence for local relaxin ligand‐receptor expression and function in arteries. FASEB J. 20, 2352–2362 (2006)
Hypertension | 1998
Salah Kassab; M. Todd Miller; Robert L. Hester; Jacqueline Novak; Joey P. Granger
Pregnancy-induced hypertension in women is associated with severe vasoconstriction and reductions in organ blood flow and cardiac output. Recent studies have indicated that nitric oxide (NO) synthesis inhibition during mid to late gestation in pregnant rats results in severe hypertension and proteinuria. The purpose of this study was to determine the systemic hemodynamic and regional blood flow alterations associated with chronic NO synthesis inhibition in the pregnant rat. The study was conducted in four groups of rats: virgin rats (n=6), pregnant rats (n=10), virgin rats treated with L-NAME (n=6), and pregnant rats treated with L-NAME (n=11). Rats were treated with L-NAME in drinking water at a dose of 1 mg/d for a week starting from day 13 of gestation in pregnant rats or an equivalent time for virgins. Mean arterial pressure (MAP), cardiac output, total peripheral resistance (TPR), and regional flows were measured by tracing radiolabeled microspheres in conscious rats. Pregnant rats that were given L-NAME showed significantly higher MAP (137+/-6 versus 96+/-2 mm Hg), higher TPR (5.08+/-0.58 versus 2.90+/-0.44 mm Hg/mL/min/100 g), and lower cardiac output (87.4+/-8.4 versus 113.3+/-11.1 mL/min) than pregnant controls. Chronic NO synthesis inhibition decreased the renal blood flow in pregnant rats at a significantly greater magnitude than in virgin rats. Significant reductions in regional blood flow to the heart, lungs, liver, diaphragm, and skeletal muscles were also observed in pregnant rats treated with L-NAME. The results of this study indicate that NO may play a role in mediating the alterations in systemic hemodynamics and regional blood flow in late pregnant rats.
Hypertension | 2011
Jonathan T. McGuane; Leslie A. Danielson; Julianna E. Debrah; J. Peter Rubin; Jacqueline Novak; Kirk P. Conrad
Relaxin is emerging as an important vasodilator of pregnancy and is being tested for afterload reduction in acute heart failure. However, the mechanisms underlying relaxin-induced vasodilation are incompletely understood. The aims of this study were to establish a new in vitro model for relaxin-induced vasodilation and to use this approach, as well as chronically instrumented, conscious rats, to investigate the role of angiogenic growth factors in the relaxin vasodilatory pathway. Incubation of rat and mouse small renal arteries with recombinant human H2 relaxin for 3 hours in vitro attenuated myogenic constriction, which was blocked by inhibitors of gelatinases, the endothelin B receptor, and NO synthase. These findings corroborate ex vivo observations in arteries isolated from relaxin-infused nonpregnant and midterm pregnant rats, thereby validating the new experimental approach and enabling the study of human arteries. Incubation of small human subcutaneous arteries with relaxin for 3 hours in vitro also attenuated myogenic constriction through the same molecular intermediates. Vascular endothelial growth factor receptor inhibitor SU5416, 3 different vascular endothelial growth factor, and 2 different placental growth factor neutralizing antibodies prevented relaxin from attenuating myogenic constriction in rat and mouse small renal and human subcutaneous arteries. SU5416 administration also prevented relaxin-induced renal vasodilation and hyperfiltration in chronically instrumented, conscious rats. Small renal arteries isolated from these rats demonstrated increased matrix metalloproteinase 2 activity in the relaxin-infused group, which was not prevented by SU5416. We conclude that there is concordance of relaxin vasodilatory mechanisms in rats, mice, and humans, and angiogenic growth factors are novel and essential intermediates.
Hypertension | 1997
Jacqueline Novak; Jane F. Reckelhoff; Leslie Bumgarner; Kathy Cockrell; Salah Kassab; Joey P. Granger
Abstract The renal circulation undergoes significant changes during pregnancy and pregnancy-induced hypertension. Although numerous studies indicate that the pressor response to angiotensin II (Ang II) is reduced during pregnancy, it is unclear as to whether this altered sensitivity to Ang II occurs in the renal circulation. The first aim of this study was to determine whether the renal vascular responsiveness to exogenous Ang II is altered in the midterm pregnant rat. All rats were pretreated with an intravenous infusion of the converting-enzyme inhibitor captopril (20 μg · kg −1 · min −1 ) to block endogenous Ang II formation. Following a control period, Ang II was infused at a dose of 10 ng · kg −1 · min −1 for 50 minutes into the renal arteries via a suprarenal aortic catheter. In anesthetized virgin rats, Ang II markedly decreased renal plasma flow (RPF) by 39% (5.0±0.4 to 3.1±0.4 mL/min), glomerular filtration rate (GFR) by 39% (1.9±0.1 to 1.16±0.2 mL/min), and urine flow by 47% (22.1±5.6 to 12.3±4.8 μL/min). In contrast, Ang II had no significant effect on RPF, GFR, and urine flow in the anesthetized pregnant rats. Since nitric oxide (NO) has been previously reported to modulate the renal vascular actions of Ang II in normal animals and NO synthesis is thought to be elevated in pregnancy, this study examined the role of NO in the attenuated renal response to Ang II. In pregnant rats pretreated with L-NAME, the arterial pressure was higher and RPF was lower than in the control pregnant rats. However, the renal response to Ang II in the L-NAME–pretreated pregnant rats was similar to control pregnant rats. These data indicate that the renal circulation has a reduced sensitivity to Ang II during pregnancy. We also found that NO synthesis inhibition does not alter the attenuated renal response to Ang II in the anesthetized pregnant rats.
Biology of Sex Differences | 2012
Jonathan Toot; John J. Reho; Rolando J. Ramirez; Jacqueline Novak; Daniel Ely
BackgroundTestosterone (T) and the sympathetic nervous system each contribute to the pathology of hypertension. Altered blood vessel reactivity is also associated with the pathology of high blood pressure. The purpose of this study was to examine the effects of T manipulation in the regulation of resistance-sized blood vessel reactivity.MethodsAdult spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) male rats at 8 weeks of age were used. The rats were divided into groups consisting of gonadally intact controls (CONT), castrate with sham implant (CAST) and castrate with T implant (CAST + T) (n = 6 to 12 per group). Following a short-term period of T treatment (approximately 4 weeks), plasma norepinephrine (NE) and plasma T were assessed by performing high-performance liquid chromatography and RIA, respectively. Resistance-sized mesenteric artery reactivity was assessed on a pressurized arteriograph for myogenic reactivity (MYO), phenylephrine (PE) responsiveness and passive structural mechanics.ResultsSHR and WKY males exhibited similar physiological trends in T manipulation, with castration significantly lowering plasma T and NE and T replacement significantly increasing plasma T and NE. T manipulation in general resulted in significant alterations in MYO of second-order mesenteric arteries, with T replacement decreasing MYO in SHR (P < 0.05) compared to CONT, T replacement increasing MYO, and CAST decreasing MYO in WKY rats (P < 0.001) compared to CONT rats. Additionally, PE-induced constriction was significantly altered in both strains following T treatment, with the effective concentration of PE to constrict the vessel to 50% of the total diameter significantly increased in the CAST + T SHR compared to CONT (P < 0.05). Comparisons of passive structural mechanics between SHR and WKY treatment groups indicated in SHR a significantly increased wall-to-lumen ratio and decreased circumferential wall stress compared to WKY treatment groups.ConclusionsThese data suggest that T and NE are involved in a complex interaction with both myogenic reactivity and structural alterations of resistance-sized blood vessels and that these factors likely contribute to the development and maintenance of hypertension.
Hypertension | 1996
Joey P. Granger; Jacqueline Novak; Christine Schnackenberg; Stuart Williams; Glenn A. Reinhart
Recent studies suggest that enhanced renal sympathetic nervous activity plays an important role in mediating the renal hemodynamic and electrolyte excretion changes associated with acute inhibition of NO synthesis. The purpose of this study was to determine the importance of renal nerves in mediating the long-term hypertensive and renal actions of NO synthesis blockade. To achieve this goal, we infused N(G)-nitro-L-arginine methyl ester (L-NAME) at a rate of 25 microg/kg per minute for 2 weeks in control dogs and in bilaterally renal-denervated dogs. NO synthesis blockade in control dogs increased arterial pressure by 18%, from 94 +/- 3 to 111 +/- 4 mm Hg, and decreased heart rate from 74 +/- 4 to 57 +/- 4 beats per minute (bpm). L-NAME also decreased renal plasma flow from 195 +/- 18 to 166 +/- 18 mL/min while having no effect on glomerular filtration rate (67 +/- 7 versus 63 +/- 6 mL/min). In the renal-denervated dogs, inhibition of NO synthesis increased arterial pressure by 14%, from 92 +/- 4 to 105 +/- 5 mm Hg, and decreased heart rate from 80 +/- 4 to 65 +/- 5 bpm. Renal plasma flow in this group decreased from 195 +/- 20 to 165 +/- 20 mL/min, whereas glomerular filtration rate remained unchanged (66+/- 6 versus 64 +/- 6 mL/min). In addition, renal excretion of sodium and water in response to L-NAME was similar in each group. The results of this study indicate that the long-term hypertensive and renal effects of NO synthesis inhibition in the dog are not dependent on activation of the renal sympathetic nervous system.
The FASEB Journal | 2012
Lenka A. Vodstrcil; Marianne Tare; Jacqueline Novak; Nicoleta Dragomir; Rolando J. Ramirez; Mary E. Wlodek; Kirk P. Conrad; Laura J. Parry
Normal pregnancy involves dramatic remodeling of the uterine vasculature, with abnormal vascular adaptations contributing to pregnancy diseases such as preeclampsia. The peptide hormone relaxin is important for the renal and systemic hemodynamic adaptations to pregnancy, and has been shown to increase arterial compliance and outward hypertrophic remodeling. Therefore, we investigated the possibility that relaxin acts on its receptor, RXFP1, to mediate uterine artery compliance in late pregnancy and increase uterine blood flow velocity in rats. RXFP1 was predominantly localized to the tunica media vascular smooth muscle cells in the uterine artery, although receptors were also detected in endothelial cells. Highest expression of Rxfp1 in the uterine artery occurred in estrus and early pregnancy. Isolated uterine arteries from late pregnant rats treated with a monoclonal antibody against circulating relaxin (MCA1) had significantly increased vessel wall stiffness compared with controls, with no reduction in wall thickness. Chronic infusion of relaxin (4 μg/h, osmotic minipump) for 5 d in nonpregnant rats significantly increased uterine artery blood flow velocity. Overall, these data demonstrate a functional role for relaxin in mediating uterine artery compliance in pregnant rats, which may be necessary to maintain adequate uterine blood flow to the uterus and placenta.—Vodstrcil, L. A., Tare, M., Novak, J., Dragomir, N., Ramirez, R. J., Wlodek, M. E., Conrad, K. P., Parry, L. J. Relaxin mediates uterine artery compliance during pregnancy and increases uterine blood flow. FASEB J. 26, 4035–4044 (2012). www.fasebj.org