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Dive into the research topics where Kurtis G. Cornish is active.

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Featured researches published by Kurtis G. Cornish.


Circulation Research | 2004

Superoxide Mediates Sympathoexcitation in Heart Failure: Roles of Angiotensin II and NAD(P)H Oxidase

Lie Gao; Wei Wang; Yu Long Li; Harold D. Schultz; Dongmei Liu; Kurtis G. Cornish; Irving H. Zucker

Chronic heart failure (CHF) is often associated with excitation of the sympathetic nervous system. This event is thought to be a negative predictor of survival in CHF. Sympathoexcitation and central angiotensin II (Ang II) have been causally linked. Recent studies have shown that NAD(P)H oxidase–derived reactive oxidant species (ROS) are important mediators of Ang II signaling. In the present study, we tested the hypothesis that central Ang II activates sympathetic outflow by stimulation of NAD(P)H oxidase and ROS in the CHF state. CHF was induced in male New Zealand White rabbits by chronic ventricular tachycardia. Using radio telemetry of arterial pressure and intracerebroventricular infusions, experiments were performed in the conscious state. Renal sympathetic nerve activity (RSNA) was recorded as a direct measure of sympathetic outflow. Intracerebroventricular Ang II significantly increased RSNA in sham (131.5±13.3% of control) and CHF (193.6±11.9% of control) rabbits. The increase in CHF rabbits was significantly greater than in sham rabbits (P<0.01). These responses were abolished by intracerebroventricular losartan, tempol, or apocynin. Resting RSNA was significantly reduced by intracerebroventricular losartan, tempol, or apocynin in CHF rabbits but not in sham rabbits. Intracerebroventricular administration of the superoxide dismutase inhibitor diethyldithio-carbamic acid increased RSNA significantly more in sham compared with CHF rabbits. NADPH-dependent superoxide anion production in the rostral ventrolateral medulla (RVLM) was increased by 2.9-fold in CHF rabbits compared with sham rabbits. Finally, increases in the RVLM mRNA and protein expression of Ang II type 1 (AT1) receptor and subunits of NAD(P)H oxidase (p40phox, p47phox, and gp91phox) were demonstrated in CHF rabbits. These data demonstrate intense radical stress in autonomic areas of the brain in experimental CHF and provide evidence for a tight relationship between Ang II and ROS as contributors to sympathoexcitation in CHF.


Circulation | 2003

Simvastatin Normalizes Autonomic Neural Control in Experimental Heart Failure

Rainer U. Pliquett; Kurtis G. Cornish; Jacob D. Peuler; Irving H. Zucker

Background—HMG-CoA reductase inhibitors (statins) have been shown to beneficially affect outcomes in chronic heart failure (CHF). We hypothesized that statins exert effects on autonomic function, as assessed by plasma norepinephrine levels, direct recordings of renal sympathetic nerve activity (RSNA), and baroreflex function. Methods and Results—Normolipidemic CHF rabbits were treated with simvastatin or vehicle. CHF was induced by continuous ventricular pacing at 320 to 340 bpm for 3 weeks. Two to 3 days after instrumentation of the rabbits with renal nerve electrodes and arterial and venous catheters, blood samples and RSNA recordings were obtained in the conscious state. Baroreflex function was assessed after administration of sodium nitroprusside and phenylephrine. Mean baseline RSNA (±SEM) in normal rabbits was 19.3±3.8%; in CHF rabbits, 39.4±2.9% (P <0.05); in CHF rabbits on low-dose (0.3 mg · kg−1 · d−1) simvastatin, 39.8±8.3% (P <0.05); and in CHF rabbits on high-dose simvastatin (3 mg · kg−1 · d−1), 21.1±4.5% (P =NS). Similar data were observed for plasma norepinephrine. In CHF rabbits treated with 3 mg · kg−1 · d−1 simvastatin, baroreflex regulation of heart rate to transient hypotension with sodium nitroprusside was normalized by 66% compared with CHF controls. Conclusions—These are the first data showing that non–lipid-lowering statin effects include a normalization of sympathetic outflow and reflex regulation in CHF. The precise neural and cellular pathways involved in these responses need further clarification. This finding may have important implications for the treatment of CHF and progression of the disease process.


Circulation | 2005

Simvastatin Therapy Normalizes Sympathetic Neural Control in Experimental Heart Failure Roles of Angiotensin II Type 1 Receptors and NAD(P)H Oxidase

Lie Gao; Wei Wang; Yu Long Li; Harold D. Schultz; Dongmei Liu; Kurtis G. Cornish; Irving H. Zucker

Background—In a previous study, we showed that simvastatin (SIM) therapy normalized sympathetic outflow and cardiovascular reflex regulation in chronic heart failure (CHF). However, the precise neural and cellular pathways for these effects are unknown. We hypothesized that SIM exerts its beneficial effect on autonomic function in CHF by downregulating central angiotensin II (Ang II) and superoxide mechanisms. Methods and Results—Experiments were carried out on 36 male New Zealand White rabbits, 13 normal and 23 CHF. All rabbits were identically instrumented to record mean arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA). Echocardiography was used to monitor cardiac function. Reverse transcription–polymerase chain reaction, Western blotting, and lucigenin-enhanced chemiluminescence were used to measure gene expression of Ang II type 1 receptor and NAD(P)H oxidase subunits and NAD(P)H oxidase activity in the rostral ventrolateral medulla. Compared with the CHF control group, SIM significantly reduced the central Ang II–induced pressor and sympathoexcitatory responses, decreased baseline RSNA (57.3±3.2% to 22.4±2.1% of maximum, P<0.05), increased baroreflex control of heart rate (gainmax, 1.6±0.3 to 4.5±0.2 bpm/mm Hg, P<0.05), and increased RSNA (gainmax, 1.7±0.2% to 4.9±0.6% of maximum/mm Hg, P<0.01). Importantly, SIM improved left ventricular function (EF, 32.4±4.1% to 51.7±3.2%, P<0.05). SIM also downregulated mRNA and protein expression of Ang II type 1 receptor and NAD(P)H oxidase subunits and inhibited NAD(P)H oxidase activity in the rostral ventrolateral medulla of CHF rabbits. Chronic intracerebroventricular infusion of Ang II completely abolished the aforementioned effects of SIM in CHF rabbits. Conclusions—These data strongly suggest that SIM normalizes autonomic function in CHF by inhibiting central Ang II mechanisms and therefore the superoxide pathway. These data also demonstrate that SIM improves left ventricular function in pacing-induced CHF rabbits.


Hypertension | 2007

Chronic Baroreceptor Activation Enhances Survival in Dogs With Pacing-Induced Heart Failure

Irving H. Zucker; Johnnie Hackley; Kurtis G. Cornish; Bradley A. Hiser; Nicholas R. Anderson; Robert S. Kieval; Eric D. Irwin; David J. Serdar; Jacob D. Peuler; Martin A. Rossing

Much of the current pharmacological therapy for chronic heart failure targets neurohormonal activation. In spite of recent advances in drug therapy, the mortality rate for chronic heart failure remains high. Activation of the carotid baroreceptor (BR) reduces sympathetic outflow and augments vagal tone. We investigated the effect of chronic activation of the carotid BR on hemodynamic and neurohormonal parameters and on mortality in dogs with chronic heart failure. Fifteen dogs were instrumented to record hemodynamics. Electrodes were applied around the carotid sinuses to allow for activation of the BR. After 2 weeks of pacing (250 bpm), electrical carotid BR activation was initiated in 7 dogs and continued for the remainder of the study. The start of BR activation was used as a time reference point for the remaining 8 control dogs that did not receive BR activation. Survival was significantly greater for dogs undergoing carotid BR activation compared with control dogs (68.1±7.4 versus 37.3±3.2 days, respectively; P<0.01), although arterial pressure, resting heart rate, and left ventricular pressure were not different over time in BR-activated versus control dogs. Plasma norepinephrine was lower in dogs receiving BR activation therapy 31 days after the start of BR activation (401.9±151.5 versus 1121.9±389.1 pg/mL in dogs not receiving activation therapy; P<0.05). Plasma angiotensin II increased less in dogs receiving activation therapy (plasma angiotensin II increased by 157.4±58.6 pg/mL in control dogs versus 10.1±14.0 pg/mL in dogs receiving activation therapy; P<0.02). We conclude that chronic activation of the carotid BR improves survival and suppresses neurohormonal activation in chronic heart failure.


Circulation Research | 2003

Alteration of NMDA NR1 Receptors Within the Paraventricular Nucleus of Hypothalamus in Rats With Heart Failure

Yi Fan Li; Kurtis G. Cornish; Kaushik P. Patel

Abstract— One of the pathophysiological characteristics of chronic heart failure (HF) is elevated sympathetic drive, which is a major factor contributing to the morbidity and mortality of HF. Resent evidence points to a central mechanism that contributes to the sympathetic abnormality in HF. The paraventricular nucleus (PVN) of the hypothalamus is an important site that integrates sympathetic nerve activity. Studies have shown that glutamate elicits excitatory effects on neurons in the PVN through the NMDA receptor. The goal of the present study was to examine the role of NMDA receptors in the altered sympathetic nerve activation during HF. The left coronary ligation-induced heart failure model in the rat was used. In &agr;-chloralose and urethane anesthetized rats, microinjection of NMDA into the PVN (50 to 200 pmol) produced dose-dependent increases in renal sympathetic nerve discharge (RSND), arterial blood pressure (BP), and heart rate (HR). This response to NMDA was significantly potentiated (27±7%) in HF compared with sham rats. On the other hand, microinjection of the NMDA receptor antagonist AP-5 (4 to 16 nmol) into the PVN caused significant decreases in RSND, BP, and HR only in rats with HF but very slight changes in sham rats. Furthermore, using microdialysis and HPLC in combination with electrochemical detection techniques, we found that the glutamate level in the PVN was not increased significantly in HF compared with sham rats. However, using RT-PCR, Western blot, and immunofluorescence techniques, it was found that NMDA NR1 subunit mRNA expression and protein level in the PVN were significantly increased in HF compared with sham rats. These data suggest that the increased glutamatergic activity on sympathetic regulation, due to the upregulation of NMDA NR1 receptor subunits within the PVN may contribute to the elevated sympathoexcitation during HF.


Circulation Research | 2005

Gene Transfer of Neuronal Nitric Oxide Synthase to Carotid Body Reverses Enhanced Chemoreceptor Function in Heart Failure Rabbits

Yu Long Li; Yifan Li; Dongmei Liu; Kurtis G. Cornish; Kaushik P. Patel; Irving H. Zucker; Keith M. Channon; Harold D. Schultz

Our previous studies showed that decreased nitric oxide (NO) production enhanced carotid body (CB) chemoreceptor activity in chronic heart failure (CHF) rabbits. In the present study, we investigated the effects of neuronal NO synthase (nNOS) gene transfer on CB chemoreceptor activity in CHF rabbits. The nNOS protein expression and NO production were suppressed in CBs (P<0.05) of CHF rabbits, but were increased 3 days after application of an adenovirus expressing nNOS (Ad.nNOS) to the CB. As a control, nNOS and NO levels in CHF CBs were not affected by Ad.EGFP. Baseline single-fiber discharge during normoxia and the response to hypoxia were enhanced (P<0.05) from CB chemoreceptors in CHF versus sham rabbits. Ad.nNOS decreased the baseline discharge (4.5±0.3 versus 7.3±0.4 imp/s at 105±1.9 mm Hg) and the response to hypoxia (18.3±1.2 imp/s versus 35.6±1.1 at 40±2.1 mm Hg) from CB chemoreceptors in CHF rabbits (Ad.nNOS CB versus contralateral noninfected CB respectively, P<0.05). A specific nNOS inhibitor, S-Methyl-l-thiocitrulline (SMTC), fully inhibited the effect of Ad.nNOS on the enhanced CB activity in CHF rabbits. In addition, nNOS gene transfer to the CBs also significantly blunted the baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in CHF rabbits (P<0.05). These results indicate that decreased endogenous nNOS activity in the CB plays an important role in the enhanced activity of the CB chemoreceptors and peripheral chemoreflex function in CHF rabbits.


Circulation Research | 2006

Neuronal Angiotensin II Type 1 Receptor Upregulation in Heart Failure. Activation of Activator Protein 1 and Jun N-Terminal Kinase

Dongmei Liu; Lie Gao; Shyamal K. Roy; Kurtis G. Cornish; Irving H. Zucker

Chronic heart failure (CHF) is a leading cause of mortality in developed countries. Angiotensin II (Ang II) plays an important role in the development and progression of CHF. Many of the important functions of Ang II are mediated by the Ang II type 1 receptor (AT1R), including the increase in sympathetic nerve activity in CHF. However, the central regulation of the AT1R in the setting of CHF is not well understood. This study investigated the AT1R in the rostral ventrolateral medulla (RVLM) of rabbits with CHF, its downstream pathway, and its gene regulation by the transcription factor activator protein 1 (AP-1). Studies were performed in 5 groups of rabbits: sham (n=5), pacing-induced (3 to 4 weeks) CHF (n=5), CHF with intracerebroventricular (ICV) losartan treatment (n=5), normal with ICV Ang II treatment (n=5), and normal with ICV Ang II plus losartan treatment (n=5). AT1R mRNA and protein expressions, plasma Ang II, and AP-1–DNA binding activity were significantly higher in RVLM of CHF compared with Sham rabbits (240.4±30.2%, P<0.01; 206.6±25.8%, P<0.01; 280±36.5%, P<0.05; 207±16.4%, P<0.01, respectively). Analysis of the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) pathway showed that phosphorylated c-Jun proteins, phosphorylated JNK proteins, and JNK activity increased significantly in RVLM of CHF compared with sham (262.9±48.1%, 213.8±27.7%, 148.2±10.1% of control, respectively). Importantly, ICV losartan in CHF rabbits attenuated these increases. ICV Ang II in normal rabbits simulated the molecular changes seen in CHF. This effect was blocked by concomitant ICV losartan. In addition, Ang II–induced AT1R expression was blocked by losartan and a JNK inhibitor, but not by extracellular signal-regulated kinase or p38 MAP kinase inhibitors in a neuronal cell culture. These data suggest that central Ang II activates the AT1R, SAPK/JNK pathway. AP-1 may further regulate gene expression in RVLM in the CHF state.


Hypertension | 2014

Cardiac Sympathetic Afferent Denervation Attenuates Cardiac Remodeling and Improves Cardiovascular Dysfunction in Rats with Heart Failure

Han Jun Wang; Wei Wang; Kurtis G. Cornish; George J. Rozanski; Irving H. Zucker

The enhanced cardiac sympathetic afferent reflex (CSAR) contributes to the exaggerated sympathoexcitation in chronic heart failure (CHF). Increased sympathoexcitation is positively related to mortality in patients with CHF. However, the potential beneficial effects of chronic CSAR deletion on cardiac and autonomic function in CHF have not been previously explored. Here, we determined the effects of chronic CSAR deletion on cardiac remodeling and autonomic dysfunction in CHF. To delete the transient receptor potential vanilloid 1 receptor–expressing CSAR afferents selectively, epicardial application of resiniferatoxin (50 &mgr;g/mL), an ultrapotent analog of capsaicin, was performed during myocardium infarction surgery in rats. This procedure largely abolished the enhanced CSAR, prevented the exaggerated renal and cardiac sympathetic nerve activity and improved baroreflex sensitivity in CHF rats. Most importantly, we found that epicardial application of resiniferatoxin largely prevented the elevated left ventricle end-diastolic pressure, lung edema, and cardiac hypertrophy, partially reduced left ventricular dimensions in the failing heart, and increased cardiac contractile reserve in response to &bgr;-adrenergic receptor stimulation with isoproterenol in CHF rats. Molecular evidence showed that resiniferatoxin attenuated cardiac fibrosis and apoptosis and reduced expression of fibrotic markers and transforming growth factor-&bgr; receptor I in CHF rats. Pressure–volume loop analysis showed that resiniferatoxin reduced the end-diastolic pressure volume relationships in CHF rats, indicating improved cardiac compliance. In summary, cardiac sympathetic afferent deletion exhibits protective effects against deleterious cardiac remodeling and autonomic dysfunction in CHF. These data suggest a potential new paradigm and therapeutic potential in the management of CHF.


Circulation Research | 2008

Role of Oxidant Stress on AT1 Receptor Expression in Neurons of Rabbits With Heart Failure and in Cultured Neurons

Dongmei Liu; Lie Gao; Shyamal K. Roy; Kurtis G. Cornish; Irving H. Zucker

We have previously reported that the expression of Angiotensin II (Ang II) type 1 receptors (AT1R) was increased in the rostral ventrolateral medulla (RVLM) of rabbits with chronic heart failure (CHF) and in the RVLM of normal rabbits infused with intracerebroventricular (ICV) Ang II. The present study investigated whether oxidant stress plays a role in Ang II–induced AT1R upregulation and its relationship to the transcription factor activator protein 1 (AP1) in CHF rabbits and in the CATHa neuronal cell line. In CATHa cells, Ang II significantly increased AT1R mRNA by 123±11%, P<0.01; c-Jun mRNA by 90±20%, P<0.01; c-fos mRNA by 148±49%, P<0.01; NADPH oxidase activity by 126±43%, P<0.01 versus untreated cells. Tempol and Apocynin reversed the increased expression of AT1R mRNA, c-Jun mRNA, c-fos mRNA, and superoxide production induced by Ang II. We also examined the effect of ICV Tempol on the RVLM of CHF rabbits. Compared to vehicle treated CHF rabbits, Tempol significantly decreased AT1R protein expression (1.6±0.29 versus 0.88±0.16, P<0.05), phosphorylated Jnk protein (0.4±0.05 versus 0.2±0.04, P<0.05), cytosolic phosphorylated c-Jun (0.56±0.1 versus 0.36±0.05, P<0.05), and nuclear phosphorylated c-Jun (0.67±0.1 versus 0.3±0.08, P<0.01). Tempol also significantly decreased the AP-1–DNA binding activity in the RVLM of CHF rabbits compared to the vehicle group (9.14×103 versus 41.95×103 gray level P<0.01). These data suggest that Ang II induces AT1R upregulation at the transcriptional level by induction of oxidant stress and activation of AP1 in both cultured neuronal cells and in intact brain of rabbits. Antioxidant agents may be beneficial in CHF and other states where brain Ang II is elevated by decreasing AT1R expression through the Jnk and AP1 pathway.


Circulation Research | 1980

Direct evidence for myogenic autoregulation of the renal microcirculation in the hamster.

J. P. Gilmore; Kurtis G. Cornish; S D Rogers; William L. Joyner

We transplanted neonatal hamster renal tissue into a hamster cheek pouch chamber and subjected the renal tissue to increases and decreases in extravascular pressure. A decrease in extra-vascular pressure decreased, and an increase in extravascular pressure increased, the diameter of preglomerular arterioles. Thus, the change in preglomerular arteriolar diameter was directly related to alterations in extravascular pressure. Neither saralasin nor indomethacin affected these changes, whereas papaverin prevented them. The efferent arterioles responded passively to changes in extra vascular pressure; i.e., the changes in their diameter were inversely related to changes in extravascular myogenic autoregulation of preglomerular vessels. CircRes 47: 226-230, 1980

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Irving H. Zucker

University of Nebraska Medical Center

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Lie Gao

University of Nebraska Medical Center

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Dongmei Liu

University of Nebraska Medical Center

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Kaushik P. Patel

University of Nebraska Medical Center

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Harold D. Schultz

University of Nebraska Medical Center

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Yu Long Li

University of Nebraska Medical Center

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J. P. Gilmore

University of Nebraska Medical Center

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Wei Wang

University of Nebraska Medical Center

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A. J. Gorman

University of Nebraska Medical Center

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Dongze Zhang

University of Nebraska Medical Center

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