Edward A Pankey

Publications (17) View all

• Article: The SGC activator BAY 60-2770 has potent erectile activity in the rat.

  George F Lasker, Edward A Pankey, Terrence J Frink, Jonathan R Zeitzer, Korey A Walter, Philip J Kadowitz
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  ABSTRACT: Nitric oxide (NO) is the principal mediator of penile erection and soluble guanylate cyclase (sGC) is the receptor for NO. In pathophysiologic conditions when sGC is inactivated and not responsive to NO or sGC stimulators a new class of agents called sGC activators increase the activity of NO-insensitive sGC and produce erection. The aim of this study was to investigate erectile responses to BAY 60-2770, a sGC activator, under physiologic and pathophysiologic conditions. In the present study increases in intracavernosal pressure (ICP) in response to ic injections of BAY 60-2770 were investigated under baseline conditions, when sGC was inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), when nitric oxide synthase (NOS) was inhibited by N-Nitro-L-Arginine Methyl Ester (L-NAME) and after cavernosal nerve crush injury. Under baseline conditions ic injections of BAY 60-2770 increase ICP, ICP/MAP and AUC and produce small decreases in MAP at the highest doses studied. BAY 60-2770 was very potent in its ability to induce erection and responses to BAY 60-2770 were enhanced by ODQ which attenuates erectile responses to SNP, DEA/NO and cavernosal nerve stimulation. Responses to BAY 60-2770 were not altered by L-NAME or cavernosal nerve crush injury. These data indicate that BAY 60-2770 has potent erectile activity that is enhanced by ODQ and show that responses to BAY 60-2770 are not attenuated by NOS inhibition or cavernosal nerve injury. These results suggest that BAY 60-2770 would be effective in the treatment of erectile dysfunction when NO bioavailability is reduced, after pelvic nerve injury, and when sGC is oxidized.
  AJP Heart and Circulatory Physiology 04/2013; · 3.71 Impact Factor
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  Available from: George F Lasker

  Article: The Selective Rho-kinase Inhibitor Azaindole-1 Has Long-lasting Erectile Activity in the Rat.

  George F Lasker, Edward A Pankey, Alexander V Allain, Subramanyam N Murthy, Johannes-Peter Stasch, Philip J Kadowitz
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  ABSTRACT: To investigate the effects of the selective Rho-associated protein kinase (ROCK) inhibitor azaindole-1 on erectile function under physiologic and pathophysiologic conditions in the rat. The effect of intracavernosal (i.c.) injections of azaindole-1 on change in intracavernous pressure (ICP), ICP/mean arterial pressure (MAP), area under the curve (AUC), and response duration were investigated in the anesthetized rat under control conditions and when nonadrenergic noncholinergic neurotransmission and cholinergic function or soluble guanylyl cyclase (sGC) were inhibited or after cavernosal nerve crush injury. The i.c. injections of azaindole-1 produced dose-related increases in ICP/MAP and AUC that were long-lasting at the highest doses studied compared with the prototypical ROCK inhibitor fasudil. Erectile responses were not altered by 7-nitroindazole and atropine in doses that reduced the response to cavernosal nerve stimulation by 86%, indicating that they were independent of NO release by cavernosal nerves or activation of muscarinic receptors in the corpora cavernosa. Erectile responses to azaindole-1 were not altered by the sGC inhibitor ODQ in a dose that attenuated responses to the NO donor sodium nitroprusside, indicating that they were independent of an action on sGC. The erectile response to i.c. injections of azaindole-1 or Y-27632, which was reported to be NO/cyclic guanosine monophosphate-dependent, was not attenuated after cavernosal nerve crush injury. The present studies indicate that azaindole-1 has long-lasting erectile activity that is independent of NO release, muscarinic receptor, or sGC activation or the integrity of the cavernosal nerves.
  Urology 02/2013; 81(2):465.e7-465.e14. · 2.43 Impact Factor
• Article: Analysis of Erectile Responses to BAY 41-8543 and Muscarinic Receptor Stimulation in the Rat.

  George F Lasker, Edward A Pankey, Alexander V Allain, Jasdeep S Dhaliwal, Johannes-Peter Stasch, Subramanyam N Murthy, Philip J Kadowitz
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  ABSTRACT: Introduction.  Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) and in pathophysiologic conditions where NO formation or bioavailability is impaired, erectile dysfunction (ED) occurs. Aim.  The aim of this study was to investigate erectile responses to the sGC stimulator BAY 41-8543 in physiologic and pathophysiologic conditions. Methods.  Increases in intracavernosal pressure (ICP) in response to intracavernosal (ic) injections of BAY 41-8543 were investigated in the anesthetized rat. Main Outcome Measures.  Increases in ICP/MAP in response to ic injections of BAY 41-8543 and the interaction of BAY 41-8543 with exogenous and endogenously released NO were investigated and the effect of the sGC stimulator on cavernosal nerve injury was assessed. The mechanism of the increase in ICP/MAP in response to ic injection of acetylcholine was investigated. Results.  The ic injections of BAY 41-8543 increased ICP/MAP and the duration of the response. BAY 41-8543 was less potent than sodium nitroprusside (SNP) and ic injections of BAY 41-8543 and SNP produced a larger response than the algebraic sum of responses to either agent alone. Simultaneous ic injection of BAY 41-8543 and cavernosal nerve stimulation produced a greater response than either intervention alone. Atropine and cavernosal nerve crush injury decreased the response to nerve stimulation and ic injection of BAY 41-8543 restored the response. Conclusion.  These data show that BAY 41-8543 has significant erectile activity and can synergize with exogenous and endogenously released NO. This study shows that atropine and nerve crush attenuate the response to cavernosal nerve stimulation and that BAY 41-8543 can restore the response. The results with atropine, L-NAME and hexamethonium indicate that the response to ic injection of acetylcholine is mediated by muscarinic receptors and the release of NO with no significant role for nicotinic receptors. These results suggest that BAY 41-8543 would be useful in the treatment of ED. Lasker GF, Pankey EA, Allain AV, Dhaliwal JS, Stasch J-P, Murthy SN, and Kadowitz PJ. Analysis of erectile responses to BAY 41-8543 and muscarinic receptor stimulation in the rat. J Sex Med **;**:**-**.
  Journal of Sexual Medicine 09/2012; · 3.55 Impact Factor
• Article: ENVIRONMENTALLY PERSISTENT FREE RADICALS DECREASE CARDIAC FUNCTION AND INCREASE PULMONARY ARTERY PRESSURE.

  Sarah Mahne, Gin C Chuang, Edward A Pankey, Lucy Kiruri, Philip J Kadowitz, Barry Dellinger, Kurt J Varner
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  ABSTRACT: Epidemiological studies consistently link inhalation of particulate matter (PM) to increased cardiac morbidity and mortality, especially in at-risk populations. However, few studies have examined the effect of PM on baseline cardiac function in otherwise healthy individuals. In addition, airborne PM contain environmentally persistent free radicals (EPFR) capable of redox cycling in biological systems. The purpose of this study was to determine whether nose-only inhalation of EPFRs (20 minutes/day/7 days) could decrease baseline left ventricular function in healthy male Sprague-Dawley rats. The model EPFR tested was 1, 2-dichlorobenzene chemisorbed to 0.2 μm diameter silica/CuO particle at 230°C (DCB230). Inhalation of vehicle or silica particles served as controls. Twenty-four hours after the last exposure the rats were anesthetized (isoflurane), ventilated (3 L/minute), and left ventricular function assessed using pressure-volume catheters. Compared to controls, inhalation of DCB230 significantly decreased baseline stroke volume, cardiac output and stroke work. End diastolic volume and end diastolic pressure were also significantly reduced; however, ventricular contractility and relaxation were not changed. DCB230 also significantly increased pulmonary arterial pressure and produced hyperplasia in small pulmonary arteries. Plasma levels of C-reactive protein were significantly increased by exposure to DCB230, as were the levels of heme oxygenase-1 and SOD2 in the left ventricle. Together, these data show that inhalation of EPFRs, but not silica particles decreases baseline cardiac function in healthy rats by decreasing cardiac filling, secondary to increased pulmonary resistance. These EPFRs also produced systemic inflammation and increased oxidative stress markers in the left ventricle.
  AJP Heart and Circulatory Physiology 08/2012; · 3.71 Impact Factor
• Article: Effects of insulin detemir on balloon catheter injured carotid artery in Zucker fatty rats.

  Subramanyam N Murthy, Edward A Pankey, Ajaz A Banka, Adeleke M Badejo, Ryan Wekerle, Vaitaitis Vilija, Reza Izadpanah, Philip J Kadowitz, Vivian A Fonseca
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  ABSTRACT: OBJECTIVE: We compared the effect of the long acting basal insulin analog detemir with neutral protamine Hagedorn (NPH) insulin, and normal saline on recovery from vascular injury (balloon catheter mediated) in an animal model of insulin resistance. METHODS: Female Zucker fatty rats were administered NPH/detemir/saline for 7days following which, they underwent balloon catheter mediated injury of left carotid artery, and were continued on the respective regimen for an additional 21days when they were sacrificed. We evaluated the injured carotid artery for intimal hyperplasia (Intima/Media ratio) and also, aortic arch protein for markers of oxidative stress and inflammation, in addition to expression and phosphorylation of eNOS using well established methods. RESULTS: There was a significant difference in intimal hyperplasia (Intima/Media ratio) between control and detemir treated rats (1.3±0.09, 0.82±0.08; p<0.001) whereas the IM ratio in NPH treated rats was not significantly different from saline (1.17±0.1). Expression of p-eNOS (ser-1177) in both NPH and insulin detemir (1.3±0.15, 1.11±0.12) was significantly higher than controls (0.56±0.13; p<0.05). We did not find significant differences in the expression of MnSOD, eNOS and NFκB-p65. CONCLUSION: We conclude that in insulin resistant states, treatment with Insulin detemir but not NPH is associated with less intimal hyperplasia, although both insulins increased eNOS phosphorylation.
  Journal of diabetes and its complications 07/2012; · 2.11 Impact Factor