Barbara Kemp-Harper

Publications of Barbara Kemp-Harper

• cGMP in the Vasculature.

  Authors: Barbara Kemp-Harper, Harald H H W Schmidt

  Handbook of experimental pharmacology. 02/2009;

  Cyclic guanosine 3', 5'-monophosphate (cGMP) plays an integral role in the control of vascular function. Generated from guanylate cyclases in response to the endogenous ligands, nitric oxide (NO) andCyclic guanosine 3', 5'-monophosphate (cGMP) plays an integral role in the control of vascular function. Generated from guanylate cyclases in response to the endogenous ligands, nitric oxide (NO) and natriuretic peptides (NPs), cGMP influences a number of vascular cell types and regulates vasomotor tone, endothelial permeability, cell growth and differentiation, as well as platelet and blood cell interactions. Reciprocal regulation of the NO-cGMP and NP-cGMP pathways is evident in the vasculature such that one cGMP generating system may compensate for the dysfunction of the other. Indeed, aberrant cGMP production and/or signalling accompanies many vascular disorders such as hypertension, atherosclerosis, coronary artery disease and diabetic complications. This chapter highlights the main vascular functions of cGMP, its role in disease and the resulting current and potential therapeutic applications. With respect to pulmonary hypertension, heart failure and erectile dysfunction, as well as cGMP signal transduction, the reader is specifically referred to other dedicated chapters.

• Antihypertrophic actions of NO-independent soluble guanylyl cyclase (sGC) ligands BAY 41-2272 and BAY 58-2667 in vitro

  Authors: Rebecca Ritchie, Jennifer Irvine, Jane Love, John Horowitz, Johannes-Peter Stasch, Barbara Kemp-Harper

  BMC Pharmacology. 01/2009;

• Nitroxyl, the novel redox sibling of NO, suppresses cerebrovascular NADPH oxidase

  Authors: Barbara Kemp-Harper, Ravina Ravi, Michelle Bullen, Rebecca Ritchie, Christopher Sobey, Alyson Miller

  BMC Pharmacology. 01/2009;

• Cardioprotective effects in aged spontaneously hypertensive rats due to chronic stimulation/activation of sGC without hypotension

  Authors: Emma Jones, Barbara Kemp-Harper, Johannes-Peter Stasch, Harald Schmidt, Robert Widdop

  BMC Pharmacology. 01/2009;

• The novel NO redox sibling, nitroxyl (HNO), prevents cardiomyocyte hypertrophy and superoxide generation via cGMP

  Authors: Rebecca Ritchie, Jennifer Irvine, Swati Gossain, Jane Love, John Horowitz, Barbara Kemp-Harper

  BMC Pharmacology. 01/2009;

• Meeting report: cGMP matters.

  Authors: Barbara Kemp-Harper, Robert Feil

  Science signaling. 02/2008; 1(9):pe12.

  The second messenger cyclic guanosine 3',5'-monophosphate (cGMP) controls many cellular functions ranging from growth to contractility. Generated from guanylyl cyclases in response to natriureticThe second messenger cyclic guanosine 3',5'-monophosphate (cGMP) controls many cellular functions ranging from growth to contractility. Generated from guanylyl cyclases in response to natriuretic peptides or nitric oxide, cGMP transduces its effects through a number of cGMP effectors, including cGMP-regulated phosphodiesterases and protein kinases. Drugs that modulate cGMP levels are emerging as promising therapies, particularly for cardiovascular disorders. This report summarizes new data on the molecular mechanisms, (patho)physiological relevance, and therapeutic potential of the cGMP signaling system that were presented at the 3rd cGMP meeting held in June 2007 in Dresden, Germany.

• Sildenafil in hypoxic pulmonary hypertension potentiates a compensatory up-regulation of NO-cGMP signaling.

  Authors: Mark Kirsch, Barbara Kemp-Harper, Norbert Weissmann, Friedrich Grimminger, Harald H H W Schmidt

  The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 02/2008; 22(1):30-40.

  The availability of inhibitors of cGMP-specific phosphodiesterase 5 (PDE 5), such as sildenafil, has revolutionized the treatment of pulmonary hypertension (PH). Sildenafil may exert its protectiveThe availability of inhibitors of cGMP-specific phosphodiesterase 5 (PDE 5), such as sildenafil, has revolutionized the treatment of pulmonary hypertension (PH). Sildenafil may exert its protective effects in a mechanism-based fashion by targeting a pathophysiologically attenuated NO-cGMP signaling pathway. To elucidate this, we analyzed changes in the pulmonary expression and activity of key enzymes of NO-cGMP signaling as well as the functional pulmonary responses to sildenafil in the 5 or 21 day hypoxia mouse model of PH. Surprisingly, we found doubled NO synthase (NOS) II and III levels, no evidence for attenuated NO bioavailability as evidenced by the nitrosative/oxidative stress marker protein nitro tyrosine, and no changes in the expression and activity of the NO receptor, soluble guanylyl cyclase (sGC). PDE 5 was either unchanged at day 5 or, after 21 days of hypoxia, even significantly decreased along with unchanged activity. Biochemically, these changes were mirrored by increased cGMP spillover into the lung perfusate and cGMP-dependent phosphorylation of the vasodilator-stimulated phosphoprotein, VASP. Sildenafil further augmented cGMP and phospho-VASP levels in lungs of mice exposed for 5 or 21 days and decreased pulmonary arterial pressure in mice after 5 days but not 21 days of hypoxia. In conclusion, NO-cGMP signaling is compensatorily up-regulated in the hypoxic mouse model of PH, and sildenafil further augments this pathway to functionally alleviate pulmonary vasoconstriction.

• The nitroxyl anion (HNO) donor, Angeli's salt, does not develop tolerance in vivo

  Authors: Jennifer Irvine, Barbara Kemp-Harper, Robert Widdop

  BMC Pharmacology. 01/2007;

• Oxidised sGC: a novel therapeutic target in the vasculature

  Authors: Barbara Kemp-Harper, Jonathan Luk, Joanne Favaloro, Johannes-Peter Stasch, Harald Schmidt

  BMC Pharmacology. 01/2007;

• Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels.

  Authors: Johannes-Peter Stasch, Peter M Schmidt, Pavel I Nedvetsky, Tatiana Y Nedvetskaya, Arun Kumar H S, Sabine Meurer, Martin Deile, Ashraf Taye, Andreas Knorr, Harald Lapp, Helmut Müller, Yagmur Turgay, Christiane Rothkegel, Adrian Tersteegen, Barbara Kemp-Harper, Werner Müller-Esterl, Harald H H W Schmidt

  The Journal of clinical investigation. 10/2006; 116(9):2552-61.

  ROS are a risk factor of several cardiovascular disorders and interfere with NO/soluble guanylyl cyclase/cyclic GMP (NO/sGC/cGMP) signaling through scavenging of NO and formation of the strongROS are a risk factor of several cardiovascular disorders and interfere with NO/soluble guanylyl cyclase/cyclic GMP (NO/sGC/cGMP) signaling through scavenging of NO and formation of the strong oxidant peroxynitrite. Increased oxidative stress affects the heme-containing NO receptor sGC by both decreasing its expression levels and impairing NO-induced activation, making vasodilator therapy with NO donors less effective. Here we show in vivo that oxidative stress and related vascular disease states, including human diabetes mellitus, led to an sGC that was indistinguishable from the in vitro oxidized/heme-free enzyme. This sGC variant represents what we believe to be a novel cGMP signaling entity that is unresponsive to NO and prone to degradation. Whereas high-affinity ligands for the unoccupied heme pocket of sGC such as zinc-protoporphyrin IX and the novel NO-independent sGC activator 4-[((4-carboxybutyl){2-[(4-phenethylbenzyl)oxy]phenethyl}amino) methyl [benzoic]acid (BAY 58-2667) stabilized the enzyme, only the latter activated the NO-insensitive sGC variant. Importantly, in isolated cells, in blood vessels, and in vivo, BAY 58-2667 was more effective and potentiated under pathophysiological and oxidative stress conditions. This therapeutic principle preferentially dilates diseased versus normal blood vessels and may have far-reaching implications for the currently investigated clinical use of BAY 58-2667 as a unique diagnostic tool and highly innovative vascular therapy.

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• cGMP signalling: from bench to bedside. Conference on cGMP generators, effectors and therapeutic implications.

  Authors: Robert Feil, Barbara Kemp-Harper

  EMBO reports. 03/2006; 7(2):149-53.

• Effects of nitric oxide on sGC redox states

  Authors: Martin Deile, César Ibarra-Alvardo, Pavel Nedvetsky, Helmut Müller, Barbara Kemp-Harper, Johannes-Peter Stasch, HHHW Schmidt

  BMC Pharmacology. 01/2005;

• The phosphodiesterase 5 inhibitor, sildenafil, further augments the compensatory upregulation of NO-cGMP signalling in hypoxic pulmonary hypertension

  Authors: Mark Kirsch, Norbert Weissmann, Barbara Kemp-Harper, Friedrich Grimminger, Harald Schmidt

  BMC Pharmacology. 01/2005;

• The nitroxyl anion (NO): a novel regulator of sGC and vascular tone

  Authors: Barbara Kemp-Harper, Joanne Favaloro

  BMC Pharmacology. 01/2005;