Cardiovascular actions of a novel NO‐independent guanylyl cyclase stimulator, BAY 41‐8543: <i>in vivo</i> studies

Stasch, Johannes‐Peter; Dembowsky, Klaus; Perzborn, Elisabeth; Stahl, Elke; Schramm, Matthias

doi:10.1038/sj.bjp.0704483

Cited by 116 publications

(84 citation statements)

References 36 publications

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“…Both impaired NO/cGMP signaling (14,15,18) and increased activity of the RAAS (9) were reported to be involved in the development of hypertension. Therefore, a combination of pharmacological inhibition of the RAAS and pharmacological stimulation of sGC may offer novel strategies to treat hypertension (71,72), especially in settings where use of classical NO donor compounds is problematic because of the development of tolerance (73).…”

Section: Figurementioning

confidence: 99%

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

Buys¹,

Raher²,

Kirby³

et al. 2012

J. Clin. Invest.

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Nitric oxide (NO) plays an essential role in regulating hypertension and blood flow by inducing relaxation of vascular smooth muscle. Male mice deficient in a NO receptor component, the α1 subunit of soluble guanylate cyclase (sGCα 1 ), are prone to hypertension in some, but not all, mouse strains, suggesting that additional genetic factors contribute to the onset of hypertension. Using linkage analyses, we discovered a quantitative trait locus (QTL) on chromosome 1 that was linked to mean arterial pressure (MAP) in the context of sGCα 1 deficiency. This region is syntenic with previously identified blood pressure-related QTLs in the human and rat genome and contains the genes coding for renin. Hypertension was associated with increased activity of the renin-angiotensin-aldosterone system (RAAS). Further, we found that RAAS inhibition normalized MAP and improved endothelium-dependent vasorelaxation in sGCα 1 -deficient mice. These data identify the RAAS as a blood pressure-modifying mechanism in a setting of impaired NO/cGMP signaling. IntroductionSystemic arterial hypertension is one of the most widespread public health problems in the developed world and the most prevalent modifiable risk factor for cardiovascular disease (CVD) in both women and men (1). The pathogenesis of essential hypertension is multifactorial, and in the vast majority of cases the etiology of hypertension is unknown. Although major advances in the treatment of hypertension have decreased CVD-related deaths over the last decade (2), many of the molecular mechanisms underlying the development of hypertension remain elusive. Genome-wide association studies (GWAS) suggest that there is a substantial heritable component to blood pressure (3, 4). Although GWAS have identified several loci associated with blood pressure in human beings, including loci containing genes that either regulate cGMP levels (4-7) or the renin-angiotensin-aldosterone system (RAAS) (8), many of the genetic factors determining blood pressure and how these factors interact remain to be identified.Renal abnormalities, such as decreased urinary sodium excretion in response to increasing renal perfusion pressure, and increased activity of the RAAS are generally considered to be a major contributor to the development of high blood pressure (9). However, other studies support the idea that hypertension can arise from primary vascular abnormalities (10, 11). The ability of NO to relax vascular smooth muscle and its essential role in the regulation of blood flow are well characterized (12, 13). Ample evidence suggests that altered NO signaling is involved in the pathogenesis of hypertension (14).One of the primary receptors for NO is soluble guanylate cyclase (sGC), a heme-containing enzyme that generates cGMP. The

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Section: Figurementioning

confidence: 99%

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

Buys¹,

Raher²,

Kirby³

et al. 2012

J. Clin. Invest.

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“…Studies were performed on anaesthetized dogs of either sex and a body weight between 20 ± 30 kg as described previously (Stasch et al, 2002b). Arterial blood pressure, electrocardiogram (lead II), left ventricular pressure, ®rst derivative of left pressure (dP dt 71 ), heart rate, coronary blood¯ow, and oxygen saturation in the coronary sinus were continuously recorded on a pen recorder after implantation of the respective catheters.…”

Section: Haemodynamics In Anaesthetized Dogsmentioning

confidence: 99%

“…After additional 20 min, the terminal 2 mm tip of the tail was removed with a sterile razor blade, and the tail was vertically immersed into normal saline at 378C. The bleeding time was then measured as described (Stasch et al, 2002b).…”

Section: Rat Tail Bleeding Timementioning

confidence: 99%

NO‐ and haem‐independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle

Stasch

Schmidt

Alonso‐Alija

et al. 2002

British J Pharmacology

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287

280

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1 Soluble guanylyl cyclase (sGC) is the only proven receptor for the ubiquitous biological messenger nitric oxide (NO) and is intimately involved in many signal transduction pathways, most notably in regulating vascular tone and platelet function. sGC is a heterodimeric (a/û) protein that converts GTP to cyclic GMP; NO binds to its prosthetic haem group. Here, we report the discovery of a novel sGC activating compound, its interaction with a previously unrecognized regulatory site and its therapeutic implications. 2 Through a high-throughput screen we identi®ed BAY 58-2667, an amino dicarboxylic acid which potently activates sGC in an NO-independent manner. In contrast to NO, YC-1 and BAY 41-2272, the sGC stimulators described recently, BAY 58-2667 activates the enzyme even after it has been oxidized by the sGC inhibitor ODQ or rendered haem de®cient. 3 Binding studies with radiolabelled BAY 58-2667 show a high anity site on the enzyme. 4 Using photoanity labelling studies we identi®ed the amino acids 371 (a-subunit) and 231 ± 310 (û-subunit) as target regions for BAY 58-2667. 5 sGC activation by BAY 58-2667 results in an antiplatelet activity both in vitro and in vivo and a potent vasorelaxation which is not in¯uenced by nitrate tolerance. 6 BAY 58-2667 shows a potent antihypertensive eect in conscious spontaneously hypertensive rats. In anaesthetized dogs the hemodynamic eects of BAY 58-2667 and GTN are very similar on the arterial and venous system. 7 This novel type of sGC activator is a valuable research tool and may oer a new approach for treating cardiovascular diseases.

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“…This finding has led to the generation of pharmacological compounds aimed at restoring cGMP levels, thereby repairing endothelial dysfunction. As such, a class of synthetic compounds termed sGC activators has been demonstrated to bypass NO signaling impairment by displacing the defective heme prosthetic group, thereby stabilizing the enzyme in an activated conformation and restoring cGMP generation (Stasch et al, 2002). Another class of compounds termed sGC stimulators is also able to increase cGMP production by sGC, but not when the heme prosthetic group has been oxidized (Stasch et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 Rat

Boustany-Kari¹,

Harrison²,

Chen³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Therapies that restore renal cGMP levels are hypothesized to slow the progression of diabetic nephropathy. We investigated the effect of BI 703704, a soluble guanylate cyclase (sGC) activator, on disease progression in obese ZSF1 rats. BI 703704 was administered at doses of 0.3, 1, 3, and 10 mg/kg/d to male ZSF1 rats for 15 weeks, during which mean arterial pressure (MAP), heart rate (HR), and urinary protein excretion (UPE) were determined. Histologic assessment of glomerular and interstitial lesions was also performed. Renal cGMP levels were quantified as an indicator of target modulation. BI 703704 resulted in sGC activation, as evidenced by dose-dependent increases in renal cGMP levels.After 15 weeks of treatment, sGC activation resulted in dosedependent decreases in UPE (from 463 6 58 mg/d in vehicle controls to 328 6 55, 348 6 23, 283 6 45, and 108 6 23 mg/d in BI 703704-treated rats at 0.3, 1, 3, and 10 mg/kg, respectively). These effects were accompanied by a significant reduction in the incidence of glomerulosclerosis and interstitial lesions. Decreases in MAP and increases in HR were only observed at the high dose of BI 703704. These results are the first demonstration of renal protection with sGC activation in a nephropathy model induced by type 2 diabetes. Importantly, beneficial effects were observed at doses that did not significantly alter MAP and HR.

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Cardiovascular actions of a novel NO‐independent guanylyl cyclase stimulator, BAY 41‐8543: in vivo studies

Cited by 116 publications

References 36 publications

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

NO‐ and haem‐independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle

A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 Rat

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