Comparison of Soluble Guanylate Cyclase Stimulators and Activators in Models of Cardiovascular Disease Associated with Oxidative Stress

Abstract

Soluble guanylate cyclase (sGC), the primary mediator of nitric oxide (NO) bioactivity, exists as reduced (NO-sensitive) and oxidized (NO-insensitive) forms. We tested the hypothesis that the cardiovascular protective effects of NO-insensitive sGC activation would be potentiated under conditions of oxidative stress compared to those of NO-sensitive sGC stimulation. The cardiovascular effects of the NO-insensitive sGC activator GSK2181236A [a low, non-depressor dose, and a high dose which lowered mean arterial pressure (MAP) by 5–10 mmHg] and those of equi-efficacious doses of the NO-sensitive sGC stimulator BAY 60-4552 were assessed in (1) Sprague Dawley rats during coronary artery ischemia/reperfusion (I/R) and (2) spontaneously hypertensive stroke prone rats (SHR-SP) on a high salt/fat diet (HSFD). In I/R, neither compound reduced infarct size 24 h after reperfusion. In SHR-SP, HSFD increased MAP, urine output, microalbuminuria, and mortality, caused left ventricular hypertrophy with preserved ejection fraction, and impaired endothelium-dependent vasorelaxation. The low dose of BAY 60-4552, but not that of GSK2181236A, decreased urine output, and improved survival. Conversely, the low dose of GSK2181236A, but not that of BAY 60-4552, attenuated the development of cardiac hypertrophy. The high doses of both compounds similarly attenuated cardiac hypertrophy and improved survival. In addition to these effects, the high dose of BAY 60-4552 reduced urine output and microalbuminuria and attenuated the increase in MAP to a greater extent than did GSK2181236A. Neither compound improved endothelium-dependent vasorelaxation. In SHR-SP isolated aorta, the vasodilatory responses to the NO-dependent compounds carbachol and sodium nitroprusside were attenuated by HSFD. In contrast, the vasodilatory responses to both GSK2181236A and BAY 60-4552 were unaltered by HSFD, indicating that reduced NO-bioavailability and not changes in the oxidative state of sGC is responsible for the vascular dysfunction. In summary, GSK2181236A and BAY 60-4552 provide partial benefit against hypertension-induced end-organ damage. The differential beneficial effects observed between these compounds could reflect tissue-specific changes in the oxidative state of sGC and might help direct the clinical development of these novel classes of therapeutic agents.

Cinaciguat prevents the development of pathologic hypertrophy in a rat model of left ventricular pressure overload

“…Furthermore, chronic oral administration of the drug in this dose did not significantly alter arterial blood pressure in the systemic circulation neither in murine models of pulmonary hypertension23 nor in a rat model of diabetic cardiomyopathy38. Similar results with oral Ataciguat and GSK2181236A, two further sGC activators have recently been reported in a rat myocardial infarction model and in spontaneously hypertensive stroke prone rats1039. Conforming these data, we did not observe any changes in MAP of the rats in response to orally administered Cinaciguat at the time of the hemodynamic assessment, 24 h after the last application of the drug.…”

Renal effects of soluble guanylate cyclase stimulators and activators: A review of the preclinical evidence

“…This was paralleled by significant decreases in systolic blood pressure, renal tubular diameter, apoptosis, and renal macrophage infiltration. sGC stimulation decreased tubulointerstitial fibrosis, as shown by tubulointerstitial volume, matrix protein accumulation, a-smooth muscle actin expression, collagen IV deposition, and TGFb1 mRNA expression stroke-prone, spontaneously hypertensive rats, BAY 60-4552 improved survival (Figure 2c), attenuated the development of hypertrophy, reduced urine output and microalbuminuria, and attenuated increases in blood pressure compared with untreated controls [29].…”

“…*P < 0.01 compared with control group, **P < 0.01 compared with L-NAME group. (c) Example of effect on survival (BAY 60-4552) (reproduced from [29]). Survival following chronic administration of BAY 60-4552 (0.3 or 3.0 mg/kg/day) or GSK2181236A (0.1 or 1.0 mg/kg/day) in spontaneously hypertensive prone Sprague rats on a high-salt/high-fat diet (HFSD) versus rats on HFSD alone or no diet (ND).…”

“…Limited published data suggest that GSK2181236A may provide partial benefit against hypertension-induced endorgan damage in rat models [29].…”

Alternative splicing impairs soluble guanylyl cyclase function in aortic aneurysm

“…The ␣1/␤1 sGC is the most highly expressed heterodimer in vascular tissues (20). Several molecular mechanisms were implicated in downregulation of sGC expression and activity in vascular disease, including inhibition of transcription (1,33,34,39,47), destabilization of mRNA (22), and protein degradation in increased oxidative environment (3,9,14). Systematic analysis of the NCBI nucleotide database identifies seven alternatively spliced transcripts for GUCY1A3 gene of the ␣1 subunit (␣1-Tr1 to ␣1-Tr7) and six splice transcripts for the GUCY1B3 gene of the ␤1 subunit (␤1-Tr1 to ␤1-Tr6) (42).…”