The treatment with soluble guanylate cyclase stimulator BAY41-8543 prevents malignant hypertension and associated organ damage

Figures

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  FIGURE 1. The experimental design of the whole study, delineating the time sequence of experimental manoeuvres and different treatment regimes. BAY, BAY41-8543-(2-[1-[2-flurophenyl)methyl]-1H-pyrazol][3,4b]pyridine-3-yl]-5(4-morpholinyl)-4,6-pyrimidinedaiamine), a stimulator of a soluble guanylyl cyclase; EMPA, empagliflozin, a sodium-glucose cotransport type 2 inhibitor; Echo, echocardiography assessment; l-NAME: Nω-nitro- l-arginine methyl ester, a nonspecific nitric oxide synthase inhibitor.

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  FIGURE 2. Series 1: effects of treatment on survival rate (a), mean arterial pressure (b) and body weight changes (c). BAY, BAY41-8543-(2-[1-[2-flurophenyl)methyl]-1H-pyrazol][3,4b]pyridine-3-yl]-5(4-morpholinyl)-4,6-pyrimidinedaiamine), a stimulator of a soluble guanylyl cyclase; EMPA, empagliflozin, a sodium-glucose cotransport type 2 inhibitor; l-NAME, Nω-nitro- l-arginine methyl ester, a nonspecific nitric oxide synthase inhibitor; TGR, heterozygous Ren-2 renin transgenic rats. ∗P < 0.05 compared with basal values of blood pressure (i.e. values from day −3), significance is always shown in the color appropriate to the experimental group. @P < 0.05 compared with values in control hypertensive rats (i.e. in TGR + placebo + untreated group) at the same time point.

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  FIGURE 3. Series 1: effects of treatments on whole heart weight (a), left ventricle weight (b), right ventricle weight (c), lung weight (d) and kidney weight (e) and glomerulosclerosis index (f). BAY, BAY41-8543-(2-[1-[2-flurophenyl)methyl]-1H-pyrazol][3,4b]pyridine-3-yl]-5(4-morpholinyl)-4,6-pyrimidinedaiamine), a stimulator of a soluble guanylyl cyclase; EMPA, empagliflozin, a sodium-glucose cotransport type 2 inhibitor; l-NAME, Nω-nitro-l-arginine methyl ester; TGR, heterozygous Ren-2 renin transgenic rats.

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  FIGURE 4. Series 1: the effects of treatment on plasma (a) and kidney (b) angiotensin II concentrations. BAY, BAY41-8543-(2-[1-[2-flurophenyl)methyl]-1H-pyrazol][3,4b]pyridine-3-yl]-5(4-morpholinyl)-4,6-pyrimidinedaiamine), a stimulator of a soluble guanylyl cyclase; EMPA, empagliflozin, a sodium-glucose cotransport type 2 inhibitor; l-NAME, Nω-nitro-l-arginine methyl ester; TGR, heterozygous Ren-2 renin transgenic rats.

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  FIGURE 5. Series 2: the effects of treatment on survival rate (a), mean arterial pressure (b), body weight (c), whole heart weight (d), kidney weight (e), lung weight (f) and glomerulosclerosis index (g). BAY, BAY41-8543-(2-[1-[2-flurophenyl)methyl]-1H-pyrazol][3,4b]pyridine-3-yl]-5(4-morpholinyl)-4,6-pyrimidinedaiamine), a stimulator of a soluble guanylyl cyclase; EMPA, empagliflozin, a sodium-glucose cotransport type 2 inhibitor. l-NAME, Nω-nitro- l-arginine methyl; TGR, heterozygous Ren-2 renin transgenic rats. ∗P < 0.05 compared with values in control hypertensive rats (i.e. TGR + placebo + untreated group). Significance is shown in the color appropriate to the experimental group.

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  FIGURE 6. Series 2: Representative histological images of the renal cortex in (a) control hypertensive rats, that is, heterozygous Ren-2 renin transgenic rats (TGR) + placebo + untreated – with normal renal morphology. (b) TGR + administration of Nω-nitro-l-arginine methyl ester (l-NAME) without treatment (i.e. TGR + l-NAME + untreated) – show substantial glomerular damage with signs of focal segmental glomerular sclerosis changes accompanied by small areas of tubular atrophy and tubulointerstitial changes (fibrosis), green arrows highlight the most prominent changes in this experimental group. (c) TGR + l-NAME + treated with BAY41-8543-(2-[1-[2-flurophenyl)methyl]-1H-pyrazol][3,4b]pyridine-3-yl]-5(4-morpholinyl)-4,6-pyrimidinedaiamine) (BAY) (i.e. TGR + l-NAME + BAY) – show principally same changes as observed in TGR + l-NAME + untreated group, and green arrows again highlights the typical changes for this group. (d) TGR + l-NAME + treated with empagliflozin, a sodium-glucose cotransport type 2 inhibitor (EMPA) (i.e. TGR + l-NAME + EMPA), principally the same changes as observed in TGR + l-NAME + untreated group, green arrow shows the typical change and red arrows show protein casts. (e)…

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  FIGURE 7. Series 2: the effects of treatment on the fractional shortening (a), ejection fraction (b), stroke volume (c), cardiac output (d) and relative wall thickness (e) of the left ventricle. BAY, BAY41-8543-(2-[1-[2-flurophenyl)methyl]-1H-pyrazol][3,4b]pyridine-3-yl]-5(4-morpholinyl)-4,6-pyrimidinedaiamine), a stimulator of a soluble guanylyl cyclase; EMPA, empagliflozin, a sodium-glucose cotransport type 2 inhibitor; l-NAME, Nω-nitro-l-arginine methyl ester; TGR, heterozygous Ren-2 renin transgenic rats. ∗P < 0.05 compared with values in control hypertensive rats (i.e. TGR + placebo + untreated group). Significance is shown in color appropriate to the experimental group.