8-Aminopurines in the Cardiovascular and Renal Systems and Beyond.

Screening of compounds comprising 8-substituted guanine revealed that 8-aminoguanosine and 8-aminoguanine cause diuresis/natriuresis/glucosuria, yet decrease potassium excretion. Subsequent investigations demonstrated that 8-aminoguanosine's effects are mediated by its metabolite 8-aminoguanine. The mechanism by which 8-aminoguanine causes diuresis/natriuresis/glucosuria involves inhibition of PNPase (purine nucleoside phosphorylase), which increases renal interstitial inosine levels. Additional evidence suggests that inosine, via indirect or direct adenosine A2B receptor activation, increases renal medullary blood flow which enhances renal excretory function. Likely, 8-aminoguanine has pleiotropic actions that also alter renal excretory function. Indeed, the antikaliuretic effects of 8-aminoguanine are independent of PNPase inhibition. 8-Aminoguanine is an endogenous molecule; nitrosative stress leads to production of biomolecules containing 8-nitroguanine moieties. Degradation of these biomolecules releases 8-nitroguanosine and 8-nitro-2'-deoxyguanosine which are converted to 8-aminoguanine. Also, guanosine and guanine per se may contribute to 8-aminoguanine formation. 8-Aminoinosine, 8-aminohypoxanthine, and 8-aminoxanthine likewise induce diuresis/natriuresis/glucosuria, yet do not reduce potassium excretion. Thus, there are several pharmacologically active 8-aminopurines with nuanced effects on renal excretory function. Chronic treatment with 8-aminoguanine attenuates hypertension in deoxycorticosterone/salt rats, prevents strokes, and increases lifespan in Dahl salt-sensitive rats on a high salt diet and attenuates the metabolic syndrome in rats; 8-aminoguanosine retards progression of pulmonary hypertension in rats and anemia and organ damage in sickle cell mice. 8-Aminoguanine reverses age-associated lower urinary tract dysfunction and retinal degeneration. 8-Aminopurines represent a new class of agents (and potentially endogenous factors) that have beneficial effects on the cardiovascular system and kidneys and may turn back the clock in age-associated diseases.

2-Methoxyestradiol Attenuates Angiotensin II-Induced Hypertension, Cardiovascular Remodeling, and Renal Injury.

Estradiol may antagonize the adverse cardiovascular effects of angiotensin II (Ang II). We investigated the effects of 2-methoxyestradiol (2-ME), a nonestrogenic estradiol metabolite, on Ang II-induced cardiovascular and renal injury in male rats. First, we determined the effects of 2-ME on Ang II-induced acute changes in blood pressure, renal hemodynamics, and excretory function. Next, we investigated the effects of 2-ME and 2-hydroxyestardiol (2-HE) on hypertension and cardiovascular and renal injury induced by chronic infusion of Ang II. Furthermore, the effects of 2-ME on blood pressure and cardiovascular remodeling in the constricted aorta (CA) rat model and on isoproterenol-induced (ISO) cardiac hypertrophy and fibrosis were examined. 2-ME had no effects on Ang II-induced acute changes in blood pressure, renal hemodynamics, or glomerular filtration rate. Both 2-ME and 2-HE reduced hypertension, cardiac hypertrophy, proteinuria, and mesangial expansion induced by chronic Ang II infusions. In CA rats, 2-ME attenuated cardiac hypertrophy and fibrosis and reduced elevated blood pressure above the constriction. Notably, 2-ME reduced both pressure-dependent (above constriction) and pressure-independent (below constriction) vascular remodeling. 2-ME had no effects on ISO-induced renin release yet reduced ISO-induced cardiac hypertrophy and fibrosis. This study shows that 2-ME protects against cardiovascular and renal injury due to chronic activation of the renin-angiotensin system. This study reports for the first time that in vivo 2-ME reduces trophic (pressure-independent) effects of Ang II and related cardiac and vascular remodeling.

Nitrite Prevents Right Ventricular Failure and Remodeling Induced by Pulmonary Artery Banding.

BACKGROUND: Nitrite has been shown to reduce right ventricle (RV) remodeling in experimental pulmonary hypertension. However, whether this effect is due to a reduction in RV afterload (ie, reduction in pulmonary artery pressure) or a direct effect on the RV itself remains unanswered. We hypothesize that nitrite has direct effects on RV remodeling and studied its effects in mice with pulmonary artery banding (PAB). METHODS AND RESULTS: PAB decreased exercise tolerance and reduced RV systolic and diastolic function. Nitrite treatment attenuated the decrease in RV systolic function and improved the RV diastolic function. Nitrite-treated mice with PAB had similar exercise tolerance compared with a control group. PAB induced RV hypertrophy and fibrosis which were associated with increased expression of phospho-Akt. Interestingly, nitrite treatment attenuated PAB-induced RV hypertrophy and reduced the expression of phospho-Akt in RV tissue from mice with PAB. In neonatal rat cardiac fibroblast, nitrite also attenuated hypoxia-induced increase in expression of phospho-Akt. CONCLUSION: Our study indicates that nitrite treatment has direct beneficial effects on RV and improves function and attenuates remodeling in RV exposed to chronic pressure overload. These beneficial effects, at least in part, could be due to the inhibition of the phospho-Akt (p-Akt) pathway activation.

Effect of dipeptidyl peptidase 4 inhibition on arterial blood pressure is context dependent.

UNLABELLED: Because the effects of dipeptidyl peptidase 4 (DPP4) inhibitors on blood pressure are controversial, we examined the long-term effects of sitagliptin (80 mg/kg per day) on blood pressure (radiotelemetry) in spontaneously hypertensive rats (SHR), Wistar-Kyoto rats, and Zucker Diabetic-Sprague Dawley rats (metabolic syndrome model). In SHR, chronic (3 weeks) sitagliptin significantly increased systolic, mean, and diastolic blood pressures by 10.3, 9.2, and 7.9 mm Hg, respectively, a response abolished by coadministration of BIBP3226 (2 mg/kg per day; selective Y1-receptor antagonist). Sitagliptin also significantly increased blood pressure in SHR treated with hydralazine (vasodilator; 25 mg/kg per day) or enalapril (angiotensin-converting enzyme inhibitor; 10 mg/kg per day). In Wistar-Kyoto rats, chronic sitagliptin slightly decreased systolic, mean, and diastolic blood pressures (-1.8, -1.1, and -0.4 mm Hg, respectively). In Zucker Diabetic-Sprague Dawley rats, chronic sitagliptin decreased systolic, mean, and diastolic blood pressures by -7.7, -5.8, and -4.3 mm Hg, respectively, and did not alter the antihypertensive effects of chronic enalapril. Because DPP4 inhibitors impair the metabolism of neuropeptide Y1-36 (NPY1-36; Y1-receptor agonist) and glucagon-like peptide (GLP)-1(7-36)NH2 (GLP-1 receptor agonist), we examined renovascular responses to NPY1-36 and GLP-1(7-36)NH2 in isolated perfused SHR and Zucker Diabetic-Sprague Dawley kidneys pretreated with norepinephrine (to induce basal tone). In Zucker Diabetic-Sprague Dawley kidneys, NPY1-36 and GLP-1(7-36)NH2 exerted little, if any, effect on renovascular tone. In contrast, in SHR kidneys, both NPY1-36 and GLP-1(7-36)NH2 elicited potent and efficacious vasoconstriction. IN CONCLUSION: (1) The effects of DPP4 inhibitors on blood pressure are context dependent; (2) The context-dependent effects of DPP4 inhibitors are due in part to differential renovascular responses to DPP4's most important substrates (NPY1­36 and GLP-1(7­36)NH2) [corrected]; (3) Y1 receptor antagonists may prevent the prohypertensive and possibly augment the antihypertensive effects of DPP4 inhibitors.