Renal effects of captopril and nitrendipine in transgenic rats with an extra renin gene

Abstract We investigated the acute effects of captopril and nitrendipine on renal function and sodium excretion in hyper-tensive, male, heterozygous transgenic rats harboring a mouse renin gene [TGR(mRen-2)27]. Both drugs reduced blood pressure dose dependently in conscious transgenic rats. The oral ED20 for captopril was 0.5 mg/kg and 2.7 mg/kg for nitrendipine. In orally salt-loaded (20 mL/kg saline) transgenic rats captopril (0.3 to 3.0 mg/kg) reduced sodium excretion by approximately 90 % in the 6 hours after administration, whereas equally antihypertensive dsses of nitrendipine in-creased sodium excretion by approximately 100%. The antina-triuretic effect of captopril was accompanied by a reduction in creatinine clearance and a decrease in the excretion of cyclic GMP. In orally water-loaded (20 mL/kg water) transgenic rats captopril also reduced sodium excretion by more than 90%

Attenuated response of ICa,L to nitric oxide in atrial fibrillation

AIM: Nitric oxide (NO) synthesized by cardiomyocytes plays an important role in the regulation of cardiac function. Here we studied the impact of NO signalling on calcium influx in human right atrial myocytes and its relation to atrial fibrillation (AF). METHODS AND RESULTS: Right atrial appendages (RAA) were obtained from patients in sinus rhythm (SR) and AF. The biotin-switch technique was used to evaluate endogenous S-nitrosylation of the alpha1C subunit of L-type calcium channels. Comparing SR to AF, S-nitrosylation of Ca2+ channels was similar.Direct effects of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) on L-type calcium current (ICa,L) were studied in cardiomyocytes with standard voltage-clamp techniques. In SR, ICa,L increased with SNAP (100 microM) by 48%, n/N=117/56, p<0.001). The SNAP effect on ICa,L involved activation of soluble guanylate cyclase and protein kinase A. Specific inhibition of PDE3 with cilostamide (1 microM) enhanced ICa,L to a similar extent as SNAP. However, when cAMP was elevated by PDE3 inhibition or beta-adrenoceptor stimulation, SNAP reduced ICa,L, pointing to cGMP-cAMP cross-regulation. In AF, the stimulatory effect of SNAP on ICa,L was attenuated, while its inhibitory effect on isoprenaline- or cilostamide-stimulated current was preserved. cGMP elevation with SNAP was comparable between SR and AF group. Moreover, expression of PDE3 and sGC was not reduced in AF. CONCLUSION: NO exerts dual effects on ICa,L in SR with increase of basal and inhibition of cAMP-stimulated current, and in AF NO only inhibits stimulated ICa,L. We conclude that in AF, cGMP regulation of PDE2 is preserved, but regulation of PDE3 is lost

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Alterations of the nitric oxide receptor, soluble guanylate cyclase (sGC) may contribute to the pathophysiology of pulmonary arterial hypertension (PAH). In the present study, the expression of sGC in explanted lung tissue of PAH patients was studied and the effects of the sGC stimulator BAY 63-2521 on enzyme activity, and haemodynamics and vascular remodelling were investigated in two independent animal models of PAH. Strong upregulation of sGC in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was demonstrated by immunohistochemistry. Upregulation of sGC was detected, similarly to humans, in the structurally remodelled smooth muscle layer in chronic hypoxic mouse lungs and lungs from monocrotaline (MCT)-injected rats. BAY 63-2521 is a novel, orally available compound that directly stimulates sGC and sensitises it to its physiological stimulator, nitric oxide. Chronic treatment of hypoxic mice and MCT-injected rats, with fully established PAH, with BAY 63-2521 (10 mg x kg(-1) x day(-1)) partially reversed the PAH, the right heart hypertrophy and the structural remodelling of the lung vasculature. Upregulation of soluble guanylate cyclase in pulmonary arterial smooth muscle cells was noted in human idiopathic pulmonary arterial hypertension lungs and lungs from animal models of pulmonary arterial hypertension. Stimulation of soluble guanylate cyclase reversed right heart hypertrophy and structural lung vascular remodelling. Soluble guanylate cyclase may thus offer a new target for therapeutic intervention in pulmonary arterial hypertension

Nitric oxide-sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) can arise from cardiac and vascular remodeling processes following long-lasting hypertension. Efficacy of common HF therapeutics is unsatisfactory in HFpEF. Evidence suggests that stimulators of the nitric oxide-sensitive soluble guanylyl cyclase (NOsGC) could be of use here. We aimed to characterize the complex cardiovascular effects of NOsGC stimulation using NO-independent stimulator BAY 41-8543 in a double-transgenic rat (dTGR) model of HFpEF. We show a drastically improved survival rate of treated dTGR. We observed less cardiac fibrosis, macrophage infiltration, and gap junction remodeling in treated dTGR. Microarray analysis revealed that treatment of dTGR corrected the dysregulateion of cardiac genes associated with fibrosis, inflammation, apoptosis, oxidative stress, and ion channel function toward an expression profile similar to healthy controls. Treatment reduced systemic blood pressure levels and improved endothelium-dependent vasorelaxation of resistance vessels. Further comprehensive in vivo phenotyping showed an improved diastolic cardiac function, improved hemodynamics, and less susceptibility to ventricular arrhythmias. Short-term BAY 41-8543 application in isolated untreated transgenic hearts with structural remodeling significantly reduced the occurrence of ventricular arrhythmias, suggesting a direct nongenomic role of NOsGC stimulation on excitation. Thus, NOsGC stimulation was highly effective in improving several HFpEF facets in this animal model, underscoring its potential value for patients