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Many acute cardiovascular disease states are associated with neutrophil infiltration of myocardium and subsequent release of superoxide (O2−) and myeloperoxidase (MPO), which contribute to inflammatory reactions. B-Type natriuretic peptide (BNP) is known to exert anti-inflammatory and antifibrotic effects, but it is not known whether these may include interactions with neutrophils. In neutrophils isolated from 20 healthy subjects, we assessed the effect of BNP on the 'neutrophil burst' (O2− production and MPO release) stimulated by phorbol myristate acetate (PMA) and N-formyl-methionyl-leucyl-phenylalanine ( fMLP), respectively. Effects of BNP on cGMP accumulation, and the effects of the cell-permeable cGMP analogue 8-(4-chlorophenylthio) guanosine- cGMP (8-p-CPT- cGMP) and protein kinase G (PKG) inhibition with KT5823 on the neutrophil-BNP interaction were also evaluated. B-Type natriuretic peptide suppressed O2− release from neutrophils by 23 ± 6% ( P < 0.001) and 24 ± 8% ( P < 0.05) following PMA and fMLP stimulation, respectively. Although BNP did not significantly increase cGMP formation, 8-p-CPT- cGMP suppressed both PMA- and fMLP-induced neutrophil O2− release by 16% and 28%, respectively ( P < 0.05). The PKG inhibitor KT5823 attenuated the effects of BNP on both fMLP- and PMA-associated O2− production. Neither BNP nor 8-p-CPT- cGMP significantly affected MPO release from neutrophils. Suppression of O2− release from neutrophils by BNP may contribute to its anti-inflammatory and antifibrotic actions. [ABSTRACT FROM AUTHOR]

Background and Purpose: Aortic valve stenosis (AVS) is associated with significant cardiovascular morbidity and mortality. To date, no therapeutic modality has been shown to be effective in retarding AVS progression. We evaluated the effect of angiotensin-converting enzyme inhibition with ramipril on disease progression in a recently developed rabbit model of AVS.Experimental Approach: The effects of 8 weeks of treatment with either vitamin D₂ at 25,000 IU for 4 days a week alone or in combination with ramipril (0.5 mg·kg⁻¹) on aortic valve structure and function were examined in New Zealand white rabbits. Echocardiographic aortic valve backscatter (AV(BS)) and aortic valve:outflow tract flow velocity ratio were utilized to quantify changes in valve structure and function.Key Results: Treatment with ramipril significantly reduced AV(BS) and improved aortic valve :outflow tract flow velocity ratio. The intravalvular content of the pro-oxidant thioredoxin-interacting protein was decreased significantly with ramipril treatment. Endothelial function, as measured by asymmetric dimethylarginine concentrations and vascular responses to ACh, was improved significantly with ramipril treatment.Conclusions and Implications: Ramipril retards the development of AVS, reduces valvular thioredoxin-interacting protein accumulation and limits endothelial dysfunction in this animal model. These findings provide important insights into the mechanisms of AVS development and an impetus for future human studies of AVS retardation using an angiotensin-converting enzyme inhibitor. [ABSTRACT FROM AUTHOR]