Search

Objectives: Using 2 sequential studies in HOPE (Heart Outcomes Prevention Evaluation) study-type patients, the aims of this study were: 1) to test the hypothesis that ramipril improves platelet nitric oxide (NO) responsiveness: and 2) to explore biochemical and physiological effects of ramipril in a cohort selected on the basis of platelet NO resistance., Background: Ramipril prevents cardiovascular events, but the bases for these effects remain uncertain. NO resistance at both the platelet and vascular levels is present in a substantial proportion of patients with diabetes or ischemic heart disease and is an independent risk factor for cardiovascular events., Methods: Study 1 was a double-blind, randomized comparison of ramipril (10 mg) with placebo in a cohort of patients (n = 119) with ischemic heart disease or diabetes plus additional coronary risk factor(s), in which effects on platelet responsiveness to NO were compared. Study 2 was a subsequent short-term evaluation of the effects of ramipril in a cohort of subjects (n = 19) with impaired platelet NO responsiveness in whom additional mechanistic data were sought., Results: In study 1, ramipril therapy increased platelet responsiveness to NO relative to the extent of aggregation (p < 0.001), but this effect occurred primarily in patients with severely impaired baseline NO responsiveness (n = 41). In study 2, ramipril also improved platelet NO responsiveness (p < 0.01), and this improvement was correlated directly with increased NO-stimulated platelet generation of cyclic guanosine monophosphate (p < 0.02) but not with changes in plasma thrombospondin-1 levels., Conclusions: Ramipril ameliorates platelet NO resistance in HOPE study-type patients, with associated increases in soluble guanylate cyclase responsiveness to NO. This effect is likely to contribute to treatment benefit and define patients in whom ramipril therapy is particularly effective., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This study sought to compare the respective effects of resistance or aerobic exercise of higher or lower intensities on the acute plasma interleukin-6 (IL-6) and C-reactive protein (CRP) response in a sedentary, middle-aged, disease-free cohort. Following baseline testing, and in a randomized cross-over design, 12 sedentary males completed four exercise protocols, including 40 min of moderate-vigorous (M-VA) or low-intensity (LA) aerobic exercise on a cycle ergometer; and a moderate-vigorous (M-VR) or low-intensity (LR) full-body resistance session matched for protocol duration. Venous blood was obtained pre-, post-, 3 h post and 24 h post-exercise and analysed for IL-6, CRP, leukocyte count, myoglobin, creatine kinase (CK), and cortisol. Diet and physical activity were standardized 24 h before and after exercise. Results indicated an elevated CRP response in the M-VR protocol in comparison to the low-intensity protocols (P < 0.05); however, no changes were evident between the moderate-vigorous intensity protocols. The moderate-vigorous intensity protocols induced significant increases of IL-6, cortisol, and leukocytes in comparison to the low-intensity protocols (P < 0.05). However, the IL-6 response showed no significant differences between the moderate-vigorous intensity protocols, despite the M-VR protocol inducing the largest response of markers indicative of muscle damage (CK, myoglobin, and neutrophil count) (P < 0.05). Hence, indicating a disassociation between the IL-6 response and markers of muscle damage within the respective exercise bouts. The highest IL-6 response was evident in the moderate-vigorous intensity protocols immediately post-exercise. Moreover, the exercise modality did not seem to influence the acute IL-6 and CRP response, with the main determinant of the IL-6 response being exercise intensity.

Platelet hyporesponsiveness to the anti-aggregatory effects of nitric oxide (NO) occurs commonly in association with myocardial ischemia and coronary risk factors, often co-exists with endothelial dysfunction and represents an independent marker of long-term cardiovascular risk. We sought to determine whether polycystic ovary syndrome (PCOS), which has been postulated as a cardiovascular risk factor in women, is independently associated with this phenomenon. Twenty-four young women with PCOS (mean age 32.1+/-1.3) were evaluated in lean (n=12) and obese (n=12) subgroups, and compared with age-matched lean normals (n=12). Platelet aggregation and its inhibition by the nitric oxide donor sodium nitroprusside (SNP) were assessed and compared with vascular endothelial function. Plasma concentrations of malondialdehyde (MDA), N(G),N(G)-dimethyl-L-arginine (ADMA) and hs-CRP were measured as markers of oxidative stress, endothelial dysfunction and inflammation, respectively. Circulating endothelial progenitor cell (EPC) counts were also documented. In both PCOS subgroups, which demonstrated hyperaggregability to ADP, responses to SNP inhibition of aggregation (the principal end-point of the study) were significantly impaired (P<0.01 for both), as were their endothelium-dependent vascular responses to salbutamol (P<0.05 for both). However, vasomotor responses to nitroglycerin and circulating EPC counts did not vary between groups. PCOS subjects also had significantly elevated ADMA, MDA and hs-CRP levels relative to normals (all P<0.05). Impairment of SNP response remained unaltered after mean 30+/-2.4 months follow-up in PCOS subjects. We conclude that in PCOS subjects, independent of obesity and associated insulin resistance, profound and reproducible impairment of platelet responsiveness to NO is an additional component of cardiovascular homeostatic disturbance.

Perhexiline, a "metabolic" anti-anginal agent currently under investigation in management of congestive heart failure and acute coronary syndromes improves platelet nitric oxide responsiveness in patients with impaired responsiveness. The current study investigated possible interactions between perhexiline and the nitric oxide donor nitroglycerin on arterial stiffness, neutrophil superoxide release and on platelet nitric oxide responsiveness. Patients (n=39) with stable angina pectoris, awaiting cardiac catheterization were randomized to additional perhexiline or unchanged drug therapy; all patients received nitroglycerin infusion for 2 h. Vasomotor responses to perhexiline and combined perhexiline/nitroglycerin were examined using changes in augmentation index, measured via applanation tonometry. Neutrophil superoxide release was measured ex vivo utilizing lucigenin mediated chemiluminescence and effect of perhexiline on inhibition of platelet aggregation by sodium nitroprusside was also measured. Perhexiline alone did not affect augmentation index, neutrophil superoxide release, or ex vivo platelet sodium nitroprusside response. Nitroglycerin decreased augmentation index (P<0.01) and superoxide release (P<0.05). Magnitude of inhibition of superoxide release was significantly enhanced by perhexiline pre-treatment (P<0.05); however perhexiline had no effect on magnitude of vasomotor response to nitroglycerin. In conclusion, perhexiline exerts no effects on arterial stiffness and does not potentiate nitroglycerin induced dilatation. In patients with normal platelet function perhexiline does not affect platelet nitric oxide responsiveness. In vivo low dose nitroglycerin inhibits neutrophil superoxide release; this effect is potentiated by pre-treatment with perhexiline. These "anti-inflammatory" effects of nitroglycerin may contribute to utility in acute coronary syndromes and congestive heart failure.