Sympathetic activities are elevated in the central SNSs (sympathetic nervous systems) of hypertensive animals, but it is not known whether sympathetic innervation is also elevated in the heart. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress. The aim of the present study was to investigate sympathetic hyperinnervation in DOCA (deoxycorticosterone acetate)-salt hypertensive rats with established hypertension. At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 8 weeks: vehicle, NAC ( N -acetylcysteine) and triple therapy (hydralazine, hydrochlorothiazide and reserpine). DOCA-salt was associated with increased oxidant release. DOCA-salt produced concentric left ventricular hypertrophy and cardiomyocyte hypertrophy. Sympathetic hyperinnervation was observed in DOCA-salt rats, as assessed by myocardial noradrenaline levels, immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and Western blotting and real-time quantitative RT–PCR (reverse transcription–PCR) of NGF (nerve growth factor). Arrhythmic scores during programmed stimulation in DOCA-salt rats were significantly higher than those in the control rats. Triple therapy, despite being effective on BP (blood pressure), offered neither attenuated cardiomyocyte hypertrophy nor anti-arrhythmia. The effects of DOCA-salt treatment on NGF expression, sympathetic hyperinnervation and arrhythmias were attenuated by NAC. Furthermore, the effects of NAC on NGF were abolished by administering BSO ( L -buthionine sulfoximine), an inhibitor of glutamate–cysteine ligase. In conclusion, DOCA-salt treatment contributes to up-regulation of NGF proteins probably through a free radical-dependent pathway in a BP-independent manner. DOCA-salt rats treated with NAC attenuate sympathetic hyperinnervation and thus show a beneficial effect on arrhythmogenic response to programmed electrical stimulation.
PH (pulmonary hypertension) often complicates the disease course of patients with COPD (chronic obstructive pulmonary disease) and is an indication of a worse prognosis. In the present study, we assessed whether pravastatin administration was effective in improving PH and exercise capacity in COPD patients with PH, and whether the pulmonary protection was mediated by inhibiting ET-1 (endothelin-1) production. In a double-blind parallel design, 53 COPD patients with PH were randomly assigned to receive either placebo or pravastatin (40 mg/day) over a period of 6 months at a medical centre. Baseline characteristics were similar in both groups. The exercise time remained stable throughout the study in the placebo group. After 6 months, the exercise time significantly increased 52% from 660±352 to 1006±316 s ( P <0.0001) in pravastatin-treated patients. With pravastatin, echocardiographically derived systolic PAP (pulmonary artery pressure) decreased significantly from 47±8 to 40±6 mmHg. There was significant improvement in the Borg dyspnoea score after administering pravastatin. Despite unchanged plasma ET-1 levels throughout the study, urinary excretion of the peptide was decreased and significantly correlated with an improvement in exercise time in pravastatin-treated patients ( r =−0.47, P =0.01). In conclusion, pravastatin significantly improved exercise tolerance, and decreased PH and dyspnoea during exercise in COPD patients with PH, probably by inhibiting ET-1 synthesis.
Systemic markers of inflammation may be increased in patients after percutaneous coronary intervention. In the present study, we evaluated whether IP (ischaemic preconditioning) attenuated inflammation by activating K ATP (ATP-sensitive potassium) channels in patients undergoing coronary angioplasty. Patients ( n =36) undergoing angioplasty of a major left coronary artery were allocated randomly to one of four groups: a control group, a group receiving nicorandil (an agonist of K ATP channels), an IP group or an IP group pretreated with glibenclamide (an antagonist of K ATP channels). To measure the release of sCD40L, P-selectin and myeloperoxidase from the ischaemic region, blood samples were drawn simultaneously from the ascending aorta and the great cardiac vein before and 15 min after coronary angioplasty. At 15 min after angioplasty, a significant increase in sCD40L and P-selectin levels in the great cardiac vein in the control group was observed. IP- and nicorandil-treated patients did not show a significant change in sCD40L and P-selectin levels in response to angioplasty. However, the IP-induced attenuation of sCD40L and P-selectin release was abolished by administering glibenclamide. The change in myeloperoxidase levels mirrored those of sCD40L and P-selectin. The levels of inflammatory markers in the aorta remained stable throughout the study. Patients undergoing angioplasty had increased sCD40L and P-selectin levels in the ischaemic region. In conclusion, IP abolished angioplasty-induced myeloperoxidase release by preventing activated platelet-induced P-selectin release via a K ATP -channel-initiated pathway. Therefore, in addition to its primary effect on cardioprotection, IP may also provide beneficial anti-inflammatory effects on the interaction between platelets and neutrophils.