Effects of simvastatin/ezetimibe on microparticles, endothelial progenitor cells and platelet aggregation in subjects with coronary heart disease under antiplatelet therapy

It is not known whether the addition of ezetimibe to statins adds cardiovascular protection beyond the expected changes in lipid levels. Subjects with coronary heart disease were treated with four consecutive 1-week courses of therapy (T) and evaluations. The courses were: T1, 100 mg aspirin alone; T2, 100 mg aspirin and 40 mg simvastatin/10 mg ezetimibe; T3, 40 mg simvastatin/10 mg ezetimibe, and 75 mg clopidogrel (300 mg initial loading dose); T4, 75 mg clopidogrel alone. Platelet aggregation was examined in whole blood. Endothelial microparticles (CD51), platelet microparticles (CD42/CD31), and endothelial progenitor cells (CD34/CD133; CDKDR/CD133, or CD34/KDR) were quantified by flow cytometry. Endothelial function was examined by flow-mediated dilation. Comparisons between therapies revealed differences in lipids (T2 and T3<T1 and T4 for total cholesterol, LDL-C, and triglycerides; P<0.002 for all), as well as for endothelial function (T2>T1 and T4, P=0.001). Decreased platelet aggregation was observed after aspirin (arachidonic acid, T1<T3 and T4, P=0.034) and clopidogrel (adenosine, T3 and T4<T1 and T2, P<0.0001) therapy. Simvastatin/ezetimibe diphosphate did not change platelet aggregation, the amount of circulating endothelial and platelet microparticles, or endothelial progenitor cells. Cardiovascular protection following therapy with simvastatin/ezetimibe seems restricted to lipid changes and improvement of endothelial function not affecting the release of microparticles, mobilization of endothelial progenitor cells or decreased platelet aggregation.

Dissociation between the circulating renin-angiotensin system and angiotensin II receptors in central losartan-induced hypertension

Losartan, an AT1 angiotensin II (ANG II) receptor non-peptide antagonist, induces an increase in mean arterial pressure (MAP) when injected intracerebroventricularly (icv) into rats. The present study investigated possible effector mechanisms of the increase in MAP induced by icv losartan in unanesthetized rats. Male Holtzman rats (280-300 g, N = 6/group) with a cannula implanted into the anterior ventral third ventricle received an icv injection of losartan (90 æg/2 æl) that induced a typical peak pressor response within 5 min. In one group of animals, this response to icv losartan was completely reduced from 18 ± 1 to 4 ± 2 mmHg by intravenous (iv) injection of losartan (2.5-10 mg/kg), and in another group, it was partially reduced from 18 ± 3 to 11 ± 2 mmHg by iv prazosin (0.1-1.0 mg/kg), an alpha1-adrenergic antagonist (P<0.05). Captopril (10 mg/kg), a converting enzyme inhibitor, injected iv in a third group inhibited the pressor response to icv losartan from 24 ± 3 to 7 ± 2 mmHg (P<0.05). Propranolol (10 mg/kg), a ß-adrenoceptor antagonist, injected iv in a fourth group did not alter the pressor response to icv losartan. Plasma renin activity and serum angiotensin-converting enzyme activity were not altered by icv losartan in other animals. The results suggest that the pressor effect of icv losartan depends on angiotensinergic and alpha1-adrenoceptor activation, but not on increased circulating ANG II

Different effects on rat arterial pressure and heart rate when losartan is injected into the third or fourth ventricle

Carciovascular responses to central losartan (LOS), a non-peptide angiotensin II (ANG II) receptor antagonist, were investigated by comparing the effects of LOS injection into the 3rd and 4th cerebral ventricles (3rdV, 4thV) on mean arterial pressure (MAP) and heart rate (HR). Adult male Holtzman rats were used (N = 6 animals per group). Average basal MAP and HR were 114 + or - 3 mmHg and 343 + or - 9 bpm (N = 23), respectively. LOS (50, 100 or 200 nmol/2 µl) injected into the 3rdV induced pressor (peak of 25 + or - 3 mmHg) and tachycardic (peak of 60 + or - 25 bpm) responses. LOS injected into the 4thV had no effect on MAP, but it induced bradycardia (peak of -35 + or - 15 bpm). KCl (200 nmol/2 µl) injected into the 3rdV or into the 4thV had no effect on either MAP or HR compared to 0.9 percent saline injection. The results indicate that LOS injected into the third ventricle acts on forebrain structures to induce its pressor and tachycardic effects and that bradycardia, likely dependent on hindbrain structures, is obtained when LOS is injected into the fourth ventricle

Effect of dehydration on the increase of arterial pressure and renal electrolyte excretion produced by central cholinergic stimulation in rats

Natriuresis, kaliuresis, diuresis, arterial pressure and heart rate were studied in rats following dehydration and cholinergic stimulation of the medial septal area (MSA). The increase in renal NA+ and K+ excretion produced by the injection of carbachol (2nmol) into the MSA in normal hydrated rats was abolished in 48-h water-deprived rats. Urinary volume was also reduced. Cholinergic stimulation of the MSA produced a smaller mincrease in arterial pressure in 48-h-deprived rats compared to normal hydrated animals. No change was observed in heart rate. These reults show that hydration state is essential for the central cholinergic control of electrolyte excretion and increase in arterial pressure