Drugs online research references
Circ Res. 2004 Jan 9;94(1):60-7. Epub 2003 Nov 13.
Angiotensin-converting enzyme is involved in outside-in signaling in endothelial cells.
Kohlstedt K, Brandes RP, Muller-Esterl W, Busse R, Fleming I.
Institut fur Kardiovaskulare Physiologie, Klinikum der J.W. Goethe-Universitat, Frankfurt am Main, Germany.
Not all of the cardiovascular effects of angiotensin-converting enzyme (ACE) inhibitors can be attributed to changes in angiotensin II and bradykinin levels. Because the cytoplasmic tail of ACE is phosphorylated, we determined whether ACE inhibitors affect the phosphorylation of ACE and whether ACE possesses the characteristics of a signal transduction molecule. The ACE inhibitors ramiprilat and perindoprilat, and the substrate bradykinin (but not angiotensin I), enhanced the activity of ACE-associated CK2 and the phosphorylation of ACE Ser1270 in cultured endothelial cells. Mitogen-activated protein kinase kinase 7 and c-Jun N-terminal kinase (JNK) coprecipitated with ACE, and stimulation of endothelial cells with ACE inhibitors increased the activity of ACE-associated JNK and elicited the accumulation of phosphorylated c-Jun in the nucleus. Ramiprilat was however unable to activate JNK or to stimulate the nuclear accumulation of c-Jun in endothelial cells expressing a S1270A ACE mutant or in ACE-deficient cells. Because the ACE inhibitor-induced increase in ACE expression has been linked to the formation of c-Jun homodimers, we investigated whether ACE signaling via JNK contributes to this response in vitro and in vivo. Prolonged ramiprilat treatment increased ACE expression in primary cultures of human endothelial cells and in vivo (mouse lung), a response that was prevented by pretreatment with the JNK inhibitor SP600125. Thus, ACE is involved in outside-in signaling in endothelial cells and "ACE signaling" may be an important cellular mechanism contributing to the beneficial effects of ACE inhibitors.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14615289&dopt=Abstract
Am J Hypertens. 2003 Nov;16(11 Pt 2):50S-54S.
Recommendations for the management of special populations: racial and ethnic populations.
Ferdinand KC.
Heartbeats Life Center, Xavier University College of Pharmacy, New Orleans, Louisiana 70117, USA.
One of the current challenges in the treatment of hypertension is the variation in the incidence and morbidity among ethnic populations. For example, in the recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), in which 35% of the patients were African American, the diuretic chlorthalidone was associated with greater reductions in blood pressure (BP) than the angiotensin-converting enzyme (ACE) inhibitor lisinopril and was also associated with a relative risk reduction in stroke compared with lisinopril. However, the increased stroke risk associated with lisinopril was experienced among African American but not non-African American patients. ALLHAT did not permit combination therapy with ACE inhibitors plus diuretics; therefore, the benefits of such regimens in this patient population could not be assessed. In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, in contrast to the overall study population, African American patients with left ventricular hypertrophy treated with atenolol were at lower risk of experiencing the primary composite end point (death, myocardial infarction, and stroke) than African Americans treated with losartan, with or without diuretics. On the other hand, in the African American Study of Kidney Disease and Hypertension, African American patients treated with the ACE inhibitor ramipril had a significantly lower incidence of the primary composite end point (glomerular filtration rate reduction, end-stage renal disease, or death) than African Americans treated with the calcium channel blocker amlodipine. Although the use of diuretics in African American patients may be a logical first-line choice for BP reduction, most patients will require combination therapy. African American patients with systolic BP > or =15 mm Hg above target level or a diastolic BP > or =10 mm Hg above target should be considered for first-line combination therapy. Although certain combinations have been shown to be effective in non-African American patients, the choice of drugs for combination therapy in African American patients may be different.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14625162&dopt=Abstract [PubMed - in process]
inha.ac.kr
AIMS: The therapeutic benefits of dual blockade of the renin-angiotensin system (RAS) have been inconsistent on renal function and proteinuria. To know the contribution of the heterogeneity of study subjects to such inconsistency, we evaluated the effects of dual blockade of RAS in 2 groups of selected renal diseases, IgA and diabetic nephropathy. To avoid confounding by the blood pressure-reducing effects, angiotensin II receptor antagonists (ATRAs) were added on the patients with long-term, optimally controlled blood pressure taking ACE inhibitors. Twenty-four-hour urinary protein excretion rate and urinary TGF-beta1 level were measured as surrogate markers of renal injury. METHODS: We conducted a prospective crossover trial with 14 IgA and 18 type-2-diabetic nephropathy patients showing moderate degree of proteinuria (> or = 1.0 g/day) and renal dysfunction (creatinine clearance 25 - 75/ml/min). Four to 8 mg once-daily dose of candesartan and placebo were alternatively added on ramipril dose of 5 - 7.5 mg/day for 16 weeks. RESULTS: All baseline data except for the age factor were statistically the same between the 2 disease groups. Twenty-four-hour mean arterial blood pressures were 91.2 +/- 1.6 and 92.3 +/- 1.8 mmHg in IgA and diabetic nephropathy patients respectively at baseline (p = NS). Mean arterial pressure did not change by the addition of candesartan or placebo in both groups. The addition of candesartan (combination) reduced 24-hour urinary protein excretion rate in IgA nephropathy patients with a mean change of -12.3 +/- 4.5%, which is significantly greater compared to a mean change of -0.1 +/- 3.3% after the addition of placebo (placebo) (mean difference 12.4 +/- 5.0, 95% CI 1.2 - 23.5; p < 0.05). Urinary TGF-beta1 level was reduced considerably by the combination therapy, with a -28.9 +/- 6.0% decrease, which was significantly different to that by the placebo, with +4.3 +/- 12.4% (33.3 +/- 13.5, 3.2 - 63.3; p < 0.05). In diabetic nephropathy patients, the addition of candesartan did not reduce 24-hour urinary protein excretion rate. Mean changes of 24-hour urinary protein excretion rate were -0.8 +/- 4.7% by the combination therapy and +0.5 +/- 6.1% by placebo (mean difference 1.3 +/- 4.7, 95% CI -6.8 - 13.5; p < NS). The level of urinary TGF-beta1 was reduced by the combination therapy, with -14.3 +/- 9.5% decrease, but it did not reach statistical significance compared to placebo of +0.7 +/- 15.5% (15.0 +/- 13.5, -14.4 - 44.5; p < NS). The changes in 24-hour urinary protein excretion rate and urinary TGF-beta1 level were neither correlated with each other, nor with the change in mean arterial pressure. Significant changes in the renal function were not detected during the study period. CONCLUSION: Definite beneficial effects of dual blockade of RAS on proteinuria and TGF-beta1 excretion were found in IgA nephropathy patients, which was independent of blood pressure-reducing effect. With our 16-week trial, such benefits were not observed in type 2 diabetic nephropathy. The reduction in urinary TGF-beta1 level suggests that the combination therapy may provide additional renoprotection through the antisclerosing effects. Based on our results, for a proper interpretation the therapeutic effects of the combination therapy should be evaluated separately according to the underlying renal disease.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14640237&dopt=Abstract [PubMed - in process]
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