RESUMEN
BACKGROUND: We examined whether and to what degree long-term angiotensin-converting enzyme (ACE) inhibition, angiotensin type 1 (AT(1))-receptor blockade, or combined inhibition in developing congestive heart failure (CHF) alter myocardial interstitial bradykinin (BF) levels. METHODS AND RESULTS: Pigs (27-30 kg) underwent rapid pacing-induced CHF (240 bpm, 3 weeks; n = 10); pacing CHF with concomitant ACE inhibition (benezaprilat, 3.75 mg/day; n = 10); pacing CHF and concomitant AT(1)-receptor blockade (valsartan, 60 mg/day; n = 10); pacing CHF and combined inhibition (benezaprilat/valsartan, 1.87/60 mg/day, respectively; n = 10); or served as controls (no pacing, no treatment; n = 10). Steady-state myocardial interstitial BK levels were quantitated by microdialysis. Cardiac output decreased to 1.95 +/- 0.18 L/min in pacing CHF compared with control (3.78 +/- 0.38; P < .05). Cardiac output increased from untreated CHF values with concomitant ACE inhibition (3.91 +/- 0.27 L/min), AT(1)-receptor blockade (3.30 +/- 0.41 L/min), or combined ACE/AT(1)-receptor inhibition (4.13 +/- 0.32 L/min; all P < .05 v CHF). With pacing CHF, myocardial interstitial BK levels were reduced by approximately 50% from control values and were normalized in the ACE inhibition and combined inhibition groups. CONCLUSIONS: Long-term ACE inhibition increases myocardial interstitial BK levels with CHF; addition of AT(1)-receptor blockade does not seem to abrogate these effects.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Estimulación Cardíaca Artificial/efectos adversos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Receptores de Angiotensina/uso terapéutico , Animales , Bradiquinina/metabolismo , Modelos Animales de Enfermedad , Hemodinámica/efectos de los fármacos , Masculino , Modelos Cardiovasculares , Miocardio/metabolismo , Receptor de Angiotensina Tipo 1 , Porcinos , Tiempo , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiologíaRESUMEN
BACKGROUND: The present study examined the effects of acute angiotensin-converting enzyme inhibition (ACEI), AT(1) receptor blockade (AT(1) block), or combined treatment on in vitro and in vivo bradykinin (BK) levels. METHODS: BK levels were measured in isolated porcine myocyte preparations (n = 13) in the presence of exogenous BK (10(-8) M); with an ACEI (benezaprilat; 0.1 mM) and BK; an AT(1) block (valsartan; 10(-5) M) and BK; and combined treatment and BK. In a second study, myocardial microdialysis was used to measure porcine interstitial BK levels in both normal (n = 14) and pacing-induced congestive heart failure (CHF) (240 beats/min, 3 weeks, n = 16) under the following conditions: baseline, following ACEI (benezaprilat, 0.0625 mg/kg) or AT(1) block (valsartan, 0.1 mg/kg), and a combined treatment (benezaprilat, 0.0625 mg/kg; valsartan, 0.1 mg/kg). RESULTS: In the left ventricular myocyte study, BK levels increased over 93% with all treatments compared to untreated values (P < 0.05). In the in vivo study, basal interstitial BK values were lower in the CHF group than in controls (2.64 +/- 0.57 vs 5.91 +/- 1.4 nM, respectively, P < 0.05). Following acute infusion of the ACEI, BK levels in the CHF state increased from baseline (57% +/- 22; P < 0.05). Following combined ACEI/AT(1) block, BK levels increased from baseline in both control (42% +/- 11) and CHF groups (60% +/- 22; P < 0.05 for both). CONCLUSION: These findings suggest that ACEI, or combined ACEI/AT(1) block increased BK at the level of the myocyte and potentiated BK levels in the CHF myocardial interstitium.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Bradiquinina/análisis , Insuficiencia Cardíaca/tratamiento farmacológico , Miocardio/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Benzazepinas/farmacología , Benzazepinas/uso terapéutico , Masculino , Miocardio/citología , Receptor de Angiotensina Tipo 1 , Receptores de Angiotensina/metabolismo , Porcinos , Tetrazoles/farmacología , Tetrazoles/uso terapéutico , Valina/análogos & derivados , Valina/farmacología , Valina/uso terapéutico , ValsartánRESUMEN
The effects of angiotensin (AT)(1) receptor antagonists on functional and morphological alterations associated with atherosclerosis are not well known. The current study was performed to examine the long-term effects of valsartan (3 or 10 mg/kg per day for 10 weeks) on endothelial function and structural changes in aorta from rabbits fed with either a control diet or a cholesterol-enriched diet. Rabbits fed with the cholesterol-rich diet showed higher (P<0.05) plasma levels of cholesterol than did controls. Treatment with valsartan (3 or 10 mg/kg per day) did not alter plasma cholesterol levels or systolic arterial pressure in any group. Contractions induced by angiotensin II were comparable in both control and hypercholesterolemic rabbits and were markedly reduced by treatment with valsartan. Relaxations induced by acetylcholine were lower in hypercholesterolemic rabbits than in controls. Treatment with valsartan (3 or 10 mg/kg per day) enhanced (P<0.05) this response in hypercholesterolemic rabbits but not in controls. Lumen and media cross-sectional areas were comparable in control and hypercholesterolemic rabbits. Vessel area was higher (P<0.05) in hypercholesterolemic rabbits than in controls. Intimal lesion was 29.5+/-6% in cholesterol-fed rabbits and nonexistent in control rabbits. Treatments with 3 and 10 mg/kg per day valsartan reduced (P<0.05) intimal lesion to 2.4+/-0.7% and 2.7+/-0.9%, respectively, and increased lumen area in hypercholesterolemic rabbits. No changes in either vessel or media cross-sectional areas were observed in these animals. In summary, angiotensin II, through AT(1) receptors, appears to play a key role in the development of the vascular functional and structural changes associated with hypercholesterolemia. AT(1) receptor antagonists, besides their antihypertensive effects, could be an important therapeutic tool to reduce the development of atherosclerosis.