RESUMEN
The adenosine subtype 1 (A1) receptor, which may influence cardiac function and modulate renal function, may have particular relevance in congestive heart failure (CHF). However, the effects of A1 receptor inhibition in the setting of CHF are poorly defined. Systemic hemodynamics and indices of renal function were measured in pigs with pacing-induced CHF at 240 bpm for 3 weeks (n = 10) before and after A1 receptor blockade with 100 microg of BG9719 (1,3-dipropyl-8-[2-(5,6-epoxynorbornyl)]xanthene) or in CHF pigs after infusion of vehicle only (n = 10). Heart rate, mean aortic pressure, and left ventricular peak pressure increased following A1 blockade in the CHF group, consistent with an adenosine inhibitory effect. However, cardiac output and global measures of vascular resistance did not significantly change following A1 blockade. Urine output increased twofold and sodium clearance increased threefold following A1 blockade (p < 0.05). Creatinine clearance increased following A1 blockade (127 +/- 17 vs. 62 +/- 7 ml/min, p < 0.05). Selective A1 receptor blockade improved glomerular filtration rate and induced a natriuresis and diuresis in a model of CHF without adverse effects on cardiac function. These unique results suggest that renal A1 receptor activation may contribute to the reduced renal function associated with CHF.
Asunto(s)
Riñón/fisiología , Receptores Purinérgicos P1/fisiología , Función Ventricular Izquierda/fisiología , Animales , Creatinina/metabolismo , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/orina , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Riñón/efectos de los fármacos , Riñón/metabolismo , Pruebas de Función Renal , Masculino , Antagonistas de Receptores Purinérgicos P1 , Sodio/metabolismo , Porcinos , Micción/fisiología , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
BACKGROUND: Although reduced pulmonary clearance of endothelin-1 (ET-1) has been suggested to contribute to increased circulating levels in congestive heart failure (CHF), the regulation of the pulmonary ET system with CHF remains to be defined. Accordingly, the aim of the present study is to investigate the expression and activity of the ET system with the development of CHF. METHODS AND RESULTS: Pulmonary tissue samples were collected from pigs with pacing CHF (240 bpm, 3 wks, n = 10) and controls (n = 10). The pulmonary messenger RNA (mRNA) and protein levels of endothelin converting enzyme-1 (ECE-1) subisoforms, ET-1, and ET receptor profiles were determined. The gene expression of ET-1 precursor, ECE-1a, and ET(A) was upregulated 4-, 3-, and 2-fold, respectively, with CHF. Pulmonary tissue ET-1 was increased to 13 +/- 2 fmol/mg protein from control values of 5 +/- 1 fmol/mg protein (P <.05), and ECE-1 activity was augmented from 3,264 +/- 665 fmol/mg protein in control animals to 14,073 +/- 654 fmol/mg protein per hour in CHF animals (P <.05). The ET(B) receptor density decreased, whereas ET(A) receptors were increased in CHF, indicating a shift in the ET(A) to ET(B) ratio. CONCLUSIONS: Both the increased synthesis and the decreased clearance of ET-1 via ET(B) receptors may contribute to the increased systemic and pulmonary ET-1 levels in CHF.
Asunto(s)
Ácido Aspártico Endopeptidasas/metabolismo , Endotelina-1/biosíntesis , Insuficiencia Cardíaca/metabolismo , Pulmón/metabolismo , Receptores de Endotelina/metabolismo , Animales , Enzimas Convertidoras de Endotelina , Metaloendopeptidasas , Modelos Animales , Reacción en Cadena de la Polimerasa/métodos , ARN Mensajero/análisis , Receptores de Endotelina/genética , PorcinosRESUMEN
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
A putative biological substrate of schizophrenia involves cellular pathology within the hippocampus. While hippocampal dysfunction is associated with impaired learning and memory, schizophrenics have been observed to acquire simple conditioned reflexes at rates superior to controls. The present study evaluates the acquisition of shuttlebox avoidance responses in animals with partial damage to hippocampus. Intraventricular microinjections of kainic acid (0.5 or 1.5 nM) were utilized to partially destroy the pyramidal cell population. Animals in the high dosage group acquired the response at rates superior to controls; the low dosage group performed at an intermediate level. Consequently, partial loss of pyramidal neurons may be sufficient to significantly alter simple acquisition. Results are discussed in reference to the "embryological hypothesis" of schizophrenia and mechanisms for induction of schizophrenic behavior in intractable seizure disorders are considered.