RESUMO
OBJECTIVE: Our objectives are 2-fold: (1) to serially measure the release of endothelin and graft-conduit endothelin sensitivity during and after coronary artery bypass grafting and (2) to define potential relationships of changes in endothelin levels to perioperative parameters. METHODS: Endothelin plasma content was measured in patients (n = 105) undergoing bypass grafting from select vascular compartments before operations and at specific intervals up to 24 hours postoperatively. Endothelin sensitivity was determined in isolated internal thoracic artery segments. RESULTS: Systemic arterial and pulmonary arterial endothelin levels were increased by approximately 50% immediately after bypass grafting and increased by another 85% during the first 24 hours postoperatively. Endothelin levels were highest in patients with prolonged ventilatory requirements and extended stays in the intensive care unit (10.2 +/- 0.8 vs 13.2 +/- 1.1 fmol/mL, P =.02, and 9.8 +/- 0.7 vs 13.9 +/- 1.2 fmol/mL, P =.01, respectively. Endothelin sensitivity of the internal thoracic artery was increased in patients requiring prolonged vasodilator support with nitroglycerin. CONCLUSIONS: Systemic and pulmonary arterial endothelin levels remained increased for at least 24 hours postoperatively. Prolonged pharmacologic management and increased intensive care unit stay were associated with increased systemic endothelin release and heightened graft-conduit sensitivity to endothelin.
Assuntos
Ponte Cardiopulmonar , Circulação Coronária , Endotelina-1/sangue , Análise de Variância , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Nitroglicerina/uso terapêutico , Respiração Artificial , Veia Safena/metabolismo , Artérias Torácicas/metabolismo , Vasodilatadores/uso terapêuticoRESUMO
BACKGROUND: A number of cellular and molecular events can be induced after cardiac procedures requiring cardiopulmonary bypass (CPB). The matrix metalloproteinases (MMPs) are a recently discovered family of enzymes that degrade the extracellular matrix, but expression during and after CPB is unknown. METHODS: Systemic plasma MMP levels were measured in patients (n = 28, 63 +/- 1 years) undergoing elective coronary revascularization requiring CPB at baseline, termination of CPB, and 30 minutes, 6 and 24 hours after CPB. Representative classes of MMP species known to degrade matrix and basement membrane components were selected for study. Specifically, the interstitial collagenases MMP-8 and MMP-13, and the gelatinases MMP-2 and MMP-9 were determined by internally validated enzyme-linked immunosorbent assay. RESULTS: The MMP-8 levels increased by fourfold at separation from CPB, and returned to within normal values within 30 minutes after CPB. The proenzyme forms of MMP-13 and MMP-9 increased by more than twofold at cross-clamp release and returned within normal limits within 6 hours after CPB. The proform of MMP-2 increased from baseline values at 6 and 24 hours postoperatively; likely indicative of de novo synthesis. CONCLUSIONS: A specific portfolio of MMPs are released and synthesized during and after CPB. Because MMPs can degrade extracellular proteins essential for maintaining normal cellular architecture and function, enhanced MMP release and activation may contribute to alterations in tissue homeostasis in the early postoperative period.
Assuntos
Ponte Cardiopulmonar , Ponte de Artéria Coronária , Metaloproteinases da Matriz/sangue , Idoso , Indução Enzimática/fisiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Estimulação Cardíaca Artificial/efeitos adversos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Receptores de Angiotensina/uso terapêutico , Animais , Bradicinina/metabolismo , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Masculino , Modelos Cardiovasculares , Miocárdio/metabolismo , Receptor Tipo 1 de Angiotensina , Suínos , Tempo , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologiaRESUMO
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.
Assuntos
Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bradicinina/análise , Insuficiência Cardíaca/tratamento farmacológico , Miocárdio/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Masculino , Miocárdio/citologia , Receptor Tipo 1 de Angiotensina , Receptores de Angiotensina/metabolismo , Suínos , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Valina/análogos & derivados , Valina/farmacologia , Valina/uso terapêutico , ValsartanaRESUMO
OBJECTIVE: To determine endothelin levels in arterial, pulmonary, and myocardial vascular compartments in patients undergoing coronary artery bypass graft surgery and to examine the influence of endothelin on postoperative recovery. DESIGN: Prospective, clinical study. SETTING: University hospital. PARTICIPANTS: Fifty patients undergoing elective coronary artery bypass graft surgery. INTERVENTIONS: Endothelin plasma content (fmol/mL) was measured in 50 patients undergoing coronary revascularization from various vascular compartments before surgery and at specific intervals up to 24 hours postoperatively. MEASUREMENTS AND MAIN RESULTS: Myocardial endothelin gradient (coronary sinus - aorta) was calculated before cardiopulmonary bypass (CPB), at release of the aortic cross-clamp, immediately after CPB, and 0.5 hour after CPB. The requirement for inotropic therapy and duration of patient stay in the intensive care unit were determined. Systemic and pulmonary endothelin levels were increased by >80% immediately after CPB when compared with preoperative values and increased again by approximately 60% during the first 24 hours postoperatively (p < 0.05). The myocardial endothelin gradient was reversed after CPB, indicating myocardial production of endothelin (pre-CPB, -0.72+/-0.39 fmol/mL v 0.5 hour post-CPB, 0.60+/-0.49 fmol/mL; p < 0.05). Longer intensive care unit times (>28 hours) were associated with higher systemic endothelin levels when compared with shorter times (<18 hours) (16.30+/-1.33 fmol/mL v 9.81+/-1.67 fmol/mL; p < 0.05). Patients with higher endothelin levels 6 hours postoperatively had greater inotropic requirements during the intensive care unit period. CONCLUSION: Endothelin levels after CPB remained persistently increased for at least 24 hours after surgery and were associated with increased myocardial production of endothelin. These results suggest that the increased endothelin observed in the early postoperative period may contribute to a complex recovery from coronary artery bypass graft surgery.
Assuntos
Ponte Cardiopulmonar , Circulação Coronária , Endotelinas/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Endotelinas/sangue , Humanos , Unidades de Terapia Intensiva , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Radial artery (RA) is being used for coronary artery bypass grafting (CABG) with greater frequency. However, RA is prone to post-CABG vasospasm, which may be neurohormonally mediated. Use of the calcium channel antagonist diltiazem has been advocated as a strategy to reduce post-CABG RA vasospasm. However, whether and to what degree different calcium channel antagonists influence neurohormonally induced RA vasoconstriction remains unknown. METHODS: RA segments were collected from patients undergoing elective CABG (n = 13), and isometric tension was examined in the presence of endothelin (10 nM) or norepinephrine (1 microM). In matched RA, endothelin- or norepinephrine-induced contractions were measured in the presence of diltiazem (277 nM), amlodipine (73 nM), or nifedipine (145 nM). These concentrations of calcium channel antagonists were based upon clinical plasma profiles. RESULTS: Endothelin and norepinephrine caused a significant increase in RA-developed tension (0.54+/-0.1 and 0.68+/-0.1 g/mg, respectively; p<0.05). Amlodipine or nifedipine significantly reduced RA vasoconstriction in the presence of endothelin (30+/-6% and 41+/-9%, respectively; p<0.05) or norepinephrine (27+/-8% and 53+/-9%, respectively; p<0.05), whereas diltiazem did not significantly reduce RA vasoconstriction. CONCLUSIONS: These results demonstrate that neurohormonal factors released post-CABG can cause RA vasoconstriction, and that calcium channel antagonists are not equally effective in abrogating that response. Both amlodipine and nifedipine, which have a higher degree of vascular selectivity, appear to be the most effective in reducing RA vasoconstriction.