Gadolinium increases the vascular reactivity of rat aortic rings

Gadolinium (Gd) blocks intra- and extracellular ATP hydrolysis. We determined whether Gd affects vascular reactivity to contractile responses to phenylephrine (PHE) by blocking aortic ectonucleoside triphosphate diphosphohydrolase (E-NTPDase). Wistar rats of both sexes (260-300 g, 23 females, 7 males) were used. Experiments were performed before and after incubation of aortic rings with 3 µM Gd. Concentration-response curves to PHE (0.1 nM to 0.1 mM) were obtained in the presence and absence of endothelium, after incubation with 100 µM L-NAME, 10 µM losartan, or 10 µM enalaprilat. Gd significantly increased the maximum response (control: 72.3 ± 3.5; Gd: 101.3 ± 6.4 percent) and sensitivity (control: 6.6 ± 0.1; Gd: 10.5 ± 2.8 percent) to PHE. To investigate the blockade of E-NTDase activity by Gd, we added 1 mM ATP to the bath. ATP reduced smooth muscle tension and Gd increased its relaxing effect (control: -33.5 ± 4.1; Gd: -47.4 ± 4.1 percent). Endothelial damage abolished the effect of Gd on the contractile responses to PHE (control: 132.6 ± 8.6; Gd: 122.4 ± 7.1 percent). L-NAME + Gd in the presence of endothelium reduced PHE contractile responses (control/L-NAME: 151.1 ± 28.8; L-NAME + Gd: 67.9 ± 19 percent AUC). ATP hydrolysis was reduced after Gd administration, which led to ATP accumulation in the nutrient solution and reduced ADP concentration, while adenosine levels remained the same. Incubation with Gd plus losartan and enalaprilat eliminated the pressor effects of Gd. Gd increased vascular reactivity to PHE regardless of the reduction of E-NTPDase activity and adenosine production. Moreover, the increased reactivity to PHE promoted by Gd was endothelium-dependent, reducing NO bioavailability and involving an increased stimulation of angiotensin-converting enzyme and angiotensin II AT1 receptors.

Systemic and regional hemodynamic effects of enalaprilat infusion in experimental normotensive sepsis

Angiotensin-converting enzyme inhibitors have been shown to improve splanchnic perfusion in distinct shock states. We hypothesized that enalaprilat potentiates the benefits of early fluid resuscitation in severe experimental sepsis, particularly in the splanchnic region. Anesthetized and mechanically ventilated mongrel dogs received an intravenous infusion of live Escherichia coli over a period of 30 min. Thereafter, two interventions were performed: fluid infusion (normal saline, 32 mL/kg over 30 min) and enalaprilat infusion (0.02 mg kg-1 min-1 for 60 min) in randomized groups. The following groups were studied: controls (fluid infusion, N = 4), E1 (enalaprilat infusion followed by fluid infusion, N = 5) and E2 (fluid infusion followed by enalaprilat infusion, N = 5). All animals were observed for a 120 min after bacterial infusion. Mean arterial pressure, cardiac output (CO), portal vein blood flow (PVBF), systemic and regional oxygen-derived variables, and lactate levels were measured. Rapid and progressive reductions in CO and PVBF were induced by the infusion of live bacteria, while minor changes were observed in mean arterial pressure. Systemic and regional territories showed a significant increase in oxygen extraction and lactate levels. Widening venous-arterial and portal-arterial pCO2 gradients were also detected. Fluid replacement promoted transient benefits in CO and PVBF. Enalaprilat after fluid resuscitation did not affect systemic or regional hemodynamic variables. We conclude that in this model of normotensive sepsis inhibition of angiotensin-converting enzyme did not interfere with the course of systemic or regional hemodynamic and oxygen-derived variables.

Interference of enalaprilat on glomerular permeability to macromolecules (IGG) in acute unilateral ureteral obstruction in rats

INTRODUCTION: Unilateral ureteral obstruction breaks out events that cause the transitory increase of glomerular permeability to macromolecules, both in the obstructed kidney and in the contralateral kidney, suggesting the presence of some factor, with a systemic action, liberated as a response to the obstruction. We know that the rennin-angiotensin system is activated by acute ureteral obstruction. We have developed an experiment to assess the role of angiotensin II on the glomerular permeability to IgG due to acute ureteral obstruction, using enalaprilat, an angiotensin enzyme conversion inhibitor, to block the effects of the activation of the rennin-angiotensin system. MATERIALS AND METHODS: We have used 45 adult Wistar female rats, distributed into 3 main groups: a control group with 5 animals and 2 experiment groups each one with 10 animals submitted to unilateral ureteral obstruction and nephrectomy at 60 and 120 minutes. Each experiment group had its simulation correspondent (sham). We have studied both kidneys through the direct immunofluorescence method. RESULTS: We have found positive permeation in animals without enalaprilat in both kidneys and negative permeation in those in which the drug was used. CONCLUSION: We have concluded that enalaprilat interferes in this alteration of permeability, suggesting that angiotensin II is involved in the loss of selectivity of the glomerular membrane.

Efecto del enalaprilato sobre la disfuncion postisquemica sistolica y diastolica (miocardio atontado) en el corazon aislado de conejo / Effect of enalaprilat on postischemic systolic and diastolic dysfunction (stunned myocardium) on the isolated rabbit heart

El objetivo principal del trabajo fue determinar en el corazón aislado de conejo el efecto del Enalaprilato administrado: a) antes de la isquemia y b) en el momento de la reperfusión, sobre la función sistólica y diastólica del "miocardio atontado", y también sobre la fase de "hiperfunción" que ocurre precozmente en la reperfusión. Un segundo objetivo fue determinar si el enalaprilato modifica la liberación de lactato, creatinfosfoquinasa (CPK) y lacticodeshidrogenasa (LDH), que ocurre en el "miocardio atontado". Para esto utilizamos corazones de conejo perfundidos con la técnica de Langendorff, sometidos a isquemia global de 15 min y reperfusión durante 30 min y en los que la colocación de un globo de látex en el ventrículo izquierdo permitió medir la presión ventricular, y calcular la presión desarrollada, la maxima velocidad de ascenso y descenso de la presión (+ DP/dtmaxy -dP/dtmax, respectivamente), el cociente entre estas dos variables de velocidad (+ P/-P), y la constante de tiempo dirante la caída de la presión venricular (tau, tau). El Enalaprilato administrado tanto antes de la isquemia, como al comienzo de la reperfusión, atenúo la disfunción postisquémica sistólica, y la fase precoz de "hiperfunción". El efecto sobre la función diastólica fue diferente según se considere el componente activo o el pasivo: mientras que no modificó las lteraciones la relajación, atenuó significantemente el aumento de la rigidez miocárdica. El Enalaprilato también disminuyó la cantidad de lactato en el efluente durante la reperfusión, pero no modificó la liberación de CPK y LDH.