Flosequinan, a new vasodilator: systemic and coronary hemodynamics and neuroendocrine effects in congestive heart failure.

OBJECTIVES: The aim of this study was to evaluate the immediate and long-term systemic and coronary hemodynamic, metabolic and neurohormonal effects of flosequinan in patients with congestive heart failure. BACKGROUND: Preliminary studies have shown that this new long-acting oral systemic vasodilator may have beneficial effects in patients with heart failure. METHODS: Thirteen patients with congestive heart failure were studied. Systemic and coronary hemodynamic, metabolic and neurohormonal effects of flosequinan were assessed acutely with repeat systemic hemodynamic studies after 6 weeks of treatment. RESULTS: The administration of flosequinan acutely and after long-term treatment, resulted in a significant increase in cardiac index, stroke work index and stroke volume index with a reduction in systemic and pulmonary vascular resistances. The improvement in ventricular function was associated with an improvement in left ventricular efficiency without a change in myocardial oxygen consumption or coronary sinus blood flow. Myocardial oxygen extraction and net myocardial lactate extraction also did not change significantly with flosequinan therapy. Systemic catecholamine levels and myocardial catecholamine balance did not change. Plasma arterial and coronary sinus atrial natriuretic factor concentrations were elevated at baseline; the latter concentrations at the level of the great cardiac vein were significantly higher than those of arterial concentrations, indicating increased left ventricular release of atrial natriuretic factor in congestive heart failure. Both arterial and coronary sinus atrial natriuretic factor levels were significantly reduced with the administration of flosequinan at peak effect in association with an improvement in systemic hemodynamics. CONCLUSIONS: Flosequinan therapy in patients with congestive heart failure results in a sustained beneficial hemodynamic action and improved cardiac performance without an increase in metabolic demand or activation of the sympathetic nervous system.

Lovastatin plus probucol for prevention of restenosis after percutaneous transluminal coronary angioplasty.

Combination lovastatin and probucol reduced total cholesterol (27%) and low-density lipoprotein levels (30%), but did not prevent restenosis or clinical events during the first 6 months after percutaneous transluminal coronary angioplasty.

Endothelin-mediated cardiorenal hemodynamic and neuroendocrine effects are attenuated by nitroglycerin in vivo.

Endothelin-1 may function pathophysiologically as a counterregulatory vasoconstrictor peptide that is modified in its activity by the opposing action of endothelium-derived relaxing factor(s) (EDRF). The present study determined in part the integrated cardiorenal and endocrine actions of pathophysiologic plasma concentrations of endothelin in the anesthetized dog. In addition, nitroglycerin, which inhibits vascular smooth muscle contraction by increasing cGMP in a mechanism similar to EDRF, acts like an endogenous nitrovasodilator. Therefore, we tested the hypothesis that nitroglycerin would effectively antagonize the cardiac and renal actions of exogenous endothelin. The results confirm that endothelin-1-mediated vasoconstriction in vivo is heterogenous with a greater renal than coronary action. Further, nitroglycerin effectively blocked endothelin-1-mediated coronary flow reductions, but only partially antagonized reductions in renal blood flow. Endothelin-1-induced reduction in cardiac output also was not antagonized by nitroglycerin despite its effects to preserve coronary blood flow. Nitroglycerin did, however, antagonize endothelin-induced elevations in plasma epinephrine, norepinephrine, and aldosterone. These results would suggest that in pathophysiologic states where endothelin-1 is elevated, such as hypertension or congestive heart failure, there is a major compromising of renal function, and also the production of cardiac ischemia. Since exogenous nitroglycerin is relatively ineffective in antagonizing the renal vasoconstrictive effects of endothelin, it may be that the endogenous vasodilating systems, such as ERDF and prostacyclin, are inadequate in such pathologic states to counter the vasoconstrictor effects of endothelin.

Low-dose atrial natriuretic factor and furosemide in experimental acute congestive heart failure.

This study was designed to address three objectives in an experimental model of acute congestive heart failure (CHF) in the dog produced by rapid ventricular pacing. The first objective was to characterize cardiorenal and humoral responses before and during 2 h of acute CHF. The second objective was to determine the modulating action of iv furosemide upon these biologic responses to acute CHF, testing the hypothesis that furosemide-mediated natriuresis is associated with activation of the renin-angiotensin-aldosterone system (RAAS) compared with the control group. The third objective was to determine the modulating action of continuous low-dose atrial natriuretic factor (ANF) administration during acute CHF upon these biologic responses, testing the hypothesis that exogenous low-dose ANF would prevent activation of the RAAS and enhance the natriuretic action of furosemide. In the control group (Group 1; N = 6), plasma ANF increased after the onset of CHF; GFR and sodium excretion were maintained without activation of this RAAS despite arterial hypotension. In Group 2 (N = 6), furosemide in acute CHF increased sodium excretion but in association with a decrease in GFR and activation of the RAAS. Low-dose exogenous ANF and furosemide (Group 3; N = 6) in acute CHF were associated with a maintenance of GFR, no activation of the RAAS, and potentiation of furosemide-induced natriuresis. In summary, these studies demonstrate that furosemide potently increases sodium excretion in acute CHF, but with a decrease in GFR and activation of the RAAS. Low-dose ANF in acute CHF with furosemide maintains GFR, attenuates activation of the RAAS, and potentiates natriuresis.

Induction and prevention of radiocontrast-induced nephropathy in dogs with heart failure.

Radiocontrast-induced nephropathy (RCIN) is a clinically important cause of acute renal failure with no effective treatment. Recognizing the high incidence of RCIN in humans with severe congestive heart failure (CHF), this study was designed to test the hypotheses that dogs with experimental CHF are at increased risk for RCIN and that pharmacologic renal levels of atrial natriuretic factor (ANF) can prevent RCIN in this model. In chronic experiments, three groups of five conscious dogs received intravenous radiocontrast (7 ml/kg). One group consisted of normal controls, while the two other groups had experimental CHF induced by eight days of ventricular pacing at 250 beats per minute. One of the CHF groups received an infusion of ANF (30 ng/kg/min) into the suprarenal aorta for one hour before, during and after the infusion of radiocontrast to achieve pharmacologic renal plasma levels. Renal function remained stable in the normal controls in contrast to the consistent decreases in daily creatinine clearance during the five days following radiocontrast in experimental CHF. In addition, ANF prevented radiocontrast-induced reductions in creatinine clearance in dogs with experimental CHF. Additional studies performed in two groups of anesthetized dogs with experimental CHF demonstrated that, in this model of RCIN, the reduction in renal function appears biphasic, and the action of ANF may be to increase glomerular filtration rate prior to radiocontrast, thus allowing a maintenance of renal function during and after radiocontrast.

Effect of orthotopic cardiac transplantation on peripheral vascular function in congestive heart failure: influence of cyclosporine therapy.

The objective of this study was to examine peripheral vascular function before and after cardiac transplantation and to assess the effect of immunosuppressive therapy on peripheral vascular reactivity. Peripheral vascular function abnormalities present in congestive heart failure may be reversed with cardiac transplantation, but immunosuppressive therapy may alter these changes in the peripheral vasculature. Venous occlusion plethysmography was used to study peripheral vascular function in nine patients with severe congestive heart failure who underwent cardiac transplantation. Forearm blood flow and forearm vascular resistance were measured in patients with congestive heart failure in response to cold stimulation, maximal hyperemia, and hand grip exercise (1) before transplantation; (2) 24 to 36 hours posttransplantation before the commencement of cyclosporine; (3) 6 to 8 days posttransplantation in the presence of therapeutic cyclosporine levels; and (4) 6 weeks posttransplantation. Venous capacitance was also measured. After cardiac transplantation, mean arterial pressure increased and remained elevated. Forearm blood flow initially increased after transplantation but subsequently decreased with cyclosporine. Cold-induced reflex sympathetic activation decreased immediately after transplantation but was significantly enhanced with cyclosporine. The maximal vasodilatory response following ischemic cuff occlusion and with 5 minutes of isometric hand grip exercise increased significantly after transplantation and remained improved at 6 weeks. Thus after cardiac transplantation, peripheral vasodilator function improves and is not altered by cyclosporine. However, with cyclosporine therapy resting forearm vascular resistance increases and reflex sympathetic vasoconstriction is enhanced, suggesting that cyclosporine may potentiate adrenergic-mediated peripheral vasoconstriction and thus may contribute to posttransplant hypertension.

Endothelin in experimental congestive heart failure in the anesthetized dog.

Studies were performed in anesthetized dogs to determine plasma endothelin (ET) concentrations in the presence and absence of experimental congestive heart failure (CHF) produced by rapid ventricular pacing for 8 days. These studies were also designed to determine the effect of exogenous low-dose ET upon integrated cardiorenal and endocrine function in the presence and absence of CHF. In these studies, plasma ET was significantly elevated in CHF (3.25 +/- 0.39 pg/ml) compared with normal (1.03 +/- 0.21 pg/ml) or sham-operated (1.08 +/- 0.27 pg/ml) groups. Compared with the control group, which was characterized by a significant cardiorenal vasoconstrictor response to low-dose ET, a significant attenuation of the vasoconstrictor and antinatriuretic actions of ET was observed in the CHF group. Despite these differential responses, exogenous ET suppressed plasma renin activity (PRA) and activated aldosterone in both control and CHF groups. Thus these studies demonstrate for the first time that experimental CHF is characterized by elevated plasma ET in association with an attenuated cardiorenal response to exogenous ET. In contrast, low-dose ET inhibited PRC and activated aldosterone in the presence and absence of experimental CHF.

Cardiorenal actions of neutral endopeptidase inhibition in experimental congestive heart failure.

The present studies were designed to determine the action of neutral endopeptidase inhibition (NEP-I), an inhibitor of the degradation of atrial natriuretic factor (ANF), in congestive heart failure (CHF). Studies were conducted in two groups of anesthetized dogs with CHF induced by 8 days of rapid right ventricular pacing. Group 1 (n = 5) received a specific NEP-I (SQ 28,603) at two doses administered sequentially -30 mg/kg followed by a 60 mg/kg i.v. bolus. Group 2 (n = 5) received intravenous infusion of exogenous ANF (100 ng/kg/min) to achieve increases in plasma ANF concentration as observed in group 1. NEP-I resulted in a diuresis and natriuresis (p less than 0.05) with increases in the fractional excretion of sodium and fractional excretion of lithium, the latter a marker for proximal tubule sodium delivery. Such tubular actions occurred in the absence of increases in glomerular filtration rate or renal blood flow but were associated with significant increases in urinary ANF and urinary cyclic GMP. Plasma ANF increased after the 30 mg/kg NEP-I dose. In contrast, in group 2 with exogenous ANF and despite a marked increase in plasma ANF, no natriuresis was observed. Arterial pressure did not change in either group. These studies demonstrate for the first time in CHF that NEP-I may potentiate the natriuretic action of endogenous ANF by a mechanism that is independent of systemic or renal hemodynamics and does not parallel increases in plasma ANF. These studies support an important therapeutic role for NEP-I in CHF.

Neutral endopeptidase inhibition potentiates the renal actions of atrial natriuretic factor.

Atrial natriuretic factor (ANF) is degraded by neutral endopeptidase. We hypothesized that neutral endopeptidase inhibition (NEP-I) increases sodium excretion and that this effect would be potentiated in the presence of an isolated increase in intrarenal ANF. In seven anesthetized dogs, ANF was infused into one renal artery to produce pathophysiologic concentrations in the supplemented kidney while the control kidney received physiologic circulating concentrations of ANF. In the control kidney, NEP-I (SQ 28,603) produced significant increases in urine flow, absolute sodium excretion and fractional sodium excretion while glomerular filtration rate (GFR) remained constant. These renal actions of NEP-I were associated with marked increases in urinary excretion of ANF and cyclic GMP consistent with decreased renal degradation and increased biologic activity of ANF. All of these effects were significantly greater in the supplemented kidney. The present study suggests that NEP-I produces natriuresis which appears to be independent of changes in GFR. In addition, while NEP-I mimics the renal action of pathophysiologic levels of ANF, NEP-I also potentiates the natriuretic effects of pathophysiologic concentrations of ANF as observed in congestive heart failure or hypertension.