Effects of milrinone and epinephrine or dopamine on biventricular function and hemodynamics in an animal model with right ventricular failure after pulmonary artery banding.

Right ventricular (RV) failure due to chronic pressure overload is a main determinant of outcome in congenital heart disease. Medical management is challenging because not only contractility but also the interventricular relationship is important for increasing cardiac output. This study evaluated the effect of milrinone alone and in combination with epinephrine or dopamine on hemodynamics, ventricular performance, and the interventricular relationship. RV failure was induced in 21 Danish landrace pigs by pulmonary artery banding. After 10 wk, animals were reexamined using biventricular pressure-volume conductance catheters. The maximum pressure in the RV increased by 113% (P < 0.0001) and end-diastolic volume by 43% (P < 0.002), while left ventricular (LV) pressure simultaneously decreased (P = 0.006). Concomitantly, mean arterial pressure (MAP; -16%, P = 0.01), cardiac index (CI; -23%, P < 0.0001), and mixed venous oxygen saturation (SvO2 ; -40%, P < 0.0001) decreased. Milrinone increased CI (11%, P = 0.008) and heart rate (HR; 21%, P < 0.0001). Stroke volume index (SVI) decreased (7%, P = 0.03), although RV contractility was improved. The addition of either epinephrine or dopamine further increased CI and HR in a dose-dependent manner but without any significant differences between the two interventions. A more pronounced increase in biventricular contractility was observed in the dopamine-treated animals. LV volume was reduced in both the dopamine and epinephrine groups with increasing doses In the failing pressure overloaded RV, milrinone improved CI and increased contractility. Albeit additional dose-dependent effects of both epinephrine and dopamine on CI and contractility, neither of the interventions improved SVI due to reduced filling of the LV.

Effects of milrinone and epinephrine or dopamine on biventricular function and hemodynamics in right heart failure after pulmonary regurgitation.

Right ventricular failure (RVF) secondary to pulmonary regurgitation (PR) impairs right ventricular (RV) function and interrupts the interventricular relationship. There are few recommendations for the medical management of severe RVF after prolonged PR. PR was induced in 16 Danish landrace pigs by plication of the pulmonary valve leaflets. Twenty-three pigs served as controls. At reexamination the effect of milrinone, epinephrine, and dopamine was evaluated using biventricular conductance and pulmonary catheters. Seventy-nine days after PR was induced, RV end-diastolic volume index (EDVI) had increased by 33% (P = 0.006) and there was a severe decrease in the load-independent measurement of contractility (PRSW) (-58%; P = 0.003). Lower cardiac index (CI) (-28%; P < 0.0001), mean arterial pressure (-15%; P = 0.01) and mixed venous oxygen saturation (SvO2) (36%; P < 0.0001) were observed compared with the control group. The interventricular septum deviated toward the left ventricle (LV). Milrinone improved RV-PRSW and CI and maintained systemic pressure while reducing central venous pressure (CVP). Epinephrine and dopamine further improved biventricular PRSW and CI equally in a dose-dependent manner. Systemic and pulmonary pressures were higher in the dopamine-treated animals compared with epinephrine-treated animals. None of the treatments improved stroke volume index (SVI) despite increases in contractility. Strong correlation was detected between SVI and LV-EDVI, but not SVI and biventricular contractility. In RVF due to PR, milrinone significantly improved CI, SvO2, and CVP and increased contractility in the RV. Epinephrine and dopamine had equal inotropic effect, but a greater vasopressor effect was observed for dopamine. SV was unchanged due to inability of both treatments to increase LV-EDVI.

Negative inotropic and hypotensive effects of the superoxide dismutase mimetic tempol in pigs.

Through interference with free radicals, the nitroxide tempol potentially increases bioavailability of nitric oxide (NO) and along with modulation of potassium channels reduces blood pressure (BP). We studied whether tempol in pigs lowers BP by mechanisms sensitive to inhibition of NO synthase or large conductance calcium-activated potassium channels (BKCa). The cardiovascular effects of intravenous tempol (25-50mg/kg) were examined in anesthetized pigs with myocardial function being evaluated by echocardiography. While saline-treated animals remained hemodynamically stable, tempol induced fast, dose-dependent and transient reductions in BP lasting 5-10 min with a simultaneous impairment of left ventricular contraction. Pretreatment with the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 4 mg/kg) or a blocker of BKCa (tetraethylammonium (TEA), 100mg/h) increased baseline BP but also enhanced BP reductions to tempol. Isolated myocardial trabeculae subjected to an identical protocol also demonstrated dose-related reductions in contractility to tempol. This effect was not affected by l-NAME, but attenuated by TEA. In isolated mesenteric resistance arteries contracted with noradrenaline, tempol caused small postjunctional l-NAME sensitive relaxations, while neurogenic contractions were inhibited by tempol by TEA-sensitive mechanisms and mechanisms insensitive to TEA and l-NAME. In conclusion intravenous tempol induces fast transient reductions in BP associated with simultaneous reductions in myocardial contraction. Tempol exerts direct negative inotropic effects which are partly sensitive to BKCa-blockade but independent of NOS inhibition. In addition tempol has direct vasodilatory effects despite NOS and potassium channel blockade. The negative inotropic and hypotensive effects raise concerns using tempol, or structurally similar drugs, for intravenous use.