Comparison of preventive effect of sildenafil and therapeutic effect of sildenafil treatment in rats with monocrotaline-induced pulmonary arterial hypertension.

This study aimed to investigate the potential effects of sildenafil on pulmonary hypertension (PH) in the monocrotaline (MCT)-induced PH rat. Twenty-four, 12-week-old, male Sprague-Dawley rats were injected with MCT or saline solution. After injection of MCT, rats received oral sildenafil immediately (early-phase treatment group: E group), 4 weeks after injection (late-phase treatment group: L group) or no treatment (MCT group) until 6 weeks after injection. Serial echocardiography and right ventricular systolic pressure (RVSP) measurements via a cardiac catheter were performed. RVSP was reduced in the E and L groups compared with the MCT group. Echocardiography indicated that sildenafil therapy prevents an increase in RVSP and preserves diastolic function, and this effect is not dependent on timing of initiation of therapy.

Preventive effect of sildenafil on right ventricular function in rats with monocrotaline-induced pulmonary arterial hypertension.

The present study aimed to evaluate the preventive effect of sildenafil treatment on pulmonary hypertension (PH) induced by monocrotaline (MCT) in rats. Fifty-four 12-week-old male Sprague-Dawley rats were injected with MCT or saline solution (MCT-injected rats: n=36; saline: n=18). Serial echocardiography and right ventricular systolic pressure (RVSP) measurements via a cardiac catheter were performed at 2, 4 and 6 weeks after the injection. After injection of MCT, rats received oral sildenafil (MCT/sildenafil group: n=18) or no treatment (MCT group: n=18) until undergoing echocardiography and cardiac catheterization. RVSP in the MCT/sildenafil group was lower than that in the MCT group at 4 (P<0.001) and 6 weeks (P<0.001). The septal curvature was improved in the MCT/sildenafil group compared with the MCT group. This finding showed that sildenafil prevented flattening of the interventricular septum because of right ventricular pressure overload. The ratio of peak trans-tricuspid early diastolic wave velocity to active filling with atrial systolic velocity showed that sildenafil improved diastolic function. Tricuspid annular plane systolic excursion and tricuspid annular systolic velocity in the MCT/sildenafil group did not show preserved myocardial contraction after administration of sildenafil. Administration of sildenafil leads to a reduction in RVSP and improvement in cardiac function in rats with PH induced by MCT. The vasodilatory action of sildenafil improves right ventricular diastolic function, but the intrinsic, positive, inotropic effect of sildenafil is minimal.

Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension.

This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed.

Comparative evaluation of calcium-sensitizing agents, pimobendan and SCH00013, on the myocardial function of canine pacing-induced model of heart failure.

Pimobendan and SCH00013 are calcium sensitizers that possess dual action of calcium sensitization and phosphodiesterase-III inhibition. This study was conducted to comparatively evaluate the effect of these medications on the myocardial function of the canine pacing-induced heart failure model using echocardiography. Heart failure was induced in 20 dogs, to which pimobendan and two different doses of SCH00013 were administered orally to 15 dogs for 3 weeks, and the remaining 5 dogs served as the control. Cardiac evaluations were performed at baseline, week 1, week 2, and week 3. Significant thinning and dilation of the left ventricles, with systolic dysfunction, indicated by reduction of fractional shortening (FS) and strain values, were observed with a low dose of SCH00013. Whereas, although systolic dysfunction was observed with reduction of FS and radial strain, significant dilation and thinning of the left ventricles and reduction of circumferential strain were not observed with pimobendan. Pimobendan had a potent positive inotropic effect, with little effect on synchronicity, while low-dose SCH00013 had a weaker positive inotropic effect but was able to sustain synchronicity. Although, it failed to show significant statistical differences, the results of this study allow speculations that administration of pimobendan and SCH00013 may have differing effect on the myocardial function in the canine pacinginduced heart failure model.

Pimobendan improves right ventricular myocardial contraction and attenuates pulmonary arterial hypertension in rats with monocrotaline-induced pulmonary arterial hypertension.

PURPOSE: The present study aimed to evaluate the therapeutic effect of pimobendan treatment for pulmonary hypertension (PH) in rats administered monocrotaline (MCT). METHODS: Fifty-four 12-week-old male Sprague-Dawley rats were injected with monocrotaline or saline solution. Serial echocardiography and right ventricular systolic pressure (RVSP) measurement via a cardiac catheter were performed. After injection of MCT, rats received oral pimobendan (MCT/pimobendan group) or no treatment (MCT group) until undergoing echocardiography and cardiac catheter insertion. RESULTS: Right ventricular systolic pressure in the MCT/pimobendan group was lower than that in the MCT group at 6 weeks. Right ventricle free wall (RVFW) myocardial systolic velocity (Sm) in the MCT group showed a reduction compared with the saline group at 2 weeks. RVFW Sm in the MCT/pimobendan group was preserved as compared with the saline group at 2 weeks. RVFW Tei index in the MCT/pimobendan group showed a reduction compared with the saline group and the MCT group at 2 weeks. Echocardiography in the MCT/pimobendan group showed improvement compared with MCT rats. CONCLUSIONS: Both a reduction in RVSP and improvement in myocardial contraction were demonstrated with administration of pimobendan in rats with PH induced by MCT. Echocardiography evaluation of systolic function seems to be useful for monitoring excess administration of pimobendan.

Extreme tetralogy of Fallot in a dog.

A four-month-old female Labrador retriever was brought to the Tokyo University of Agriculture and Technology Animal Medical Center for examination of its main symptoms of cough, tachypnea and exercise intolerance. Upon examination, the dog was found to have cyanosis and inadequate growth. Echocardiography revealed tetralogy of Fallot. Cardiac catheterization confirmed that the main pulmonary artery was completely occluded and that blood flowed from the aorta to the pulmonary artery. Accordingly, the animal was diagnosed with extreme tetralogy of Fallot.

Comparative effects of amlodipine and benazepril on left atrial pressure in dogs with experimentally-induced mitral valve regurgitation.

BACKGROUND: One of the purposes of treatment for dogs with mitral regurgitation (MR) is lowering left atrial pressure (LAP). There has been few study of the amlodipine in dogs with MR and amlodipine's effect on LAP has not been fully evaluated in a quantitative manner because of difficulties in directly measuring LAP. The objective of our study was to compare the short-term effects of amlodipine (0.2 mg/kg PO q12h) vs benazepril (0.5 mg/kg PO q12h), on LAP and echocardiographic parameters in five beagle dogs with experimentally-induced MR. LAP of eight dogs that has own control were measured using radiotelemetry system at baseline and again on days 1, 2, 3, 4, 5, 6, 7 of the drug administration. RESULTS: Mean LAP decreased significantly after amlodipine (11.20 ± 4.19 mmHg vs 14.61 ± 3.81 mmHg at baseline, p < .01) but not after benazepril treatment (13.19 ± 3.47 mmHg, p > .05). LAP was lower after 7 days of amlodipine treatment than after 7 days of benazepril treatment. Significant reduction was seen for the first time 4 days after the administration amlodipine. The rate of the maximal area of the regurgitant jet signals to the left atrium area (ARJ/LAA) of the amlodipine treatment was significantly lower (p < .05) after 7 days compared to baseline. Other echocardiographic parameters did not change significantly. CONCLUSIONS: LAP was significantly decreased after amlodipine treatment in dogs with surgically-induced MR but not after benazepril treatment. Although this study did not focus on adverse effects, amlodipine may be an effective drug for helping the patients with acute onset of severe MR, such as rupture of chordae tendinae or end stage patients were the LAP is likely to be elevated. Additional studies in clinical patients with degenerative mitral valve disease and acute chordal rupture are warranted because the blood-pressure lowering effects of amlodipine can decrease renal perfusion and this can further activate the RAAS.