Rieko Yoshiyuki

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.

Abstract: 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.

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.

Echocardiographic Evaluation of Myocardial Changes Observed After Closure of Patent Ductus Arteriosus in Dogs

Background Closure of PDA can be associated with echocardiographic changes including deterioration of LV systolic function. Although PDA is commonly encountered in dogs, few comprehensive reports of echocardiographic changes in dogs with PDA closure are available. Objectives To evaluate the short‐term echocardiographic changes observed after PDA closure in dogs using strain analysis. Animals Seventeen client‐owned dogs with left‐to‐right PDA. Methods Echocardiographic evaluations, including standard echocardiography and two‐dimensional tissue tracking (2DTT), were performed before and within 3 days of PDA closure. Results Preclosure examination showed LV and left atrial dilatation indicating volume overload as a result of PDA. Closure of PDA resulted in significant reduction of LVIDd (<.0001) and LA/Ao (0.01) without change in LVIDs, suggestive of decreased preload. Postclosure LV systolic dysfunction was observed with significant decreased in FS (<.0001) and strain values (P = .0039 for radial strains, P = .0005 for circumferential strains). Additionally, significant LV dyssynchrony (P = .0162) was observed after closure of PDA. Conclusions and Clinical Importance Closure of PDA resulted in decreased preload as a result of alleviation of LV volume overload, which in turn caused transient deterioration of LV systolic function. Additionally, this study demonstrated that strain analysis is load dependent. Therefore, care should be taken when interpreting strain measurements as an indicator of LV systolic function.

Comparative effects of amlodipine and benazepril on Left Atrial Pressure in Dogs with experimentally-induced Mitral Valve Regurgitation

BackgroundOne 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.ResultsMean 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.ConclusionsLAP 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.

Transarterial Coil Embolization of an Abdominal Aortocaval Fistula in a Dog

A 3-year-old, 5 kg, male Toy Poodle with a mast cell tumor on the left pelvic limb was referred to Tokyo University of Agriculture and Technology Animal Hospital for an oncologic evaluation. On physical examination, a continuous bruit was auscultated over the left inguinal region with a palpable thrill. Cardiac auscultation identified a grade II/VI systolic and a grade I/VI diastolic murmur over the mitral and the aortic valves, respectively. No signs of peripheral cyanosis or congestion were noted. On thoracic radiographs, moderate, generalized enlargement of the cardiac silhouette was observed without evidence of pulmonary edema or pleural effusion. Color Doppler echocardiography identified mild pulmonic, mitral, and aortic valve regurgitation. Measurements of the left ventricle (LV) indicated an increased internal diameter with normal LV wall and septal thicknesses, normal fractional shortening and mild left atrial (LA) enlargement, with normal sinus rhythm. Normal mean arterial blood pressure was obtained on the thoracic limb using the oscillometric method. Laboratory test results (complete blood count, serum biochemistry profile, electrolytes, coagulation profile) were within the normal reference ranges. Ultrasonography of the caudal abdomen showed a caudal vena cava (CVC) with a diameter of 24.6 mm (dog <10 kg, reference values 0.65 0.12 mm) at the site of shunt. Color Doppler with simultaneous electrocardiogram showed turbulent flow in the CVC during the arterial phase. Continuous-wave Doppler interrogation showed continuous low-velocity flow with a pulsatile pattern and spectral broadening of Doppler waveform and peak flow velocity of 3 m/s across the aortocaval shunt (Fig 1). Contrast-enhanced computed tomography (CT) was performed under general anesthesia for anatomic evaluation of the arteriovenous shunt. The contrast timing bolus method was used to synchronize image acquisition. Iodinated contrast medium (2 mL/kg of iodine) was injected into the cephalic vein at flow rate of 1 mL/s. After a 20-second delay, the entire abdomen was scanned with a dual-slice spiral CT scanner. Reconstruction was carried out using contiguous images with a slice thickness of 1.0 mm (total of 149 slices). Post imaging processing showed an aortocaval connection by an anomalous vessel (shunt) located caudal to the renal arteries and a saccular dilatation of the CVC elongating in the caudal direction. The major dilatation was observed caudal to the fistula, 2.6-fold greater than the dilatation observed cranial to the fistula (Fig 2A,B). Endovascular repair was performed under general anesthesia that was maintained with isoflurane. The dog was positioned in right lateral recumbency for a cervical left lateral approach and a small incision in the skin was made to access the left common carotid artery. A 4-Fr multipurpose catheter was inserted through a puncture in the artery and advanced over a guide wire. The catheter tip was positioned in the abdominal aorta, cranial to the fistula to perform aortography. A 5-mL bolus injection of iodinated contrast medium showed the contrast medium being diverted from the aorta into the CVC (Fig 3A). Blood flow in the renal arteries was preserved as observed by contrast filling of the arteries and renal excretion. The tip of the catheter then was repositioned into the AVF over a guide wire to deliver the embolization coil, because contrast injection showed that adequate coil deployment could be achieved through the aorta. An embolization coil of 6.5 mm diameter, 5 loops, and 10 cm in length was deployed along the fistula lumen under fluoroscopic guidance. Aortography a few minutes after coil deployment identified residual flow through the fistula (Fig 3B). Residual flow was also observed on Doppler ultrasonography, but the shunt flow velocity had decreased to 1.5 m/s. Recovery from the anesthesia was uneventful. Postoperative mean arterial blood pressure ranged from From the Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan (Nakata, Tanaka, Hamabe, Yoshiyuki, Kim, Suzuki, Aytemiz, Huai-Che, Shimizu, Fukushima). Corresponding author: Ryou Tanaka, DVM, PhD, Department of Veterinary Surgery, Tokyo University of Agriculture and Technology, Saiwai-cho 3-5-8, Fuchu, Tokyo 183-8509, Japan; e-mail: ryo@vet.ne.jp. Submitted May 17, 2013; Revised November 19, 2013; Accepted December 16, 2013. Copyright

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.

Effects of a Sustained-Release Form of Isosorbide Dinitrate on Left Atrial Pressure in Dogs with Experimentally Induced Mitral Valve Regurgitation

BACKGROUND The effects of isosorbide dinitrate (ISDN) have not been sufficiently investigated in conscious dogs with mitral valve regurgitation (MR). OBJECTIVE The objective was to investigate the effects of a sustained-release form of ISDN (sr-ISDN) on hemodynamics and the autonomic nervous system in dogs with MR. ANIMALS Six healthy Beagles weighing 11.2 ± 2.2 kg (2 years of age; 2 males and 4 females) were used. METHODS Experimental, crossover, and interventional study. Dogs with experimentally induced MR were administered placebo, 2, 5, and 10 mg/kg sr-ISDN PO on separate days with a 7-day washout period between randomized dosings. Left atrial pressure (LAP) had been recorded continuously from 30 minutes before administration of sr-ISDN to 12 hours after administration. RESULTS LAP was significantly decreased after administration in the 5 and 10 mg/kg groups. Significant decrease was observed at 3 and 4 hours after administration in the 5 mg/kg group. In the 10 mg/kg group, significant decrease was observed at 2, 3, 4, 5, 6, 7, 10, and 11 hours after administration. The lowest value was observed at 4 hours after administration in the 5 and 10 mg/kg groups (20.9 ± 4.2 to 15.9 ± 3.9 mmHg, P < .01, and 21.3 ± 4.0 to 13.6 ± 4.2 mmHg, P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE Sustained-release form of ISDN showed significant decrease of LAP in the 5 mg/kg and 10 mg/kg groups, and duration of effect was dose related.

Comparative effect of carperitide and furosemide on left atrial pressure in dogs with experimentally induced mitral valve regurgitation.

BACKGROUND The effects of carperitide on left atrial pressure (LAP) in dogs with mitral valve disease (mitral regurgitation, MR) have not been documented. OBJECTIVE The objective was to compare the short-term effects of carperitide versus furosemide on LAP and neurohumoral factors in MR dogs. ANIMALS Six healthy Beagle dogs weighing 9.8-12.6 kg (2 males and 4 females; aged 3 years) were used. METHODS Experimental, randomized, cross-over, and interventional study. Carperitide 0.1 μg/kg/min or furosemide 0.17 mg/kg/h (1 mg/kg/6 h) was administered to dogs with surgically induced MR for 6 hours, and after a 14 day wash-out period, the other drug was administered. LAP, plasma renin activity, plasma aldosterone, and echocardiographic variables were measured. RESULTS Left atrial pressure was decreased similarly after the administration of carperitide 0.1 μg/kg/min and furosemide 0.17 mg/kg/h (1 mg/kg/6 h) compared with baseline in dogs with MR (Baseline 14.75 ± 3.74 mmHg, carperitide 10.24 ± 4.97 mmHg, P < .01, furosemide 10.77 ± 5.06 mmHg, P < .05). Plasma renin activity and plasma aldosterone were significantly lower after the administration of carperitide than after the administration of furosemide (P < .05, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE Carperitide significantly decreased LAP in dogs with acute MR caused by experimental chordal rupture. Carperitide can have additional benefits from the viewpoint of minimal activation of neurohumoral factors in the treatment of dogs with MR. Additional studies in dogs with spontaneous disease are warranted.