Acute effect of pimobendan and furosemide on the circulating renin-angiotensin-aldosterone system in healthy dogs.

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is activated in states of decreased cardiac output and by certain cardiovascular therapeutic agents, such as loop diuretics and vasodilators. HYPOTHESIS: Short-term treatment with the inodilator, pimobendan, will not activate the circulating RAAS because its vasodilatory action will be offset by its positive inotropic property, thereby ameliorating RAAS stimulation at the juxtaglomerular apparatus. Furthermore, pimobendan will suppress RAAS activation produced by furosemide. ANIMALS: Nine healthy laboratory dogs were used in this study. METHODS: Experimental, cross-over study. Dogs were administered pimobendan (0.5 mg/kg q12h) for 4 days followed by furosemide (2 mg/kg q12h) and then, after a wash-out period, a combination of the drugs. Aldosterone : creatinine (A : Cr) was measured at the end of each treatment cycle. RESULTS: There was no significant increase in the average urinary A : Cr with the administration of pimobendan (control urinary A : Cr = 0.46, standard deviation (SD) 0.33; pimobendan A : Cr = 0.48, SD 0.28). There was a significant increase in the average urinary A : Cr after administration of furosemide (urinary A : Cr = 1.3, SD 0.70) and with the combination of furosemide and pimobendan (urinary A : Cr = 2.9, SD 1.6). CONCLUSIONS AND CLINICAL RELEVANCE: Short-term administration of high-dose pimobendan, does not activate the RAAS in healthy dogs. Pimobendan did not prevent RAAS activation associated with furosemide therapy. These results in healthy dogs suggest that furosemide therapy, with or without pimobendan, should be accompanied by RAAS suppressive therapy.

Assessment of drug-induced QT interval prolongation in conscious rabbits.

INTRODUCTION: Most preclinical trials are designed to identify potential torsadogenicity test only for surrogates of torsade de pointes, most commonly prolongation of the heart rate corrected QT interval (QTc). This study was conducted to determine which correction method best accounts for the effects of changes in the RR interval on the QT interval of conscious rabbits. This study was also conducted to validate the use of conscious, sling-trained rabbits to assess the QTc interval, and to evaluate the reliability and accuracy of this preparation in predicting drug-induced QTc prolongation in humans. METHODS: ECGs were recorded via bipolar transthoracic ECG leads in 7 conscious rabbits previously trained to rest quietly in slings. The heart rate was slowed with 2.0 mg/kg zatebradine to assess the effects of heart rate on the QT interval. The same ECG and sling preparation was used to evaluate the effects in of three drugs known to be torsadogenic in humans (cisapride, dofetilide and haloperidol), two drugs known to be non-torsadogenic in humans (propranolol and enalaprilat) and a control article (vehicle). All of the test articles were administered intravenously to 4 rabbits, and both RR and QT intervals were measured and the corrected QT values were calculated by an investigator blinded to the test article, utilizing our own algorithm (QTc=QT/(RR)(0.72)) which permitted the least dependency of QTc on RR interval. RESULTS: The following regression equations were obtained relating QT to RR: QT=2.4RR(0.72), r(2)=0.79, with RR intervals varying between 210 and 350 ms. QTc lengthened significantly in all conscious rabbits given intravenous cisapride, dofetilide and haloperidol (p<0.05), and QTc did not change with DMSO (vehicle control), propranolol or enalaprilat. DISCUSSION: Results indicate that a bipolar transthoracic ECG recorded in conscious, sling-trained rabbits may provide an easy and economical methodology useful in predicting QTc lengthening of novel pharmacological entities.

Fanconi's syndrome in a dog with primary hypoparathyroidism.

An 11-year-old castrated male mixed breed dog was referred for evaluation of muscle twitching, polyuria, polydipsia, anorexia, and periocular alopecia. Primary hypoparathyroidism was diagnosed by documenting decreased serum concentrations of parathyroid hormone and ionized calcium. Neurological, gastrointestinal, and dermatological signs resolved after calcium repletion. Initially, 1,25-dihydroxycholecalciferol PO was required to correct the hypocalcemia. Dihydrotachysterol, in combination with oral calcium supplementation, was used for long-term maintenance of normal serum calcium concentration. Aminoaciduria, glucosuria, and hyperchloremic metabolic acidosis were consistent with a diagnosis of Fanconi's syndrome. This diagnosis was further supported by the presence of hypokalemia and increased urinary fractional excretion of sodium, potassium, calcium, phosphorus, and magnesium. Renal tubular dysfunction resolved after oral supplementation with calcium and vitamin D3. Fanconi's syndrome in this dog may have been caused by decreased serum concentration of 1,25-dihydroxycholecalciferol, which was secondary to decreased parathyroid hormone production.

L-carnitine supplementation in the therapy of canine dilated cardiomyopathy.

In evaluating any novel therapeutic agent or intervention, the clinician must question the need for as well as the efficacy and safety of the proposed therapy. In an attempt to address these critical questions with regard to the role of L-carnitine supplementation in the therapy of dilated cardiomyopathy, this article reviews the currently available scientific evidence and clinical experience regarding carnitine metabolism and supplementation in the dog.

Myocardial L-carnitine deficiency in a family of dogs with dilated cardiomyopathy.

Dilated cardiomyopathy in a family of dogs was found to be associated with decreased myocardial L-carnitine concentrations, when compared with those in control dogs. In 2 affected dogs, treatment with high doses of L-carnitine was associated with increased myocardial L-carnitine concentration and greatly improved health and myocardial function. Withdrawal of L-carnitine supplementation from these dogs resulted in development of myocardial dysfunction and clinical signs of dilated cardiomyopathy.

Efficacy of digoxin for treatment of cats with dilated cardiomyopathy.

The role of digoxin in treatment of cats with dilated cardiomyopathy and other forms of myocardial failure is unclear. We evaluated the chronotropic and inotropic effects of digoxin by comparing baseline, noninvasive indices of cardiac performance with those obtained after 9 +/- 1.3 (mean +/- SEM) days of digoxin treatment in 6 cats with heart failure attributable to dilated cardiomyopathy. Two-dimensionally directed, M-mode echocardiography and electrocardiography were used to determine left ventricular shortening fraction, preejection period (PEP), ejection time (LVET), PEP to LVET ratio, velocity of circumferential fiber shortening, electromechanical systole, heart rate, and PR interval. Treatment consisted of administration of furosemide (mean dosage, 2.4 mg/kg of body weight/day), digoxin in tablet form (approximately 0.01 mg/kg, q 48 h), aspirin (80 mg, q 48 h), and a commercial low-salt diet. In addition, 2 cats were administered short-term, low-dose fluids IV, and 2 were given taurine supplementation at rates of 500 and 1,000 mg/day. Other off-loading or inotropic agents were not administered. Therapeutic or toxic serum digoxin concentration was achieved in all cats. Significant (P less than 0.05) improvement was detected in mean values for shortening fraction, PEP, PEP to LVET ratio, and velocity of circumferential fiber shortening. Mean electromechanical systole and LVET did not change significantly. Improvement, as assessed by indices of cardiac function, was documented in 4 of the 6 cats treated with digoxin, including the 2 cats given taurine supplementation. In the cats given taurine, positive inotropic effect was observed prior to the time when taurine-induced improvement in ventricular function is detectable.(ABSTRACT TRUNCATED AT 250 WORDS)