Effects of dobutamine on coronary circulation and cardiac metabolism of the dog

Effects of (+/-)-4-[2-(3-p-hydroxyphenyl-1-methyl-amino)ethyl]pyrocatechol (dobutamine) on coronary circulation and cardiac metabolism were investigated using the heart in vivo and the isolated perfused heart of dogs. In the heart in vivo dobutamine 1--30 microgram/kg i.v. and 1--100 microgram i.c. produced dose-dependent increases in coronary perfusion pressure, coronary blood flow, heart rate and left intraventricular pressure. In the perfused heart dobutamine 10 microgram i.c. increased coronary flow, heart rate, cardiac contractility and myocardial oxygen consumption. Delta redox potentials decreased but did not show negative values. Propranolol 0.1 mg/kg i.v. and 0.1 mg i.c. inhibited these effects of dobutamine. Dobutamine shows basically the same actions as isoproterenol, but does not reduce the coronary perfusion pressure by the relatively high dose applied. The results suggest that dobutamine may have a selective adrenergic beta 1 receptor stimulating action on the heart and have a merit in maintaining the coronary perfusion pressure.     

Effects of secretin infusion on myocardial performance and metabolism in the dog

The effects of pharmacological doses of secretin were studied in closed-chest, pentobarbital anesthetized dogs. Infusion of secretin 16 clinical units (CU)/kg-h caused a rise in cardiac output (p less than 0.01), peak first derivative of the left ventricular pressure (p less than 0.01), and heart rate (p less than 0.01) and a fall in systemic arteriolar resistance (p less than 0.01) and left ventricular end-diastolic pressure (p less than 0.01). Stroke volume did not change significantly. Myocardial blood flow and oxygen consumption were unchanged. Secretin caused reductions in arterial lactate (p less than 0.01) and glucose (p less than 0.05) concentrations, and arterial concentrations of free fatty acids and insulin were unaltered. There was no change in myocardial uptake of lactate, glucose, or FFA. Secretin 64 CU/kg-h infused in two dogs caused further changes of the hemodynamic variables. Thus, secretin enhances left ventricular function in intact anesthetized dog by combined vasodilating, inotropic, and chronotropic effects, without changing myocardial oxygen or substrate uptake.     

Effects of chlorpromazine on the metabolism of catecholamines in dog brain

1. The effect of chlorpromazine (CPZ) on the metabolism of dopamine and 5-hydroxytryptamine in dog brain was investigated by following the concentrations of the acid metabolites of these amines, homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid, in the ventricular cerebrospinal fluid (C.S.F.) of dogs over a period of 5 hr after intravenous administration of CPZ (2.5, 5, 10 and 15 mg/kg), using the technique of serial sampling of lateral ventricular C.S.F. "Low" doses (2.5-10 mg/kg) produced a rise in the concentration of homovanillic acid and smaller increases in the concentrations of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid. "High" doses (10-15 mg/kg) had a lesser effect on the concentration of homovanillic acid and had no effect on, or decreased, the concentrations of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid. The concentration of 3,4-dihydroxyphenylacetic acid was maximal in the ventricular C.S.F. 2 hr after CPZ 5 mg/kg and was unaltered from the control level 2 hr after 15 mg/kg.2. The effects on the metabolism of brain amines of CPZ (5 mg/kg), doses which the serial sampling of C.S.F. experiments had indicated as producing maximal and minimal effects on dopamine metabolism in brain tissue, were studied by estimating the concentrations of adrenaline, noradrenaline, dopamine, metanephrine, methoxydopamine, homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid in the hypothalamus, midbrain, thalamus, hindbrain, cortex, globus pallidus and caudate nucleus of control dogs and of dogs treated with CPZ intravenously 2 hr before killing. The concentrations of homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid were estimated in samples of ventricular C.S.F. withdrawn from these dogs 2 hr after the injection of CPZ (i.e., immediately before death).3. The following changes in concentrations were observed. Dopamine: CPZ 5 mg/kg produced no change in the concentration in the caudate nucleus, globus pallidus and midbrain and increased the concentration in the thalamus; CPZ 15 mg/kg appeared to cause a reduction in the concentration of this amine in the caudate nucleus and globus pallidus. Homovanillic acid and 3,4-dihydroxyphenylacetic acid: CPZ 5 mg/kg increased the concentrations of both acids in the caudate nucleus and had no effect on the concentrations of the acids in the globus pallidus, hypothalamus and thalamus; CPZ 15 mg/kg produced no change in the concentrations of the acids in any area of the brain. Methoxydopamine: CPZ 5 mg/kg and 15 mg/kg reduced the concentration in the caudate nucleus. Noradrenaline: The concentrations in the hypothalamus, midbrain, thalamus and hindbrain were slightly increased by CPZ 5 mg/kg and 15 mg/kg. Only in the thalamus was a statistically significant increase in noradrenaline observed.4. It was concluded that the actions of chlorpromazine on catecholamine synthesis and metabolism in the brain of the dog are dose dependent. A dose of CPZ 5 mg/kg was postulated to have the following actions: (i) to increase dopamine synthesis; (ii) to activate mitochondrial monoamine oxidase. A dose of CPZ 15 mg/kg was postulated to act as follows: (i) to decrease dopamine synthesis; or (ii) to release dopamine from its storage sites.5. The ratios of the concentrations of homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid in the caudate nucleus to the concentrations of these acids in the ventricular C.S.F. were the same in the control dogs as in the dogs treated with CPZ (5 mg/kg and 15 mg/kg). It was concluded that the levels of the acid metabolites of dopamine in lateral ventricular C.S.F. reflect the levels of these acids in the caudate nucleus.     

Effects of 5-([2-(diethylamino)-ethyl]amino)-3-phenyl-1,2,4-oxadiazole dihydrochloride (DEPO) on cardiac functions and myocardial metabolism of the dog

Effects of 5-([2-(diethylamino)-ethyl]amino)-3-phenyl-1,2,4-oxadiazole (DEPO) on cardiac functions and myocardial metabolism were examined using the heart in vivo and the isolated perfused heart of dogs. In the heart in vivo DEPO i.v. produced dose-dependent decreases in coronary perfusion pressure (PP), heart rate (HR), left ventricular pressure (LVP), dP/dt max of LVP and coronary vascular resistance (VR). DEPO i.c. dose-dependently increased left circumflex coronary flow (LCCF) and decreased PP, LVP and dP/dt max of LVP, but did not change HR. In the isolated perfused heart, DEPO induced a marked increase in coronary blood flow (CBF) and depressed HR and myocardial contractile force. Myocardial oxygen consumption and myocardial redox potential were not significantly changed. DEPO could not modify the effects of isoproterenol, adenosine and reactive hyperaemia on the heart. The results suggest that DEPO may have a coronary vasodilating action and some direct inhibitory actions on the heart.     

Effects of beta 2-adrenoceptor stimulation on cardiac metabolism in the conscious dog.

1 The effects of the beta 2-adrenoceptor stimulant, salbutamol, on cardiac metabolism have been studied in conscious mongrel dogs. The potential effects of anaesthesia on the study of cardiac metabolism have been avoided by prior implantation of arterial (A) and coronary sinus (CS) catheters for blood sampling and a central venous catheter for infusion. Extraction of substrates for myocardial energy metabolism (CA-CS) was assessed 3 to 24 days post-operatively. A 100 micrograms bolus of salbutamol was given followed by an infusion of 3 micrograms/min for 1 h. 2 Although heart rate increased significantly from 106 to 165 beats/min, fractional extraction of oxygen tended to fall from 84% to 77%. Thus an increase in coronary blood flow rather than in oxygen extraction must have maintained an oxygen supply commensurate with the salbutamol-induced tachycardia. 3 Neither CA-CS glucose nor fractional glucose extraction altered significantly during salbutamol infusion despite increases in arterial concentration (CA) of glucose and arterial insulin immunoreactivity and a decrease in CA of free fatty acids (FFA). This suggests that an insulin-antagonistic action accompanies the infusion of salbutamol. 4 The fractional extraction of lactate increased during salbutamol infusion. In part, this may have been a reflection of a decreased myocardial extraction of FFA with salbutamol in this model.     

Comparative metabolism of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and dog

1. There is a significant species difference in the toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D). The oral no overall adverse effect level (NOAEL) for chronic toxicity of 2,4-D in rat is 5?mg kg ? 1 day ? 1 and in dog is 1?mg kg ? 1 day ? 1. The maximum tolerated dose (MTD) in rat is 150 and 75 kg ? 1 day ? 1 for male and females, respectively. The MTD in dog is 7.5?mg kg ? 1 day ? 1 for males and females. 2. In an attempt to explain the increased sensitivity to 2,4-D in dog, male and female rats and dogs were orally dosed with either 5 or 50?mg kg ? 1 14 C-2,4-D. The rates and routes of excretion were investigated along with plasma toxicokinetics and biotransformation of the compound. 3. Elimination of the radioactive dose of 2,4-D from rat plasma was significantly faster than in dog. The approximate t ½ were 1.3-3.4?h for rat and 99-134?h for dog following a 5 or 50?mg kg ? 1 dose, respectively. This led to large differences in the calculated AUC (0- ∝) 21-57 μ eq.?h?g ? 1 for rat and 4889-5298 µg eq.?h?g ? 1 for dog at 5?mg kg ? 1, and 122-2358 µg eq.?h?g ? 1 for rat and 34 110-44 296 µg eq.?h?g ? 1 for dog at 50?mg kg ? 1). 4. In rat, the major route of excretion was in the urine. Excretion was essentially complete after 24?h for the low dose and after 48?h for the high dose. For dog, elimination was incomplete over the sampling period with only about 50% of the dose recovered. Urine was the principal route of excretion at the low dose, but about equal amounts were excreted in urine and faeces at the high dose over 120?h. 5. In rat, 2,4-D was unmetabolized and excreted in urine as the parent compound. In dog, the dose was excreted mainly following metabolism. 2,4-D in dog was conjugated forming the taurine, serine, glycine, glutamic acid, cysteine, sulphate and glucuronide conjugates, plus an unidentified metabolite, which were excreted in urine. Plasma, however, only contained unmetabolized 2,4-D. 6. The results show that the body burden of 2,4-D in dog is significantly higher than in rat for an equivalent dose, which is consistent with the increased sensitivity of dog to 2,4-D toxicity.     

The metabolism and excretion of 7-mono-0-(beta-hydroxyethyl) rutoside in the dog

Following i.v. administration of mono-HR to the beagle, plasma levels of both mono-HR and its glucuronide conjugates fell rapidly, neither being detectable 8 h after injection. Following oral administration of 14C-mono-HR, mono-HR-glucuronide was detected in plasma, confirming the absorption of mono-HR, and low levels of 14C were detectable up to 72 h after dosage. Following either oral or i.v. administration of mono-HR, the major route of excretion was fecal elimination of the compound as its aglycone form. Urinary excretion was slight being less than 15% following i.v. dosage and 4% following oral administration. Metabolism of mono-HR was confined to glucuronidation and hydrolytic cleavage of the glycoside side chain. Ring fission products of mono-HR were not detected.     

Comparative metabolism of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and dog

1. There is a significant species difference in the toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D). The oral no overall adverse effect level (NOAEL) for chronic toxicity of 2,4-D in rat is 5 mg kg(-1) day(-1) and in dog is 1 mg kg(-1) day(-1). The maximum tolerated dose (MTD) in rat is 150 and 75 kg(-1) day(-1) for male and females, respectively. The MTD in dog is 7.5 mg kg(-1) day(-1) for males and females. 2. In an attempt to explain the increased sensitivity to 2,4-D in dog, male and female rats and dogs were orally dosed with either 5 or 50 mg kg(-1) 14C-2,4-D. The rates and routes of excretion were investigated along with plasma toxicokinetics and biotransformation of the compound. 3. Elimination of the radioactive dose of 2,4-D from rat plasma was significantly faster than in dog. The approximate t(1/2) were 1.3-3.4 h for rat and 99-134 h for dog following a 5 or 50 mg kg(-1) dose, respectively. This led to large differences in the calculated AUC(0-infinity) 21-57 microg eq. h g(-1) for rat and 4889-5298 microg eq. h g(-1) for dog at 5 mg kg(-1), and 122-2358 microg eq. h g(-1) for rat and 34,110-44,296 microg eq. h g(-1) for dog at 50 mg kg(-1)). 4. In rat, the major route of excretion was in the urine. Excretion was essentially complete after 24 h for the low dose and after 48 h for the high dose. For dog, elimination was incomplete over the sampling period with only about 50% of the dose recovered. Urine was the principal route of excretion at the low dose, but about equal amounts were excreted in urine and faeces at the high dose over 120 h. 5. In rat, 2,4-D was unmetabolized and excreted in urine as the parent compound. In dog, the dose was excreted mainly following metabolism. 2,4-D in dog was conjugated forming the taurine, serine, glycine, glutamic acid, cysteine, sulphate and glucuronide conjugates, plus an unidentified metabolite, which were excreted in urine. Plasma, however, only contained unmetabolized 2,4-D. 6. The results show that the body burden of 2,4-D in dog is significantly higher than in rat for an equivalent dose, which is consistent with the increased sensitivity of dog to 2,4-D toxicity.     

Effects of female sex hormones on histamine metabolism in guinea-pigs.

Determination of the urinary excretion of histamine and methylhistamine was performed in intact and gonadectomized male and female guinea-pigs. The excretion of methylhistamine varied more than that of histamine both in the same animal and between different animals. The urinary excretion of histamine and methylhistamine reflects fairly well the total histamine turnover in the animal, provided that aminoguanidine is administered to inhibit diamine oxidase activity. There was no sex difference in the excretion of histamine and methylhistamine and gonadectomy did not influence the urinary output. Female sex steroids had little ifany effect upon histamine turnover in the guinea-pig which is in contrast to the situation in rats and mice.     

Effects of tendamistate (alpha-amylase inactivator) on starch metabolism

1 Tendamistate (Hoe 467) reduces gastrointestinal absorption of starch by inactivating α-amylase.

2 Two trials were performed to investigate the influence of timing and mode of administration of tendamistate, relative to starch intake, on the pharmacodynamics of the drug.

(i) In the first trial 400 mg enteric coated capsules, 400 mg non-enteric coated capsules and placebo were compared in 12 volunteers.

Medication (400 mg tendamistate capsules or placebo) was administered after 10 h fasting, 15 min before a starch meal. Post-prandial plasma glucose concentration-time curves were plotted. No significant differences could be shown between tendamistate capsules and placebo in respect of areas under the curve (AUC), maximal concentration (C_max) and time to maximal concentration (t_max). No side effects were reported.

(ii) In a second trial tendamistate powder, mixed with a starch meal, was compared with placebo in eight volunteers. Blood specimens for measurement of glucose, insulin and C-peptide were taken up to 8 h after this starch meal. AUC as well as C_max in respect of glucose values were significantly lower after Hoe 467 plus starch than after placebo plus starch. Insulin and C-peptide values were closely correlated with glucose. Flatulence and diarrhoea were reported by two subjects.

3 It is concluded that the administration of tendamistate with, but not prior to, starch ingestion is effective in reducing post-prandial glucose levels.

     

Stereochemical aspects of the metabolism of 5-ethyl-5-phenylhydantoin (Nirvanol) in the dog

Enantiomers of 5-ethyl-5-phenylhydantoin (EPH) were administered to dogs, and urinary metabolites were quantitated. After administration of (R)-EPH, the urinary products included unchanged drug, 5-ethyl-5-(4-hydroxyphenyl)hydantoin (p-EHPH), 5-ethyl-5-(3-hydroxyphenyl)hydantoin (m-EHPH), and an N-glucuronide of EPH. Administration of (S)-EPH gave urinary products consisting of unchanged drug, p-EHPH, m-EHPH, an N-glucuronide of EPH, and a dihydrodiol metabolite, which has been isolated and identified as (5 S)-5-[(3R,4R)-3,4-dihydroxy-1,5-cyclohexadien-1-yl]-5-ethylhydantoin. The levorotatory isomers of p- and m-EHPH have been assigned the (R)-configuration. An unidentified metabolite of EPH has been detected through its reactivity under basic conditions to yield 2-ethyl-2-phenylhydantoic acid, which can be cyclized with acid to EPH. Quantitative studies of the disposition of single oral doses of (R)-, (S)-, and (RS)-EPH by these metabolic routes suggest that the metabolism of one enantiomer is unaffected by the presence of the other enantiomer. Stereoselectivities of metabolic pathways are discussed in relation to stereoselectivities observed for phenytoin metabolism in the dog.     

Biotransformation of zeranol: disposition and metabolism in the female rat, rabbit, dog, monkey and man

The disposition of [3H]zeranol has been studied in the female Wistar rat, New Zealand rabbit, beagle dog, rhesus monkey and man. The blood elimination half-life of total radioactivity in rabbit was 26 h, monkey 18 h and man 22 h. In all species studied the drug was absorbed, oxidized and/or conjugated, and was extensively excreted via the bile in all species except rabbit and man, in which urinary excretion predominated. Blood total radioactivity in man probably consisted entirely of conjugates of zeranol and/or its metabolites. Urinary metabolites in all species included conjugates (beta-glucuronides and/or sulphates) of zeranol and the major metabolite zearalanone. A more polar minor metabolite was isolated from human urine and was shown to be hydroxy-zeranol. Taleranol (7 beta-zearalanol, the lower-melting diastereoisomer), a probable metabolite of zeranol (7 alpha-zearalanol, the higher-melting diastereoisomer) in animals and in man, was shown to be a urinary metabolite in a female New Zealand white rabbit which had received [3H]zeranol (8 mg/kg per day) for seven days. A reverse isotope dilution method was developed for the quantification of both diastereoisomers of zearalanol, and also zearalanone, in urine.     

Effects of propiverine hydrochloride (propiverine) on isolated rat and dog urinary bladder]

Propiverine is a drug for the treatment of incontinence and pollakiuria. The effects of propiverine on isolated rat and dog urinary bladder were investigated. At doses of 10(-6)-3 x 10(-5) M, propiverine caused both a rightward shift and inhibition of the maximum response in the acetylcholine (ACh) dose-response curve. The pA2 values for rat and dog urinary bladder were 5.97 and 6.62, respectively. At doses of 10(-5)-10(-5) M, propiverine also dose-dependently inhibited KCl (100 mM)-induced contractions. The IC50 values for rat and dog urinary bladder were 3.9 x 10(-6) M and 3.8 x 10(-6) M, respectively. The pA2 value and the IC50 value of terodiline for rat urinary bladder were 6.08 and 6.6 x 10(-6) M, respectively. In contrast, the pA2 value and the IC50 value of oxybutynin for rat urinary bladder were 7.69 and 4.5 x 10(-6) M, respectively, suggesting that oxybutynin exerts an anti-muscarinic effect at doses at which no discernible anti-KCl effect was observed, whereas propiverine and terodiline exerted both effects at the same doses. The inhibitory effect of drugs on the contraction induced by electrical field stimulation was tested. At a dose of 10(-7) g/ml, tetrodotoxin inhibited the contraction of rat and dog urinary bladder by 76.6% and 92.6%, respectively. Propiverine and verapamil dose-dependently inhibited the contractile response induced by electrical field stimulation at doses of 10(-5) M or more and 3 x 10(-6) M or more, respectively. At these concentrations, a marked anti-KCl effect of the drugs on smooth muscle was observed. On the other hand, atropine caused no inhibition of the contractile response in rat urinary bladder at a dose of 3 x 10(-5) M, and it inhibited the contraction in dog urinary bladder by 14.9% at a dose of 10(-5) M. These findings suggest that although propiverine exhibits both anti-muscarinic and anti-KCl effects in isolated rat and dog urinary bladder, the inhibitory effects of propiverine on the atropine-resistant part of contraction may be mainly due to its anti-KCl effect.