Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Guanilina (GN), uroguanilina (UGN) e a enterotoxina termo-estÃvel da Escherichia coli (STa) fazem parte de uma nova famÃlia de peptÃdeos que ativam a formaÃÃo de cGMP. A ingestÃo de sal na dieta induz a secreÃÃo de GN e UGN no lÃmen intestinal, inibindo a reabsorÃÃo de sÃdio e induzindo a secreÃÃo de Cl-, HCO3- e Ãgua. Simultaneamente, esses hormÃnios estimulam a excreÃÃo renal de eletrÃlitos atravÃs da induÃÃo de natriurese, caliurese e diurese. Esse mecanismo altamente integrado permite a manutenÃÃo do sÃdio corporal, atravÃs da eliminaÃÃo desse excesso de sÃdio pela urina. Entretanto, essa regulaÃÃo fisiolÃgica entre o intestino e o rim na tem sido muito bem estudada. O objetivo desse trabalho à estudar as alteraÃÃes no metabolismo diÃrio e na funÃÃo renal de ratos submetidos a uma alta ingestÃo de cloreto de sÃdio. Os efeitos forma examinados usando ratos Wistar mantidos por 10 dias em gaiolas metabÃlicas. O grupo controle recebeu somente Ãgua destilada, enquanto que os grupos tratados receberam 1% e 2% de soluÃÃo de NaCl. Forma analisadas diariamente o volume urinÃrio, o peso corporal e o consumo de Ãgua e alimento. A funÃÃo renal foi avaliada atravÃs da perfusÃo de rim isolado de ratos apÃs dez dias de tratamento em gaiolas metabÃlicas, onde a perfusÃo foi realizada com soluÃÃo de Krebs-Henseleit modificada com 6g% de albumina bovina. Os dados foram comparados atravÃs de teste t de Student e ANOVA, com significÃncia p<0,05. O peso dos ratos tratados com 2% de NaCl apresentou uma reduÃÃo a partir do dia 8, em relaÃÃo ao controle, enquanto que 1% nÃo apresentou reduÃÃo significativa. O volume urinÃrio e o consumo de Ãgua apresentaram um aumento em ambos os tratamentos a partir do dia 2. O consumo de alimento ingerido nÃo apresentou grandes variaÃÃes entre os grupos. Em rim isolado de rato ambos os tratamentos aumentou a pressÃo de perfusÃo (PP). A resistÃncia vascular renal (RVR), o fluxo urinÃrio (FU), o ritmo de filtraÃÃo glomerular (RFG) e o clearance osmolar (Cosm) aumentou no grupo de 1% comparado ao controle, porÃm esses mesmos parÃmetros diminuÃram no grupo de 2%. Em relaÃÃo ao transporte de eletrÃlitos observa-se alteraÃÃo somente no grupo de 2%, onde reduziu o transporte de sÃdio (%TNa+, %pTNa+), potÃssio (%TK+, %pTK+) e cloreto (%TCl-, %pTCl-). Esses resultados sugerem que a alta ingestÃo de NaCl na dieta promove significativa alteraÃÃes no metabolismo diÃrio e na funÃÃo renal. / Guanylin (GN), uroguanylin (UGN), and the bacterial heat-stable enterotoxin (ST) peptides comprise a new family of cyclic guanosine 3â-5â monophosphate (cGMP)-regulating agonist. Ingestion of a salt meal induces secretion of GN and UGN into the intestinal lumen, where they inhibit Na+ absorption and induces Cl-, HCO3- , and water secretion. Simultaneously, these hormones stimulate renal electrolyte excretion by inducing natriuresis, kaliuresis, and diuresis. The highly integrated mechanism allows the organism to maintain sodium balance by eliminating excess NaCl in the urine. However, their physiological regulation within the kidney has not been studied. The aim of this study was showing changes on daily metabolism and renal function of rat under high sodium chloride ingestion. Its effects were examined using wistar rats maintained for ten days in metabolic cages. Control group received only water, two more groups received 1% and 2% solutions of sodium chlroride. We daily analyzed urinary volume, weigh, and food and water consume. The renal function was evaluated using isolated perfused kidneys, in which the kidneys were perfused after ten days in metabolic cages, only with Krebs-Henseleit solution containing 6g% of a previously dialysed bovine albumine serum. All data were analyzed by ANOVA and Student t-test with level of significance set at *p<0,05. Ratâs weights of 2% group decreased after eighth day, compared with control group, while 1% group did not show significative weight lost. Urinary volume and water consume increased, in both treatments, from second day. Food consume did not show significative among groups. In isolated kidney both treatments increase perfusion pressure (PP). The renal vascular resistence (RVR), urinary flow (UF), glomerular filtration rate (GFR) and the osmolar clearance (Cosm) increased in the 1% group compared with control group, however decreased in 2% NaCl group. Treatment with 2% NaCl decreased the sodium (%TNa+, %pTNa+), potassium (%TK+, %pTK+) and chloride (%TCl-, %pTCl-). These results suggest that a high salt ingestion on diet promote significative changes on daily metabolism and the renal function of rats.

No description available.

The lumen-to-cell transport, cellular accumulation, and toxicity of ionic cadmium (109Cd2+) and cadmium-cysteine conjugate (Cys-S-109Cd-S-Cys) were studied in isolated perfused S2 segments of the proximal tubule of the rabbit kidney. All perfusion solutions were HEPES buffered and contained 3H-L-glucose which functioned as a volume and leak marker along with 250 nM FD & C Green dye as a vital dye. When ionic cadmium, 0.73µM Cd2+, or 0.73µM cadmium-cysteine conjugate (Cys-S-109Cd-S-Cys) containing solution was perfused through the lumen of the tubule there was no visual evidence of toxicity such as blebbing of the luminal membrane, cellular vital dye uptake, and cellular swelling. Ionic Cd2+ transport was temperature dependent (87% reduction at 22°C and 100% at 11°C) and inhibited by FeCl2 (42% reduction at 10µM) and ZnCl2 (48% reduction at 20µM), and high Ca2+ concentrations (27% reduction at 1.95mM and 69% at 2.6mM). The ionic Cd2+ transport was not affected by verapamil and diltiazem. The cadmium conjugate (Cys-S-Cd-S-Cys) transport was also temperature dependent (76% reduction at 22°C and 100% at 11°C) and inhibited by the amino acids L-cystine and L-arginine (55% and 50% respectively), stimulated by L-methionine (56%), but not affected by L-aspartate, L-glutamate and Gly-Sar. 2, 3-Dimercaptopropane-1-Sulfonate (DMPS) co-perfused with Cd2+ decreased absorption of 20µM Cd2+ (39% reduction at 30 µM and 94.6% reduction at 200 µM), while DMPS added to the bathing solution has no effect on the luminal transport of Cd2+. DMPS co-perfused with 20 µM Cys-S-Cd-S-Cys substantially reduced Cd2+ transport (62% reduction at 30 µM). We conclude that cadmium can be transported at the luminal membrane of the S2 segment of the proximal tubule by multiple mechanisms, depending on the form which it is presented to membrane. Ionic cadmium appears to be transported by iron (DCT1), zinc (ZTL1) transporters and some kind of calcium-selective channel while cadmium conjugate of L-cysteine appears to be transported by L-cystine transporters (system b0+). Dipeptide transporter is not involved in the transport of cadmium. DMPS appears to be a chelator for cadmium.

The effect of cold acclimation on body of mammals has been studied for many decades by using relatively low temperatures for acclimation (6-10 řC). The results of these experiments have shown the important role of the adrenergic and thyroid system during acclimation and negative impact on renal system at the same time. In contrast, a recent study on winter swimmers suggests a possibility of positive influence of hardening on cardiovascular system. There is no available study investigating a relationship between cold adaptation and ischemia-reperfusion injury. The aim of this study was to establish a protocol of isolated rat heart and its fixation at our workplace. Furthermore, to find the impact of mild cold acclimation on the ischemia-reperfusion injury of rat. Methods of ex vivo heart perfusion and fixation were successfully established. The effect of 5 weeks long cold acclimation in 10 ± 2 řC on left ventricle ischemia-reperfusion injury was observed. Powered by TCPDF (www.tcpdf.org)

Bien que le changement dans le choix des substrats énergétiques des acides gras (AGs) vers les glucides soit considéré comme bénéfique pour le cœur insuffisant, il n’est pas clair à savoir pourquoi les patients atteints de désordres de la β-oxydation (β-OX) des AGs à chaîne longue (AGCLs) développent des troubles du rythme et des cardiomyopathies. De plus, le traitement actuel ne permet pas de prévenir l’apparition du phénotype clinique chez tous les patients, spécifiquement en condition de jeûne ou de stress. Ainsi, plusieurs modèles de souris déficientes pour des enzymes impliquées dans l’oxydation des acides gras ont été développés de manière à améliorer les connaissances de la maladie ainsi que les traitements offerts aux patients. À cet égard, cette étude vise à évaluer le phénotype métabolique et fonctionnel des cœurs de souris déficientes pour le récepteur activé de la prolifération des peroxysomes-α (PPARα), un facteur de transcription des gènes impliqués notamment dans la β-OX des AGs, et pour la déshydrogénase des acyl-CoA à très longue chaîne (very-long chain acyl-CoA dehydrogenase, VLCAD), le déficit de l’oxydation des AGCLs le plus commun chez l’humain. L’approche expérimentale utilisée comprend plusieurs techniques dont (i) la perfusion ex vivo de cœur de souris au travail combinée à l’utilisation de substrats marqués au carbone 13 (13C) et à l’analyse par chromatographie gazeuse-spectrométrie de masse (GCMS), (ii) l’analyse de l’expression génique par qPCR et (iii) l’analyse de l’activité électrique du cœur in vivo par télémétrie. De manière inattendue, les résultats de cette étude menée chez la souris ont permis de mettre en évidence que des déficits pour des protéines impliquées dans l’oxydation des AGCLs sont associés à des altérations du métabolisme (i) des glucides, (ii) des AGs polyinsaturés (AGPIs), et (iii) mitochondrial, incluant l’anaplérose, en plus d’être liés à des désordres de la fonction électrique du cœur, à savoir une prolongation du segment QTc. Pris dans leur ensemble, les résultats de cette thèse pourraient servir à l’élaboration de nouvelles interventions métaboliques destinées à améliorer les traitements possibles et donc, la qualité de vie des patients atteints de désordres héréditaires de la β-OX des AGCLs. / While a shift from fatty acids to carbohydrate is considered beneficial for the failing heart, it is unclear why patients with fatty acid oxidation disorders present clinical manifestations such as cardiomyopathy, arrhythmia and conduction defects. Unfortunately, the current nutritional treatment for these patients is limited in its ability to prevent these symptoms, especially under fasting and stress conditions. Many mouse models of fatty acid oxidation deficiency have been developed to improve the knowledge of the disease and the treatment of these patients. In this regard, this study aims to characterize the metabolic and functional phenotype of hearts from mice that are deficient for the peroxisome proliferator-activated receptor α, a transcription factor for gene involved in fatty acid oxidation, and very long chain acyl-CoA dehydrogenase, the most common inherited long chain fatty acid oxidation disorder in human, under various conditions. In this study, numerous approaches have been used, which includes validated experimental paradigms, namely, (i) ex vivo heart perfusion in the working mode with concomitant evaluation of myocardial contractility and metabolic fluxes, employing 13C-labeled substrates combined with mass isotopomer analysis by gas chromatography coupled to mass spectrometry, (ii) gene expression analysis by qPCR and (iii) electrocardiogram monitoring in vivo by telemetry. Unexpectedly, results from the present thesis demonstrate that fatty acid oxidation disorders cause alterations in metabolism of (i) carbohydrates (ii) polyunsaturated fatty acids of the omega-3 type, specifically docosahaexanoic acid, and (iii) mitochondria including anaplerosis, in addition to lead to functional abnormalities, namely a prolongation of the QT interval. Altogether, results from this thesis could contribute to new metabolic therapy development to improve the quality of life of the patients with inherited long chain fatty acid oxidation disorder.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / IntroduÃÃo: Guanilinas, peptÃdeos natriurÃticos (ANP e urodilatina) e bradicinina estÃo implicados na fisiopatologia, com potencial terapÃutico, do metabolismo do sal e da hipertensÃo. Objetivo: Estudar o mecanismo de aÃÃo e possÃveis interaÃÃes destes peptÃdeos, pelo emprego de inibidores da guanilato ciclase isatina e ODQ. MÃtodo: Foram realizadas experiÃncias no rim isolado e perfundido de rato com ferramentas farmacolÃgicas, isatina (IS; 0,3 ou 10&#956;M) ou com ODQ (37&#956;M), nos estudos com uroguanilina (UGN; 0,3 ou 0,6&#956;M), bradicinina (BK; 0,3 ou 0,9 ou 1,8nM) ou urodilatina (UD; 0,03nM). Investigaram-se ainda possÃveis interaÃÃes entre os referidos petÃdeos. Resultados: Isoladamente, IS (0,3&#956;M), ODQ, UGN (0,3&#956;M), BK (0,9 ou 0,3nM) nÃo interferiram signficativamente na presssÃo de perfusÃo, na diurese ou na reabsorÃÃo tubular fracionada renal de eletrÃlitos (sÃdio - %TNa+; potÃssio - %TK+; cloreto - %TCl- ). Nas condiÃÃes experimentais, ODQ mostrou-se eficaz (p<0,05) em inibir os efeitos de BK (1,8nM) sobre a pressÃo de perfusÃo (ODQ+BK120min: 111+3mmHg; BK120min: 139+5mmHg) e %TNa+ (ODQ+BK120min: 80+1%; BK120min: 76+2%). IS (3&#956;M) mostrou-se parcialmente eficaz em inibir efeitos de UGN (0,6&#956;M; IS+UGN90min: 76+2%; UGN90min: 72+2%) e de BK (1,8nM; IS+BK90min: 81+2%; BK60min: 0,76+2%) sobre %TNa+. UD (0,03nM90min: 86+2%; UGN+UD90min: 73+4%; p<0,05) potencializou a natriurese produzida por UGN (0,3&#956;M90min: 83+2%), cujos efeitos vasculares foram inibidos com BK (0,3nM90min: 104+5mmHg; UGN0,6&#956;M; 90min: 135+4mmHg; UGN+BK90min: 110+2mmHg). ConclusÃes: IS e ODQ comprovaram a participaÃÃo da via de sinalizaÃÃo NO-GMP no mecanismo de aÃÃo dos peptÃdeos estudados. A perfusÃo simultÃnea com mais de um peptÃdio, comprovou que hà interaÃÃes em suas diferentes vias de sinalizaÃÃo. / Introduction: Guanylins, natriuretic peptides (ANP and urodilatina) and bradykinin are involved in the pathophysiology, with therapeutic potential, of salt metabolism and hypertension. Objective: To study the mechanism of action and possible interactions of these peptides, with the employment of guanylate cyclase inhibitors isatina and ODQ. Method: Experiments were performed on isolated perfused rat kidney with pharmacological tools, isatin (IS; 0.3 or 10&#956;M) or with ODQ (37&#956;M), in studies with uroguanylin (UGN, 0.3 or 0.6&#956;M), bradykinin (BK , 0.3 or 0.9 or 1.8nM) or urodilatin (UD, 0.03nM). It was also investigated possible interactions between those peptides. Results: Alone, IS (0.3&#956;M), ODQ, UGN (0.3&#956;M), BK (0.9 or 0.3nM) did not interfere significantly in perfusion perfusion (PP), in diuresis or in fractional renal tubular reabsorption of electrolytes (sodium - %TNa+; potassium - %TK+; chloride - %TCl-). In experimental conditions, ODQ proved to be effective (p<0.05) in inhibiting the effects of BK (1.8nM) on the PP (ODQ+BK120min: 111+3mmHg; BK120min: 139+5mm Hg) and %TNa+ (ODQ+BK120min: 80+1%; BK120min: 76+2%). IS (3&#956;M) proved to be partially effective in inhibiting effects of UGN (0.6&#956;M; IS+UGN90min: 76+2%; UGN90min: 72+2%) and BK (1.8nM; IS+BK90min: 81+2%; BK60min: 0.76+2%) on %TNa+. UD (0.03nM90min: 86+2%; UGN+UD90min: 73+4%, p<0.05) increased the natriuresis produced by UGN (0.3&#956;M90min: 83+2%), whose vascular effects were inhibited with BK (0.3nM90min: 104+5mmHg; UGN0, 6&#956;M; 90min: 135+4mmHg; UGN+BK90min: 110+2mmHg). Conclusions: IS and ODQ confirmed the participation of the NO-GMP signalling pathway in the mechanism of action of peptides studied. The infusion simultaneously over a peptide, proved that there are interactions in their different signalling pathway.

<p>Although, pulmonary drug delivery is a well established means for targeting of drugs to the lungs for the treatment of respiratory diseases as well as for the systemic delivery of volatile anesthetic agents, drug absorption kinetics in the lung have not been subjected to extensive research. The main objective of this thesis was to investigate drug absorption characteristics of the lung barrier, using the isolated and perfused rat lung model and in vivo pharmacokinetic studies in rats. Physicochemically diverse drugs (i.e. atenolol, budesonide, cromolyn, cyanocobalamin, enalapril, enalaprilate, formoterol, imipramine, losartan, metoprolol, propranolol, talinolol, terbutaline, and the tetrapeptide TArPP) were used as model compounds. In connection to these investigations, a nebulization catheter device was successfully adapted and evaluated as a new technique for delivery of defined aerosol doses to the rat lung. In addition, a physicochemical profile of the inhaled drugs on the market worldwide during 2001 was made.</p><p>The pulmonary first-order absorption rate constant and bioavailability were found to correlate to the drug lipophilicity, the molecular polar surface area, and the apparent permeability of Caco-2 cell monolayers. In contrast to the intestinal mucosa and the blood-brain barrier, the pulmonary epithelium was highly permeable to drugs with a high molecular polar surface area. Accordingly, a small hydrophilic tetrapeptide (oral bioavailability ~0.5%) showed a complete bioavailability after pulmonary delivery to rats in vivo. Regional differences in bioavailability, absorption rate, and first-pass metabolism of the peptide was demonstrated after targeted delivery to different regions of the respiratory tract in rats in vivo. The high pulmonary bioavailability of the efflux transporter substrates losartan and talinolol provides functional evidence for an insignificant role of efflux transporters such as P-glycoprotein in limiting the absorption of these drugs from the rat lung. </p><p>The results of this thesis demonstrate that the lung efficiently absorbs drugs with a wide range of lipophilicity. The pulmonary route should thus be regarded as a potential alternative for administration of drugs with low oral bioavailability. In addition, drug inhalation present an opportunity to attain a more rapid onset of drug action than can be attained by the oral route.</p>

Although, pulmonary drug delivery is a well established means for targeting of drugs to the lungs for the treatment of respiratory diseases as well as for the systemic delivery of volatile anesthetic agents, drug absorption kinetics in the lung have not been subjected to extensive research. The main objective of this thesis was to investigate drug absorption characteristics of the lung barrier, using the isolated and perfused rat lung model and in vivo pharmacokinetic studies in rats. Physicochemically diverse drugs (i.e. atenolol, budesonide, cromolyn, cyanocobalamin, enalapril, enalaprilate, formoterol, imipramine, losartan, metoprolol, propranolol, talinolol, terbutaline, and the tetrapeptide TArPP) were used as model compounds. In connection to these investigations, a nebulization catheter device was successfully adapted and evaluated as a new technique for delivery of defined aerosol doses to the rat lung. In addition, a physicochemical profile of the inhaled drugs on the market worldwide during 2001 was made. The pulmonary first-order absorption rate constant and bioavailability were found to correlate to the drug lipophilicity, the molecular polar surface area, and the apparent permeability of Caco-2 cell monolayers. In contrast to the intestinal mucosa and the blood-brain barrier, the pulmonary epithelium was highly permeable to drugs with a high molecular polar surface area. Accordingly, a small hydrophilic tetrapeptide (oral bioavailability ~0.5%) showed a complete bioavailability after pulmonary delivery to rats in vivo. Regional differences in bioavailability, absorption rate, and first-pass metabolism of the peptide was demonstrated after targeted delivery to different regions of the respiratory tract in rats in vivo. The high pulmonary bioavailability of the efflux transporter substrates losartan and talinolol provides functional evidence for an insignificant role of efflux transporters such as P-glycoprotein in limiting the absorption of these drugs from the rat lung. The results of this thesis demonstrate that the lung efficiently absorbs drugs with a wide range of lipophilicity. The pulmonary route should thus be regarded as a potential alternative for administration of drugs with low oral bioavailability. In addition, drug inhalation present an opportunity to attain a more rapid onset of drug action than can be attained by the oral route.

Bien que le changement dans le choix des substrats énergétiques des acides gras (AGs) vers les glucides soit considéré comme bénéfique pour le cœur insuffisant, il n’est pas clair à savoir pourquoi les patients atteints de désordres de la β-oxydation (β-OX) des AGs à chaîne longue (AGCLs) développent des troubles du rythme et des cardiomyopathies. De plus, le traitement actuel ne permet pas de prévenir l’apparition du phénotype clinique chez tous les patients, spécifiquement en condition de jeûne ou de stress. Ainsi, plusieurs modèles de souris déficientes pour des enzymes impliquées dans l’oxydation des acides gras ont été développés de manière à améliorer les connaissances de la maladie ainsi que les traitements offerts aux patients. À cet égard, cette étude vise à évaluer le phénotype métabolique et fonctionnel des cœurs de souris déficientes pour le récepteur activé de la prolifération des peroxysomes-α (PPARα), un facteur de transcription des gènes impliqués notamment dans la β-OX des AGs, et pour la déshydrogénase des acyl-CoA à très longue chaîne (very-long chain acyl-CoA dehydrogenase, VLCAD), le déficit de l’oxydation des AGCLs le plus commun chez l’humain. L’approche expérimentale utilisée comprend plusieurs techniques dont (i) la perfusion ex vivo de cœur de souris au travail combinée à l’utilisation de substrats marqués au carbone 13 (13C) et à l’analyse par chromatographie gazeuse-spectrométrie de masse (GCMS), (ii) l’analyse de l’expression génique par qPCR et (iii) l’analyse de l’activité électrique du cœur in vivo par télémétrie. De manière inattendue, les résultats de cette étude menée chez la souris ont permis de mettre en évidence que des déficits pour des protéines impliquées dans l’oxydation des AGCLs sont associés à des altérations du métabolisme (i) des glucides, (ii) des AGs polyinsaturés (AGPIs), et (iii) mitochondrial, incluant l’anaplérose, en plus d’être liés à des désordres de la fonction électrique du cœur, à savoir une prolongation du segment QTc. Pris dans leur ensemble, les résultats de cette thèse pourraient servir à l’élaboration de nouvelles interventions métaboliques destinées à améliorer les traitements possibles et donc, la qualité de vie des patients atteints de désordres héréditaires de la β-OX des AGCLs. / While a shift from fatty acids to carbohydrate is considered beneficial for the failing heart, it is unclear why patients with fatty acid oxidation disorders present clinical manifestations such as cardiomyopathy, arrhythmia and conduction defects. Unfortunately, the current nutritional treatment for these patients is limited in its ability to prevent these symptoms, especially under fasting and stress conditions. Many mouse models of fatty acid oxidation deficiency have been developed to improve the knowledge of the disease and the treatment of these patients. In this regard, this study aims to characterize the metabolic and functional phenotype of hearts from mice that are deficient for the peroxisome proliferator-activated receptor α, a transcription factor for gene involved in fatty acid oxidation, and very long chain acyl-CoA dehydrogenase, the most common inherited long chain fatty acid oxidation disorder in human, under various conditions. In this study, numerous approaches have been used, which includes validated experimental paradigms, namely, (i) ex vivo heart perfusion in the working mode with concomitant evaluation of myocardial contractility and metabolic fluxes, employing 13C-labeled substrates combined with mass isotopomer analysis by gas chromatography coupled to mass spectrometry, (ii) gene expression analysis by qPCR and (iii) electrocardiogram monitoring in vivo by telemetry. Unexpectedly, results from the present thesis demonstrate that fatty acid oxidation disorders cause alterations in metabolism of (i) carbohydrates (ii) polyunsaturated fatty acids of the omega-3 type, specifically docosahaexanoic acid, and (iii) mitochondria including anaplerosis, in addition to lead to functional abnormalities, namely a prolongation of the QT interval. Altogether, results from this thesis could contribute to new metabolic therapy development to improve the quality of life of the patients with inherited long chain fatty acid oxidation disorder.

Doctor Pharmaceuticae - DPharm / An aqueous extract prepared from the leaves and smaller stems of Leonotis leonurus was used to investigate the potential effects on certain cardiovascular parameters, such as left ventricular systolic pressure, end-diastolic pressure, developed pressure, heart rate, cardiac work and coronary perfusion pressure in isolated rat hearts. Hearts were perfused at constant flow for 3min using the modified Langendorf! perfused model of the heart. Effects of adrenaline and digoxin solutions on the isolated heart were compared to that of the plant extract. Adrenaline produced both positive inotropic and chronotropic effects. Adrenaline increased (p<O.Ol) the left ventricular systolic pressure and hence the left ventricular developed pressure by 40.6% and 43.9% at peak, and 24.3% and 31.9%, after 3min, respectively. Simultaneously, the heart rate and the cardiac work were increased (p<0.01) by 22.5% and 89.4% at peak, and 24.6% and 63%, after 3rnin, respectively. There were no significant effects on the left ventricular diastolic pressure and the coronary perfusion pressure. Digoxin solution (2.5ng/ml) significantly (p<O.Ol) increased the left ventricular systolic pressure by 5.1% after 3min and the left ventricular diastolic pressure by 9.7% at peak and 5.3% after 3min. The heart rate was significantly (p<O.OI) decreased by 3.7% at peak. The cardiac work was increased by 4.5% after 3rnin. Digoxin did not significantly affect the left end diastolic pressure and the coronary perfusion pressure. The extract of Leonons leonurus at O.lmg/ml increased (p<O.OI) the left ventricular systolic pressure and hence the left ventricular diastolic pressure by 9.7% and 10.7% at peak, and 5.4% and 5.5% after 3rnin, respectively. The cardiac work was increased (p<O.Ol) by 10.1% at peak. Leonotis leonurus (0.1mg/ml) did not significantly affect the left ventricular end diastolic pressure, the heart rate and the coronary perfusion pressure. At 0.5mg/ml, the left ventricular systolic pressure and hence the left ventricular diastolic pressure were increased (p<0.01) by 14.8% and 15.4% at peak and 7.4% and 7.8% after 3rnin, respectively with a corresponding decrease (p<O.OI) in the coronary perfusion pressure of 8.5% at peak and 4.4% after 3rnin. The cardiac work was increased (p<O.OI) by 13.6% at peak and 5.2% after 3rnin. The extract at 1.0mg/ml increased (p<O.Ol) the left ventricular systolic pressure and hence the left ventricular diastolic pressure by 25.4% and 29.4% at Peak, and 23.1% and 26.3% after 3rnin, respectively. The heart rate was reduced (p<O.OI) by 34.7% at peak and 28.3% after 3min. The cardiac work and the coronary perfusion pressure were decreased (p<O.OI) by 15.9% and 12.1% at Peak and 3.3% and 11.4% after 3rnin. However, at 2.0mg/ml, the left ventricular systolic pressure and the left ventricular diastolic pressure were increased (p<O.OI) by 14.9% at peak. The left ventricular diastolic pressure was decreased (p<O.OI)by 9.8% over the 3rnin. The heart rate was drastically decreased (p<O.OI) by 42.7% after 3rnin. The cardiac work was reduced (p<O.Ol) by 48.8% over the 3min period. Also, the coronary perfusion pressure was decreased (p<0.01) by 16.9% at peak. Thus, Leonatis leonurus produced both positive inotropic and negative chronotropic effects after 3min perfusion, accompanied by a decreased coronary perfusion pressure. Thus, it appears that the extract seemed to contain certain constituents associated with positive inotropic and negative chronotropic agents as wel! as constituents associated with coronary vasodilation. However, at the higher concentration, it seemed to contain some constituents associated with toxic effects on the isolated heart. Therefore, further studies are needed to isolate the various constituents and examine their possible pharmacological effects on the heart individually before it could be considered safe to recommend this plant for its use in the treatment of cardiovascular disease.