S Navaratnam

University of Manitoba, Winnipeg, Manitoba, Canada

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Publications (14)39.85 Total impact

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    ABSTRACT: We report some of the unique pharmacological properties of a semipurified endogenous inotropic factor (EIF) present in the extract of the porcine left ventricle. EIF produced the following effects: (a) increase in isometric contractile force developed by electrically driven canine right ventricular trabecula, reaching a maximum with 60-100 microliters/ml concentration; (b) inhibition of Na-pump activity in canine portal vein; (c) no digitalis-like cardiac toxicity, e.g., increased diastolic tension or spontaneous diastolic mechanical oscillatory activity, despite inhibition of the sodium pump; (d) a small increase in sarcoplasmic reticular Ca release from the heart but a large increase in transsarcolemmal Ca influx as seen in biphasic contractions, an action similar to that produced by digitalis-like substances; and (e) prolongation of the action potential duration and refractory period of the canine isolated trabeculae. This latter action may confer a unique antiarrhythmic property to EIF.
    Journal of Cardiovascular Pharmacology 02/1993; 22 Suppl 2:S93-5. · 2.38 Impact Factor
  • Jagdish C. Khatter, Srisala Navaratnam
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    ABSTRACT: In the present study, age-related alterations in cardiovascular response to Ca2+ agonist BAY K 8644 were investigated in rats. Dose response of BAY K 8644 (1-30 micrograms/kg) was studied in open chest rats by intravenous bolus administration. Maximum elevation of mean arterial pressure and (+)dp/dt of left ventricular pressure were significantly higher and the dose of BAY K 8644 required to produce half maximal response was substantially lower in 12 months old (4 micrograms/kg) than in 2 months old (10 micrograms/kg) rats. Larger doses of BAY K 8644 produced arrhythmias only in 12 months old rats, which was not totally abolished by nitroglycerine pretreatment. Perfusion of isolated rat hearts with 10(-6) M BAY K 8644 produced positive inotropic response, which was on the average 50% greater and developed much faster in 12 months old than in 2 months old rats. It is therefore concluded that the myocardial sensitivity to BAY K 8644 increases during adult maturation.
    European Journal of Pharmacology 07/1992; 216(3):351-5. · 2.59 Impact Factor
  • S Navaratnam, J C Khatter
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    ABSTRACT: To study the effects of maturation and aging on calcium channels, we investigated the characteristics of binding of a radioligand, [3H]nitrendipine, to relatively pure sarcolemmal membranes from 2-, 12- and 24-month-old Sprague-Dawley rat hearts. Specific binding of [3H]nitrendipine was saturable, and the Scatchard analysis of the binding revealed a single class of binding sites. Binding of [3H]nitrendipine to the membrane of 12-month-old-rats was 50-75% greater than to the membrane of 2-month-old young adult rats with no further changes in binding during aging from 12 to 24 months. The maximum number of dihydropyridine binding sites (Bmax) was 70% higher in 12- and 24-month-old rat hearts (0.45 and 0.43 pmol/mg protein) than in 2-month-old rats (0.27 pmol/mg protein). The affinity for [3H]nitrendipine binding, on the other hand, was similar in all three age groups (KD values of 0.27, 0.31 and 0.29 nM in 2-, 12- and 24-month-old rats, respectively, at 25 degrees). Membranes of all three age groups showed a similar degree of enrichment in sarcolemmal marker enzymes, indicating that the difference in membrane purity was not a contributing factor to the observed increase in density. Furthermore, increased binding of [3H]nitrendipine to the membranes of older rat hearts was observed throughout the purification scheme. Since [3H]nitrendipine binding sites are considered to be specific sites for voltage-gated Ca2+ channels of the sarcolemma, it is concluded that the density of these channels in the myocardium increases during adult maturation and is maintained through senescence.
    Biochemical Pharmacology 03/1991; 41(4):593-600. · 4.58 Impact Factor
  • J C Khatter, M Agbanyo, S Navaratnam
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    ABSTRACT: In the past few years, we developed an extraction procedure which we successfully used to isolate a crude fraction containing digitalis-like substance (DLS) from porcine left ventricular tissue. In this study, the crude fraction was found to cross-react with digoxin antibodies and showed immunoreactivity of 4.25 +/- 0.6 ng digoxin equivalent/ml. On further purification of the crude fraction using silica gel G column chromatography, a fraction C was obtained, which was highly positive inotropic on canine trabeculae and it dose-dependently inhibited ouabain sensitive 86Rb+ uptake in rat heart slices. A 50% inhibition of uptake was obtained by 25 microliters of fraction C. Fraction C also inhibited canine kidney Na+, K(+)-ATPase (Sigma, U.S.A.) dose-dependently and a 50% inhibition of this enzyme required 17 microliters of fraction C. Ashing of the fraction C at 500 degrees C resulted in loss of inotropic and enzyme inhibitory activities, indicating an organic nature of the unknown digitalis-like substance.
    Life Sciences 02/1991; 48(5):387-96. · 2.56 Impact Factor
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    S Navaratnam, T Chau, M Agbanyo, D Bose, J C Khatter
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    ABSTRACT: 1. We previously isolated an extract from porcine left ventricle that possessed digitalis-like properties such as inhibition of cardiac and kidney Na+, K(+)-ATPase, displacement of [3H]-ouabain from its binding sites and cross reactivity with digoxin antibodies. The extract also had a positive inotropic effect on the guinea-pig heart. 2. In the present study the positive inotropic response of the extract was characterized in canine right ventricular trabeculae. Maximum inotropic response (501 +/- 20%) was produced by 300 microliters and the half maximal increase occurred with 125 microliters of the extract. 3. Ouabagenin produced aftercontractions in rapidly paced trabeculae. Equipotent and even greater amounts of the extract did not produce aftercontractions. 4. The extract increased the amplitude of the delayed component (P2) of biphasic contractions produced by replacing about 92-96% of the external Ca with Sr. A smaller increase in the size of the early component (P1) was also seen. 5. The extract decreased post-rest potentiation after rest for 30s and 2 min. After 8 min of rest, post-rest potentiation was converted to post-rest depression. 6. The extract (20 microliters) produced a decrease in the amplitude of the post-rest rapid cooling contracture (RCC) at all rest intervals. The steady state RCC, although greater than that in the control muscle, was increased to a lesser extent than the size of the steady state electrically driven contractions. 7. It is suggested that the extract from porcine left ventricle produces a positive inotropic response by increasing the trans-sarcolemmal influx of Ca. It also has additional effect(s) on the sarcoplasmic reticulum in that it may facilitate the loss of Ca from the sarcoplasmic reticulum and/or inhibit the uptake of Ca by the organelle.
    British Journal of Pharmacology 11/1990; 101(2):370-4. · 5.07 Impact Factor
  • J C Khatter, S Navaratnam, M Agbanyo
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    ABSTRACT: In the present study, arrhythmogenic toxicity of cardiac glycoside ouabain was investigated in guinea pigs after intravenous infusion (5 micrograms/kg/min). Guinea pigs of 18-24 months of age required significantly (P less than 0.05) lower doses of ouabain that 3-month-old animals (72 +/- 3 vs 100 +/- 3 micrograms/kg) for the initiation of cardiac arrhythmias. Investigation of Na(+)-Ca2+ exchange in the isolated sarcolemmal vesicles revealed a marked reduction in the Na(+)-dependent Ca2+ uptake. Kinetic analysis of these data has demonstrated a 70% reduction in Vmax and reduced affinity for Ca2+ in vesicles from 18-month-old as compared to 3-month-old guinea pigs. The rate of Na(+)-dependent Ca2+ efflux was also markedly lower in the vesicles of older animals, and the vesicles retained more Ca2+ after 3 min of Na(+)-dependent Ca2+ extrusion than did those from 3-month-old animals. The results suggest that the sensitivity to cardiac glycocide increases with age and may be associated with altered sarcolemmal Na(+)-Ca2+ exchange activity.
    Biochemical Pharmacology 10/1990; 40(5):997-1003. · 4.58 Impact Factor
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    S Navaratnam, J C Khatter
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    ABSTRACT: In the present study we investigated the binding properties of [3H]BAY K 8644 to the purified sarcolemmal membrane, isolated from 2- and 12-month old Sprague-Dawley rats. Specific binding of [3H]BAY K 8644 was saturable and the Scatchard plot analysis revealed a single class of binding sites in purified sarcolemmal membrane. The estimated maximum number of binding sites in the membrane of 12-month-old rat was 2.4 +/- 0.1 pmol/mg protein, which was significantly greater than the maximum number of binding sites in 2-month-old rats (1.7 +/- 0.2 pmol/mg protein). The affinity to bind [3H]BAY K 8644 was, however, reduced in older rats (KD, 14.5 +/- 0.8 vs. 4.8 +/- 0.3 nM). Measurement of activities of sarcolemmal and subcellular marker enzymes showed that the purification of membrane was virtually identical in two age groups. This would suggest that membrane purity was not a contributing factor to the observed increase in [3H]BAY K 8644 receptor density. Since dihydropyridine receptor sites are very likely to represent voltage-gated calcium channels of sarcolemma, it is concluded that the density of myocardial voltage-gated calcium channels increases during adult maturation.
    Canadian Journal of Physiology and Pharmacology 08/1990; 68(7):877-81. · 1.56 Impact Factor
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    ABSTRACT: In the present study we examined (1) the arrhythmogenic toxicity of ouabain (5 micrograms/kg/min intravenously) in anesthetized guinea pigs of 1-5 days and 3 months of age, and (2) the state of Na+-Ca2+ in the sarcolemmal vesicles isolated from these age groups. Guinea pigs of 1-5 days old tolerated 75% more ouabain than the young adults without significant alteration in the maximal inotropic response. Sodium-dependent 45Ca2+ uptake was substantially lower in the vesicles isolated from hearts of 3-day-old animals, which was characterized by a lower rate of 45Ca2+ uptake (60% Vmax), as compared to the young adults. There was no significant difference in the affinity for 45Ca2+ (Km). The apparent rate of Na+-dependent 45Ca2+ efflux was also lower in the vesicles from 3-day-old guinea pigs. However, the percent extrusion of 45Ca2+ appeared to be unchanged.
    Developmental pharmacology and therapeutics 02/1989; 12(3):128-36.
  • S Navaratnam, J C Khatter
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    ABSTRACT: The present study was undertaken to determine the effect of diabetes on the manifestation of digitalis cardiotoxicity in whole animal model. Animals after 4, 8, 12 and 16 weeks of streptozotocin treatment (60 mg/kg i.v.) were anesthetized (45 mg/kg alpha-chloralose and 500 mg/kg urethane), chest opened and instrumented for the recording of EKG, carotid pressure, left ventricular pressure and dp/dt. Ouabain was infused at a fixed rate (0.4 mg/kg/min) via the femoral vein. Animals at all stages of diabetes had sinus bradycardia, but the basal mechanical function was found to be depressed only after 12 weeks of streptozotocin treatment. After 16 weeks of streptozotocin injection, 40% of the animals showed some spontaneous arrhythmic activity, which lasted only a few seconds, and prolonged QTc (QT interval corrected for heart rate). In response to ouabain infusion, diabetic animals showed less maximal inotropic effect (30-40% reduction from the weight-matched control rats) and required at least 3-fold more ouabain for the initiation of cardiac arrhythmias than the nondiabetic rats (24.031 +/- 1.52 mg/kg vs 8.05 +/- 1.3 mg/kg). The reduced sensitivity to ouabain could not be explained by the presence of bradycardia. Response to a toxic dose of ouabain was restored to the nondiabetic state on treatment with insulin. These observations suggest that the diseased diabetic myocardium shows diminished sensitivity to digitalis toxicity.
    Archives internationales de pharmacodynamie et de thérapie. 01/1989; 301:151-64.
  • J C Khatter, S Navaratnam, R J Hoeschen
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    ABSTRACT: Protective influence of verapamil upon ouabain-induced cardiac arrhythmias was investigated in anesthetized (alpha-chloralose 60 mg/kg and urethane 500 mg/kg) open-chest guinea pigs. Verapamil in doses between 100 and 150 micrograms/kg significantly increased (80-90%) the dose of ouabain, necessary to cause ventricular arrhythmias. This was also associated with a larger survival rate. A larger dose of verapamil (225 micrograms/kg) caused a further increase in the dose of ouabain, necessary for the initiation of arrhythmias, but in all the cases second or third degree heart block occurred. Verapamil (150 micrograms/kg) also prevented the development of fatal arrhythmias and death, when it was administered at the onset of ventricular ectopy. However, once the arrhythmias were firmly established, verapamil was ineffective in reversing the toxic response. The data suggests that verapamil exerts a protective effect against the development of digitalis-induced cardiac arrhythmias in doses which are comparable to therapeutic levels in humans. The larger doses of verapamil, however, will be contradicted because of the slowing of AV node and the likelihood of complete heart block.
    Pharmacology 02/1988; 36(6):380-9. · 1.60 Impact Factor
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    ABSTRACT: In the in vitro perfusion of the isolated heart, toxic doses of cardiac glycosides produce an inotropic response which is followed by a decline in contractile force and an increase in the resting tension. Several reports in the literature indicate that the subsequent decline in contractile force may be related to cardiac cellular Ca++ overload. The purpose of the present study was to determine if the slow Ca++ channel blockers such as verapamil and nifedipine, which block Ca++ influx through voltage-dependent gated channels, can reduce or prevent the digitalis-induced decline in contractile force (mechanical toxicity). Langendorff preparations of isolated perfused guinea pig heart were used for the present study. The data obtained demonstrate that 1 to 2 microM ouabain in the perfusion medium produced mechanical toxicity in the hearts after an initial inotropic response. Verapamil or nifedipine, when combined with ouabain in the perfusion medium, increased the magnitude of the inotropic response and delayed or abolished the mechanical toxicity in a dose-dependent manner. No changes in the sarcolemmal Na+,K+-adenosine triphosphatase or ouabain binding were observed in the presence of verapamil or nifedipine. The data suggest that simultaneous use of verapamil or nifedipine may protect against digitalis-induced mechanical toxicity.
    Journal of Pharmacology and Experimental Therapeutics 11/1986; 239(1):206-10. · 3.89 Impact Factor
  • S NAVARATNAM, J KHATTER
    Journal of Molecular and Cellular Cardiology - J MOL CELL CARDIOL. 01/1986; 18:51-51.
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    ABSTRACT: Isolated perfused guinea pig (Langendorff) heart was employed to determine if the myocardial mechanical dysfunction (mechanical toxicity) produced by toxic concentration of ouabain (1 microM) was accompanied by alterations in mitochondrial function. Ouabain (1 microM) produces a transient increase in the myocardial contractile force and then a continuous decline in the left ventricular mechanical function. Mitochondria isolated from ouabain perfused hearts showed a significantly higher rate of 45Ca2+ uptake and reduction in oxidative phosphorylation. The rate of ATP generation was reduced by almost 50% at the time of contracture development. Verapamil or nifedipine, when combined with ouabain in the perfusion medium, delayed or abolished the mechanical toxicity in a dose dependent manner. The mitochondria isolated from these hearts demonstrated normal rate of Ca2+ uptake and ATP generation capacity. The data indicate that the cardiac mechanical dysfunction induced by toxic doses of ouabain may be associated with mitochondrial Ca2+ overload and dysfunction and that the Ca2+ channel blockers may have a protective effect.
    Archiv für Kreislaufforschung 01/1986; 84(6):553-63. · 5.90 Impact Factor
  • Jagdish C. Khatter, Srisala Navaratnam
    Journal of Molecular and Cellular Cardiology 22:S8. · 5.15 Impact Factor