The triterpene oleanolic acid (OA) is known to possess antihypertensive actions. In the present s... more The triterpene oleanolic acid (OA) is known to possess antihypertensive actions. In the present study we to compared the effects of the triterpene on mean arterial blood pressure (MAP) and kidney function following acute administration in normotensive animals with those of its related oleanane synthetic derivatives (brominated oleanolic acid, Br-OA and oleanolic acid methyl ester, Me-OA). We also used experimental models of hypertension to further explore the effects of sub-chronic oral OA treatment and evaluated influences on oxidative status. OA was extracted from dried flower buds of Syzygium aromaticum using a previously validated protocol in our laboratory. Me-OA and Br-OA were synthesized according to a method described. Rats were supplemented with lithium chloride (12 mmol L-1) prior to experimentation in order to raise plasma lithium to allow measurements of lithium clearance and fractional excretion (FELi) as indices of proximal tubular Na+ handling. Anaesthetized animals were continuously infused via the right jugular with 0.077M NaCl. MAP was measured via a cannula inserted in the carotid artery, and urine was collected through a cannula inserted in the bladder. After a 3.5 h equilibration, MAP, urine flow, electrolyte excretion rates were determined for 4 h of 1 h control, 1.5 h treatment and 1.5 h recovery periods. OA, Me-OA and Br-OA were added to the infusate during the treatment period. We evaluated sub-chronic effects on MAP and kidney function in normotensive Wistar rats and in two animal models of hypertension, spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DSS) rats, during 9-week administration of OA (p.o.). Tissue oxidative status was examined in these animals at the end of the study. Increasing evidence suggests that and renal function disturbances and oxidative stress play major roles in the pathogenesis of hypertension. Acute infusion OA and oleanane derivatives displayed qualitatively similar effects in decreasing MAP and increasing urinary Na+ outputs. The drugs increased the FENa and FELi without influencing GFR indicating that at least part of the overall natriuretic effect involved proximal tubular Na+ reabsorption. Sub-chronic OA administration (p.o.) also elicited hypotensive responses in Wistar, DSS and SHR rats. The MAP lowering effect was more marked in hypertensive animals and were positively correlated with increased urinary Na+ excretion. Compared with respective control rats, OA treatment reduced malondialdehyde (MDA, a marker of lipid peroxidation) and increased activities of antioxidant enzymes; superoxide dismutase and glutathione peroxidase in hepatic, cardiac and renal tissues. OA and oleanane derivatives have similar effects on MAP, kidney function and oxidative stress. The amelioration of oxidative stress and blood pressure lowering effects by OA are more marked in hypertensive animals and correlated with an increased urinary Na+ output. The results of this study are novel in that they show 1) a correlation between blood pressure reduction and increased urinary Na+ excretion by OA, 2) a more marked MAP reduction in hypertensive animals and 3) a drug-induced decrease in proximal tubule Na+ reabsorption. The results may also be clinically relevant because OA is effective via oral administration.
... [14] Brayden JE, Nelson MT. Regulation of arterial tone by activation of calcium-dependent po... more ... [14] Brayden JE, Nelson MT. Regulation of arterial tone by activation of calcium-dependent potassium channels. Science 1992; 256: 532-5. [15] Brayden JE. ... J Physiol 1997; 499: 715-20. [21] Thorneloe KS, Maruyama Y, Malcolm AT, Light PE, Walsh MP, Cole WC. ...
Purkinje cells were isolated from both ventricles of young adult domestic pigs and examined by tr... more Purkinje cells were isolated from both ventricles of young adult domestic pigs and examined by transmitted light or laser scanning confocal microscopy. Purkinje cells in free running Purkinje fibres were organised in multicellular strands where individual cells were tightly connected end-to-end and closely side-to-side. After isolation, single cells gradually lost the elongated appearance and became more rounded, but the cell membrane remained smooth and undamaged. The contractile material was not very dense and was seen most clearly in the submembraneous area. Staining of the cell membrane with the lipophilic fluorescent (lye di-8-ANNEPS, and visualization with confocal microscopy, confirmed that the cell surface membrane was smooth without blebs. This staining also showed that Purkinje cells had no transversal tubules. We reconstructed the three-dimensional geometry of the Purkinje cells and determined the cell size. The average values were 62 +/- 9 microm for length, 32 +/- 3 mic...
American journal of physiology. Heart and circulatory physiology, 2002
In cardiac cells that lack macroscopic transient outward K(+) currents (I(to)), the removal of ex... more In cardiac cells that lack macroscopic transient outward K(+) currents (I(to)), the removal of extracellular Ca(2+) can unmask "I(to)-like" currents. With the use of pig ventricular myocytes and the whole cell patch-clamp technique, we examined the possibility that cation efflux via L-type Ca(2+) channels underlies these currents. Removal of extracellular Ca(2+) and extracellular Mg(2+) induced time-independent currents at all potentials and time-dependent currents at potentials greater than -50 mV. Either K(+) or Cs(+) could carry the time-dependent currents, with reversal potential of +8 mV with internal K(+) and +34 mV with Cs(+). Activation and inactivation were voltage dependent [Boltzmann distributions with potential of half-maximal value (V(1/2)) = -24 mV and slope = -9 mV for activation; V(1/2) = -58 mV and slope = 13 mV for inactivation]. The time-dependent currents were resistant to 4-aminopyridine and to DIDS but blocked by nifedipine at high concentrations (IC(...
Despite the recognized role of traditional healers in helping patients with mental health problem... more Despite the recognized role of traditional healers in helping patients with mental health problems, there is a need for modern mental healthcare facilities in Africa. When made available, these are used by the local population, but less by those at remote locations. Data from the SOSAME centre indicate the high prevalence of mental diseases, especially in urban population and during the active decades of life. To decrease the burden imposed on mental health institutions by patients consulting for non-mental problems, it is desirable to integrate these institutions with the other components of the healthcare system.
The Journal of pharmacology and experimental therapeutics, 2001
The whole-cell patch-clamp technique was used in adult mouse ventricular myocytes at 22 degrees C... more The whole-cell patch-clamp technique was used in adult mouse ventricular myocytes at 22 degrees C to study the transient outward current (I(to)) and its sensitivity to the antimycotics miconazole and clotrimazole, as well as to glybenclamide. I(to) elicited by depolarizing steps from a holding potential of -80 mV consisted of a fast inactivating component and a slowly inactivating component. In the presence of miconazole (IC50 of approximately 8 microM) or clotrimazole, I(to) peak amplitude was reduced and its inactivation accelerated, due to a selective suppression of the slow component, without an effect on the fast component or on the noninactivating current. The effect did not reverse upon washout, was not induced by intracellular drug application, and occurred without a change of the steady-state inactivation. In the presence of glybenclamide I(to) peak amplitude was reduced and its inactivation accelerated. In contrast to the antimycotics, glybenclamide suppressed both the fas...
To investigate mechanisms underlying the contractile dysfunction during myocardial "stunning... more To investigate mechanisms underlying the contractile dysfunction during myocardial "stunning," potentiated contractions were studied in Langendorff-perfused rabbit hearts paced at 2.5 Hz. Isovolumetric left ventricular pressure (LVP) and the first derivative of LVP (dP/dt) were measured via a balloon. Potentiated contractions, elicited after 3 s of rest (postrest potentiation, PRP) or with paired pulses (paired-pulse potentiation, PPP) were first characterized in nonischemic conditions. Exposure to 5 nM ryanodine changed PRP into postrest depression [control, 134 +/- 1.7% (SE); ryanodine, 65 +/- 3.4%; n = 5] but did not decrease PPP (control, 125 +/- 7.2%; ryanodine, 141 +/- 14.5%). When sarcolemmal Ca2+ influx was decreased by 0.2-2 microM verapamil, PRP increased (control, 136 +/- 3.7%; 1 microM verapamil, 214 +/- 23.8%; n = 5), whereas PPP was maintained (control, 134 +/- 8.0%; 1 microM verapamil, 154 +/- 11.5%). During ischemia, both PRP and PPP were increased above pr...
The effects of the alkylating agent N-ethylmalemide (NEM) on the L-type Ca current (ICa) of guine... more The effects of the alkylating agent N-ethylmalemide (NEM) on the L-type Ca current (ICa) of guinea-pig ventricular myocytes were studied with the whole-cell voltage-clamp technique at 21-23 degrees C. NEM (50-100 microM) produced an increase in ICa comparable to that produced by cAMP-increasing agents (isoprenaline, forskolin, phosphodiesterase inhibitors). The effects of NEM on ICa were not additive with those of the phosphodiesterase blockers papaverine and isobutylmethylxanthine. They were neither suppressed nor prevented by carbachol (100 microM) and could also not be prevented by pertussis toxin treatment or by cell dialysis with GDP beta S (300 microM) or GTP gamma S (300 microM). NEM, at low concentration (50 microM), increased twitch contraction measured in right ventricular strips. At a higher concentration (> or = 100 microM), this effect was followed by a decrease of the twitch and an increase in basal tension. It is proposed that NEM acts by transiently increasing cAM...
The phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX; 100 microM) and papaverine (1... more The phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX; 100 microM) and papaverine (100 microM) increased peak L-type Ca current (ICa) more than fivefold in a way similar to isoproterenol, forskolin, or intracellular adenosine 3',5'-cyclic monophosphate in guinea pig ventricular myocytes studied with the whole cell voltage-clamp technique at 22-24 degrees C. IBMX and papaverine could also induce a chloride current. Both drugs caused an apparent increase of ICa inactivation as revealed by 1) a negative shift of the ICa inactivation curve between -40 and 0 mV and 2) a suppression of the relief from inactivation at potentials positive to 0 mV. In the presence of IBMX or papaverine, the amplitudes of both the rapidly and slowly inactivating components of ICa were increased; the effect on the fast component was more pronounced. The drugs did not accelerate the inactivation time course of either component. Carbachol (CCh; 100 microM) reversed the increase in ICa produc...
The influence of the organic calcium channel blockers D600 and verapamil on cardiac cholinergic e... more The influence of the organic calcium channel blockers D600 and verapamil on cardiac cholinergic effects was studied using standard electrophysiological techniques on rabbit atrial strips, and using the two-microelectrode voltage-clamp technique on rabbit Purkinje fibers. The interaction between the above drugs as well as between AQA-39, diltiazem or nifedipine and muscarinic receptors was investigated using tritiated quinuclidinylbenzilate ([3H]QNB) binding on rabbit atrial homogenates. The electrophysiological experiments show that D600 and verapamil, at high concentrations (greater than 10(-6) M), inhibit the hyperpolarization and the increase in K+ conductance induced by acetylcholine. The binding experiments show that this inhibitory action of Ca2+ antagonists is due to an interaction at the level of muscarinic receptors. All the Ca2+ channel blockers used, except nifedipine, behave like classical muscarinic antagonists as shown by a 1 to 1 reaction between drug and receptor mol...
African journal of medicine and medical sciences, 1990
Binding and electrophysiological studies were carried out in order to investigate the mechanisms ... more Binding and electrophysiological studies were carried out in order to investigate the mechanisms underlying the cardiac anticholinergic action of chloroquine. Muscarinic receptors of guinea-pig heart homogenates were labelled with tritiated quinuclidinyl-benzilate [( 3H]QNB) in the absence and in the presence of chloroquine. Chloroquine (10(-5)-10(-4) M) produced a shift of the QNB saturation binding curve to the right. Increasing the chloroquine concentration in the presence of a constant QNB concentration produced a progressive decrease in QNB binding, but the QNB-chloroquine competition curves were shallow (Hill coefficients = 0.65). Chloroquine also shifted the QNB-carbachol competition curve to the right without changing its Hill slope. In electrophysiological experiments, chloroquine inhibited the negative chronotropic effect of carbachol in Langendorff-perfused hearts. This inhibitory effect of chloroquine was obtained at concentrations lower than those expected to produce si...
Intracellular Na and K concentrations as well as ouabain-induced transmembrane net Na and K fluxe... more Intracellular Na and K concentrations as well as ouabain-induced transmembrane net Na and K fluxes were measures in erythrocytes (TBC) of 22 adult Black male Zimbabweans. The intracellular Na concentration was 9.1 +/- 0.44 mmol/l RBC, the K concentration 90.7 +/- 1.33 mmol/l RBC and the ouabain (0.1 mM)-induced Na influx 1.55 +/- 0.132 mmol/hr.1 RBC. The intracellular Na concentration is higher than most values reported from studies of Whites, but the intracellular K concentration and the ouabain-induced Na influx compare with literature values. No significant correlation was found between intracellular Na concentration and blood pressure.
An investigation was undertaken into possible vagolytic effects of chloroquine. A single oral dos... more An investigation was undertaken into possible vagolytic effects of chloroquine. A single oral dose of chloroquine was given to healthy human volunteers and its influence on vagally mediated heart rate changes studied. Chloroquine at a dose of 600 mg significantly increased lying and standing heart rates, reduced the beat-to-beat variation of the R-R interval and reduced the heart rate changes induced by deep breathing, by the Valsalva manoeuvre and by standing. Chloroquine at a dose of 225 mg did not produce significant changes of these parameters. The effects of 600 mg chloroquine resemble those obtained with atropine and are consistent with an antimuscarinic receptor effect.
Brain death can have an impact on donor organ function. This is often attributed to an altered ho... more Brain death can have an impact on donor organ function. This is often attributed to an altered hormonal, mainly thyroidal, status after brain death. A second possible explanation is that during the brain death process, blood flow is redistributed, causing ischemic damage in underperfused organs or regions. We investigated blood flow redistribution with colored microspheres in the rat early and late after brain death, induced by inflation of an intracranial balloon, and correlated this with the global hemodynamic situation and plasma catecholamine concentrations. Brain death was proven by the demonstration of lasting absence of brain perfusion in all animals. Myocardial blood flow closely followed the myocardial oxygen need as estimated by the rate-pressure product. The abdominal organs showed intense vasoconstriction early after brain death, which led to significantly decreased perfusion of these organs despite the highly increased perfusion pressure, followed by significant vasodilation. Total plasma catecholamine concentration was 57 times higher at 30 sec after brain death as compared with basal levels. Plasma noradrenaline concentration fell significantly below basal levels late after brain death. We conclude that brain death importantly alters regional perfusion, with possible implications for donor organ function. These changes are probably due to the tremendous alterations in the activity of the sympathetic nervous system.
The triterpene oleanolic acid (OA) is known to possess antihypertensive actions. In the present s... more The triterpene oleanolic acid (OA) is known to possess antihypertensive actions. In the present study we to compared the effects of the triterpene on mean arterial blood pressure (MAP) and kidney function following acute administration in normotensive animals with those of its related oleanane synthetic derivatives (brominated oleanolic acid, Br-OA and oleanolic acid methyl ester, Me-OA). We also used experimental models of hypertension to further explore the effects of sub-chronic oral OA treatment and evaluated influences on oxidative status. OA was extracted from dried flower buds of Syzygium aromaticum using a previously validated protocol in our laboratory. Me-OA and Br-OA were synthesized according to a method described. Rats were supplemented with lithium chloride (12 mmol L-1) prior to experimentation in order to raise plasma lithium to allow measurements of lithium clearance and fractional excretion (FELi) as indices of proximal tubular Na+ handling. Anaesthetized animals were continuously infused via the right jugular with 0.077M NaCl. MAP was measured via a cannula inserted in the carotid artery, and urine was collected through a cannula inserted in the bladder. After a 3.5 h equilibration, MAP, urine flow, electrolyte excretion rates were determined for 4 h of 1 h control, 1.5 h treatment and 1.5 h recovery periods. OA, Me-OA and Br-OA were added to the infusate during the treatment period. We evaluated sub-chronic effects on MAP and kidney function in normotensive Wistar rats and in two animal models of hypertension, spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DSS) rats, during 9-week administration of OA (p.o.). Tissue oxidative status was examined in these animals at the end of the study. Increasing evidence suggests that and renal function disturbances and oxidative stress play major roles in the pathogenesis of hypertension. Acute infusion OA and oleanane derivatives displayed qualitatively similar effects in decreasing MAP and increasing urinary Na+ outputs. The drugs increased the FENa and FELi without influencing GFR indicating that at least part of the overall natriuretic effect involved proximal tubular Na+ reabsorption. Sub-chronic OA administration (p.o.) also elicited hypotensive responses in Wistar, DSS and SHR rats. The MAP lowering effect was more marked in hypertensive animals and were positively correlated with increased urinary Na+ excretion. Compared with respective control rats, OA treatment reduced malondialdehyde (MDA, a marker of lipid peroxidation) and increased activities of antioxidant enzymes; superoxide dismutase and glutathione peroxidase in hepatic, cardiac and renal tissues. OA and oleanane derivatives have similar effects on MAP, kidney function and oxidative stress. The amelioration of oxidative stress and blood pressure lowering effects by OA are more marked in hypertensive animals and correlated with an increased urinary Na+ output. The results of this study are novel in that they show 1) a correlation between blood pressure reduction and increased urinary Na+ excretion by OA, 2) a more marked MAP reduction in hypertensive animals and 3) a drug-induced decrease in proximal tubule Na+ reabsorption. The results may also be clinically relevant because OA is effective via oral administration.
... [14] Brayden JE, Nelson MT. Regulation of arterial tone by activation of calcium-dependent po... more ... [14] Brayden JE, Nelson MT. Regulation of arterial tone by activation of calcium-dependent potassium channels. Science 1992; 256: 532-5. [15] Brayden JE. ... J Physiol 1997; 499: 715-20. [21] Thorneloe KS, Maruyama Y, Malcolm AT, Light PE, Walsh MP, Cole WC. ...
Purkinje cells were isolated from both ventricles of young adult domestic pigs and examined by tr... more Purkinje cells were isolated from both ventricles of young adult domestic pigs and examined by transmitted light or laser scanning confocal microscopy. Purkinje cells in free running Purkinje fibres were organised in multicellular strands where individual cells were tightly connected end-to-end and closely side-to-side. After isolation, single cells gradually lost the elongated appearance and became more rounded, but the cell membrane remained smooth and undamaged. The contractile material was not very dense and was seen most clearly in the submembraneous area. Staining of the cell membrane with the lipophilic fluorescent (lye di-8-ANNEPS, and visualization with confocal microscopy, confirmed that the cell surface membrane was smooth without blebs. This staining also showed that Purkinje cells had no transversal tubules. We reconstructed the three-dimensional geometry of the Purkinje cells and determined the cell size. The average values were 62 +/- 9 microm for length, 32 +/- 3 mic...
American journal of physiology. Heart and circulatory physiology, 2002
In cardiac cells that lack macroscopic transient outward K(+) currents (I(to)), the removal of ex... more In cardiac cells that lack macroscopic transient outward K(+) currents (I(to)), the removal of extracellular Ca(2+) can unmask "I(to)-like" currents. With the use of pig ventricular myocytes and the whole cell patch-clamp technique, we examined the possibility that cation efflux via L-type Ca(2+) channels underlies these currents. Removal of extracellular Ca(2+) and extracellular Mg(2+) induced time-independent currents at all potentials and time-dependent currents at potentials greater than -50 mV. Either K(+) or Cs(+) could carry the time-dependent currents, with reversal potential of +8 mV with internal K(+) and +34 mV with Cs(+). Activation and inactivation were voltage dependent [Boltzmann distributions with potential of half-maximal value (V(1/2)) = -24 mV and slope = -9 mV for activation; V(1/2) = -58 mV and slope = 13 mV for inactivation]. The time-dependent currents were resistant to 4-aminopyridine and to DIDS but blocked by nifedipine at high concentrations (IC(...
Despite the recognized role of traditional healers in helping patients with mental health problem... more Despite the recognized role of traditional healers in helping patients with mental health problems, there is a need for modern mental healthcare facilities in Africa. When made available, these are used by the local population, but less by those at remote locations. Data from the SOSAME centre indicate the high prevalence of mental diseases, especially in urban population and during the active decades of life. To decrease the burden imposed on mental health institutions by patients consulting for non-mental problems, it is desirable to integrate these institutions with the other components of the healthcare system.
The Journal of pharmacology and experimental therapeutics, 2001
The whole-cell patch-clamp technique was used in adult mouse ventricular myocytes at 22 degrees C... more The whole-cell patch-clamp technique was used in adult mouse ventricular myocytes at 22 degrees C to study the transient outward current (I(to)) and its sensitivity to the antimycotics miconazole and clotrimazole, as well as to glybenclamide. I(to) elicited by depolarizing steps from a holding potential of -80 mV consisted of a fast inactivating component and a slowly inactivating component. In the presence of miconazole (IC50 of approximately 8 microM) or clotrimazole, I(to) peak amplitude was reduced and its inactivation accelerated, due to a selective suppression of the slow component, without an effect on the fast component or on the noninactivating current. The effect did not reverse upon washout, was not induced by intracellular drug application, and occurred without a change of the steady-state inactivation. In the presence of glybenclamide I(to) peak amplitude was reduced and its inactivation accelerated. In contrast to the antimycotics, glybenclamide suppressed both the fas...
To investigate mechanisms underlying the contractile dysfunction during myocardial "stunning... more To investigate mechanisms underlying the contractile dysfunction during myocardial "stunning," potentiated contractions were studied in Langendorff-perfused rabbit hearts paced at 2.5 Hz. Isovolumetric left ventricular pressure (LVP) and the first derivative of LVP (dP/dt) were measured via a balloon. Potentiated contractions, elicited after 3 s of rest (postrest potentiation, PRP) or with paired pulses (paired-pulse potentiation, PPP) were first characterized in nonischemic conditions. Exposure to 5 nM ryanodine changed PRP into postrest depression [control, 134 +/- 1.7% (SE); ryanodine, 65 +/- 3.4%; n = 5] but did not decrease PPP (control, 125 +/- 7.2%; ryanodine, 141 +/- 14.5%). When sarcolemmal Ca2+ influx was decreased by 0.2-2 microM verapamil, PRP increased (control, 136 +/- 3.7%; 1 microM verapamil, 214 +/- 23.8%; n = 5), whereas PPP was maintained (control, 134 +/- 8.0%; 1 microM verapamil, 154 +/- 11.5%). During ischemia, both PRP and PPP were increased above pr...
The effects of the alkylating agent N-ethylmalemide (NEM) on the L-type Ca current (ICa) of guine... more The effects of the alkylating agent N-ethylmalemide (NEM) on the L-type Ca current (ICa) of guinea-pig ventricular myocytes were studied with the whole-cell voltage-clamp technique at 21-23 degrees C. NEM (50-100 microM) produced an increase in ICa comparable to that produced by cAMP-increasing agents (isoprenaline, forskolin, phosphodiesterase inhibitors). The effects of NEM on ICa were not additive with those of the phosphodiesterase blockers papaverine and isobutylmethylxanthine. They were neither suppressed nor prevented by carbachol (100 microM) and could also not be prevented by pertussis toxin treatment or by cell dialysis with GDP beta S (300 microM) or GTP gamma S (300 microM). NEM, at low concentration (50 microM), increased twitch contraction measured in right ventricular strips. At a higher concentration (> or = 100 microM), this effect was followed by a decrease of the twitch and an increase in basal tension. It is proposed that NEM acts by transiently increasing cAM...
The phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX; 100 microM) and papaverine (1... more The phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX; 100 microM) and papaverine (100 microM) increased peak L-type Ca current (ICa) more than fivefold in a way similar to isoproterenol, forskolin, or intracellular adenosine 3',5'-cyclic monophosphate in guinea pig ventricular myocytes studied with the whole cell voltage-clamp technique at 22-24 degrees C. IBMX and papaverine could also induce a chloride current. Both drugs caused an apparent increase of ICa inactivation as revealed by 1) a negative shift of the ICa inactivation curve between -40 and 0 mV and 2) a suppression of the relief from inactivation at potentials positive to 0 mV. In the presence of IBMX or papaverine, the amplitudes of both the rapidly and slowly inactivating components of ICa were increased; the effect on the fast component was more pronounced. The drugs did not accelerate the inactivation time course of either component. Carbachol (CCh; 100 microM) reversed the increase in ICa produc...
The influence of the organic calcium channel blockers D600 and verapamil on cardiac cholinergic e... more The influence of the organic calcium channel blockers D600 and verapamil on cardiac cholinergic effects was studied using standard electrophysiological techniques on rabbit atrial strips, and using the two-microelectrode voltage-clamp technique on rabbit Purkinje fibers. The interaction between the above drugs as well as between AQA-39, diltiazem or nifedipine and muscarinic receptors was investigated using tritiated quinuclidinylbenzilate ([3H]QNB) binding on rabbit atrial homogenates. The electrophysiological experiments show that D600 and verapamil, at high concentrations (greater than 10(-6) M), inhibit the hyperpolarization and the increase in K+ conductance induced by acetylcholine. The binding experiments show that this inhibitory action of Ca2+ antagonists is due to an interaction at the level of muscarinic receptors. All the Ca2+ channel blockers used, except nifedipine, behave like classical muscarinic antagonists as shown by a 1 to 1 reaction between drug and receptor mol...
African journal of medicine and medical sciences, 1990
Binding and electrophysiological studies were carried out in order to investigate the mechanisms ... more Binding and electrophysiological studies were carried out in order to investigate the mechanisms underlying the cardiac anticholinergic action of chloroquine. Muscarinic receptors of guinea-pig heart homogenates were labelled with tritiated quinuclidinyl-benzilate [( 3H]QNB) in the absence and in the presence of chloroquine. Chloroquine (10(-5)-10(-4) M) produced a shift of the QNB saturation binding curve to the right. Increasing the chloroquine concentration in the presence of a constant QNB concentration produced a progressive decrease in QNB binding, but the QNB-chloroquine competition curves were shallow (Hill coefficients = 0.65). Chloroquine also shifted the QNB-carbachol competition curve to the right without changing its Hill slope. In electrophysiological experiments, chloroquine inhibited the negative chronotropic effect of carbachol in Langendorff-perfused hearts. This inhibitory effect of chloroquine was obtained at concentrations lower than those expected to produce si...
Intracellular Na and K concentrations as well as ouabain-induced transmembrane net Na and K fluxe... more Intracellular Na and K concentrations as well as ouabain-induced transmembrane net Na and K fluxes were measures in erythrocytes (TBC) of 22 adult Black male Zimbabweans. The intracellular Na concentration was 9.1 +/- 0.44 mmol/l RBC, the K concentration 90.7 +/- 1.33 mmol/l RBC and the ouabain (0.1 mM)-induced Na influx 1.55 +/- 0.132 mmol/hr.1 RBC. The intracellular Na concentration is higher than most values reported from studies of Whites, but the intracellular K concentration and the ouabain-induced Na influx compare with literature values. No significant correlation was found between intracellular Na concentration and blood pressure.
An investigation was undertaken into possible vagolytic effects of chloroquine. A single oral dos... more An investigation was undertaken into possible vagolytic effects of chloroquine. A single oral dose of chloroquine was given to healthy human volunteers and its influence on vagally mediated heart rate changes studied. Chloroquine at a dose of 600 mg significantly increased lying and standing heart rates, reduced the beat-to-beat variation of the R-R interval and reduced the heart rate changes induced by deep breathing, by the Valsalva manoeuvre and by standing. Chloroquine at a dose of 225 mg did not produce significant changes of these parameters. The effects of 600 mg chloroquine resemble those obtained with atropine and are consistent with an antimuscarinic receptor effect.
Brain death can have an impact on donor organ function. This is often attributed to an altered ho... more Brain death can have an impact on donor organ function. This is often attributed to an altered hormonal, mainly thyroidal, status after brain death. A second possible explanation is that during the brain death process, blood flow is redistributed, causing ischemic damage in underperfused organs or regions. We investigated blood flow redistribution with colored microspheres in the rat early and late after brain death, induced by inflation of an intracranial balloon, and correlated this with the global hemodynamic situation and plasma catecholamine concentrations. Brain death was proven by the demonstration of lasting absence of brain perfusion in all animals. Myocardial blood flow closely followed the myocardial oxygen need as estimated by the rate-pressure product. The abdominal organs showed intense vasoconstriction early after brain death, which led to significantly decreased perfusion of these organs despite the highly increased perfusion pressure, followed by significant vasodilation. Total plasma catecholamine concentration was 57 times higher at 30 sec after brain death as compared with basal levels. Plasma noradrenaline concentration fell significantly below basal levels late after brain death. We conclude that brain death importantly alters regional perfusion, with possible implications for donor organ function. These changes are probably due to the tremendous alterations in the activity of the sympathetic nervous system.
Uploads