Fezolamine [N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine-(E)-2- butenedioate] is a new, no... more Fezolamine [N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine-(E)-2- butenedioate] is a new, nontricyclic agent under investigation as a potential antidepressant. In vitro, it was 3 to 4 times more selective in blocking synaptosomal uptake of [3H]norepinephrine than uptake of [3H]serotonin or [3H]dopamine. In classical behavioral tests using monoamine-depleted animals, it prevented the depressant effects of reserpine and tetrabenzine. In addition, it was active in the "behavioral despair" procedure. Its potency in three of these models was similar to that of standard tricyclics (e.g., imipramine, amitriptyline) or newer nontricyclic antidepressants (e.g., bupropion). In the mouse mydriasis and oxotremorine antagonism models, anticholinergic properties of fezolamine were weak or absent compared with imipramine and amitriptyline. Locomotor activity in mice was not increased by fezolamine at doses 2 to 16 times greater than effective antidepressant doses, suggesting the absence of central nervous system stimulant properties. Fezolamine did not inhibit monoamine oxidase activity in ex vivo studies and, unlike pargyline, did not produce locomotor hyperactivity in mice pretreated with L-tryptophan. In vitro studies using canine Purkinje tissue suggest that fezolamine has significantly less ability to depress myocardial conduction parameters than similar concentrations of imipramine. In a myocardially infarcted cat model, plasma levels of fezolamine 19 to 28 times greater than those achieved with imipramine were required before inducing significant depression of cardiac function and mean arterial pressure. Fezolamine, unlike imipramine, did not increase sinus rate. Fezolamine may thus show antidepressant efficacy in man with minimal anticholinergic or cardiovascular side effects common to tricyclic antidepressants.
The cardiovascular effects of the low Km cAMP phosphodiesterase inhibitor milrinone (0.01-0.3 mg/... more The cardiovascular effects of the low Km cAMP phosphodiesterase inhibitor milrinone (0.01-0.3 mg/kg, i.v.) were characterized in anaesthetized dogs with or without beta-adrenoreceptor blockade (nadolol, 1 mg/kg, i.v.). Heart rate was increased by milrinone at greater than or equal to 0.1 mg/kg in non-blocked dogs (61 +/- 5 beats/min [mean +/- SEM, max. change] or 40.5 +/- 6.0%) and at greater than or equal to 0.03 mg/kg in beta-blocked dogs (33 +/- 5 beats/min or 26 +/- 4%). Mean arterial pressure was decreased at greater than or equal to 0.03 mg/kg in non-blocked dogs (-34 +/- 6mmHg or -27 +/- 5%) and at greater than or equal to 0.1 mg/kg in beta-blocked dogs (-17 +/- 4 mmHg or -15 +/- 3%). These changes were or tended to be greater in non-blocked than beta-blocked dogs. The maximum rate of rise in left ventricular pressure was increased at all doses in non-blocked (3747 +/- 388 mmHg/sec or 131 +/- 14%) and beta-blocked dogs (2517 +/- 445 mmHg/sec or 131 +/- 25%), with the absolute but not percent increase being greater in non-blocked than beta-blocked dogs. Left ventricular end diastolic pressure (LVEDP) was or tended to be reduced at greater than or equal to 0.03 mg/kg in beta-blocked dogs (-3 +/- 1 mmHg or -64 +/- 20%) and at 0.01-0.1 mg/kg in non-blocked dogs (-1.4 +/- 0.9 mmHg or -50 +/- 29%). The absolute, but not percent, decrease in LVEDP at 0.03 mg/kg was greater in beta-blocked than non-blocked dogs (-2.2 +/- 0.8 mmHg or 32 +/- 10% vs. 0.0 +/- 0.7 mmHg or 0 +/- 8%). Cardiac output (CO) was or tended to be similarly increased at 0.01-0.03 mg/kg in beta-blocked (0.2 +/- 0.1/min or 15 +/- 5%) and non-blocked dogs (1.2 +/- 0.7 1/min or 40 +/- 16%). In conclusion, beta-blockade attenuated the hypotensive and chronotropic effects, but did not eliminate the positive inotropism, the reduction in cardiac preload or the increase in CO induced by milrinone in anaesthetized dogs.
Journal of Cardiovascular Pharmacology, Nov 1, 1982
The electrophysiological effects of diltiazem were studied in right ventricular muscle fibers fro... more The electrophysiological effects of diltiazem were studied in right ventricular muscle fibers from normal cats and cats with experimentally induced right ventricular systolic hypertension (RVSH). Two types of action potential (AP) abnormalities were observed in preparations from cats with RVSH: Type I cells, found in most areas of the right ventricular free wall, demonstrated reduced maximum diastolic potential (MDP) (-64.4 mV) and Vmax (89.6 V/s) while Type II cells showed a "slow response" AP configuration (MDP, -48.8 mV; AP amplitude, 48.9 mV; AP duration at 50% repolarization, 47.5 ms; AP duration at 90% repolarization, 90.2 ms; Vmax, 13.1 V/s) and were often monitored near the tricuspid valve. Diltiazem (2.2 X 10(-7) and 2.2 X 10(-6) M) had no effect on MDP of normal, Type I, or Type II cells. Diltiazem at 2.2 X 10(-6) M significantly reduced AP amplitude and Vmax of both Type I and normal cells. In contrast, even at 2.2 X 10(-7) M, diltiazem significantly reduced AP amplitude and Vmax of the Type II cells. Diltiazem, 2.2 X 10(-6) M, would often abolish AP of Type II cells, while Type I cells were more sensitive to tetrodotoxin. AP duration of normal cells was unaffected by diltiazem while that of Type I and II cells was significantly shortened.
Extracellular matrix formation is the major component of the restenosis lesion that develops afte... more Extracellular matrix formation is the major component of the restenosis lesion that develops after balloon angioplasty. Although ex vivo studies have shown that the synthesis of collagen is stimulated early after balloon angioplasty, there is a delay in accumulation in the vessel wall. The objectives of this study were to assess collagen turnover and its possible regulation by matrix metalloproteinases (MMPs) in a double-injury iliac artery rabbit model of restenosis. Rabbits were killed at four time points (immediately and at 1, 4, and 12 weeks) after balloon angioplasty. In vivo collagen synthesis and collagen degradation were measured after a 24-hour incubation with [ 14 C]proline. Arterial extracts were also run on gelatin zymograms to determine MMP (gelatinase) activity. Collagen turnover studies were repeated in a group of 1-week postangioplasty rabbits that were treated with daily subcutaneous injections of either a nonspecific MMP inhibitor, GM6001 (100 mg/kg per day), or placebo. Collagen synthesis and degradation showed similar temporal profiles, with significant increases in the balloon-injured iliac arteries compared with control nondilated contralateral iliac arteries immediately after angioplasty and at 1 and 4 weeks. Peak collagen synthesis and degradation occurred at 1 week and were increased (approximately four and three times control values, respectively). Gelatin zymography was consistent with the biochemical data by showing an increase of a 72-kD gelatinase (MMP-2) in the balloon-injured side immediately after the second injury, peaking at 1 week, and still detectable at 4 and 12 weeks (although at lower levels). In balloon-injured arteries, the MMP inhibitor reduced both collagen synthesis and degradation. Overall, at 1 week after balloon angioplasty, GM6001 resulted in a 33% reduction in collagen content in balloon-injured arteries compared with placebo (750±143 to 500±78 μg hydroxyproline per segment, P <.004), which was associated with a nonsignificant 25% reduction in intimal area. Our data suggest that degradation of newly synthesized collagen is an important mechanism regulating collagen accumulation and that MMPs have an integral role in collagen turnover after balloon angioplasty.
Journal of Cardiovascular Electrophysiology, Nov 1, 2005
Introduction: RSD1235 is a novel drug recently shown to convert AF rapidly and safely in patients... more Introduction: RSD1235 is a novel drug recently shown to convert AF rapidly and safely in patients.1 Its mechanism of action has been investigated in a rat model of ischemic arrhythmia, along with changes in action potential (AP) morphology in isolated rat ventricular myocytes and effects on cloned channels. Methods and Results: Ischemic arrhythmias were inhibited with an ED50 of 1.5 μmol/kg/min, and repolarization times increased with non‐significant effects on PR and QRS durations. AP prolongation was observed in rat myocytes at low doses, with plateau elevation and a reduction in the AP overshoot at higher doses. RSD1235 showed selectivity for voltage‐gated K+ channels with IC50 values of 13 μM on hKv1.5 (1 Hz) versus 38 and 30 μM on Kv4.2 and Kv4.3, respectively, and 21 μM on hERG channels. RSD1235 did not block IK1 (IC50 > 1 mM) nor ICa,L (IC50= 220 μM) at 1 Hz in guinea pig ventricular myocytes (n = 4–5). The drug displayed mild (IC50= 43 μM at 1 Hz) open‐channel blockade of Nav1.5 with rapid recovery kinetics after rate reduction (10→1 Hz, 75% recovery with τ= 320 msec). Nav1.5 blocking potency increased with stimulus frequency from an IC50= 40 μM at 0.25 Hz, to an IC50= 9 μM at 20 Hz, and with depolarization increasing from 107 μM at −120 mV to 31 μM at −60 mV (1 Hz). Conclusions: These data suggest that RSD1235's clinical selectivity and AF conversion efficacy result from block of potassium channels combined with frequency‐ and voltage‐dependent block of INa.
Advances in Experimental Medicine and Biology, 1991
The recent gain in knowledge over the last ten years on the intracellular mechanisms which regula... more The recent gain in knowledge over the last ten years on the intracellular mechanisms which regulate vascular smooth muscle tone has expanded opportunities for the potential discovery of novel vasodilator/antihypertensive agents. This review focuses on three intracellular enzyme systems: myosin light chain kinase (MLCK) and protein kinase C (PKC), which are Ca2+-regulated protein kinases implicated in the control of smooth muscle tone, and the cGMP phosphodiesterases (PDEs), which regulate the levels of cGMP in smooth muscle (Fig. 1).
Fezolamine [N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine-(E)-2- butenedioate] is a new, no... more Fezolamine [N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine-(E)-2- butenedioate] is a new, nontricyclic agent under investigation as a potential antidepressant. In vitro, it was 3 to 4 times more selective in blocking synaptosomal uptake of [3H]norepinephrine than uptake of [3H]serotonin or [3H]dopamine. In classical behavioral tests using monoamine-depleted animals, it prevented the depressant effects of reserpine and tetrabenzine. In addition, it was active in the "behavioral despair" procedure. Its potency in three of these models was similar to that of standard tricyclics (e.g., imipramine, amitriptyline) or newer nontricyclic antidepressants (e.g., bupropion). In the mouse mydriasis and oxotremorine antagonism models, anticholinergic properties of fezolamine were weak or absent compared with imipramine and amitriptyline. Locomotor activity in mice was not increased by fezolamine at doses 2 to 16 times greater than effective antidepressant doses, suggesting the absence of central nervous system stimulant properties. Fezolamine did not inhibit monoamine oxidase activity in ex vivo studies and, unlike pargyline, did not produce locomotor hyperactivity in mice pretreated with L-tryptophan. In vitro studies using canine Purkinje tissue suggest that fezolamine has significantly less ability to depress myocardial conduction parameters than similar concentrations of imipramine. In a myocardially infarcted cat model, plasma levels of fezolamine 19 to 28 times greater than those achieved with imipramine were required before inducing significant depression of cardiac function and mean arterial pressure. Fezolamine, unlike imipramine, did not increase sinus rate. Fezolamine may thus show antidepressant efficacy in man with minimal anticholinergic or cardiovascular side effects common to tricyclic antidepressants.
The cardiovascular effects of the low Km cAMP phosphodiesterase inhibitor milrinone (0.01-0.3 mg/... more The cardiovascular effects of the low Km cAMP phosphodiesterase inhibitor milrinone (0.01-0.3 mg/kg, i.v.) were characterized in anaesthetized dogs with or without beta-adrenoreceptor blockade (nadolol, 1 mg/kg, i.v.). Heart rate was increased by milrinone at greater than or equal to 0.1 mg/kg in non-blocked dogs (61 +/- 5 beats/min [mean +/- SEM, max. change] or 40.5 +/- 6.0%) and at greater than or equal to 0.03 mg/kg in beta-blocked dogs (33 +/- 5 beats/min or 26 +/- 4%). Mean arterial pressure was decreased at greater than or equal to 0.03 mg/kg in non-blocked dogs (-34 +/- 6mmHg or -27 +/- 5%) and at greater than or equal to 0.1 mg/kg in beta-blocked dogs (-17 +/- 4 mmHg or -15 +/- 3%). These changes were or tended to be greater in non-blocked than beta-blocked dogs. The maximum rate of rise in left ventricular pressure was increased at all doses in non-blocked (3747 +/- 388 mmHg/sec or 131 +/- 14%) and beta-blocked dogs (2517 +/- 445 mmHg/sec or 131 +/- 25%), with the absolute but not percent increase being greater in non-blocked than beta-blocked dogs. Left ventricular end diastolic pressure (LVEDP) was or tended to be reduced at greater than or equal to 0.03 mg/kg in beta-blocked dogs (-3 +/- 1 mmHg or -64 +/- 20%) and at 0.01-0.1 mg/kg in non-blocked dogs (-1.4 +/- 0.9 mmHg or -50 +/- 29%). The absolute, but not percent, decrease in LVEDP at 0.03 mg/kg was greater in beta-blocked than non-blocked dogs (-2.2 +/- 0.8 mmHg or 32 +/- 10% vs. 0.0 +/- 0.7 mmHg or 0 +/- 8%). Cardiac output (CO) was or tended to be similarly increased at 0.01-0.03 mg/kg in beta-blocked (0.2 +/- 0.1/min or 15 +/- 5%) and non-blocked dogs (1.2 +/- 0.7 1/min or 40 +/- 16%). In conclusion, beta-blockade attenuated the hypotensive and chronotropic effects, but did not eliminate the positive inotropism, the reduction in cardiac preload or the increase in CO induced by milrinone in anaesthetized dogs.
Journal of Cardiovascular Pharmacology, Nov 1, 1982
The electrophysiological effects of diltiazem were studied in right ventricular muscle fibers fro... more The electrophysiological effects of diltiazem were studied in right ventricular muscle fibers from normal cats and cats with experimentally induced right ventricular systolic hypertension (RVSH). Two types of action potential (AP) abnormalities were observed in preparations from cats with RVSH: Type I cells, found in most areas of the right ventricular free wall, demonstrated reduced maximum diastolic potential (MDP) (-64.4 mV) and Vmax (89.6 V/s) while Type II cells showed a "slow response" AP configuration (MDP, -48.8 mV; AP amplitude, 48.9 mV; AP duration at 50% repolarization, 47.5 ms; AP duration at 90% repolarization, 90.2 ms; Vmax, 13.1 V/s) and were often monitored near the tricuspid valve. Diltiazem (2.2 X 10(-7) and 2.2 X 10(-6) M) had no effect on MDP of normal, Type I, or Type II cells. Diltiazem at 2.2 X 10(-6) M significantly reduced AP amplitude and Vmax of both Type I and normal cells. In contrast, even at 2.2 X 10(-7) M, diltiazem significantly reduced AP amplitude and Vmax of the Type II cells. Diltiazem, 2.2 X 10(-6) M, would often abolish AP of Type II cells, while Type I cells were more sensitive to tetrodotoxin. AP duration of normal cells was unaffected by diltiazem while that of Type I and II cells was significantly shortened.
Extracellular matrix formation is the major component of the restenosis lesion that develops afte... more Extracellular matrix formation is the major component of the restenosis lesion that develops after balloon angioplasty. Although ex vivo studies have shown that the synthesis of collagen is stimulated early after balloon angioplasty, there is a delay in accumulation in the vessel wall. The objectives of this study were to assess collagen turnover and its possible regulation by matrix metalloproteinases (MMPs) in a double-injury iliac artery rabbit model of restenosis. Rabbits were killed at four time points (immediately and at 1, 4, and 12 weeks) after balloon angioplasty. In vivo collagen synthesis and collagen degradation were measured after a 24-hour incubation with [ 14 C]proline. Arterial extracts were also run on gelatin zymograms to determine MMP (gelatinase) activity. Collagen turnover studies were repeated in a group of 1-week postangioplasty rabbits that were treated with daily subcutaneous injections of either a nonspecific MMP inhibitor, GM6001 (100 mg/kg per day), or placebo. Collagen synthesis and degradation showed similar temporal profiles, with significant increases in the balloon-injured iliac arteries compared with control nondilated contralateral iliac arteries immediately after angioplasty and at 1 and 4 weeks. Peak collagen synthesis and degradation occurred at 1 week and were increased (approximately four and three times control values, respectively). Gelatin zymography was consistent with the biochemical data by showing an increase of a 72-kD gelatinase (MMP-2) in the balloon-injured side immediately after the second injury, peaking at 1 week, and still detectable at 4 and 12 weeks (although at lower levels). In balloon-injured arteries, the MMP inhibitor reduced both collagen synthesis and degradation. Overall, at 1 week after balloon angioplasty, GM6001 resulted in a 33% reduction in collagen content in balloon-injured arteries compared with placebo (750±143 to 500±78 μg hydroxyproline per segment, P <.004), which was associated with a nonsignificant 25% reduction in intimal area. Our data suggest that degradation of newly synthesized collagen is an important mechanism regulating collagen accumulation and that MMPs have an integral role in collagen turnover after balloon angioplasty.
Journal of Cardiovascular Electrophysiology, Nov 1, 2005
Introduction: RSD1235 is a novel drug recently shown to convert AF rapidly and safely in patients... more Introduction: RSD1235 is a novel drug recently shown to convert AF rapidly and safely in patients.1 Its mechanism of action has been investigated in a rat model of ischemic arrhythmia, along with changes in action potential (AP) morphology in isolated rat ventricular myocytes and effects on cloned channels. Methods and Results: Ischemic arrhythmias were inhibited with an ED50 of 1.5 μmol/kg/min, and repolarization times increased with non‐significant effects on PR and QRS durations. AP prolongation was observed in rat myocytes at low doses, with plateau elevation and a reduction in the AP overshoot at higher doses. RSD1235 showed selectivity for voltage‐gated K+ channels with IC50 values of 13 μM on hKv1.5 (1 Hz) versus 38 and 30 μM on Kv4.2 and Kv4.3, respectively, and 21 μM on hERG channels. RSD1235 did not block IK1 (IC50 > 1 mM) nor ICa,L (IC50= 220 μM) at 1 Hz in guinea pig ventricular myocytes (n = 4–5). The drug displayed mild (IC50= 43 μM at 1 Hz) open‐channel blockade of Nav1.5 with rapid recovery kinetics after rate reduction (10→1 Hz, 75% recovery with τ= 320 msec). Nav1.5 blocking potency increased with stimulus frequency from an IC50= 40 μM at 0.25 Hz, to an IC50= 9 μM at 20 Hz, and with depolarization increasing from 107 μM at −120 mV to 31 μM at −60 mV (1 Hz). Conclusions: These data suggest that RSD1235's clinical selectivity and AF conversion efficacy result from block of potassium channels combined with frequency‐ and voltage‐dependent block of INa.
Advances in Experimental Medicine and Biology, 1991
The recent gain in knowledge over the last ten years on the intracellular mechanisms which regula... more The recent gain in knowledge over the last ten years on the intracellular mechanisms which regulate vascular smooth muscle tone has expanded opportunities for the potential discovery of novel vasodilator/antihypertensive agents. This review focuses on three intracellular enzyme systems: myosin light chain kinase (MLCK) and protein kinase C (PKC), which are Ca2+-regulated protein kinases implicated in the control of smooth muscle tone, and the cGMP phosphodiesterases (PDEs), which regulate the levels of cGMP in smooth muscle (Fig. 1).
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Papers by Alan Ezrin