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D S Reddy

Publications and source records attributed to D S Reddy.

At least 37 records · Page 2Linked to original sources
PubMed1998

Inhibition of neuronal nitric oxide synthase (n-cNOS) reverses the corticotrophin-induced behavioral effects in rats.

The nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine (N-NMMA) and the competitive substrate for NO synthase L-arginine were used to determine the role of endogenous NO on the behavioral and neuroendocrine responsiveness following systemic corticotrophin in dexamethasone-suppressed rats. Corticotrophin (50-200 mU/kg, s.c.) dose-dependently decreased behavioral activity in the actimeter and produced significant anxiolytic and anti-risk activity in the plus-maze behavior test, without affecting systolic blood pressure. Rats given corticotrophin showed significant increased plasma corticosterone and reduced adrenal ascorbic acid level. These behavioral and adrenal responses of corticotrophin were dose dependently blocked by metyrapone (20 and 50 mg/kg, i.p.), an inhibitor of steroid 11beta-hydroxylase in adrenal and neural tissues that block steroidogenesis. Intracerebroventricular administration of L-NMMA (20 microg/rat in 10 microl) significantly prevented the behavioral hypoactivity and anxiolytic-like responses of corticotrophin without influencing the adrenal responsiveness. The effect of L-NMMA was completely reversed by preadministration of L-arginine (300 mg/kg, i.p.). These results suggest that neuronal nitric oxide pathway plays an important modulating role in the behavioral effects of corticotrophin by mechanisms other than those involving cardiovascular effects.

Adrenocorticotropic Hormone↗
PubMed1998

Newer thrombolytic drugs for acute myocardial infarction.

Arterial thrombosis is the underlying cause of a wide variety of cardiovascular diseases such as myocardial infarction, stroke and pulmonary thromboembolism. All the currently used thrombolytic agents are plasminogen activators, which are very efficient in restoring the blood flow. The fibrinolytic system comprises an inactive proenzyme plasminogen, that is converted by plasminogen activators to the enzyme plasmin, that degrades fibrin. Despite the widespread use of established thrombolytic agents such as streptokinase, tissue-plasminogen activator and urokinase, all these agents suffer from a number of inadequacies including resistance to reperfusion, occurrence of acute coronary reocclusion and bleeding complications. The quest continues for thrombolytic agents with a higher potency, specific thrombolytic activity and fibrin selectivity. Several lines of research towards improvement of thrombolytic agents are being explored including the construction of mutants and variants of plasminogen activators, chimeric plasminogen activators and conjugates of plasminogen activators with monoclonal antibodies. Newer molecules such as pro-urokinase, saruplase, alteplase, K1K2Pu and staphylokinase have shown promise in animal models of arterial and venous thrombosis and also in pilot scale clinical studies in patients with myocardial infarction. However, more clinical trials are needed to determine whether these novel recombinant thrombolytic agents shows improved efficacy and fibrin specificity with minimal bleeding tendencies.

Animals↗
PubMed1997

Chronic neurosteroid treatment prevents the development of morphine tolerance and attenuates abstinence behavior in mice.

The effect of neurosteroids on the development of morphine tolerance and dependence was examined in mice. Development of tolerance to the antinociceptive effect of morphine sulfate (10 mg/kg, twice daily for 9 days) was measured in the tail-flick test and dependence was assessed from naloxone (2 mg/kg)-precipitated withdrawal jumps on day 10 of testing. Concomitant chronic administration of neurosteroids, allopregnanolone (0.5 mg/kg), pregnenolone sulfate (2 and 5 mg/kg) or dehydroepiandrosterone sulfate (2 and 5 mg/kg), followed by morphine (10 mg/kg) prevented the development of tolerance to the antinociceptive effect of morphine and suppressed the naloxone-precipitated withdrawal jumps. In contrast, dehydroepiandrosterone acetate (5 mg/kg) failed to modulate the morphine tolerance and dependence. The inhibitory effect was also seen upon concomitant administration of a neurosteroid precursor, progesterone (1-10 mg/kg), and a mitochondrial diazepam binding inhibitor receptor agonist, 4'-chlordiazepam (0.25-1 mg/kg), while an adrenocorticosteroid, hydrocortisone (1 and 10 mg/kg), failed to do so. However, acute treatment with these neurosteroids was not associated with any decrease in withdrawal jumping behavior in morphine-dependent mice. Neurosteroids themselves, at doses employed in the study, did not exert any effects on antinociception. These results support a role for neurosteroids in the development of tolerance to and dependence on morphine and suggest the potential utility of specific neuroactive steroids in its treatment.

Analgesics, Opioid↗
PubMed1997

Differential anxiolytic effects of neurosteroids in the mirrored chamber behavior test in mice.

This study examined the effects of neurosteroids on the behavior of mice in the mirrored chamber test of anxiety, and determined the potential mechanisms by which neurosteroids alter the behavior in animal models of anxiety. Allopregnanolone (AP) (0.5 and 1 mg/kg) and pregnenolone sulfate (PS) (0.5 and 2 mg/kg) significantly reduced the latency to enter the chamber, and increased both number of entries and total time spent in the chamber in a dose-dependent manner, without affecting the spontaneous locomotor activity. In contrast, dehydroepiandrosterone sulfate (DHEAS) (1 and 2 mg/kg) increased motor activity and caused an anxiogenic response, i.e., an increase in latency to enter the mirrored chamber, and a decrease in the number of entries and time spent in the chamber. Progesterone (PROG) (1-10 mg/kg), a neurosteroid precursor, and 4'-chlordiazepam (4'-CD) (0.25-1 mg/kg), a specific ligand for the mitochondrial diazepam binding inhibitor (DBI) receptor (MDR), produced a clear dose-dependent anxiolytic response in the mirrored chamber. The AP-, PROG- and 4'-CD-elicited anxiolytic behavior was blocked by picrotoxin (1 mg/kg), a GABA-A chloride channel antagonist, but not by flumazenil (2 mg/kg), a selective benzodiazepine (BZD) antagonist. In contrast, the anxiolytic effect of PS was not blocked by picrotoxin. The 4'-CD-induced anxiolytic effect was prevented by pretreatment with PK11195 (2 mg/kg), a selective partial MDR antagonist. Nifedipine (2 and 5 mg/kg), a dihydropyridine-type Ca2+ channel blocker, produced a flumazenil-resistant anxiolytic effect. Combined administration of nifedipine (2 and 5 mg/kg) and PS (0.5 and 2 mg/kg) exerted a significant additive effect in the mirrored chamber test. The potent anxiolytic effect of dizocilpine (0.5 and 1 mg/kg), an NMDA receptor antagonist, was blocked by pretreatment with DHEAS (2 mg/kg). Neurosteroids evoked changes in mirrored chamber activities resembling those elicited by triazolam (0.25 and 0.5 mg/kg). However, these effects were seen at doses that did not markedly affect locomotor activity, thereby suggesting these changes in behavior represent anxiolytic actions. Together, these results provide evidence for differential behavioral actions of the neurosteroids AP, PS and DHEAS in the mirrored chamber test of anxiety. The anxiolytic effect of PROG may be imputed to its metabolism to neurosteroid AP, while the 4'-CD-induced anxiolytic response is related to its MDR-stimulated neurosteroidogenesis and subsequent modulation of GABA-A receptor. Further, these differential effects reaffirm the contention that neurosteroids could be involved in the homeostasis of stress response.

Animals↗
PubMed1997

Reversal of benzodiazepine inverse agonist FG 7142-induced anxiety syndrome by neurosteroids in mice.

We have previously shown that neurosteroids produce GABA-A receptor mediated antistress, anxiolytic and other behavioral effects in rodents. In the present study, the effects of neuroactive steroids on benzodiazepine receptor inverse agonist FG 7142-induced anxiogenesis were investigated using mirrored chamber and elevated plus-maze paradigms in mice. FG 7142 (5-20 mg/kg) not only produced a dose-dependent reduction in the duration of open arm exploration and the total number of open arm entries, but also increased the latency to enter the mirrored chamber, decreased the number of entries and total time spent in the chamber, indicative of anxiogenic-like effects. Neurosteroids allopregnanolone (0.5 and 1.5 mg/kg) and pregnenolone sulfate (2 mg/kg) significantly reversed the FG 7142 (10 mg/kg)-induced anxiogenic response in both the paradigms, without producing any neurotoxicity. While dehydroepiandrosterone sulfate (1 and 2 mg/kg) failed to influence the anxiogenic effects of FG 7142. The neuroactive steroid progesterone (1-10 mg/kg), and the mitochondrial diazepam binding inhibitor (DBI) receptor agonist 4'-chlordiazepam (0.5 and 1 mg/kg) dose-dependently blocked the FG 7142-induced anxiogenesis in a flumazenil (2 mg/kg)-insensitive manner. The 4'-chlordiazepam-induced reversal response was, however, prevented by pretreatment with PK11195 (2 mg/kg), a selective mitochondrial DBI receptor antagonist. Further, at the anxiolytic doses, these neurosteroids did not produce locomotor inhibition and ataxia. These data suggest that neurosteroids allopregnanolone, pregnenolone sulfate, progesterone and the mitochondrial DBI receptor agonist 4'-chlordiazepam reverses the anxiogenic-like effects of benzodiazepine receptor inverse agonist FG 7142 in the mouse models of anxiety.

Animals↗
PubMed1996

Role of cardiac renin-angiotensin system in the development of pressure-overload left ventricular hypertrophy in rats with abdominal aortic constriction.

Possible involvement of cardiac renin-angiotensin system (RAS) in pressure overload induced left ventricular hypertrophy (LVH) was investigated. Rats were subjected to abdominal aortic constriction (AAC) and examined the effects of 4 weeks treatments with an angiotensin converting enzyme (ACE) inhibitor, captopril and a vasodilator, hydralazine on haemodynamics and ventricular RNA, DNA, protein and myosin isoform pattern in sham and hypertrophied rats. AAC increased the mean arterial pressure (MAP) and systolic blood pressure (SBP), and resulted in increased left ventricle/body weight ratio, LV thickness, RNA and protein content, however total DNA was not changed. The expression of fetal isogene, beta-myosin heavy chain (beta-MHC), was markedly enhanced where as alpha-MHC was reduced. High-dose captopril (100 mg/kg p.o.,) significantly prevented the increase in haemodynamics, development of LVH, LV remodeling, increase in total protein, RNA and antithetical expression of myosin isoforms. Hydralazine (15 mg/kg p.o.,), did not modulate hypertrophic changes and low-dose captopril (1.5 mg/kg p.o.,) which has not produced any marked fall in MAP and SBP also modulated favourably the development of LVH and its biochemical markers. Thus, the prevention of the development of LVH and induction of beta-MHC by non-hypotensive doses of captopril may be related to the blockade of intracardiac production of angiotensin II rather than circulating system. These results suggest that cardiac RAS may play an important role in pressure overload induced LVH.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Role of GABA-A and mitochondrial diazepam binding inhibitor receptors in the anti-stress activity of neurosteroids in mice.

Neuroactive steroidal modulation of immobilization-stress and possible involvement of GABA-A and mitochondrial diazepam binding inhibitor (DBI) receptors (MDR) has been investigated in mice. Immobilization of mice for 2 h induced intense antinociception, anxiety state, and associated with a fall in adrenal ascorbic acid levels. Pretreatment with high dose of progesterone (10 mg/kg), a precursor of neurosteroids, significantly decreased the stress-induced antinociception, anxiety and fall in adrenal ascorbic acid, while low doses (1 and 5 mg/kg) or hydrocortisone (10 and 100 mg/kg) were ineffective. In contrast, progesterone (1 mg/kg, for 9 days) produced a significant antistress effect, which was blocked by GABA-A antagonists picrotoxin (1 mg/kg) and bicuculline (1 mg/kg), but not by flumazenil (2 mg/kg), a specific benzodiazepine (BZD) antagonist. 4'-chlordiazepam (0.1 and 0.25 mg/kg), a specific high affinity MDR agonist, produced significant anti-stress effect in a flumazenil-insensitive manner, but was blocked by pretreatment with PK11195 (1.5 mg/kg), a selective partial agonist of MDR, and with bicuculline (1 mg/kg), a potent GABA-A receptor antagonist. At higher doses, progesterone and 4'-chlordiazepam which are effective in immobilization stress also reduced locomotion. However, lower doses of progesterone (6.5 mg/kg) neither affected locomotion, nor produced any motor toxicity on rota-rod test. At the lower doses, the MDR ligand 4'-chlordiazepam (50 micrograms/kg) decreased locomotor activity, without altering motor toxicity on rota-rod test. Further, the per se effects of these treatments on unstressed mice were not significantly different from those of untreated controls, except for plus-maze test. The antistress profile of progesterone may be attributed to the in vivo production of neurosteroid allopregnanolone, thus resembled that of BZDs. Furthermore, the antistress actions are flumazenil-resistant, reaffirming that there may be an increase in the levels of pregnane neurosteroids in vivo, which may act on a specific allosteric site on GABA-A receptors distinct from BZD site. Because 4'-chlordiazepam binds to MDRs and stimulate mitochondrial neurosteroidogenesis, the anti-stress effects of 4'-chlordiazepam may be imputed to its MDR-induced neurosteroids, which then act on GABA-A receptors. These data suggest a pivotal role for GABA-A and mitochondrial DBI receptors in the antistress actions of neurosteroids and reinforces their ameliorative effect in physiological stress.

Analysis of Variance↗
PubMed1996

Effects of long-term hydralazine treatment on myocardial structure and expression of myosin isogenes in cardiac pressure overload in rats.

The long-term effects of an arterial vasodilator, hydralazine, on myocardial structure and cardiac myosin isogene expression in pressure overload in rats were investigated. Portan rats were subjected to pressure overload by partial abdominal aortic constriction in order to study the effects of a 4-week treatment with hydralazine (15 mg/kg p.o.) on hemodynamics, ventricular structure, and ventricular total RNA, DNA, protein and myosin isoform expression pattern in sham (SO) and pressure-overloaded (p.o.) rats. P.o. increased the mean arterial pressure (MAP) and systolic blood pressure (SBP) and resulted in increased ventricular weight, LV wall thickness, total RNA and protein content; however, total DNA remained unchanged. The expression of fetal isogene beta-myosin heavy chain (beta-MHC) was markedly enhanced, whereas alpha-MHC was reduced. Hydralazine (15 mg/kg p.o.) normalized MAP and SBP, but did not modulate the hypertrophic changes of pressure-overloaded myocardium. It did not prevent an increase in ventricular total RNA and protein content and antithetical expression of myosin isoforms. Overall growth rate of rats was unaffected by hydralazine treatment. These results suggest that hydralazine has no direct effect in preventing the progression of cardiac hypertrophy and expression of beta-MHC, in spite of lowering blood pressure in pressure-overloaded rats. Thus, it further reaffirms that factors other than hemodynamics may play a pivotal role in the development of cardiac hypertrophy and induction of fetal isogene expression.

Analysis of Variance↗
PubMed1996

Comparative antioxidant effects of beta-adrenoceptor blockers, calcium antagonists and U-74500A against iron-dependent lipid peroxidation in murine ventricular microsomal membranes.

Recently we have shown that ACE inhibitors and platelet activating factor antagonists inhibit iron-dependent lipid peroxidation in murine ventricular membranes and possess beneficial effects on ischemia and ischemia reperfusion-induced myocardial injury, which has been ascribed to their capacity to scavenge or impair oxygen free radical generation. In the present study we investigated the effects of beta-adrenoceptor blockers and calcium antagonists on iron-dependent lipid peroxidation (LPO) in murine ventricular membranes and compared them with the lazaroid U-74500A, a potent antioxidant. Fe(2+)-vitamin C induced LPO in a concentration- and time-dependent manner, measured as thiobarbituric acid reactive substances (TBARS) formation. Pretreatment of ventricular membranes with gallopamil, verapamil, propranolol and metaprolol at concentrations of 5 microM and higher inhibited Fe(2+)-vitamin C-induced LPO in a concentration-dependent manner with IC50 values of 192.8-208.3 microM; however, they were less potent than U-74500A (IC50 6.8 microM). In contrast, atenolol, timolol, diltiazem and nifedipine inhibited LPO at very high concentrations with IC50 values of 864.5-971.5 microM. Inhibition of LPO may not be due to the drugs' classical pharmacological actions, but rather to their characteristic chemical structures or physicochemical interactions with biological membranes. In view of the pathological importance of LPO in cardiac ischemic injury, inhibition of LPO by gallopamil, verapamil, propranolol and metaprolol may provide additional cardioprotective activity and thus reinforces their beneficial effects in the treatment of ischemic heart disease.

Adrenergic beta-Antagonists↗
PubMed1987

Inactivation of clostridial ferredoxin and pyruvate-ferredoxin oxidoreductase by sodium nitrite.

Clostridial ferredoxin and pyruvate-ferredoxin oxidoreductase activity was investigated after in vitro or in vivo treatment with sodium nitrite. In vitro treatment of commercially available Clostridium pasteurianum ferredoxin with sodium nitrite inhibited ferredoxin activity. Inhibition of ferredoxin activity increased with increasing levels of sodium nitrite. Ferredoxin was isolated from normal C. pasteurianum and Clostridium botulinum cultures and from cultures incubated with 1,000 micrograms of sodium nitrite per ml for 45 min. The activity of in vivo nitrite-treated ferredoxin was decreased compared with that of control ferredoxin. Pyruvate-ferredoxin oxidoreductase isolated from C. botulinum cultures incubated with 1,000 micrograms of sodium nitrite per ml showed less activity than did control oxidoreductase. It is concluded that the antibotulinal activity of nitrite is due at least in part to inactivation of ferredoxin and pyruvate-ferredoxin oxidoreductase.

Clostridium↗
PubMedDate not supplied

Antiperoxidative effects of platelet activating factor antagonists against iron-dependent lipid peroxidation in murine ventricular membranes.

Platelet activating factor (PAF) antagonists have been recently documented to possess beneficial effects on ischemia and ischemia-reperfusion-induced myocardial injury. Moreover, their ameliorative effect has been ascribed to their capacity to scavenge or impair oxygen free radical generation. In the present study, the effect of PAF antagonists BN 52021, BN 52030 and BN 52039 on iron-initiated lipid peroxidation (LPO) was investigated in murine ventricular membranes and compared with a potent antioxidant, U-74500A ( a lazaroid). Fe2+ -Vitamin C induced a concentration and time-dependent LPO, measured as thiobarbituric acid reactive substances (TBARS) by standard malondialdehyde (MDA) curve. PAF antagonists were pretreated to ventricular membranes in 5 microM and higher concentrations. All three agents inhibited Fe2+ -Vitamin C-initiated LPO in a concentration-dependent manner with an IC50 value ranging from 103.7 to 373.5 microM; however, they were less potent than U-74500A (IC50 6.8 microM). Inhibition of LPO may not be due to their classical pharmacological actions, but may be attributed to characteristic chemical structure or their physicochemical interactions with biological membranes. Inhibition of LPO may provide additional cardioprotective activity and thus reaffirms their use in ischemic heart disease.

Animals↗