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In the past 10 years, mortality from acute myocardial infarction has not decreased despite the widespread introduction of percutaneous coronary intervention. The reason for this situation is the absence in clinical practice of drugs capable of preventing reperfusion injury of the heart with high efficiency. In this regard, noteworthy natriuretic peptides (NPs) which have the infarct-limiting effect, prevent reperfusion cardiac injury, prevent adverse post-infarction remodeling of the heart. Atrial natriuretic peptide does not have the infarct-reducing effect in rats with alloxan-induced diabetes mellitus. NPs have the anti-apoptotic and anti-inflammatory effects. There is indirect evidence that NPs inhibit pyroptosis and autophagy. Published data indicate that NPs inhibit reactive oxygen species production in cardiomyocytes, aorta, heart, kidney and the endothelial cells. NPs can suppress aldosterone, angiotensin II, endothelin-1 synthesize and secretion. NPs inhibit the effects aldosterone, angiotensin II on the post-receptor level through intracellular signaling events. NPs activate guanylyl cyclase, protein kinase G and protein kinase A, and reduce phosphodiesterase 3 activity. NO-synthase and soluble guanylyl cyclase are involved in the cardioprotective effect of NPs. The cardioprotective effect of natriuretic peptides is mediated via activation of kinases (AMPK, PKC, PI3 K, ERK1/2, p70s6 k, Akt) and inhibition of glycogen synthase kinase 3β. The cardioprotective effect of NPs is mediated via sarcolemmal KATP channel and mitochondrial KATP channel opening. The cardioprotective effect of brain natriuretic peptide is mediated via MPT pore closing. The anti-fibrotic effect of NPs may be mediated through inhibition TGF-β1 expression. Natriuretic peptides can inhibit NF-κB activity and activate GATA. Hemeoxygenase-1 and peroxisome proliferator-activated receptor γ may be involved in the infarct-reducing effect of NPs. NPs exhibit the infarct-limiting effect in patients with acute myocardial infarction. NPs prevent post-infarction remodeling of the heart. To finally resolve the question of the feasibility of using NPs in AMI, a multicenter, randomized, blind, placebo-controlled study is needed to assess the effect of NPs on the mortality of patients after AMI. [ABSTRACT FROM AUTHOR]

We have established that the continuous cold exposure (CCE, 4°C, 4 weeks) causes cold adaptation, increases systolic blood pressure, exerts infarct-limiting effect during coronary artery occlusion (45 min) and reperfusion (2 h). The CCE increases adrenal weight, heart weight and triiodothyronine (T3) level but does not change thymus, spleen weight, serum cortisol, corticosterone and thyroxin (T4) levels. The long-term (4°C, 8 h/day, 4 weeks) intermittent cold exposure (LICE) induces adaptation to the cold and increases T4 level. The brief (4°C, 1.5 h/day, 4 weeks) intermittent cold exposure (BICE) also evokes adaptation to the cold but had no effect on the blood pressure, the cardiac tolerance to ischemia/reperfusion, and does not change thymus, spleen weight, serum cortisol, corticosterone, T3 and T4 levels. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate the efficacy of selective ETA receptor antagonist, ambrisentan on hyperhomocysteinemia-induced experimental vascular dementia. L-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats. Ambrisentan was administered to L-methionine-treated effect rats for 4 weeks (starting from 5th to 8th week of L-methionine treatment). On 52nd day onward, the animals were exposed to the Morris water maze (MWM) for testing their learning and memory abilities. Vascular endothelial function, serum nitrite/nitrate levels, brain thiobarbituric acid reactive species (TBARS), brain reduced glutathione (GSH) levels, and brain acetylcholinesterase (AChE) activity were also measured. L-methionine- treated animals showed significant learning and memory impairment, endothelial dysfunction, decrease in/serum nitrite/nitrate and brain GSH levels along with an increase in brain TBARS levels and AChE activity. Ambrisentan significantly improved hyperhomocysteinemia-induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. These effects were comparable to that of donepezil serving as positive control. It is concluded that ambrisentan, a selective ETA receptor antagonist may be considered as a potential pharmacological agent for the management of hyperhomocysteinemia-induced vascular dementia. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate the potential of aliskiren, a direct renin inhibitor, in chronic constriction injury (CCI)-induced neuropathic pain in rats. Neuropathic pain was induced by placing four loose ligatures around the sciatic nerve. Acetone drop, von Frey hair, pin-prick and hot plate tests were performed to assess cold allodynia, mechanical allodynia, mechanical and heat hyperalgesia, respectively. The levels of Tumor necrosis factor-alpha (TNF-α) were measured in the sciatic nerve as an inflammatory marker. CCI was associated with the development of cold allodynia, mechanical allodynia, mechanical and heat hyperalgesia along with a rise in the levels of Tumor necrosis factor-alpha (TNF-α). Administration of aliskiren (25 or 50 mg/kg intraperitoneal (i.p.)) for 14 days in CCI-subjected rats significantly attenuated CCI-induced pain-related behavior and rise in TNF-α level. It may be concluded that aliskiren-mediated anti-inflammatory actions may be responsible for its beneficial effects in neuropathic pain in rats. [ABSTRACT FROM PUBLISHER]

This study investigates the beneficial role of lisinopril, an angiotensin converting enzyme inhibitor (ACEI) and telmisartan, an angiotensin receptor blocker (ARB), in intracerebroventricular (i.c.v.) streptozotocin (STZ) induced dementia of Alzheimer’s disease (AD) type in mice. This study also aimed to explore the role of PPAR-γ in lisinopril and telmisartan mediated effects in i.c.v. STZ mice. Donepezil served as the positive control in the study. Mice underwent i.c.v. injection of STZ. The Morris water maze (MWM) test was employed for assessment of learning and memory. Various biochemical estimations, namely brain acetylcholinesterase (AChE) activity, myeloperoxidase (MPO) activity, nitrite/nitrate and thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels, were also performed. The study showed that i.c.v. STZ significantly impaired learning and memory of the animals along with a significant enhancement in brain AChE, MPO, TBARS, nitrite/nitrate levels and reduction in brain GSH levels. Treatments of lisinopril/telmisartan/donepezil significantly attenuated STZ induced behavioral and biochemical changes. Pre-treatment with bisphenol-A-diglycidyl ether (BADGE), a selective PPAR-γ antagonist, significantly abolished the beneficial effect of lisinopril/telmisartan in i.c.v. STZ treated animals. The results of this investigation document a potential role of PPAR-γ in the beneficial effects of lisinopril and telmisartan in i.c.v. STZ dementia of AD type. [ABSTRACT FROM PUBLISHER]

We have established that the continuous cold exposure (CCE, 4°C, 4 weeks) causes cold adaptation, increases systolic blood pressure, exerts infarct-limiting effect during coronary artery occlusion (45 min) and reperfusion (2 h). The CCE increases adrenal weight, heart weight and triiodothyronine (T3) level but does not change thymus, spleen weight, serum cortisol, corticosterone and thyroxin (T4) levels. The long-term (4°C, 8 h/day, 4 weeks) intermittent cold exposure (LICE) induces adaptation to the cold and increases T4 level. The brief (4°C, 1.5 h/day, 4 weeks) intermittent cold exposure (BICE) also evokes adaptation to the cold but had no effect on the blood pressure, the cardiac tolerance to ischemia/reperfusion, and does not change thymus, spleen weight, serum cortisol, corticosterone, T3 and T4 levels.

The present study was designed to investigate the efficacy of selective ETA receptor antagonist, ambrisentan on hyperhomocysteinemia-induced experimental vascular dementia. L-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats. Ambrisentan was administered to L-methionine-treated effect rats for 4 weeks (starting from 5(th) to 8(th) week of L-methionine treatment). On 52(nd) day onward, the animals were exposed to the Morris water maze (MWM) for testing their learning and memory abilities. Vascular endothelial function, serum nitrite/nitrate levels, brain thiobarbituric acid reactive species (TBARS), brain reduced glutathione (GSH) levels, and brain acetylcholinesterase (AChE) activity were also measured. L-methionine-treated animals showed significant learning and memory impairment, endothelial dysfunction, decrease in/serum nitrite/nitrate and brain GSH levels along with an increase in brain TBARS levels and AChE activity. Ambrisentan significantly improved hyperhomocysteinemia-induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. These effects were comparable to that of donepezil serving as positive control. It is concluded that ambrisentan, a selective ETA receptor antagonist may be considered as a potential pharmacological agent for the management of hyperhomocysteinemia-induced vascular dementia.

Opioid withdrawal syndrome is a debilitating manifestation of opioid dependence and responds poorly to the available clinical therapies. Studies from various in vivo and in vitro animal models of opioid withdrawal syndrome have led to understanding of its pathobiology which includes complex interrelated pathways leading to adenylyl cyclase superactivation based central excitation. Advancements in the elucidation of opioid withdrawal syndrome mechanisms have revealed a number of key targets that have been hypothesized to modulate clinical status. The present review discusses the neurobiology of opioid withdrawal syndrome and its therapeutic target recptors like calcitonin gene related peptide receptors (CGRP), N-methyl-D-aspartate (NMDA) receptors, gamma aminobutyric acid receptors (GABA), G-proteingated inwardly rectifying potassium (GIRK) channels and calcium channels. The present review further details the potential role of second messengers like calcium (Ca2+) / calmodulin-dependent protein kinase (CaMKII), nitric oxide synthase, cytokines, arachidonic acid metabolites, corticotropin releasing factor, fos and src kinases in causing opioid withdrawal syndrome. The exploitation of these targets may provide effective therapeutic agents for the management of opioid dependence-induced abstinence syndrome.

The present study has been undertaken to investigate the possible link between calcitonin gene related peptide (CGRP) and opioid receptor transduction systems in the neuroprotective mechanism of pharmacological preconditioning. Occlusion of the bilateral carotid artery for 17 min, followed by reperfusion for 24 h, was employed to produce ischemia and reperfusion (I/R) induced cerebral injury in mice. Cerebral infarct size was measured by using triphenyltetrazolium chloride staining. Memory was assessed using the Morris water maze (MWM) test. Degree of motor incoordination was evaluated using the inclined beam walk test, rota-rod test, and lateral push test. Morphine (8 mg/kg, ip), an opioid agonist, and capsaicin (0.1 mg/kg, iv), a CGRP releasing agent, were administered 24 h before surgery to separate groups of animals to induce pharmacological preconditioning. Bilateral carotid artery occlusion, followed by reperfusion, produced a significant increase in the cerebral infarct size and impaired memory as well as motor coordination. Morphine and capsaicin treatment produced both a significant decrease in the cerebral infarct size and a reversal of I/R-induced impairment of memory and motor-coordination. Morphine-induced (8 mg/kg, ip) neuroprotective effects were completely decreased by sumatriptan (8 mg/kg, ip, a CGRPrelease inhibitor) administered 1 h before and 6 h and 12 h after morphine administration. Capsaicin-induced neuroprotection was decreased by naloxone (5 mg/kg, ip, an opioid antagonist) administered 1 h before and 6 h and 12 h after capsaicin administration. These findings indicate that the transduction systems mediating morphine- and capsaicin-induced pharmacological preconditioning in brain are possibly interlinked with one another.

The present study has been designed to investigate the role of insulin, endogenous opioids and calcitonin gene related peptide (CGRP) on remote mesenteric ischaemic preconditioning induced reversal of global cerebral ischaemia-reperfusion injury in mice. Bilateral carotid artery occlusion of 10 min followed by reperfusion for 24 hour was employed in present study to produce ischaemia and reperfusion induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Short-term memory was evaluated using elevated plus maze. Inclined beam walking and resistance to lateral push response, tests were employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired short-term memory, motor co-ordination and lateral push response. A preceding episode of mesenteric artery occlusion for 15 min and reperfusion of 15 min (remote mesenteric ischaemic preconditioning) prevented markedly, ischaemia-reperfusion-induced cerebral injury measured in terms of infarct size, loss of short-term memory, motor coordination and lateral push response. Anti-insulin serum, naloxone (an opioid receptor antagonist) and alpha-CGRP (8-37) (a selective CGRP receptor blocker) attenuated the neuroprotective effect of remote mesenteric ischaemic preconditioning. It may be concluded that neuroprotective effect of remote mesenteric ischaemic preconditioning probably is mediated through insulin, endogenous opioids and CGRP released as a consequence of mesenteric ischaemia and reperfusion in mice.