Toxicity studies with pure trans-capsaicin delivered to dogs via intravenous administration

Chanda, Sanjay; Mould, A.; Esmail, A.F.; Bley, Keith

doi:10.1016/j.yrtph.2005.06.003

Cited by 25 publications

(27 citation statements)

References 29 publications

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“…In the same study, however, the authors also reported that 2 of 6 rats showed transient hypotension and bradycardia (14). Intravenous infusion of capsaicin in dogs, at doses lower than 0.1 mg/kg, did not show any effect on BP and HR while doses higher than 0.3 mg/kg showed a transient rise in BP and HR (7). While it is not fully understood how intravenous DHC affects HR and BP, it is known that TRPV1 is expressed within unmyelinated C-fibers within the aortic arch and stimulation of these fibers with lumenally delivered TRPV1 agonists contributes to decreased baroreceptor sensitivity (33,39).…”

Section: Discussionmentioning

confidence: 85%

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Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

Cao

Balasubramanian

Marrelli

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Cao Z, Balasubramanian A, Marrelli SP. Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 minutes after reperfusion. Am J Physiol Regul Integr Comp Physiol 306: R149-R156, 2014. First published December 4, 2013; doi:10.1152/ajpregu.00329.2013.-Traditional methods of therapeutic hypothermia show promise for neuroprotection against cerebral ischemia-reperfusion (I/R), however, with limitations. We examined effectiveness and specificity of pharmacological hypothermia (PH) by transient receptor potential vanilloid 1 (TRPV1) channel agonism in the treatment of focal cerebral I/R. Core temperature (Tcore) was measured after subcutaneous infusion of TRPV1 agonist dihydrocapsaicin (DHC) in conscious C57BL/6 WT and TRPV1 knockout (KO) mice. Acute measurements of heart rate (HR), mean arterial pressure (MAP), and cerebral perfusion were measured before and after DHC treatment. Focal cerebral I/R (1 h ischemia ϩ 24 h reperfusion) was induced by distal middle cerebral artery occlusion. Hypothermia (Ͼ8 h) was initiated 90 min after start of reperfusion by DHC infusion (osmotic pump). Neurofunction (behavioral testing) and infarct volume (TTC staining) were measured at 24 h. DHC (1.25 mg/kg) produced a stable drop in Tcore (33°C) in naive and I/R mouse models but not in TRPV1 KO mice. DHC (1.25 mg/kg) had no measurable effect on HR and cerebral perfusion but produced a slight transient drop in MAP (Ͻ6 mmHg). In stroke mice, DHC infusion produced hypothermia, decreased infarct volume by 87%, and improved neurofunctional score. The hypothermic and neuroprotective effects of DHC were absent in TRPV1 KO mice or mice maintained normothermic with heat support. PH via TRPV1 agonist appears to be a well-tolerated and effective method for promoting mild hypothermia in the conscious mouse. Furthermore, TRPV1 agonism produces effective hypothermia in I/R mice and significantly improves outcome when initiated 90 min after start of reperfusion. cerebral ischemia-reperfusion; hypothermia; neuroprotection; TRPV1 STROKE is the second highest cause of death in the world and the main cause of long-term disability in the United States (43). However, current treatment options for stroke are quite limited (51). Thrombolysis is the only approved method for stroke therapy (41), but it can be applied to less than 10% of the patients due to the stringent treatment criteria (26) and in some cases may even produce further reperfusion injury (2). Mild hypothermia (32-34°C) has been demonstrated to reduce stroke injury and improve neurofunctional recovery in animal studies and has shown promise in small-scale clinical trials (20,25,37,49,50). At present, most clinical therapeutic hypothermia (TH) protocols involve methods of forced cooling such as with cold blankets and ice baths or intravenous methods of cooling (25). Although TH seems to have significant promise in stroke therapy, current protocols are accompanied by many adverse complications, which reduce effectiveness...

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Section: Discussionmentioning

confidence: 85%

“…As noted above, we found a mild decrease in BP immediately after DHC infusion. In addition, other labs have found acute effects of TRPV1 agonist infusion in other species when delivered intravenously (7,14). TRPV1 agonism has also been demonstrated to produce vasodilation in certain vascular beds (8,18,55).…”

Section: Resultsmentioning

confidence: 99%

Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

Cao

Balasubramanian

Marrelli

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…It is, thus, tempting to speculate that using pharmacological TRPV1 agonists to produce or enhance therapeutic hypothermia may bring an additional benefit of blunting tachycardia, limiting the load on the heart and preventing cardiac tachyarrhythmias. However, TRPV1 agonists seem to have complex and variable effects on the cardiovascular system at baseline conditions in the absence of cooling (4,9,13,35,36). Since there is no clear and unified picture of how TRPV1 activation affects heart function, this area deserves further study.…”

Section: Discussionmentioning

confidence: 99%

Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition

Feketa

Balasubramanian

Flores

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Feketa VV, Balasubramanian A, Flores CM, Player MR, Marrelli SP. Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition. Am J Physiol Regul Integr Comp Physiol 305: R1040-R1050, 2013. First published September 4, 2013 doi:10.1152/ajpregu.00296.2013.-Mild decrease of core temperature (32-34°C), also known as therapeutic hypothermia, is a highly effective strategy of neuroprotection from ischemia and holds significant promise in the treatment of stroke. However, induction of hypothermia in conscious stroke patients is complicated by cold-defensive responses, such as shivering and tachycardia. Although multiple thermoregulatory responses may be altered by modulators of thermosensitive ion channels, TRPM8 (transient receptor potential melastatin 8) and TRPV1 (TRP vanilloid 1), it is unknown whether these agents affect cold-induced shivering and tachycardia. The current study aimed to determine the effects of TRPM8 inhibition and TRPV1 activation on the shivering and tachycardic responses to external cooling. Conscious mice were treated with TRPM8 inhibitor compound 5 or TRPV1 agonist dihydrocapsaicin (DHC) and exposed to cooling at 10°C. Shivering was measured by electromyography using implanted electrodes in back muscles, tachycardic response by electrocardiography, and core temperature by wireless transmitters in the abdominal cavity. The role of TRPM8 was further determined using TRPM8 KO mice. TRPM8 ablation had no effect on total electromyographic muscle activity (vehicle: 24.0 Ϯ 1.8; compound 5: 23.8 Ϯ 2.0; TRPM8 KO: 19.7 Ϯ 1.9 V·s/min), tachycardia (⌬HR ϭ 124 Ϯ 31; 121 Ϯ 13; 121 Ϯ 31 beats/min) and drop in core temperature (Ϫ3.6 Ϯ 0.1; Ϫ3.4 Ϯ 0.4; Ϫ3.6 Ϯ 0.5°C) during cold exposure. TRPV1 activation substantially suppressed muscle activity (vehicle: 25.6 Ϯ 3.0 vs. DHC: 5.1 Ϯ 2.0 V·s/min), tachycardia (⌬HR ϭ 204 Ϯ 25 vs. 3 Ϯ 35 beats/min) and produced a profound drop in core temperature (Ϫ2.2 Ϯ 0.6 vs. Ϫ8.9 Ϯ 0.6°C). In conclusion, external cooling-induced shivering and tachycardia are suppressed by TRPV1 activation, but not by TRPM8 inhibition. This suggests that TRPV1 agonists may be combined with external physical cooling to achieve more rapid and effective hypothermia. therapeutic hypothermia; pharmacological hypothermia; shivering; transient receptor potential; physical cooling; electromyography; dihydrocapsaicin MILD DECREASE OF CORE TEMPERATURE to 32-34°C has been shown to effectively protect the brain from ischemia and has become a basis for the clinical method of therapeutic hypo-

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“…The TRPV1 agonist capsaicin is reported to affect both vasorelaxation and vasoconstriction [7,90]. Acute activation by capsaicin either lowers or elevates arterial pressure in animal models [12,111]. However, these studies did not clarify whether this action of capsaicin was associated with the activation of vascular TRPV1 or with the stimulation of sensory nerve endings.…”

Section: Hypertension Ms and Trp Channelsmentioning

confidence: 99%

TRP channels and their implications in metabolic diseases

Zhu

Luo

et al. 2010

Pflugers Arch - Eur J Physiol

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The transient receptor potential (TRP) channel superfamily is composed of 28 nonselective cation channels that are ubiquitously expressed in many cell types and have considerable functional diversity. Although changes in TRP channel expression and function have been reported in cardiovascular disease and renal disorders, the pathogenic roles of TRP channels in metabolic diseases have not been systemically reviewed. In this review, we summarised the distribution of TRP channels in several metabolic tissues and discussed their roles in mediating and regulating various physiological and pathophysiological metabolic processes and diseases including diabetes, obesity, dyslipidaemia, metabolic syndrome, atherosclerosis, metabolic bone diseases and electrolyte disturbances. This review provides new insight into the involvement of TRP channels in the pathogenesis of metabolic disorders and implicates these channels as potential therapeutic targets for the management of metabolic diseases.

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Toxicity studies with pure trans-capsaicin delivered to dogs via intravenous administration

Cited by 25 publications

References 29 publications

Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition

TRP channels and their implications in metabolic diseases

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