Increased susceptibility to cardiovascular effects of dihydrocapcaicin in resuscitated rats. Cardiovascular effects of dihydrocapsaicin

Fosgerau, Keld; Ristagno, Giuseppe; Jayatissa, Magdalena Niepsuj; Axelsen, Mads; Gotfredsen, Jacob W; Weber, U.; Køber, Lars; Torp‐Pedersen, Christian; Videbæk, Charlotte

doi:10.1186/1471-2261-10-39

Cited by 9 publications

(12 citation statements)

References 35 publications

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“…In contrast to our findings with subcutaneous delivery, intravenous infusion of DHC showed a dose-dependent increase in mean BP and HR in rats (14). 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).…”

Section: Discussioncontrasting

confidence: 56%

“…Interestingly, the effect of capsacinoids on cardiovascular function may vary depending on the delivery route. In contrast to our findings with subcutaneous delivery, intravenous infusion of DHC showed a dose-dependent increase in mean BP and HR in rats (14). In the same study, however, the authors also reported that 2 of 6 rats showed transient hypotension and bradycardia (14).…”

Section: Discussioncontrasting

confidence: 54%

“…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%

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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: Discussioncontrasting

confidence: 56%

Section: Discussioncontrasting

confidence: 54%

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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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“…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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“…Several endogenous and exogenous TRPV1 agonists have been identified, some of which can modulate body temperature. For instance, dihydrocapsaicin induces a sustainable mild hypothermia in rats, cynomologus monkeys and young cattle [59]. Rinvanil is a synthetic TRPV1 agonist that possesses ultrapotent activating effects [60].…”

Section: Transient Receptor Potential Vanilloid 1 (Trpv1)mentioning

confidence: 99%

Drug-Induced Hypothermia in Stroke Models: Does it Always Protect?

Zhang¹,

Wang²,

Zhao³

et al. 2013

CNSNDDT

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Ischemic stroke is a common neurological disorder lacking a cure. Recent studies show that therapeutic hypothermia is a promising neuroprotective strategy against ischemic brain injury. Several methods to induce therapeutic hypothermia have been established; however, most of them are not clinically feasible for stroke patients. Therefore, pharmacological cooling is drawing increasing attention as a neuroprotective alternative worthy of further clinical development. We begin this review with a brief introduction to the commonly used methods for inducing hypothermia; we then focus on the hypothermic effects of eight classes of hypothermia-inducing drugs: the cannabinoids, opioid receptor activators, transient receptor potential vanilloid, neurotensins, thyroxine derivatives, dopamine receptor activators, hypothermia-inducing gases, adenosine, and adenine nucleotides. Their neuroprotective effects as well as the complications associated with their use are both considered. This article provides guidance for future clinical trials and animal studies on pharmacological cooling in the setting of acute stroke. KeywordsBrain ischemia; Hypothermic; Neuroprotection; Pharmacological cooling Send correspondence to: Dr. Feng Zhang, Department of Neurology, University of Pittsburgh School of Medicine, 3500 Terrace Street, Pittsburgh, PA, 15213, USA, Telephone: 412-383-7604, Fax: 412-648-1239, zhanfx2@upmc.edu NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 1. Hypothermia and strokes IntroductionTherapeutic hypothermia is defined as a 2-6°C reduction of core body temperature [1][2][3] and is a promising neuroprotective approach against brain injury induced by strokes. In hemorrhagic stroke, hypothermia reduces brain edema [4,5] and improves neurologic function [4][5][6][7]. In ischemic stroke, hypothermia is also protective, which has been proven in randomized clinical trials in human cardiac arrest and in animal studies of focal and global ischemia [8,9]. However, the impact of hypothermia on patients with acute ischemic stroke still needs to be explored [10]. During the past decades, studies on hypothermia and ischemic stroke have suggested that the required amplitude of protective hypothermia depends on its time of initiation relative to stroke onset, duration, and depth of hypothermia [1,9,11]. Optimal protection is typically gained when hypothermia is induced as early as possible after stroke onset, with a mild-to-moderate hypothermia of 32 to 35°C that lasts at least one to two hours [1, 2, 12-14]. Protective mechanism of hypothermia in ischemic strokeAlthough hypothermia is effective in protecting against experimental models of ischemic stroke, the precise protective mechanisms are not yet fully understood. It has been suggested that the protective mechanisms are multifold, including reductions in metabolic rate, cerebral blood flow, blood-brain barrier damage, as well as decreases in excitotoxicity, apoptosis, inflammation and free radical production [15]. On average, hypothermia red...

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Increased susceptibility to cardiovascular effects of dihydrocapcaicin in resuscitated rats. Cardiovascular effects of dihydrocapsaicin

Cited by 9 publications

References 35 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

Drug-Induced Hypothermia in Stroke Models: Does it Always Protect?

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