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Curcumin mediates both dilation and constriction of peripheral arterioles via adrenergic receptors.

ABSTRACT: Curcumin has wound healing attributes mediated through a plethora of biological activities that in general are not ascribed to specific receptors. Recently, we have demonstrated that intravenous administration of curcumin limits burn injury progression in a rat model. As decreased microvascular perfusion is a central element of burn injury progression, we hypothesized that curcumin may induce vasodilation in peripheral arterioles, to improve perfusion. Using mucosal microcirculation as an in situ assay, cheek pouch tissue was exteriorized in anesthetized (phentobarbital 70?mg?kg(-1) intraperitoneal) male hamsters (N=60) to observe the terminal feed arterioles (?8??m diameter) and the immediately upstream arcade arterioles (?20??m). Curcumin (10(-12)-10(-4)?mol?l(-1)) was applied dose-wise (micropipette, 60?seconds). Subnanomolar curcumin dilated, whereas micromolar doses constricted, the arterioles. For the terminal arteriole: vasodilation logEC(50) -10.3±0.2, peak dilation +39±1%; vasconstriction logEC(50) -8.0±0.4, peak constriction -14±2%. Simultaneous atropine (muscarinic antagonist) or PD142893 (endothelin antagonist) had no effect. Propranolol (?-adrenergic receptor (?-Ad) antagonist) enhanced constriction by removing the vasodilation response to curcumin. Phentolamine (?-adrenergic receptor (?-Ad) antagonist) enhanced dilation to curcumin by removing the vasoconstriction response. Thus, the curcumin vasomotor activity on microcirculation was ?-Ad and ?-Ad receptor-dependent and its net vasoactive effect was concentration- and time-dependent.

SUBMITTER: Dewar AM

PROVIDER: S-EPMC3136562 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Curcumin mediates both dilation and constriction of peripheral arterioles via adrenergic receptors.

Dewar Anthony M AM Clark Richard A RA Singer Adam J AJ Frame Mary D MD

The Journal of investigative dermatology 20110428 8

Curcumin has wound healing attributes mediated through a plethora of biological activities that in general are not ascribed to specific receptors. Recently, we have demonstrated that intravenous administration of curcumin limits burn injury progression in a rat model. As decreased microvascular perfusion is a central element of burn injury progression, we hypothesized that curcumin may induce vasodilation in peripheral arterioles, to improve perfusion. Using mucosal microcirculation as an in sit ...[more]

PMID: 21525885

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Project description:1. Little is known about serotonin (5-HT) receptors present on brain microvessels that are innervated by brainstem serotonergic neurons. Using 5-HT, sumatriptan and subtype selective 5-HT(1) receptor agonists and/or the 5-HT(1) receptor antagonist GR127935, we characterized the 5-HT receptors involved in regulating microvascular tone of pressurized intracortical arterioles (approximately 40--50 microm) isolated from human and bovine cerebral cortex. The role of nitric oxide (NO) on these responses was assessed with the N(omega)-nitro-L-arginine (L-NNA, 10(-5) M), an inhibitor of NO synthesis. Bovine pial arteries were studied for comparative purposes. 2. At spontaneous tone, 5-HT induced a dose-dependent constriction of human and bovine microarteries (respective pD(2) values of 7.3+/-0.2 and 6.9+/-0.1); a response potently inhibited by GR127935 (pIC(50) value of 8.5+/-0.1) in bovine microvessels. 3. In both species, the 5-HT(1) receptor agonist sumatriptan induced a biphasic response consisting of a small but significant dilation at low concentrations (1 and/or 10 nM) followed by a constriction at higher doses (pD(2) for contraction of 6.9+/-0.1 and 6.6+/-0.2 in human and bovine vessels, respectively). Pre-incubation with L-NNA abolished the sumatriptan-induced dilation and significantly shifted the dose-response of the constriction curve to the left. In contrast, the selective 5-HT(1D) (PNU-109291) and 5-HT(1F) (LY344864) receptor agonists were devoid of any vasomotor effect. 4. In bovine pial vessels, 5-HT and sumatriptan elicited potent constrictions (respective pD(2) of 7.2+/-0.1 and 6.6+/-0.1), a weak dilation being occasionally observed at low sumatriptan concentrations. 5. A significant negative correlation was observed between pial and intracortical vessels diameter and the extent of the dilatory response to 10(-9) M sumatriptan. Together, these results indicate that sumatriptan, most likely via activation of distinctly localized microvascular 5-HT(1B) receptors, can induce a constriction and/or a dilation which is sensitive to inhibition of NO synthesis and dependent on the size and, possibly, the existing tone of the vessels.

Project description:Background and purposeThe α₁-adrenoceptor family plays a critical role in regulating ocular perfusion by mediating responses to catecholamines. The purpose of the present study was to determine the contribution of individual α₁-adrenoceptor subtypes to adrenergic vasoconstriction of retinal arterioles using gene-targeted mice deficient in one of the three adrenoceptor subtypes (α₁A-AR(-/-), α₁B-AR(-/-) and α₁D-AR(-/-) respectively).Experimental approachUsing real-time PCR, mRNA expression for individual α₁-adrenoceptor subtypes was determined in murine retinal arterioles. To assess the functional relevance of the three α₁-adrenoceptor subtypes for mediating vascular responses, retinal vascular preparations from wild-type mice and mice deficient in individual α₁-adrenoceptor subtypes were studied in vitro using video microscopy.Key resultsRetinal arterioles expressed mRNA for all three α₁-adrenoceptor subtypes. In functional studies, arterioles from wild-type mice with intact endothelium responded only negligibly to the α₁-adrenoceptor agonist phenylephrine. In endothelium-damaged arterioles from wild-type mice, phenylephrine evoked concentration-dependent constriction that was attenuated by the α₁-adrenoceptor blocker prazosin. Strikingly, phenylephrine only minimally constricted endothelium-damaged retinal arterioles from α₁B-AR(-/-) mice, whereas arterioles from α₁A -AR(-/-) and α₁D-AR(-/-) mice constricted similarly to arterioles from wild-type mice. Constriction to U46619 was similar in endothelium-damaged retinal arterioles from all four mouse genotypes.Conclusions and implicationsThe present study is the first to demonstrate that α₁-adrenoceptor-mediated vasoconstriction in murine retinal arterioles is buffered by the endothelium. When the endothelium is damaged, a vasoconstricting role of the α₁B-adrenoceptor subtype is unveiled. Hence, the α₁B-adrenoceptor may represent a target to selectively modulate retinal blood flow in ocular diseases associated with endothelial dysfunction.

Project description:BackgroundPatients with chronic pain disorders exhibit increased levels of catecholamines alongside diminished activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. The authors found that acute pharmacologic inhibition of COMT in rodents produces hypersensitivity to mechanical and thermal stimuli via β-adrenergic receptor (βAR) activation. The contribution of distinct βAR populations to the development of persistent pain linked to abnormalities in catecholamine signaling requires further investigation.MethodsHere, the authors sought to determine the contribution of peripheral, spinal, and supraspinal βARs to persistent COMT-dependent pain. They implanted osmotic pumps to deliver the COMT inhibitor OR486 (Tocris, USA) for 2 weeks. Behavioral responses to mechanical and thermal stimuli were evaluated before and every other day after pump implantation. The site of action was evaluated in adrenalectomized rats receiving sustained OR486 or in intact rats receiving sustained βAR antagonists peripherally, spinally, or supraspinally alongside OR486.ResultsThe authors found that male (N = 6) and female (N = 6) rats receiving sustained OR486 exhibited decreased paw withdrawal thresholds (control 5.74 ± 0.24 vs. OR486 1.54 ± 0.08, mean ± SEM) and increased paw withdrawal frequency to mechanical stimuli (control 4.80 ± 0.22 vs. OR486 8.10 ± 0.13) and decreased paw withdrawal latency to thermal heat (control 9.69 ± 0.23 vs. OR486 5.91 ± 0.11). In contrast, adrenalectomized rats (N = 12) failed to develop OR486-induced hypersensitivity. Furthermore, peripheral (N = 9), but not spinal (N = 4) or supraspinal (N = 4), administration of the nonselective βAR antagonist propranolol, the β2AR antagonist ICI-118,511, or the β3AR antagonist SR59230A blocked the development of OR486-induced hypersensitivity.ConclusionsPeripheral adrenergic input is necessary for the development of persistent COMT-dependent pain, and peripherally-acting βAR antagonists may benefit chronic pain patients.

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Curcumin mediates both dilation and constriction of peripheral arterioles via adrenergic receptors.

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Curcumin mediates both dilation and constriction of peripheral arterioles via adrenergic receptors.

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