The impact of temperature on vascular function in connection with vascular laser treatment.

Pulsed dye lasers are used effectively in the treatment of psoriasis with long remission time and limited side effects. It is, however, not completely understood which biological processes underlie its favorable outcome. Pulsed dye laser treatment at 585-595 nm targets hemoglobin in the blood, inducing local hyperthermia in surrounding blood vessels and adjacent tissues. While the impact of destructive temperatures on blood vessels has been well studied, the effects of lower temperatures on the function of several cell types within the blood vessel wall and its periphery are not known. The aim of our study is to assess the functionality of isolated blood vessels after exposure to moderate hyperthermia (45 to 60°C) by evaluating the function of endothelial cells, smooth muscle cells, and vascular nerves. We measured blood vessel functionality of rat mesenteric arteries (n=19) by measuring vascular contraction and relaxation before and after heating vessels in a wire myograph. To this end, we elicited vascular contraction by addition of either high potassium solution or the thromboxane analogue U46619 to stimulate smooth muscle cells, and electrical field stimulation (EFS) to stimulate nerves. For measurement of endothelium-dependent relaxation, we used methacholine. Each vessel was exposed to one temperature in the range of 45-60°C for 30 seconds and a relative change in functional response after hyperthermia was determined by comparison with the response per stimulus before heating. Non-linear regression was used to fit our dataset to obtain the temperature needed to reduce blood vessel function by 50% (Half maximal effective temperature, ET50). Our findings demonstrate a substantial decrease in relative functional response for all three cell types following exposure to 55°C-60°C. There was no significant difference between the ET50 values of the different cell types, which was between 55.9°C and 56.9°C (P>0.05). Our data show that blood vessel functionality decreases significantly when exposed to temperatures between 55°C-60°C for 30 seconds. The results show functionality of endothelial cells, smooth muscle cells, and vascular nerves is similarly impaired. These results help to understand the biological effects of hyperthermia and may aid in tailoring laser and light strategies for selective photothermolysis that contribute to disease modification of psoriasis after pulsed dye laser treatment.

Blue laser-induced selective vasorelaxation by the activation of NOSs.

Phototherapy has been tried for treating cardiovascular diseases. In particular, ultraviolet and blue visible lights were suggested to be useful due to their nitric oxide (NO)-production ability in the skin. However, the effects of blue light on the arterial contractility are controversial. Here, we hypothesized that appropriate protocol of blue laser can induce selective vasorelaxation by activating vasodilating signaling molecules in arteries. Using organ chamber arterial mechanics, NO assay, Matrigel assay, and microarray, we showed that a 200-Hz, 300-µs, 445-nm pulsed-laser (total energy of 600 mJ; spot size 4 mm) induced selective vasorelaxation, without vasocontraction in rat mesenteric arteries. The laser stimulation increased NO production in the cord blood-endothelial progenitor cells (CB-EPCs). Both the laser-induced vasorelaxation and NO production were inhibited by a non-selective, pan-NO synthase inhibitor, L-NG-Nitro arginine methyl ester. Microarray study in CB-EPCs suggested up-regulation of cryptochrome (CRY)2 as well as NO synthase (NOS)1 and NOSTRIN (NOS trafficking) by the laser. In conclusion, this study suggests that the 445-nm blue puled-laser can induce vasorelaxation possibly via the CRY photoreceptors and NOSs activation. The blue laser-therapy would be useful for treating systemic hypertension as well as improving local blood flow depending on the area of irradiation.

Retinal vessel caliber and caliber responses in true normotensive black and white adults: The African-PREDICT study.

PURPOSE: Globally, a detrimental shift in cardiovascular disease risk factors and a higher mortality level are reported in some black populations. The retinal microvasculature provides early insight into the pathogenesis of systemic vascular diseases, but it is unclear whether retinal vessel calibers and acute retinal vessel functional responses differ between young healthy black and white adults. METHODS: We included 112 black and 143 white healthy normotensive adults (20-30 years). Retinal vessel calibers (central retinal artery and vein equivalent (CRAE and CRVE)) were calculated from retinal images and vessel caliber responses to flicker light induced provocation (FLIP) were determined. Additionally, ambulatory blood pressure (BP), anthropometry and blood samples were collected. RESULTS: The groups displayed similar 24 h BP profiles and anthropometry (all p > .24). Black participants demonstrated a smaller CRAE (158 ±â€¯11 vs. 164 ±â€¯11 MU, p < .001) compared to the white group, whereas CRVE was similar (p = .57). In response to FLIP, artery maximal dilation was greater in the black vs. white group (5.6 ±â€¯2.1 vs. 3.3 ±â€¯1.8%; p < .001). CONCLUSIONS: Already at a young age, healthy black adults showed narrower retinal arteries relative to the white population. Follow-up studies are underway to show if this will be related to increased risk for hypertension development. The reason for the larger vessel dilation responses to FLIP in the black population is unclear and warrants further investigation.

Association between Radiation Exposure and Endothelium-Dependent Vasodilation: Results from Clinical and Experimental Studies.

PURPOSE: The association between occupational radiation exposure and endothelium-dependent vasodilation (EDV) remains unclear. This study evaluated the association between radiation exposure and EDV among fluoroscopy-guided interventional procedure specialists and explored the possible mechanisms. MATERIALS AND METHODS: Brachial flow-mediated dilation was compared in 21 interventional cardiologists (the radiation group) and 15 noninterventional cardiologists (the nonradiation group). Animal radiation experiments were also performed to observe the impact of radiation on EDV. RESULTS: Flow-mediated dilation in both the left (radiation group, 3.63% vs. nonradiation group, 6.77%; P < .001) and right brachial arteries (5.36% vs. 7.33%, respectively; P = .04) and serum nitric oxide (NO) level (343.69 vs. 427.09 µmol/L, respectively; P = .02) were significantly reduced in the radiation group compared to those in the nonradiation group. EDV was significantly impaired in acetylcholine concentrations of 3 × 10-6 mol/L and 10-5 mol/L (60.09% vs.74.79%, respectively; P = .03; and 62.73% vs. 80.56%, respectively; P = .002), and reactive oxygen species levels in the aorta intima and media layers were significantly increased in mice after a single x-ray exposure, which could be partly rescued by pretreatment with folic acid (P < .05). CONCLUSIONS: Radiation exposure can lead to impairment of flow-mediated vasodilation in human or EDV in mice. In mice acutely exposed to radiation, folic acid alleviated radiation-induced EDV impairment by possible reduction of reactive oxidative species.

Microwave Assisted Synthesis of 4-Phenylquinazolin-2(1H)-one Derivatives that Inhibit Vasopressor Tonus in Rat Thoracic Aorta.

Quinazolinones have pharmacological effects on vascular reactivity through different mechanisms. We synthesized 4-phenylquinazolin-2(1H)-one derivatives under microwave irradiation and tested them on the rat thoracic aorta. The prepared compounds 2a-2f were obtained in about 1 h with suitable yields (31-92%). All derivatives produced vasorelaxant effects with IC50 values ranging from 3.41 ± 0.65 µM to 39.72 ± 6.77 µM. Compounds 2c, 2e and 2f demonstrated the highest potency in endothelium-intact aorta rings (IC50 4.31 ± 0.90 µM, 4.94 ± 1.21 µM and 3.41 ± 0.65 µM respectively), and they achieved around 90% relaxation (30 µM). In aorta rings without an endothelium, the effect of compound 2f was abolished. Using the MTT assay to test for cell viability, only compound 2b induced cytotoxicity at the maximum concentration employed (30 µM). The results show that vasorelaxation by 4-phenylquinazolin-2(1H)-one derivatives might depend on the activation of a signalling pathway triggered by endothelium-derived factors.

Sunscreen or simulated sweat minimizes the impact of acute ultraviolet radiation on cutaneous microvascular function in healthy humans.

NEW FINDINGS: What is the central question of this study? Are ultraviolet radiation (UVR)-induced increases in skin blood flow independent of skin erythema? Does broad-spectrum UVR exposure attenuate NO-mediated cutaneous vasodilatation, and does sunscreen or sweat modulate this response? What are the main findings and their importance? Erythema and vascular responses to UVR are temporally distinct, and sunscreen prevents both responses. Exposure to UVR attenuates NO-mediated vasodilatation in the cutaneous microvasculature; sunscreen or simulated sweat on the skin attenuates this response. Sun over-exposure may elicit deleterious effects on human skin that are separate from sunburn, and sunscreen or sweat on the skin may provide protection. ABSTRACT: Exposure to ultraviolet radiation (UVR) may result in cutaneous vascular dysfunction independent of erythema (skin reddening). Two studies were designed to differentiate changes in erythema from skin vasodilatation throughout the 8 h after acute broad-spectrum UVR exposure with (+SS) or without SPF-50 sunscreen (study 1) and to examine NO-mediated cutaneous vasodilatation after acute broad-spectrum UVR exposure with or without +SS or simulated sweat (+SW) on the skin (study 2). In both studies, laser-Doppler flowmetry was used to measure red cell flux, and cutaneous vascular conductance (CVC) was calculated (CVC = flux/mean arterial pressure). In study 1, in 14 healthy adults (24 ± 4 years old; seven men and seven women), the skin erythema index and CVC were measured over two forearm sites (UVR only and UVR+SS) before, immediately after and every 2 h for 8 h post-exposure (750 mJ cm-2 ). The erythema index began to increase immediately post-UVR (P < 0.05 at 4, 6 and 8 h), but CVC did not increase above baseline for the first 4-6 h (P ≤ 0.01 at 6 and 8 h); +SS prevented both responses. In study 2, in 13 healthy adults (24 ± 4 years old; six men and seven women), three intradermal microdialysis fibres were placed in the ventral skin of the forearm [randomly assigned to UVR (450 mJ cm-2 ), UVR+SS or UVR+SW], and one fibre (non-exposed control; CON) was placed in the contralateral forearm. After UVR, a standardized local heating (42°C) protocol quantified the percentage of NO-mediated vasodilatation (%NO). The UVR attenuated %NO compared with CON (P = 0.01). The diminished %NO was prevented by +SS (P < 0.01) and +SW (P < 0.01). Acute broad-spectrum UVR attenuates NO-dependent dilatation in the cutaneous microvasculature, independent of erythema. Sunscreen protects against both inflammatory and heating-induced endothelial dysfunction, and sweat might prevent UVR-induced reductions in NO-dependent dilatation.

Opsin 3 and 4 mediate light-induced pulmonary vasorelaxation that is potentiated by G protein-coupled receptor kinase 2 inhibition.

We recently demonstrated that blue light induces vasorelaxation in the systemic mouse circulation, a phenomenon mediated by the nonvisual G protein-coupled receptor melanopsin (Opsin 4; Opn4). Here we tested the hypothesis that nonvisual opsins mediate photorelaxation in the pulmonary circulation. We discovered Opsin 3 (Opn3), Opn4, and G protein-coupled receptor kinase 2 (GRK2) in rat pulmonary arteries (PAs) and in pulmonary arterial smooth muscle cells (PASMCs), where the opsins interact directly with GRK2, as demonstrated with a proximity ligation assay. Light elicited an intensity-dependent relaxation of PAs preconstricted with phenylephrine (PE), with a maximum response between 400 and 460 nm (blue light). Wavelength-specific photorelaxation was attenuated in PAs from Opn4-/- mice and further reduced following shRNA-mediated knockdown of Opn3. Inhibition of GRK2 amplified the response and prevented physiological desensitization to repeated light exposure. Blue light also prevented PE-induced constriction in isolated PAs, decreased basal tone, ablated PE-induced single-cell contraction of PASMCs, and reversed PE-induced depolarization in PASMCs when GRK2 was inhibited. The photorelaxation response was modulated by soluble guanylyl cyclase but not by protein kinase G or nitric oxide. Most importantly, blue light induced significant vasorelaxation of PAs from rats with chronic pulmonary hypertension and effectively lowered pulmonary arterial pressure in isolated intact perfused rat lungs subjected to acute hypoxia. These findings show that functional Opn3 and Opn4 in PAs represent an endogenous "optogenetic system" that mediates photorelaxation in the pulmonary vasculature. Phototherapy in conjunction with GRK2 inhibition could therefore provide an alternative treatment strategy for pulmonary vasoconstrictive disorders.

Wavelength-dependence of vasodilation and NO release from S-nitrosothiols and dinitrosyl iron complexes by far red/near infrared light.

Far red/near infrared (R/NIR) energy is a novel therapy, but its mechanism of action is poorly characterized. Cytochrome c oxidase (Cco) of the mitochondrial electron transport chain is considered the primary photoacceptor for R/NIR to photolyze a putative heme nitrosyl in Cco to liberate free nitric oxide (NO). We previously observed R/NIR light directly liberates NO from nitrosylated hemoglobin and myoglobin, and recently suggested S-nitrosothiols (RSNO) and dinitrosyl iron complexes (DNIC) may be primary sources of R/NIR-mediated NO. Here we indicate R/NIR light exposure induces wavelength dependent dilation of murine facial artery, with longer wavelengths (740, and 830 nm) exhibiting reduced potency when compared to 670 nm. R/NIR also stimulated NO release from pure solutions of low molecular weight RSNO (GSNO and SNAP) and glutathione dinitrosyl iron complex (GSH-DNIC) in a power- and wavelength-dependent manner, with the greatest effect at 670 nm. NO release from SNAP using 670 was nearly ten-fold more than GSNO or GSH-DNIC, with no substantial difference in NO production at 740 nm and 830 nm. Thermal effects of irradiation on vasodilation or NO release from S-nitrosothiols and DNIC was minimal. Our results suggest 670 nm is the optimal wavelength for R/NIR treatment of certain vascular-related diseases.

Experimental and numerical investigation on the transient vascular thermal response to multi-pulse Nd:YAG laser.

BACKGROUND AND OBJECTIVE: Port wine stains (PWS) are congenital vascular malformations that progressively darken and thicken with age. Laser therapy is currently the most effective way in clinical practice for PWS. A 1,064 nm Nd:YAG laser in the near-infrared band can achieve a deeper treatment depth compared to the current widely adopted pulsed dye laser. However, because of its relatively weak absorption by blood, single-pulse Nd:YAG laser requires high energy density to cause effective vessel damage, but may inflict undesirable burning to surrounding collagen. Multi-pulse laser has great potential in clinical treatment because it needs less energy density for each pulse. This paper presented an experimental and theoretical study of the transient thermal effects of low-energy multi-pulse Nd:YAG laser on blood vessels. STUDY DESIGN/MATERIALS AND METHODS: In vivo experiments were performed on dorsal skin chamber. By using a high speed camera (up to 2,000 fps), the complete and dynamic thermal response of blood vessels during laser irradiation and between pulse intervals was obtained. In vitro experiment in capillary tubes and Numerical simulations by two-scale heat transfer model were also conducted to further explore the in vivo experimental findings. RESULTS: The complete and dynamic response of blood vessels were obtained, including vessel dilation, thrombus formation, partial vessel constriction, thread-like constriction, cavitation and bubbles, and hemorrhage. Thread-like constriction is the desirable treatment end point, which will only occur after thrombus completely occludes the vessel lumen. Cavitation can cause hemorrhage when thrombus fails to occlude the vessel lumen. In vitro experiment found that vessel constriction was due to the constriction of thrombus induced by laser irradiation. Theoretical investigation revealed that the mechanism for the effective reduction of energy density by multi-pulse Nd:YAG laser was due to enhanced light absorption of the blood with thrombus formation. CONCLUSIONS: For multi-pulse treatment, laser parameters are recommended as repetition rate of 10 Hz and pulse number of 10. The incident energy in each pulse should be strong enough to induce blood coagulation through seven or eight pulses and should be lower than the threshold of blood cavitation. Lasers Surg. Med. 49:852-865, 2017. © 2017 Wiley Periodicals, Inc.

Melanopsin mediates light-dependent relaxation in blood vessels.

Melanopsin (opsin4; Opn4), a non-image-forming opsin, has been linked to a number of behavioral responses to light, including circadian photo-entrainment, light suppression of activity in nocturnal animals, and alertness in diurnal animals. We report a physiological role for Opn4 in regulating blood vessel function, particularly in the context of photorelaxation. Using PCR, we demonstrate that Opn4 (a classic G protein-coupled receptor) is expressed in blood vessels. Force-tension myography demonstrates that vessels from Opn4(-/-) mice fail to display photorelaxation, which is also inhibited by an Opn4-specific small-molecule inhibitor. The vasorelaxation is wavelength-specific, with a maximal response at ∼430-460 nm. Photorelaxation does not involve endothelial-, nitric oxide-, carbon monoxide-, or cytochrome p450-derived vasoactive prostanoid signaling but is associated with vascular hyperpolarization, as shown by intracellular membrane potential measurements. Signaling is both soluble guanylyl cyclase- and phosphodiesterase 6-dependent but protein kinase G-independent. ß-Adrenergic receptor kinase 1 (ßARK 1 or GRK2) mediates desensitization of photorelaxation, which is greatly reduced by GRK2 inhibitors. Blue light (455 nM) regulates tail artery vasoreactivity ex vivo and tail blood blood flow in vivo, supporting a potential physiological role for this signaling system. This endogenous opsin-mediated, light-activated molecular switch for vasorelaxation might be harnessed for therapy in diseases in which altered vasoreactivity is a significant pathophysiologic contributor.

Radiation-induced afferent arteriolar endothelial-dependent dysfunction involves decreased epoxygenase metabolites.

Chronic kidney disease is a known complication of hematopoietic stem cell transplant (HSCT) and can be caused by irradiation at the time of the HSCT. In our rat model there is a 6- to 8-wk latent period after irradiation that leads to the development of proteinuria, azotemia, and hypertension. The current study tested the hypothesis that decreased endothelial-derived factors contribute to impaired afferent arteriolar function in rats exposed to total body irradiation (TBI). WAG/RijCmcr rats underwent 11 Gy TBI, and afferent arteriolar responses to acetylcholine were determined at 1, 3, and 6 wk. Blood pressure and blood urea nitrogen were not different between control and irradiated rats. Afferent arteriolar diameters were not altered in irradiated rats. Impaired endothelial-dependent responses to acetylcholine were evident at 3 and 6 wk following TBI. Nitric oxide synthase (NOS), cyclooxygenase (COX), and epoxygenase (EPOX) contribution to acetylcholine dilator responses were evaluated. NOS inhibition with N(G)-nitro-l-arginine methyl ester (l-NAME) reduced acetylcholine responses by 50% in controls and 90% in 3-wk TBI rats. COX inhibition with indomethacin did not significantly alter the acetylcholine response in the presence or absence of l-NAME. EPOX inhibition with N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide significantly decreased acetylcholine responses (35%) in controls but did not significantly alter acetylcholine responses (4%) in TBI rats. Biochemical analysis revealed decreased urinary EPOX metabolites but no change in COX, NOS, or reactive oxygen species at 3 wk TBI. Taken together, these results indicate that afferent arteriolar endothelial dysfunction involves a decrease in EPOX metabolites that precedes the development of proteinuria, azotemia, and hypertension in irradiated rats.

Mast cells are required for phototolerance induction and scratching abatement.

Dermal mast cells protect the skin from inflammatory effects of ultraviolet (UV) radiation and are required for UV-induced immune suppression. We sought to determine a potential mechanistic role of mast cells in reducing the sensitivity to UV radiation (i.e. phototolerance induction) through photohardening. We administered single UV exposures as well as a chronic UV irradiation regime to mast cell-deficient Kit(W-Sh/W-Sh) mice and their controls. The chronic irradiation protocol was similar to that given for prophylaxis in certain photodermatoses in humans. Compared to controls, UV-exposed Kit(W-Sh/W-Sh) mice were more susceptible to epidermal hyperplasia and dermal oedema which was linked to blood vessel dilation. Unexpectedly, Kit(W-Sh/W-Sh) mice exhibited an excessive scratching behaviour following broadband UVB plus UVA or solar simulated UV irradiation at doses far below their minimal skin-swelling dose. Protection from this UV-induced scratching phenotype was dependent on mast cells, as engraftment of bone marrow-derived cultured mast cells abated it entirely. Kit(W-Sh/W-Sh) mice were entirely resistant to phototolerance induction by photohardening treatment. Compared to controls, these mice also showed reduced numbers of regulatory T cells and neutrophils in the skin 24 h after UV irradiation. While it is well known that mast cell-deficient mice are resistant to UV-induced immune suppression, we have discovered that they are prone to develop photo-itch and are more susceptible to UV-induced epidermal hyperplasia and skin oedema.

Short-Term Statin Treatment Reduces, and Long-Term Statin Treatment Abolishes, Chronic Vascular Injury by Radiation Therapy.

BACKGROUND: The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. We examined whether irradiation causes chronic vascular injury and whether short-term administration of statins during and after irradiation is sufficient to prevent chronic injury compared with long-term administration. METHODS AND RESULTS: C57Bl/6 mice were pretreated with pravastatin for 72 hours and then exposed to 12 Gy X-ray head-and-neck irradiation. Pravastatin was then administered either for an additional 24 hours or for 1 year. Carotid arteries were tested for vascular reactivity, altered gene expression, and collagen deposition 1 year after irradiation. Treatment with pravastatin for 24 hours after irradiation reduced the loss of endothelium-dependent vasorelaxation and protected against enhanced vasoconstriction. Expression of markers associated with inflammation (NFκB p65 [phospho-nuclear factor kappa B p65] and TNF-α [tumor necrosis factor alpha]) and with oxidative stress (NADPH oxidases 2 and 4) were lowered and subunits of the voltage and Ca2+ activated K+ BK channel (potassium calcium-activated channel subfamily M alpha 1 and potassium calcium-activated channel subfamily M regulatory beta subunit 1) in the carotid artery were modulated. Treatment with pravastatin for 1 year after irradiation completely reversed irradiation-induced changes. CONCLUSIONS: Short-term administration of pravastatin is sufficient to reduce chronic vascular injury at 1 year after irradiation. Long-term administration eliminates the effects of irradiation. These findings suggest that a prospective treatment strategy involving statins could be effective in patients undergoing radiation therapy. The optimal duration of treatment in humans has yet to be determined.

Is the effect of mobile phone radiofrequency waves on human skin perfusion non-thermal?

OBJECTIVE: To establish whether SkBF can be modified by exposure to the radiofrequency waves emitted by a mobile phone when the latter is held against the jaw and ear. METHODS: Variations in SkBF and Tsk in adult volunteers were simultaneously recorded with a thermostatic laser Doppler system during a 20-minute "radiofrequency" exposure session and a 20-minute "sham" session. The skin microvessels' vasodilatory reserve was assessed with a heat challenge at the end of the protocol. RESULTS: During the radiofrequency exposure session, SkBF increased (vs. baseline) more than during the sham exposure session. The sessions did not differ significant in terms of the Tsk time-course response. The skin microvessels' vasodilatory ability was found to be greater during radiofrequency exposure than during sham exposure. CONCLUSIONS: Our results reveal the existence of a specific vasodilatory effect of mobile phone radiofrequency emission on skin perfusion.

[Endothelium dependent vascular reactivity and autonomic homeostasis in children living in radiation-contaminated areas].

In order to study the mechanisms of development of pathological changes in children living in contaminated areas and chronically exposed to radionuclides as a result of exposure through the food chain, studied the vegetative homeostasis and thermographic study endothelium-dependent vascular reactions with occlusive tests. Showed signs of dysregulation of the autonomic nervous system dysfunction, the secretory activity of the endothelium and increased secretion of substances endothelial origin.

[The influence of general infrared sauna on the antioxidant systems in the blood of volunteers].

This comprehensive clinical and laboratory study was designed to elucidate the antioxidant status of the volunteers before and after a course of general infrared irradiation. It was shown that the effect of high temperatures promotes the development of oxidative stress that is followed by the formation of adaptive reactions in the form of activation of antioxidant protection, enhancement of non-specific responses of the cells, increase of stability and restoration of structural homeostasis of erythrocyte membranes. The molecular mechanism of endothelium-independent vasodilation develops by the end of the treatment period; it may serve as the compensatory-adaptive reaction needed to maintain the adequate tone of the vascular wall and thereby to support the functioning of mechanisms supporting physical thermoregulation. The results of the study give evidence of the stimulatory influence of the described method on the adaptive and protective potential of the organism. It is concluded that the proposed scheme of physiotherapeutic treatment may be used for prophylactic purposes.

Novel versus traditional risk markers for diabetic retinopathy.

AIMS/HYPOTHESIS: To explore the relative contribution of novel and traditional risk markers for diabetic retinopathy (DR). METHODS: A clinic-based study of 224 diabetic patients (85 type 1, 139 type 2) from a diabetes clinic was performed. DR was graded from fundus photographs according to the Airlie House Classification system and classified as absent or present (at least ETDRS level 14). Novel risk markers assessed included serum apolipoprotein (Apo) AI and B, skin microvascular responses to acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) iontophoresis, flicker-light-induced retinal vasodilation and retinal vascular tortuosity. Relative contribution was determined by semi-partial correlation coefficient generated from a logistic regression model containing all traditional and novel risk markers simultaneously. RESULTS: There were 144 (64.3%) participants with DR. Of the novel markers, ApoAI, flicker-light-induced vasodilation and retinal arteriolar tortuosity were significantly associated with DR, independently of traditional measures (all p < 0.03). Diabetes duration contributed most (51%) to the risk of DR, followed by ApoAI (16%), systolic blood pressure (13%), retinal arteriolar tortuosity (8%) and flicker-light-induced venular and arteriolar dilation (3% and 0.5%, respectively). CONCLUSIONS/INTERPRETATION: ApoAI and retinal arteriolar tortuosity made considerable contributions to DR risk, independently of traditional risk markers. Findings from this study suggest that serum ApoAI and retinal arteriolar tortuosity may be novel and independent risk markers of DR.

Nitrite- and nitroxyl-induced relaxation in porcine coronary (micro-) arteries: underlying mechanisms and role as endothelium-derived hyperpolarizing factor(s).

To investigate the vasorelaxant efficacy of nitrite and nitroxyl (HNO) in porcine coronary (micro)arteries (PC(M)As), evaluating their role as endothelium-derived hyperpolarizing factors (EDHFs), preconstricted PCAs and PCMAs were exposed to UV light (a well-known inductor of nitrite; wave-length: 350-370nm), nitrite, the HNO donor Angeli's salt, or bradykinin. UV light-induced relaxation of PCAs increased identically after endothelium removal and endothelial nitric oxide (NO) synthase (eNOS) blockade. UV light-induced relaxation diminished during Na(+)-K(+)-ATPase inhibition and S-nitrosothiol-depletion, and disappeared during NO scavenging with hydroxocobalamin or soluble guanylyl cyclase (sGC) inhibition with ODQ. Nitrite-induced relaxation of PCAs required millimolar levels, i.e., >1000 times endogenous vascular nitrite. Angeli's salt relaxed PCMAs more potently than PCAs, and this was due to the fact that HNO directly activated sGC in PCMAs, whereas in PCAs this occurred following its conversion to NO only. sGC activation by NO/HNO resulted in Na(+)-K(+)-ATPase stimulation and K(v) channel activation. The HNO scavenger l-cysteine blocked bradykinin-induced relaxation in PCAs, and potentiated it in PCMAs. The latter did not occur in the presence of hydroxocobalamin, suggesting that it depended on l-cysteine-induced generation of vasorelaxant S-nitrosothiols. In all experimental setups, incubation with red wine extract mimicked the effects of ODQ. In conclusion, nitrite, via its conversion to NO and S-nitrosothiols, and HNO, either directly, or via its conversion to NO, mediate relaxant effects involving the sGC-cGMP pathway, Na(+)-K(+)-ATPase and/or K(v) channels. Red wine extract counteracts these beneficial effects. NO blocks nitrite activation, and HNO, but not nitrite, may act as EDHF in the coronary vascular bed.

Low-level-laser irradiation induces photorelaxation in coronary arteries and overcomes vasospasm of internal thoracic arteries.

BACKGROUND AND OBJECTIVE: As low-level laser irradiation (LLLI) seems to induce vasodilation besides many other known biological effects, LLLI has been increasingly used in therapy of medical conditions with various irradiation parameters. The aim of this study was to investigate the effect of LLLI on photorelaxation of human coronary and internal thoracic arteries (ITA). MATERIALS AND METHODS: Thirty vessel segments of ITA used for routine coronary artery bypass grafting as well as left anterior descending coronary arteries (LAD) of patients undergoing cardiac transplantation were cut into 4-mm rings stored in a modified Krebs-Henseleit solution and evaluated in a myograph. Both types of vessel segments were irradiated by a semiconductor non-thermal GaAs diode laser operating at a wavelength of 680 nm. After precontraction with thromboxane agonist U44619, respective relaxation responses were evaluated and compared to pharmacological dilatation induced by substance P. RESULTS: Mean pharmacological vasodilation by substance P was 22.6 ± 3.3%, 12.8 ± 1.4%, and 20.4 ± 3.2% in macroscopic healthy LAD, LAD with atheromatous plaque, and ITA, respectively. Average photorelaxation induced by LLLI was 16.5 ± 2.0%, 1.9 ± 1.7%, and 6.8 ± 4.7%, accordingly. Vasodilatatory responses induced either by substance P or administration of LLLI were significantly decreased in LAD with atheromatous plaque (P < 0.0001). Vasospasms of ITA segments occurring during experiments could be abandoned when LLLI was administered. CONCLUSION: Macroscopic healthy LAD exposed to LLLI revealed significant photorelaxation. With the administration of LLLI, 73% of the maximal obtainable effect by an endothelium-dependent vasodilator could be reached. Furthermore, LLLI has the potential to overcome vasospasms of ITA.

Changes in middle cerebral artery blood flow velocity during sonolysis using a diagnostic transcranial probe with a 2-MHz Doppler frequency in healthy volunteers.

OBJECTIVES: Ultrasound has various biological effects in the human body. The effects of continuous monitoring with ultrasound (sonolysis) on vasodilatation of the radial artery were described recently. We wanted to ascertain whether similar changes in the blood flow velocity during sonolysis could also be detected in the middle cerebral artery. METHODS: Fifteen healthy volunteers (6 male and 9 female; age range, 23-68 years; mean ± SD, 47.1 ± 15.1 years) were subjected to 1 hour of middle cerebral artery sonolysis using a diagnostic transcranial probe with a 2-MHz Doppler frequency and measurement of the blood flow velocity at 2-minute intervals. During a second session, a flow curve was recorded for 10 seconds at 2-minute intervals. The peak systolic velocity, end-diastolic velocity, mean flow velocity, pulsatility index, and resistive index were recorded during both measurements. RESULTS: Irregular changes in the measured blood flow parameters were recorded during both sessions. Changes in particular hemodynamic parameters during both measurements were similar. The changes in the peak systolic velocity, end-diastolic velocity, mean flow velocity, pulsatility index, and resistive index were not significantly different between the two measurements (P < .05 in all cases). CONCLUSIONS: As opposed to sonolysis of the radial artery, sonolysis of the middle cerebral artery using a diagnostic 2-MHz frequency in healthy volunteers did not lead to changes in the flow curve or peripheral vasodilatation.