Cellular Senescence in Idiopathic Pulmonary Fibrosis.

Cellular senescence (CS) is increasingly implicated in the etiology of age-related diseases. While CS can facilitate physiological processes such as tissue repair and wound healing, senescent cells also contribute to pathophysiological processes involving macromolecular damage and metabolic dysregulation that characterize multiple morbid and prevalent diseases, including Alzheimer's disease, osteoarthritis, atherosclerotic vascular disease, diabetes mellitus, and idiopathic pulmonary fibrosis (IPF). Preclinical studies targeting senescent cells and the senescence-associated secretory phenotype (SASP) with "senotherapeutics" have demonstrated improvement in age-related morbidity associated with these disease states. Despite promising results from these preclinical trials, few human clinical trials have been conducted. A first-in-human, open-label, pilot study of the senolytic combination of dasatinib and quercetin (DQ) in patients with IPF showed improved physical function and mobility. In this review, we will discuss our current understanding of cellular senescence, its role in age-associated diseases, with a specific focus on IPF, and potential for senotherapeutics in the treatment of fibrotic lung diseases.

Cholinergic mechanisms of cutaneous active vasodilation during heat stress in cystic fibrosis.

To test the hypothesis that cutaneous active vasodilation in heat stress is mediated by a redundant cholinergic cotransmitter system, we examined the effects of atropine on skin blood flow (SkBF) increases during heat stress in persons with (CF) and without cystic fibrosis (non-CF). Vasoactive intestinal peptide (VIP) has been implicated as a mediator of cutaneous vasodilation in heat stress. VIP-containing cutaneous neurons are sparse in CF, yet SkBF increases during heat stress are normal. In CF, augmented ACh release or muscarinic receptor sensitivity could compensate for decreased VIP; if so, active vasodilation would be attenuated by atropine in CF relative to non-CF. Atropine was administered into skin by iontophoresis in seven CF and seven matched non-CF subjects. SkBF was monitored by laser-Doppler flowmetry (LDF) at atropine treated and untreated sites. Blood pressure [mean arterial pressure (MAP)] was monitored (Finapres), and cutaneous vascular conductance was calculated (CVC = LDF/MAP). The protocol began with a normothermic period followed by a 3-min cold stress and 30-45 min of heat stress. Finally, LDF sites were warmed to 42 degrees C to effect maximal vasodilation. CVC was normalized to its site-specific maximum. During heat stress, CVC increased in both CF and non-CF (P < 0.01). CVC increases were attenuated by atropine in both groups (P < 0.01); however, the responses did not differ between groups (P = 0.99). We conclude that in CF there is not greater dependence on redundant cholinergic mechanisms for cutaneous active vasodilation than in non-CF.

In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans during thermoregulatory challenges.

This review focuses on the neural and local mechanisms that have been demonstrated to effect cutaneous vasodilation and vasoconstriction in response to heat and cold stress in vivo in humans. First, our present understanding of the mechanisms by which sympathetic cholinergic nerves mediate cutaneous active vasodilation during reflex responses to whole body heating is discussed. These mechanisms include roles for cotransmission as well as nitric oxide (NO). Next, the mechanisms by which sympathetic noradrenergic nerves mediate cutaneous active vasoconstriction during whole body cooling are reviewed, including cotransmission by neuropeptide Y (NPY) acting through NPY Y1 receptors. Subsequently, current concepts for the mechanisms that effect local cutaneous vascular responses to direct skin warming are examined. These mechanisms include the roles of temperature-sensitive afferent neurons as well as NO in causing vasodilation during local heating of skin. This section is followed by a review of the mechanisms that cause local cutaneous vasoconstriction in response to direct cooling of the skin, including the dependence of these responses on intact sensory and sympathetic, noradrenergic innervation as well as roles for nonneural mechanisms. Finally, unresolved issues that warrant further research on mechanisms that control cutaneous vascular responses to heating and cooling are discussed.

Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin.

Acetylcholine (ACh) can effect vasodilation by several mechanisms, including activation of endothelial nitric oxide (NO) synthase and prostaglandin (PG) production. In human skin, exogenous ACh increases both skin blood flow (SkBF) and bioavailable NO levels, but the relative increase is much greater in SkBF than NO. This led us to speculate ACh may dilate cutaneous blood vessels through PGs, as well as NO. To test this hypothesis, we performed a study in 11 healthy people. We measured SkBF by laser-Doppler flowmetry (LDF) at four skin sites instrumented for intradermal microdialysis. One site was treated with ketorolac (Keto), a nonselective cyclooxygenase antagonist. A second site was treated with NG-nitro-L-arginine methyl ester (L-NAME) to inhibit NO synthase. A third site was treated with a combination of Keto and L-NAME. The fourth site was an untreated control site. After the three treated sites received the different inhibiting agents, ACh was administered to all four sites by intradermal microdialysis. Finally, sodium nitroprusside (SNP) was administered to all four sites. Mean arterial pressure (MAP) was monitored by Finapres, and cutaneous vascular conductance (CVC) was calculated (CVC = LDF/MAP). For data analysis, CVC values for each site were normalized to their respective maxima as effected by SNP. The results showed that both Keto and L-NAME each attenuated the vasodilation induced by exogenous ACh (ACh control = 79 +/- 4% maximal CVC, Keto = 55 +/- 7% maximal CVC, L-NAME = 46 +/- 6% maximal CVC; P < 0.05, ACh vs. Keto or L-NAME). The combination of the two agents produced an even greater attenuation of ACh-induced vasodilation (31 +/- 5% maximal CVC; P < 0.05 vs. all other sites). We conclude that a portion of the vasodilation effected by exogenous ACh in skin is due to NO; however, a significant portion is also mediated by PGs.

Selected contribution: Gender differences in the endothelin-B receptor contribution to basal cutaneous vascular tone in humans.

To test whether the contribution of endothelin-B (ET-B) receptors to resting vascular tone differs between genders, we administered the ET-B receptor antagonist BQ-788 into the forearm skin of 11 male and 11 female subjects by intradermal microdialysis. Skin blood flow was measured using laser-Doppler flowmetry at the microdialysis site. The probe was perfused with Ringer solution alone, followed by BQ-788 (150 nM) and finally sodium nitroprusside (28 mM) to effect maximal cutaneous vasodilation. Cutaneous vascular conductance (CVC) was calculated (laser-Doppler flowmetry/mean arterial pressure) and normalized to maximal levels (%max). In male subjects, baseline CVC was (mean +/- SE) 19 +/- 3%max and increased to 26 +/- 5%max with BQ-788 (P < 0.05 vs. baseline). In female subjects, baseline CVC was 13 +/- 1%max and decreased to 10 +/- 1%max in response to BQ-788. CVC responses to BQ-788 differed with gender (P < 0.05); thus the contribution of ET-B receptors to resting cutaneous vascular tone differs between men and women. In men, ET-B receptors mediate tonic vasoconstriction, whereas, in women, ET-B receptors mediate tonic vasodilation.

Nitric oxide concentration increases in the cutaneous interstitial space during heat stress in humans.

To examine the role of nitric oxide (NO) in cutaneous active vasodilation, we measured the NO concentration from skin before and during whole body heat stress in nine healthy subjects. A forearm site was instrumented with a NO-selective, amperometric electrode and an adjacent intradermal microdialysis probe. Skin blood flow (SkBF) was monitored by laser-Doppler flowmetry (LDF). NO concentrations and LDF were measured in normothermia and heat stress. After heat stress, a solution of ACh was perfused through the microdialysis probe to pharmacologically generate NO and verify the electrode's function. During whole body warming, both SkBF and NO concentrations began to increase at the same internal temperature. Both SkBF and NO concentrations increased during heat stress (402 +/- 76% change from LDF baseline, P < 0.05; 22 +/- 5% change from NO baseline, P < 0.05). During a second baseline condition after heat stress, ACh perfusion led to increases in both SkBF and NO concentrations (496 +/- 119% change from LDF baseline, P < 0.05; 16 +/- 10% change from NO baseline, P < 0.05). We conclude that NO does increase in skin during heat stress in humans, attendant to active vasodilation. This result suggests that NO has a role beyond that of a permissive factor in the process; rather, NO may well be an effector of cutaneous vasodilation during heat stress.

Control of internal temperature threshold for active cutaneous vasodilation by dynamic exercise.

Exercise induces shifts in the internal temperature threshold at which cutaneous vasodilation begins. To find whether this shift is accomplished through the vasoconstrictor system or the cutaneous active vasodilator system, two forearm sites (0.64 cm2) in each of 11 subjects were iontophoretically treated with bretylium tosylate to locally block adrenergic vasoconstrictor control. Skin blood flow was monitored by laser-Doppler flowmetry (LDF) at those sites and at two adjacent untreated sites. Mean arterial pressure (MAP) was measured noninvasively. Cutaneous vascular conductance was calculated as LDF/MAP. Forearm sweat rate was also measured in seven of the subjects by dew point hygrometry. Whole body skin temperature was raised to 38 degrees C, and supine bicycle ergometer exercise was then performed for 7-10 min. The internal temperature at which cutaneous vasodilation began was recorded for all sites, as was the temperature at which sweating began. The same subjects also participated in studies of heat stress without exercise to obtain vasodilator and sudomotor thresholds from rest. The internal temperature thresholds for cutaneous vasodilation were higher during exercise at both bretylium-treated (36.95 +/- 0.07 degrees C rest, 37.20 +/- 0.04 degrees C exercise, P less than 0.05) and untreated sites (36.95 +/- 0.06 degrees C rest, 37.23 +/- 0.05 degrees C exercise, P less than 0.05). The thresholds for cutaneous vasodilation during rest or during exercise were not statistically different between untreated and bretylium-treated sites (P greater than 0.05). The threshold for the onset of sweating was not affected by exercise (P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of nitric oxide in the vascular effects of local warming of the skin in humans.

Local warming of skin induces vasodilation by unknown mechanisms. To test whether nitric oxide (NO) is involved, we examined effects of NO synthase (NOS) inhibition with NG-nitro-L-arginine methyl ester (L-NAME) on vasodilation induced by local warming of skin in six subjects. Two adjacent sites on the forearm were instrumented with intradermal microdialysis probes for delivery of L-NAME and sodium nitroprusside. Skin blood flow was monitored by laser-Doppler flowmetry (LDF) at microdialysis sites. Local temperature (Tloc) of the skin at both sites was controlled with special LDF probe holders. Mean arterial pressure (MAP; Finapres) was measured and cutaneous vascular conductance calculated (CVC = LDF/MAP = mV/mmHg). Data collection began with a control period (Tloc at both sites = 34 degrees C). One site was then warmed to 41 degrees C while the second was maintained at 34 degrees C. Local warming increased CVC from 1.44 +/- 0.41 to 4.28 +/- 0.60 mV/mmHg (P < 0.05). Subsequent L-NAME administration reduced CVC to 2.28 +/- 0.47 mV/mmHg (P < 0.05 vs. heating), despite the continued elevation of Tloc. At a Tloc of 34 degrees C, L-NAME reduced CVC from 1.17 +/- 0.23 to 0.75 +/- 0.11 mV/mmHg (P < 0.05). Administration of sodium nitroprusside increased CVC to levels no different from those induced by local warming. Thus NOS inhibition attenuated, and sodium nitroprusside restored, the cutaneous vasodilation induced by elevation of Tloc; therefore, the mechanism of cutaneous vasodilation by local warming requires NOS generation of NO.

Cutaneous laser-Doppler flowmetry: influence of underlying muscle blood flow.

To find whether the measurement of skin blood flow (SkBF) by laser-Doppler flowmetry (LDF) is influenced by blood flow to underlying skeletal muscle, five subjects performed mild forearm exercise to induce a metabolic hyperemia in muscle in both forearms. This exercise consisted of alternative opening and closing of both hands at a frequency of approximately 1/s for a duration of 3 min. This exercise was performed twice by each subject. Forearm blood flow (FBF) by plethysmography increased from 2.64 +/- 0.49 (rest) to 31.11 +/- 9.95 ml.100 ml-1.min-1 (immediately after exercise) (P less than 0.001). No statistically significant postexercise increase was observed in LDF measured on the dorsal (110 +/- 21 to 105 +/- 21 mV) or ventral surface (266 +/- 113 to 246 +/- 77 mV) of the forearm. LDF measured from the chest also showed no significant change, indicating that the exercise was too mild to have reflex effects on SkBF. Moreover, the slope of the logarithmic linear regression and the half-time for recovery during the postexercise period for FBF were not reflected in LDF measurements from any of the three sites. We conclude that LDF measured from the skin surface is not influenced by blood flow to underlying skeletal muscle.

Bioactive nitric oxide concentration does not increase during reactive hyperemia in human skin.

This study examined whether nitric oxide (NO) is involved in the cutaneous response to reactive hyperemia (RH) in the human forearm. We enrolled seven healthy volunteers. NO concentrations were monitored using a NO selective amperometric electrode (ISO-NOP200, World Precision Instruments) inserted into the skin of the forearm. Laser-Doppler flowmetry (Moor Instruments) was used for monitoring skin blood flow (SkBF) at the same site. SkBF and NO levels were monitored and recorded continuously throughout the experiment. An intradermal microdialysis probe was inserted adjacent to the NO electrode for drug delivery. Data collection began 140 min after the NO electrodes and microdialysis probes were inserted. RH was achieved by the inflation of a blood pressure cuff to 25 mmHg above systolic pressure for 7 min after which the pressure in the cuff was abruptly released. Acetylcholine (ACh) was given by microdialysis probe at the end of RH study to verify the ability of the electrode system to detect changes in the NO concentration. SkBF and NO data before RH and immediately, 2, 5, 7, and 10 min after cuff deflation were used for analysis. SkBF increased immediately after release of the occlusion (P < 0.0001) and remained elevated for 2 min. No significant NO changes occurred with the increases in LDF. ACh induced increases in both SkBF and NO (P < 0.000 and P < 0.037, respectively). We conclude that RH increases SkBF by mechanisms that do not require a measurable increase in NO concentrations.

Nitric oxide and cutaneous active vasodilation during heat stress in humans.

Whether nitric oxide (NO) is involved in cutaneous active vasodilation during hyperthermia in humans is unclear. We tested for a role of NO in this process during heat stress (water-perfused suits) in seven healthy subjects. Two forearm sites were instrumented with intradermal microdialysis probes. One site was perfused with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) dissolved in Ringer solution to abolish NO production. The other site was perfused with Ringer solution only. At those sites, skin blood flow (laser-Doppler flowmetry) and sweat rate were simultaneously and continuously monitored. Cutaneous vascular conductance, calculated from laser-Doppler flowmetry and mean arterial pressure, was normalized to maximal levels as achieved by perfusion with the NO donor nitroprusside through the microdialysis probes. Under normothermic conditions, L-NAME did not significantly reduce cutaneous vascular conductance. During hyperthermia, with skin temperature held at 38-38.5 degreesC, internal temperature rose from 36.66 +/- 0.10 to 37.34 +/- 0.06 degreesC (P < 0.01). Cutaneous vascular conductance at untreated sites increased from 12 +/- 2 to 44 +/- 5% of maximum, but only rose from 13 +/- 2 to 30 +/- 5% of maximum at L-NAME-treated sites (P < 0.05 between sites) during heat stress. L-NAME had no effect on sweat rate (P > 0.05). Thus cutaneous active vasodilation requires functional NO synthase to achieve full expression.

Baroreceptor control of the cutaneous active vasodilator system.

We sought to identify whether reductions in cutaneous active vasodilation during simulated orthostasis could be assigned solely to cardiopulmonary or to carotid baroreflexes by unloading cardiopulmonary baroreceptors with low levels of lower body negative pressure (LBNP) or unloading carotid baroreceptors with external pressure applied over the carotid sinus area [carotid pressure (CP)]. Skin blood flow was measured at a site at which adrenergic function was blocked via bretylium tosylate iontophoresis and at an unblocked site. During LBNP of -5 and -10 mmHg in hyperthermia, neither heart rate (HR) nor cutaneous vascular conductance (CVC) at either site changed (P > 0.05 for both), whereas forearm vascular conductance (FVC) was reduced (-5 mmHg: from 21.6 +/- 4.8 to 19.8 +/- 4.1 FVC units, P = 0.05; -10 mmHg: from 22.3 +/- 4.0 to 19.3 +/- 3.7 FVC units, P = 0.002). LBNP of -30 mmHg in hyperthermia reduced CVC at both sites (untreated: from 51.9 +/- 5.7 to 43.2 +/- 5.1% maximum, P = 0.02; bretylium tosylate: from 60.9 +/- 5.4 to 53.2 +/- 4.4% maximum, P = 0.02), reduced FVC (from 23.2 +/- 3.6 to 18.1 +/- 3.3 FVC units; P = 0.002), and increased HR (from 83 +/- 4 to 101 +/- 3 beats/min; P = 0.003). Pulsatile CP (45 mmHg) did not affect FVC or CVC during normothermia or hyperthermia (P > 0.05). However, HR and mean arterial pressure were elevated during CP in both thermal conditions (both P < 0.05). These results suggest that neither selective low levels of cardiopulmonary baroreceptor unloading nor selective carotid baroreceptor unloading can account for the inhibition of cutaneous active vasodilator activity seen with simulated orthostasis.

Cutaneous vascular and sudomotor responses to isometric exercise in humans.

To identify whether isometric handgrip exercise (IHG) affects cutaneous vasoconstrictor and/or active vasodilator activities, seven subjects (6 men and 1 woman) performed 30% maximal voluntary contraction of a forearm under normothermic (1 bout) and hyperthermic (2 bouts) conditions. Skin blood flow was indexed by laser-Doppler flowmetry at a contralateral forearm site at which adrenergic vasoconstrictor function was blocked by iontophoresis of bretylium tosylate (BT) and therefore only has active vasodilation as a mechanism for reflex control. Skin blood flow was also monitored at an adjacent untreated site. Cutaneous vascular conductance (CVC) was calculated from the flow signal and noninvasive blood pressure. CVC was normalized to the value obtained from maximal vasodilation at that site. Sweat rate (SR) was measured at the same locations. During normothermia, IHG did not affect CVC at the control or BT-treated sites, nor did IHG affect SR (P > 0.05). The second bout of IHG in hyperthermia evoked significant reductions in CVC at the untreated (69.4 +/- 3.4 to 58.9 +/- 2.5% of maximum, P < 0.05) and BT-treated sites (75.4 +/- 6.1 to 64.4 +/- 6.2% of maximum, P < 0.05), whereas SR significantly increased (0.62 +/- 0.16 to 0.70 +/- 0.17 mg.cm-2.min-1, P < 0.05). These findings uniquely show that, in hyperthermia, IHG reduces active vasodilator activity while at the same time sudomotor activity is increasing. This suggests independent control of these effectors.

Skin of the dorsal aspect of human hands and fingers possesses an active vasodilator system.

To test for an active vasodilator system in human hand and finger skin, seven subjects had a small area of dorsal hand, palm, or dorsal finger pretreated with bretylium (BT) to block adrenergic vasoconstriction. Skin blood flow was monitored at a BT-treated site, a comparable untreated site, and the forearm by laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was evaluated from the ratio of blood flow to arterial pressure. Body cooling, to evaluate vasoconstrictor system blockade, caused CVC at untreated sites of forearm, palm, dorsal hand, and dorsal finger to fall by 45 +/- 4, 85 +/- 5, 51 +/- 9, and 63 +/- 7%, respectively (all P < 0.05). At BT-treated sites of palm, dorsal hand, and dorsal finger, reductions in CVC were only 13 +/- 3, 2 +/- 18, and 13 +/- 4%, respectively (dorsal hand not significant, others P < 0.05). With body heating, increases in CVC at untreated sites of forearm, palm, dorsal hand, and dorsal finger were 881 +/- 165, 779 +/- 368, 423 +/- 115, and 1,430 +/- 716%, respectively (all P < 0.05). At BT-treated sites of palm, dorsal hand, and dorsal finger, increases were 35 +/- 15, 342 +/- 107, and 343 +/- 34%, respectively (palm not significant, others P < 0.05). Increased CVC at the palm began after 1.2 +/- 0.2 min of heating, significantly earlier than forearm (11.8 +/- 2.5 min), dorsal hand (16.4 +/- 3.4 min), or dorsal finger (15.6 +/- 3.6 min), which did not differ significantly from one another.(ABSTRACT TRUNCATED AT 250 WORDS)

Bradykinin does not mediate cutaneous active vasodilation during heat stress in humans.

To test the hypothesis that bradykinin effects cutaneous active vasodilation during hyperthermia, we examined whether the increase in skin blood flow (SkBF) during heat stress was affected by blockade of bradykinin B(2) receptors with the receptor antagonist HOE-140. Two adjacent sites on the forearm were instrumented with intradermal microdialysis probes for local delivery of drugs in eight healthy subjects. HOE-140 was dissolved in Ringer solution (40 microM) and perfused at one site, whereas the second site was perfused with Ringer alone. SkBF was monitored by laser-Doppler flowmetry (LDF) at both sites. Mean arterial pressure (MAP) was monitored from a finger, and cutaneous vascular conductance (CVC) was calculated (CVC = LDF/MAP). Water-perfused suits were used to control body temperature and evoke hyperthermia. After hyperthermia, both microdialysis sites were perfused with 28 mM nitroprusside to effect maximal vasodilation. During hyperthermia, CVC increased at HOE-140 (69 +/- 2% maximal CVC, P < 0.01) and untreated sites (65 +/- 2% maximal CVC, P < 0.01). These responses did not differ between sites (P > 0.05). Because the bradykinin B(2)-receptor antagonist HOE-140 did not alter SkBF responses to heat stress, we conclude that bradykinin does not mediate cutaneous active vasodilation.

Thermoregulatory reflexes and cutaneous active vasodilation during heat stress in hypertensive humans.

During dynamic exercise in the heat, increases in skin blood flow are attenuated in hypertensive subjects when compared with normotensive subjects. We studied responses to passive heat stress (water-perfused suits) in eight hypertensive and eight normotensive subjects. Forearm blood flow was measured by venous-occlusion plethysmography, mean arterial pressure (MAP) was measured by Finapres, and forearm vascular conductance (FVC) was calculated. Bretylium tosylate (BT) iontophoresis was used to block active vasoconstriction in a small area of skin. Skin blood flow was indexed by laser-Doppler flowmetry at BT-treated and untreated sites, and cutaneous vascular conductance was calculated. In normothermia, FVC was lower in hypertensive than in normotensive subjects (P < 0.01). During heat stress, FVC rose to similar levels in both groups (P > 0.80); concurrent cutaneous vascular conductance increases were unaffected by BT treatment (P > 0.60). MAP was greater in hypertensive than in normotensive subjects during normothermia (P < 0.05, hypertensive vs. normotensive subjects). During hyperthermia, MAP fell in hypertensive subjects but showed no statistically significant change in normotensive subjects (P < 0.05, hypertensive vs. normotensive subjects). The internal temperature at which vasodilation began did not differ between groups (P > 0.80). FVC is reduced during normothermia in unmedicated hypertensive subjects; however, they respond to passive heat stress in a fashion no different from normotensive subjects.

Intradermal microdialysis: kinetics of iontophoretically delivered propranolol in forearm dermis.

Intradermal microdialysis permits us to measure the concentration in dermis of drugs applied to the skin. Microdialysis is especially efficient in sampling water-soluble molecules. Consequently, it appears particularly suitable to study current based delivery systems like iontophoresis that deliver ions or highly polar molecules. The purpose of this work was to evaluate the adequacy of a skin microdialysis technique to characterize and quantify the dermatopharmacokinetics of iontophoretically delivered propranolol in the dermis of healthy human volunteers. Linear microdialysis probes were inserted in the subject's forearm skin and an iontophoresis device was installed above them. Constant current was applied for two periods of 1 h each separated by a 1-h interval. Dialysate samples were collected every 6 min for 4.4 h and analyzed by HPLC. Probes were always placed in the dermis as measured by ultrasonography. Propranolol was detectable in the dialysate. It was possible to build detailed concentration vs. midtime profiles that mirrored the current applied. Elimination rate from the dermis had first-order kinetics and was similar in all subjects. Quantification of the absorption process, indexed by lag-time and area under the concentration curve showed a high inter- and intrasubject variability that did not correlate with probe depth.

Iontophoretic current and intradermal microdialysis recovery in humans.

When microdialysis (MD) is used to study dermal delivery by iontophoresis, the effects of current may alter MD recovery through an increase in temperature, a change of pH, hyperemia, and dermal hydration. The objective of this work is to assess whether these effects of current may cause a measurable change in the retrodialysis of a model compound (sodium fluorescein, Fl). Two linear MD-probes were inserted in the forearm dermis of healthy human volunteers and perfused with Ringer's solution containing Fl. Two identical iontophoresis chambers (IC, filled with NaCl in propylene glycol) were placed over the MD-probes. Each IC included a laser Doppler flowmetry probe to monitor skin blood flow. At one IC, current was applied for two periods of 30 min each, separated by 30 min of no current. No current was applied to the control site. Dialysate samples were collected every 5 min and analyzed for Fl by HPLC. Skin blood flow increased in response to iontophoresis, on average, 570% compared to the control site. However, there was no difference in the recovery of Fl between the current-active site versus the control site, and between the period with applied current versus the period with no current. In conclusion, iontophoretic current did not affect intradermal MD recovery.

Hazard potential of ejection with canopy fragmentation.

The hazard potential of ejection with canopy fragmentation was evaluated by horizontal sled tests. A series of 14 ejections of tandem seats with 1st or 95th percentile anthropometric dummies were performed at sled speeds of 0, 150, 350, and 600 knots. Canopy-mounted miniature detonating cords (MDC) were fired in nine and not fired in five ejections. Maximal impact loads on each dummy's neck, knees, and shoulders were measured, and noise levels inside and outside the helmet recorded. The acceleration waveform for each dummy was recorded and used to calculate a dynamic response index (DRI) to assess the risk of spinal injury. Impacts with canopy fragments during ejections resulted in minor visible damages to the dummies and their equipment regardless of MDC firing. It was noted that MDC firing significantly attenuated the mean neck load (231 +/- 63 kg, unfired, to 108 +/- 20 kg, fired, p < 0.05). Noise levels with MDC firing averaged 162 dB. The mean DRI of dummy Gz for the small dummies was significantly greater than for large dummies (20.8 +/- 0.44 and 18.05 +/- 0.98, respectively, p < 0.05). We conclude that superficial injuries to ejecting pilots and their equipment is not a hazard with the canopy fragmentation system; however, spinal injury may occur at rates of 5 to 50% depending on the size of the pilot.

Selective abolition of adrenergic vasoconstrictor responses in skin by local iontophoresis of bretylium.

Skin blood flow (SkBF) in humans is controlled by a noradrenergic active vasoconstrictor system and an active vasodilator system of an uncertain neurotransmitter. Understanding how these systems interact would be aided if the vasodilator system could be studied in the absence of effects of the vasoconstrictor system. To accomplish this we combined laser-Doppler velocimetry (LDV) with the local iontophoresis of bretylium in 10 studies with eight healthy subjects. Each subject had two forearm sites (0.64 cm2) treated with bretylium to block local norepinephrine release. LDV was monitored at those sites and at two untreated sites during 3-4 min of cold stress, 35-45 min of heat stress, and a final cold stress to verify blockade. In five studies, local temperature was raised to 39 degrees C at the LDV sites before the final cold stress. Whole body skin temperature was controlled by water-perfused suits. Mean arterial pressure (MAP) was measured noninvasively. Heart rate and internal temperature were also recorded. Cutaneous vascular conductance (CVC) was calculated as LDV/MAP. During the initial cold stress, performed 130 min after bretylium treatment, CVC at treated sites fell by an average of 0.3 +/- 3.2% (P greater than 0.10) and at untreated sites by 29.2 +/- 4.1% (P less than 0.001 between sites). During heat stress, CVC at treated sites rose by 419 +/- 66% and at control sites, by 517 +/- 90% (P greater than 0.10 between sites). The internal temperature threshold for cutaneous vasodilation was not statistically different between sites (P greater than 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)