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PubMed1993

Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.

BACKGROUND: Endothelium-dependent vasodilation is abnormal in experimental models of diabetes mellitus. We postulated that abnormalities of endothelial function are also present in patients with insulin-dependent diabetes mellitus and may contribute to the pathogenesis of vascular disease in these individuals. METHODS AND RESULTS: Vascular reactivity was measured in the forearm resistance vessels of 15 patients with insulin-dependent diabetes mellitus and 16 age-matched normal subjects. No patient had hypertension or dyslipidemia. Each subject was pretreated with aspirin to inhibit endogenous production of prostanoids. Methacholine chloride (0.3 to 10 micrograms/min) was administered via the brachial artery to assess endothelium-dependent vasodilation. Sodium nitroprusside (0.3 to 10 micrograms/min) and verapamil (10 to 300 micrograms/min) were infused intra-arterially to assess endothelium-independent vasodilation; phenylephrine (0.3 to 3 micrograms/min) was administered to examine vasoconstrictor responsiveness. Forearm blood flow was determined by venous occlusion plethysmography, and dose-response curves were generated for each drug. Basal forearm blood flow in diabetic and normal subjects was comparable (2.6 +/- 0.2 versus 2.1 +/- 0.3 mL x 100 mL-1 x min-1, respectively; P = NS). The forearm vasodilative response to methacholine was less in diabetic than in normal subjects. At the highest dose of methacholine, the forearm blood flow increased 9.5 +/- 1.1 mL x 100 mL-1 x min-1 in diabetic subjects and 15.3 +/- 1.4 mL.100 mL-1 x min-1 in normal subjects (P < .01). The forearm blood flow responses to nitroprusside and verapamil and the forearm vasoconstrictor responses to phenylephrine were similar in diabetic and healthy subjects. In diabetic subjects, endothelium-dependent vasodilation correlated inversely with serum insulin concentration but not with glucose concentration, glycosylated hemoglobin, or duration of diabetes. CONCLUSIONS: Endothelium-dependent vasodilation is abnormal in forearm resistance vessels of patients with insulin-dependent diabetes mellitus. This abnormality may be relevant to the high prevalence of vascular disease that occurs in these individuals.

Adult↗

PubMed1991

Muscarinic modulation of the vasodilatory effects of vasoactive intestinal peptide at the rat thyroid gland.

In the thyroid gland, vasoactive intestinal peptide (VIP) and acetylcholine (ACh) are found in nerve fibers associated with secretory cells and blood vessels. We have, therefore, initiated studies to explore the actions of and interactions between cholinergic agents and VIP in the regulation of thyroid vascular conductance (VC). Thyroid and other organ blood flows were measured using radiolabelled (141Ce) microspheres injected directly into the left cardiac ventricle of anesthetized male rats. The mean systemic arterial pressure was monitored and used in the calculation of organ VC (blood flow/arterial pressure). Plasma TSH, T3, and T4 levels before and after infusions were measured by RIA. The acute administration of ACh (3 x 10(-8) mol/100 g BW) over 4 min increased thyroid VC, whereas nicotine (10(-7) mol/100 g BW) had no such effect. Circulating TSH and thyroid-hormone levels following ACh or nicotine were not different from those in vehicle-treated animals at 20 min or 2 h after infusion. This observation suggested that ACh acts through muscarinic receptors at the thyroid gland to increase VC. In order to extend these observations and to evaluate whether VIP might exert any of its thyroidal effects on VC via muscarinic receptors, we assessed the effects of ACh, methacholine chloride (MCC), and VIP in the presence and absence of the muscarinic receptor blocker atropine. Rats were treated intravenously with saline or atropine (3 mg/kg) 20 min before intravenous infusions of vehicle, ACh (3 x 10(-8) mol/100 g BW), MCC (5 x 10(-9) mol/100 g BW), or VIP (10(-11) mol/100 g BW).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1993

Ferret tracheal mucus rheology, clearability and volume following administration of substance P or methacholine.

We studied the effects of substances P administration on tracheal mucus viscoelasticity, water content, clearability and secretion rate. Six neutered adult male ferrets (weight 1.1-1.5 kg) were studied, on four occasions each. They were anaesthetized with ketamine and xylazine, and intubated shallowly. Control mucus (pre- and post-Ringer instillation) was compared with the mucus obtained following instillation of 200 microliters of 10(-6), 10(-5), and 10(-4) M substance P (SP), and 10(-4) M methacholine chloride as a reference. Tracheal mucus was collected by inserting a soft-bristled cytology brush to the level of the carina, and leaving it in contact with the mucosa for 30 min. After withdrawing the brush, the adherent mucus was quickly scraped off and layered with paraffin oil to prevent evaporation. The mucus was analysed for viscoelasticity by magnetic rheometry and solids content by evaporation to dryness. Mucus transportability was assessed by comparison with model gels, and also by means of the frog palate assay, which indicates how well mucus is cleared by normal ciliary action. There was a dose-related increase in mucus volume, and a dose-related decrease in mucus viscosity and elasticity, with substance P administration. Mucus transportability increased with both substance P and methacholine. The effects of 10(-4) SP and methacholine were comparable in terms of viscoelasticity and volume; with both methacholine and SP, there appeared to be an additive effect. The mucus solids content did not correlate with the viscoelastic changes for SP administration, whereas it did for methacholine. These observations suggest that the hypersecretion induced by these two agents might involve different pathways.

Analysis of Variance↗

PubMed2000

Ethnic differences: word descriptors used by African-American and white asthma patients during induced bronchoconstriction.

STUDY OBJECTIVES: To determine if African-American and white patients with asthma (1) differ in the words they use to describe their breathlessness, and (2) differ in their perception of breathlessness. DESIGN: Descriptive cross-sectional design. SETTING AND PARTICIPANTS: The study setting was located in Northern California, an ethnically and economically diverse area. A total of 32 subjects, 16 per group, completed the study. MEASUREMENTS: All had a provocation concentration of methacholine chloride causing a 30% fall in FEV(1) (PC(30)) of </= 8 mg/mL. Serial pulmonary function testing was performed. Breathlessness was measured using the Borg scale and the visual analog scale. Word descriptors were measured by an open-ended word descriptor questionnaire. RESULTS: Significant ethnic differences in the words used to describe the sensation of breathlessness were present at PC(30). African Americans used upper airway word descriptors: tight throat (p < 0. 0004), scared-agitated (p < 0.006), voice tight (p < 0.04), itchy throat (p < 0.03), and tough breath (p < 0.04). Whites used lower airway or chest-wall symptom descriptors: deep breath (p < 0.03), light-headed (p < 0.03), out of air (p < 0.01), aware of breathing (p < 0.03), and hurts to breathe (p < 0.06). In addition, African Americans required a significantly smaller, 44.3% (mean), dose of methacholine to achieve PC(30) (p < 0.02). CONCLUSION: This study provides valuable new information about ethnicity and the words used to describe breathlessness during airflow obstruction. Asthmatic African Americans used primarily upper airway word descriptors; whites used lower airway or chest-wall word descriptors. Effective symptom monitoring requires asking the correct question and awareness that ethnic differences in the words used to describe breathlessness may exist.

Administration, Inhalation↗

PubMed1994

Modification of forearm resistance vessels by exercise training in young men.

The aim of this study was to determine whether a 4-wk handgrip training program would elicit changes in endothelium-dependent and endothelium-independent vasodilatation in resistance vessels of the human forearm. Minimum vascular resistance after a 10-min ischemic stimulus, an index of peak vasodilator capacity, was also determined. Forearm blood flow response to the endothelium-dependent vasodilator methacholine chloride did not change over the 4-wk-intervention period either in the group undertaking training (n = 11) or in control subjects (n = 6). Similarly, the response to sodium nitroprusside was not influenced by the handgrip training program. Peak vasodilator capacity of the trained forearms significantly increased, whereas no change was evident in the untrained limbs. These results suggest that 4 wk of forearm exercise training enhances peak vasodilator capacity of the vasculature without influencing stimulated activity of the nitric oxide dilator system.

Adult↗

PubMed1994

Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release.

The purpose of this study was to examine whether insulin's effect to vasodilate skeletal muscle vasculature is mediated by endothelium-derived nitric oxide (EDNO). N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO synthase, was administered directly into the femoral artery of normal subjects at a dose of 16 mg/min and leg blood flow (LBF) was measured during an infusion of saline (NS) or during a euglycemic hyperinsulinemic clamp (HIC) designed to approximately double LBF. In response to the intrafemoral artery infusion of L-NMMA, LBF decreased from 0.296 +/- 0.032 to 0.235 +/- 0.022 liters/min during NS and from 0.479 +/- 0.118 to 0.266 +/- 0.052 liters/min during HIC, P < 0.03. The proportion of NO-dependent LBF during NS and HIC was approximately 20% and approximately 40%, respectively, P < 0.003 (NS vs. HIC). To elucidate whether insulin increases EDNO synthesis/release or EDNO action, vasodilative responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (MCh) or the endothelium-independent vasodilator sodium nitroprusside (SNP) were studied in normal subjects during either NS or HIC. LBF increments in response to intrafemoral artery infusions of MCh but not SNP were augmented during HIC versus NS, P < 0.03. In summary, insulin-mediated vasodilation is EDNO dependent. Insulin vasodilation of skeletal muscle vasculature most likely occurs via increasing EDNO synthesis/release. Thus, insulin appears to be a novel modulator of the EDNO system.

Adult↗

PubMed2003

Acute elevations of medium- and long-chain fatty acid have different impacts on endothelium-dependent vasodilation in humans.

It has previously been shown that acute elevation of long-chain fatty acids (LCFA) impairs endothelium-dependent vasodilation (EDV) in humans. In this study, we tested the hypothesis that an elevation of both medium-chain fatty acids (MCFA) and LCFA affects the endothelium differently from LCFA elevation alone. Ten healthy volunteers received an intravenous infusion of Structolipid (structured TG, MCFA/LCFA ratio 1:1) and heparin for 2 h, while another 10 subjects received an infusion of Intralipid (LCFA only) and heparin. EDV and endothelium-independent vasodilation (EIDV) were studied in the forearm after local administration of methacholine chloride (2 and 4 microg/min) and sodium nitroprusside (5 and 10 microg/min). Forearm blood flow was determined by venous occlusion plethysmography. Intralipid and heparin increased circulating FA levels from 0.2 +/- 0.1 to 1.4 +/- 0.5 mmol/L (P < 0.001) and reduced EDV by 20% (P < 0.01). Although Structolipid and heparin increased circulating FA levels to a similar extent (from 0.4 +/- 0.1 to 1.8 +/- 0.4 mmol/L after 2 h), EDV was not significantly changed. EIDV increased slightly during both interventions (P < 0.05). In conclusion, an acute elevation of LCFA attenuated EDV, whereas an elevation of both MCFA and LCFA did not influence EDV. Thus, FA composition seems to be of importance for EDV in healthy humans.

Adult↗

PubMed2001

Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans.

BACKGROUND: Endothelium-dependent vasodilation is impaired in patients with insulin-dependent and non-insulin-dependent diabetes mellitus and restored by vitamin C administration, implicating a causative role for oxidant stress. Hyperglycemia per se attenuates endothelium-dependent vasodilation in healthy subjects. Accordingly, this study investigated whether impaired endothelium-dependent vasodilation caused by hyperglycemia in nondiabetic humans is restored by administration of the antioxidant vitamin C. METHODS AND RESULTS: Endothelium-dependent vasodilation was measured by incremental brachial artery administration of methacholine chloride (0.3 to 10 microg/min) during euglycemia, after 6 hours of hyperglycemia (300 mg/dL) created by dextrose (50%) intra-arterial infusion, and with coadministration of vitamin C (24 mg/min) during hyperglycemia. Endothelium-dependent vasodilation was significantly diminished by hyperglycemia (P:=0.02 by ANOVA) and restored by vitamin C (P:=0.04). In contrast, endothelium-dependent vasodilation was not affected by equimolar infusions of mannitol, with and without vitamin C coinfusion (P:=NS). Endothelium-independent vasodilation was measured by incremental infusion of verapamil chloride (10 to 300 microg/min) without and with coadministration of N:(G)-monomethyl-L-arginine (L-NMMA). In the absence of L-NMMA, endothelium-independent vasodilation was not significantly altered during hyperglycemia (P:=NS) but was augmented by vitamin C (P:=0.04). The coadministration of L-NMMA eliminated the vitamin C-related augmentation in verapamil-mediated vasodilation. CONCLUSIONS: Vitamin C administration restores endothelium-dependent vasodilation impaired by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia may contribute in part to impaired vascular function through production of superoxide anion.

Acute Disease↗

PubMed1997

Effect of SR-140333, a neurokinin-1 receptor antagonist, on airway reactivity to methacholine in sedated rats.

AIM: To study the roles of neurokinins in the airway reactivity (AR) to methacholine chloride (MC). METHODS: The effects of (S)-1-(2-[3, 4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl) piperidin-3-yl]ethyl)-4-phenyl-1-azoniabicyclo [2.2.2]octane.chloride (SR-140333), a neurokinin-1 receptor antagonist, on AR to inhaled MC in diazepam-sedated rats, and on MC-induced contraction of isolated tracheal spiral strips were observed. RESULTS: SR-140333 inhibited the increase in respiratory rate (RR) induced by MC aerosol (10-1000 mumol/m3), and the ID50 for inhibiting the response to MC aerosol (1 mmol/m3) was 4.9 micrograms.kg-1 (95% confidence limits 1.4-17.2 micrograms.kg-1). SR-140333 1 mumol.L-1 had no inhibitory effect on MC-induced tracheal contraction. Atropine blocked responses to MC both in vivo and in vitro. CONCLUSION: Endogenous neurokinins are involved in the AR to MC in rats, at least partly mediated via neurokinin-1 receptors.

Albuterol↗

PubMed1999

Prospective follow-up and pulmonary functions from a placebo-controlled randomized trial of ribavirin therapy in respiratory syncytial virus bronchiolitis. Ribavirin Study Group.

OBJECTIVE: To determine any long-term differences in adverse effects and pulmonary function between infants with respiratory syncytial virus and lower respiratory tract infection who were treated with ribavirin and a control group. STUDY DESIGN: Long-term follow-up included enumeration of episodes of respiratory illness, wheezing, and pneumonia and, ultimately, administration of pulmonary function tests (PFTs). Pulse oximetry was done at each visit. During the first 3 years we conducted follow-up in the fall and spring. In years 4 and 5 we conducted 1 visit per year. During years 5 through 7 we conducted PFTs, and starting with year 7 a methacholine chloride challenge was done if forced expiratory volume in 1 second (FEV1) was greater than 70% of predicted value. RESULTS: We prospectively enrolled (December 1983 to February 1985) in a randomized trial of ribavirin vs placebo children who were previously healthy, were premature, or had chronic pulmonary disease. One pulmonologist (R.F.; blinded) scored and interpreted the results of the PFTs. We studied 42 patients aged 1 to 33 months; 2 patients died (1 receiving ribavirin and 1 receiving placebo) and 5 patients receiving placebo were lost to follow-up; 35 patients (24 taking ribavirin and 11 taking placebo) attended 212 visits. Four patients were premature (3 in the ribavirin and 1 in the placebo group), and 3 of these had bronchopulmonary dysplasia (2 in the ribavirin and 1 in the placebo group). From years 1 to 3, there was more reactive airway disease, wheezing, and pneumonia in the placebo than in the ribavirin group (mean score, 22.3 for 12 placebo-treated patients vs. 15.8 for 23 ribavirin-treated patients; P = .07 by Kruskal-Wallis test); for all years, it was 22.0 for 11 placebo-treated patients vs. 16.0 for 22 ribavirin-treated patients (P = .10). After informed consent was given, 19 patients completed PFTs (13 receiving ribavirin and 6 receiving placebo); 7 of 13 ribavirin-treated patients (53%) had normal or mild PFT results vs. 0 of 6 placebo-treated patients (P = .04 by Fisher exact test). On methacholine challenge (7 ribavirin-treated patients and 5 placebo-treated patients), there was more reactivity in the placebo vs. the ribavirin group (exact P = .07). Scoring done by weighting for severity for 19 patients (13 ribavirin-treated patients and 6 placebo-treated patients) (even after correcting for asthma) showed a significant difference in favor of previously ribavirin-treated patients (exact P = .02). CONCLUSIONS: No outward effects were identified from ribavirin exposure. We observed no increase in reactive airway disease, wheezing, and pneumonia in the ribavirin compared with the placebo group. Weighted severity scores suggest long-term beneficial effect of ribavirin therapy; however, larger numbers should be evaluated.

Antiviral Agents↗

PubMed2002

Blood flow distribution within the airway wall.

Altered perfusion of the bronchial mucosal plexus relative to the adventitial plexus may contribute to geometric changes in the airway wall and lumen. We studied bronchial perfusion distribution in sheep by using fluorescent microspheres at baseline and during intrabronchial artery challenge with methacholine chloride (MCh; n = 7). Additionally, we measured airway resistance (Raw) during MCh with control or increased perfusion (n = 9). Raw with MCh was significantly greater for high than control flow. Microspheres in histological sections lodged predominantly in the mucosa (60%), and this was not altered by MCh. However, more microspheres lodged in airways >1-mm in diameter during MCh and increased perfusion than MCh and control flow. In airways < or =1 mm in diameter, fewer microspheres lodged during control than increased flow. If the number of microspheres represents regional agonist access to airway smooth muscle, then the differences observed in Raw can be explained by the distribution of agonist. During challenge, there was greater MCh delivery to larger airways during increased flow and less delivery to smaller airways during control flow. The results demonstrate the effects of axial perfusion distribution on Raw.

Animals↗

PubMed1999

Latanoprost and respiratory function in asthmatic patients: randomized, double-masked, placebo-controlled crossover evaluation.

OBJECTIVE: To evaluate the effects of single and multiple administrations of the ocular hypotensive drug latanoprost on respiratory function, asthma symptoms, and use of asthma medication in patients with bronchial asthma. METHODS: Twenty-four stable patients with asthma (forced expiratory volume in 1 second: 70% to 90% of predicted and a minimum of 10% reversibility after inhalation of albuterol sulfate) with no previous exposure to inhaled corticosteroids participated in this randomized, double-masked crossover trial. Patients received latanoprost, 0.005%, or placebo, 1 drop per day, in each eye during two 6-day treatment periods separated by a 2-week washout period. Acute latanoprost or placebo provocation, methacholine chloride airway reactivity, and 12-stimulator reversibility tests were performed. MAIN OUTCOME MEASURES: Morning and evening peak expiratory flow, spirometric performance throughout treatment periods and during different provocation tests, asthma symptoms, and use of asthma medications were evaluated. RESULTS: There were no statistically significant differences between treatments in morning and evening peak expiratory flow, scored daytime and nocturnal asthma symptoms, or daily consumption of asthma medication. During placebo provocation, there was a small increase in forced expiratory volume in 1 second that was not seen during latanoprost provocation. This small difference (-0.09 L) was statistically significant but without clinical importance. CONCLUSIONS: Resting and provoked airway function and asthma symptoms were unaffected by latanoprost treatment in patients with asthma with no previous exposure to corticosteroids. Latanoprost can be used in patients with glaucoma and concomitant bronchial asthma.

Adolescent↗

PubMed1995

Contribution of pulmonary versus systemic perfusion of airway smooth muscle.

Recent studies suggest a significant contribution of the pulmonary circulation to the perfusion of large airways. In this study we used anesthetized ventilated sheep (n = 19) to determine the functional contribution of the pulmonary circulation to airway smooth muscle. We performed sequential intravenous challenge with methacholine chloride (MCh; 0.25-2.5 mg/ml) to determine airway resistance (Raw) changes in the intact animal, after bronchial artery cannulation that essentially removed bronchial arterial delivery of MCh, and in an isolated lung preparation. After blocking the vagal reflex component of this response, we found that intravenous MCh in the intact preparation resulted in an average 2.2 +/- 0.5 cmH2O.l-1.s increase (181%) in Raw. After prevention of bronchial arterial delivery of MCh, Raw increased by 0.8 +/- 0.3 cmH2O.l-1.s (64%; P < 0.01 compared with intact preparation). In the isolated lung preparation, Raw increased by 0.6 +/- 0.2 cmH2O.l-1.s (63%; P < 0.01 compared with intact preparation). These results demonstrate that in sheep, the bronchial artery provides the major route for delivery of intravenously administered agonists to airway smooth muscle. Considering the large dilutional effect of an intravenously administered agonist by the time it reaches the bronchial artery, we conclude that the pulmonary component of agonist delivery to large airways is < 10% and unlikely to play a major physiological role.

Airway Resistance↗

PubMed1997

Interpretation of positive results of a methacholine inhalation challenge and 1 week of inhaled bronchodilator use in diagnosing and treating cough-variant asthma.

BACKGROUND: In diagnosing cough due to asthma, methacholine chloride inhalation challenge (MIC) interpreted in a traditional fashion has been shown to have positive predictive values from 60% to 82%. OBJECTIVE: To determine whether any features of positive results of an MIC or the results of a 1-week trial of inhaled beta-agonist therapy were helpful in predicting when the cough was due to asthma. METHODS: The study design was a prospective, randomized, double-blind, placebo-controlled, crossover format performed in adult, nonsmoking subjects, who were referred for diagnosis and treatment of chronic cough. The subjects had no other respiratory complaints or medical conditions for which they were taking medications, the results of baseline spirometry and chest roentgenograms were normal, and the results of MIC were positive. After obtaining baseline data, including MICs on 2 separate days, objective cough counting, and self-assessment of cough severity using a visual analog scale, subjects were randomized to receive 2 inhalations (1.3 mg) of metaproterenol sulfate or placebo by metered dose inhaler attached to a spacer device every 4 hours while awake. At 1 week, data identical to baseline were collected, and subjects received the other metered dose inhaler for 7 days. At 1 week, data identical to baseline were collected. After completion of the protocol, subjects were followed up in the clinic to observe the final response of the cough to specific therapy. RESULTS: Based on the disappearance of the cough with specific therapy, the cough was due to asthma in 9 of 15 subjects and nonasthma in 6 of 15 subjects. Baseline data were similar between groups. With respect to MICs, there were no significant differences between groups in the cumulative dose of methacholine that provoked a 20% decrease in forced expiratory volume in 1 second from the postsaline baseline value (PD20 values), slopes of dose-response curves, and maximal-response plateaus. Cough severity significantly improved after 1 week of metaproterenol use compared with the severity of the cough at baseline (P = .03) and with placebo (P = .02) only in subjects with asthma. CONCLUSIONS: No matter how the results are analyzed, positive MIC results, without observing response to therapy, are only consistent with asthma as the cause of the cough. The results are only diagnostic of asthma when they are followed by a favorable response to asthma therapy. After 1 week of inhaled beta-agonist, only the cough due to cough-variant asthma is significantly better.

Administration, Inhalation↗

PubMed2004

L-carnitine may attenuate free fatty acid-induced endothelial dysfunction.

We have recently shown that elevated levels of free fatty acid (FFA) seen in insulin-resistant obese subjects are associated with endothelial dysfunction. L-carnitine, which is required for mitochondrial FFA transport/oxidation, has been reported to improve vascular function in subjects with diabetes and heart disease. Here, we tested the hypothesis that L-carnitine attenuates FFA-induced endothelial dysfunction. We studied leg blood flow (LBF) responses and leg vascular resistance (LVR) to graded intrafemoral artery infusions of the endothelium-dependent vasodilator, methacholine chloride (MCh). A group (n = 7) of normal lean subjects was studied under basal conditions (saline), after 2 h of FFA elevation (FFA), and then after 2 h of superimposing L-carnitine on FFA elevation. FFA elevation caused the maximal LBF increment in response to MCh to decrease from 0.388 +/- 0.08 to 0.212 +/- 0.071 L/min (P < 0.05). Similarly, FFA blunted the maximum decrease in LVR in response to MCh from -315 +/- 41 U to -105 +/- 46 U (P < 0.05). The superimposed L-carnitine restored the LBF increment in response to MCh to 0.488 +/- 0.088 L/min (P < 0.05 vs. FFA) and the maximum fall in LVR to -287 +/- 75 U (P < 0.05 vs. FFA), indicating that L-carnitine elevation may attenuate FFA-induced endothelial dysfunction. In conclusion, our data suggest that increasing L-carnitine levels may improve FFA-induced and obesity-associated endothelial dysfunction. This improved endothelial function may delay or prevent the development of excess cardiovascular disease.

Adult↗

PubMed2004

Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs.

We delivered controlled radio frequency energy to the airways of anesthetized, ventilated dogs to examine the effect of this treatment on reducing airway narrowing caused by a known airway constrictor. The airways of 11 dogs were treated with a specially designed bronchial catheter in three of four lung regions. Treatments in each of the three treated lung regions were controlled to a different temperature (55, 65, and 75 degrees C); the untreated lung region served as a control. We measured airway responsiveness to local methacholine chloride (MCh) challenge before and after treatment and examined posttreatment histology to 3 yr. Treatments controlled to 65 degrees C as well as 75 degrees C persistently and significantly reduced airway responsiveness to local MCh challenge (P < or = 0.022). Airway responsiveness (mean percent decrease in airway diameter after MCh challenge) averaged from 6 mo to 3 yr posttreatment was 79 +/- 2.2% in control airways vs. 39 +/- 2.6% (P < or = 0.001) for airways treated at 65 degrees C, and 26 +/- 2.7% (P < or = 0.001) for airways treated at 75 degrees C. Treatment effects were confined to the airway wall and the immediate peribronchial region on histological examination. Airway responsiveness to local MCh challenge was inversely correlated to the extent of altered airway smooth muscle observed in histology (r = -0.54, P < 0.001). We conclude that the temperature-controlled application of radio frequency energy to the airways can reduce airway responsiveness to MCh for at least 3 yr in dogs by reducing airway smooth muscle contractility.

Animals↗

PubMed1991

[Local effect of calcitonin gene-related peptide on human sweat gland function].

The effect of local administration of calcitonin gene-related peptide (CGRP) on sweating activity was evaluated on normal human volunteers. CGRP and methacholine chloride (MCH) was dissolved in 0.1 ml of 0.9% NaCl solution to a specified concentration, and was injected intradermally at the center of a 1.3 cm2 forearm test area. The sweat rate was recorded continuously by capacitance hygrometry in a relatively cool environment (Ta, 23 degrees C). CGRP did not elicit any sweat secretion when administrated by alone, but significantly increased the sweat rate when it was administrated with MCH. The maximum enhancement of MCH-induced sweating by CGRP was observed at a concentration of 10(-5) g/ml of CGRP. There was clear dose-dependent relationship between the dose of CGRP and its enhancement. Recently, CGRP-like immunoreactivity is demonstrated to be present in cholinergic nerve terminals around the human sweat glands. These observations have strongly suggested that CGRP enhances the cholinergic sweating activity. Although the underlying mechanism is still obscure, CGRP may enhance the sweating as a consequence of vasodilation which has been known to be a major activity of CGRP. As for the evaluation of human sweat gland function, CGRP-induced peptidergic regulation should be considered as well as cholinergic regulation.

Acetylcholine↗

PubMed1995

Pancreatic digestive enzyme secretion in the rabbit: rapid cyclic variations in enzyme composition.

The role and mechanism of nonparallel pancreatic secretion of digestive enzymes, in which enzyme proportions change in rapidly regulated fashion, remain controversial. Secretion was collected from male 2.2-kg New Zealand rabbits in 5-min intervals for 3 h under basal conditions or constant stimulation with cholecystokinin (CCK; 0.1 microgram per kg per h i.v.) or methacholine chloride (MCh; 40 micrograms per kg per h i.v.). Both CCK and MCh produced an 8-fold stimulation of protein output. Enzymes were separated by SDS/PAGE and quantitated by densitometry of Coomassie blue-stained gels. Under both basal conditions and constant MCh infusion, rapid neurosecretory-like 12-min cyclic changes occurred in the proportions of amylase, lipase I, chymotrypsinogen, and trypsinogen. During constant infusion their percentages changed as much as 10-fold, and their ratios cycled by as much as 30-fold. The mean percentage for the entire infusion period for lipase I declined > 25% with CCK or MCh, for amylase it rose approximately 30%, and for chymotrypsinogen and trypsinogen it doubled (for all, P < 0.05). CCK and MCh elicited subtly but significantly different mean enzyme percentages and enzyme ratios (P < 0.05) for amylase, chymotrypsinogen, and trypsinogen; these differences were also confirmed by regression and correlation analyses. The changes in enzyme percentages and ratios were explicitly consistent with secretagogue-caused shifts in the intrapancreatic enzyme secretory sources. Nonparallel secretion of digestive enzymes occurs routinely, even during constant stimulation, and is due to cyclic neurosecretory-like secretion from heterogeneous intrapancreatic sources.

Activity Cycles↗