Biomedical subjects

Brett M Mitchell

Publications and source records attributed to Brett M Mitchell.

10 recordsLinked to original sources

PubMed2004

Plasma volume restoration with salt tablets and water after bed rest prevents orthostatic hypotension and changes in supine hemodynamic and endocrine variables.

Head-down bed rest changes the values of many cardiovascular and endocrine variables and also elicits significant hypovolemia. Because previous studies had not controlled for hypovolemia, it is unknown whether the reported changes were primary effects of bed rest or secondary effects of bed rest-induced hypovolemia. We hypothesized that restoring plasma volume with salt tablets and water after 12 days of head-down bed rest would result in an absence of hemodynamic and endocrine changes and a reduced incidence of orthostatic hypotension. In 10 men, we measured changes from pre-bed-rest to post-bed-rest in venous and arterial pressures; heart rate; stroke volume; cardiac output; vascular resistance; plasma norepinephrine, epinephrine, vasopressin, renin activity (PRA), and aldosterone responses to different tilt levels (0 degrees, -10 degrees, 20 degrees, 30 degrees, and 70 degrees); and plasma volume and platelet alpha2- and lymphocyte beta2-adrenoreceptor densities and affinities (0 degrees tilt only). Fluid loading at the end of bed rest restored plasma volume and resulted in the absence of post-bed-rest orthostatic hypotension and changes in supine hemodynamic and endocrine variables. Fluid loading did not prevent post-bed-rest increases in beta2-adrenoreceptor density or decreases in the aldosterone-to-PRA ratio (P = 0.05 for each). Heart rate, epinephrine, and PRA responses to upright tilt after bed rest were increased (P < 0.05), despite the fluid load. These results suggest that incidents of orthostatic hypotension and many of the changes in supine hemodynamic and endocrine variables in volume-depleted bed-rested subjects occur secondarily to the hypovolemia. Despite normovolemia after bed rest, beta2-adrenoreceptors were upregulated, and heart rate, epinephrine, and PRA responses to tilt were augmented, indicating that these changes are independent of volume depletion.

Adult↗

PubMed2004

Short-duration spaceflight does not prolong QTc intervals in male astronauts.

Although ventricular dysrhythmias are not increased during, and QTc intervals are not prolonged after, short-duration (5 to 16 days) spaceflights, QTc intervals have not previously been reported during these shorter flights. Holter monitor recordings, obtained in 11 male astronauts who flew on shuttle missions ranging from 5 to 10 days, showed that QTc intervals did not change significantly 10 days before launch, on 2 separate days of spaceflight, and 2 days after landing. Taken together, these data and our previous report show that QTc interval prolongation occurs sometime between the 9th and 30th days of spaceflight.

Adult↗

PubMed2004

Glucocorticoids decrease GTP cyclohydrolase and tetrahydrobiopterin-dependent vasorelaxation through glucocorticoid receptors.

Excess glucocorticoids result in decreased aortic dilation and expression of guanosine triphosphate (GTP) cyclohydrolase 1 (GTPCH1) messenger RNA (mRNA), the rate-limiting enzyme in the production of the nitric oxide synthase (NOS) cofactor tetrahydrobiopterin (BH4). It was hypothesized that this response is a genomic effect mediated through the glucocorticoid receptor (GR). Endothelium-intact rat aortas were incubated with dexamethasone (DEX; 1.3 x 10(-6) M) or vehicle for 2 or 6 hours and isometric force generation was measured. Maximum acetylcholine-induced relaxation in DEX-2hr aortas was not different compared with control values; however, acetylcholine-induced relaxations in DEX-6hr aortas were significantly decreased. Coincubation with sepiapterin (10(-4) M), which produces BH4 via a salvage pathway, restored relaxation in DEX-6hr aortas to that of controls. Coincubation with the GR antagonist mifepristone (10(-6) M) completely blocked the DEX-induced decrease in relaxation. Spironolactone (10(-5) M), a mineralocorticoid receptor antagonist, had no effect. GTPCH1 mRNA expression was significantly decreased in DEX-6hr aortas compared with control values. This was blocked by mifepristone; however, spironolactone and cycloheximide did not prevent the decrease of GTPCH1 by DEX. These results support the hypothesis that GTPCH1 downregulation by glucocorticoids is mediated through the GR and contributes to reduced endothelium-dependent relaxation.

Animals↗

PubMed2004

Sepiapterin decreases vasorelaxation in nitric oxide synthase inhibition-induced hypertension.

Exogenous BH4 (tetrahydrobiopterin) has been shown to improve endothelial function in cardiovascular disease; however, in the presence of elevated superoxide levels and decreased nitric oxide synthase (NOS) activity, BH4 may become autoxidized, resulting in reduced vasodilation. The authors tested the hypothesis that increasing BH4 will further reduce endothelium-dependent relaxation in aortas from rats made hypertensive by NOS inhibition. N omega-nitro-L-arginine (L-NNA, approximately 49 mg/kg/d) was administered in the rats' drinking water for 4 days. Systolic blood pressures, measured by tail-cuff technique, were significantly increased in L-NNA-treated rats. Endothelium-intact aortic segments were isolated and hung in organ chambers for the measurement of isometric force generation. Aortas from L-NNA-treated rats had decreased relaxation to acetylcholine compared with controls, and this was further decreased after incubation with sepiapterin. Superoxide dismutase (SOD) restored relaxation in aortas from L-NNA-treated rats to that of control. In addition, SOD or ascorbic acid reversed the sepiapterin-induced decrease in relaxation in aortas from L-NNA treated rats. Aortas from L-NNA-treated rats in the absence and presence of sepiapterin, and sepiapterin-treated control aortas, had increased dihydroethidium staining for superoxide compared with untreated controls. These results support the hypothesis that sepiapterin further reduces vasodilation in the presence of NOS inhibition and may be caused by BH4 autoxidation.

Animals↗

PubMed2004

Phenylalanine improves dilation and blood pressure in GTP cyclohydrolase inhibition-induced hypertensive rats.

GTP cyclohydrolase (GTPCH), the rate-limiting enzyme in the production of the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), is partly regulated by the GTPCH feedback regulatory protein (GFRP). GFRP can inhibit GTPCH by end-product negative feedback, and L-phenylalanine (L-Phe) reverses this inhibition and increases BH4 biosynthesis in vitro. We hypothesized that L-Phe would increase endothelium-dependent relaxation and decrease blood pressure in rats made hypertensive by GTPCH inhibition. Di-amino-hydroxypyrimidine (DAHP, 10 mmol/L), a known inhibitor of GTPCH, was given with or without L-Phe or D-Phe (2 mmol/L) in the drinking water of rats for 3 days and blood pressure was measured via tail-cuff. Endothelium-intact aortic segments were hung in organ chambers for measurement of isometric force generation. Systolic blood pressure was increased significantly in DAHP-treated rats compared with controls. The addition of L-Phe attenuated the hypertensive effect, whereas D-Phe had no effect. Acetylcholine- and A23187-induced relaxation was decreased in aortas from DAHP-treated rats compared with controls, but was restored in aortas from DAHP+L-Phe-treated rats. Following NOS inhibition, sensitivity to sodium nitroprusside was increased in aortas from DAHP-treated rats, but restored in DAHP+L-Phe-treated rats. These results suggest that L-Phe can reverse GTPCH inhibition in vivo leading to increased vasodilation and decreased blood pressure.

Animals↗

PubMed2004

Midodrine prescribed to improve recurrent post-spaceflight orthostatic hypotension.

Many astronauts exhibit post-spaceflight orthostatic hypotension due to inadequate norepinephrine release when in an upright posture. We hypothesized that an alpha1-adrenergic agonist, midodrine, would be an effective countermeasure. A female astronaut, who had problems with postflight orthostatic hypotension after a previous flight, consumed 10 mg midodrine after a subsequent flight, prior to her tilt test. Hemodynamic variables were compared between the two flights. Midodrine prevented severe falls in stroke volume, cardiac output and systolic pressure, and severe increases in heart rate without increasing vascular resistance, thus preventing orthostatic hypotension. This is the first report showing that midodrine has the potential to improve post-spaceflight orthostatic hypotension and suggesting that reduced venous return contributes to the etiology.

Adrenergic alpha-Agonists↗

PubMed2003

GTP cyclohydrolase 1 inhibition attenuates vasodilation and increases blood pressure in rats.

GTP cyclohydrolase 1 is the rate-limiting enzyme in production of tetrahydrobiopterin, a necessary cofactor for endothelial nitric oxide synthase. We tested the hypothesis that inhibition of tetrahydrobiopterin synthesis impairs endothelium-dependent relaxation and increase blood pressure in rats. 2,4-Diamino-6-hydroxypyrimidine (DAHP), a GTP cyclohydrolase 1 inhibitor, was given in drinking water (approximately 120 mg.kg(-1).day(-1)) to male Sprague-Dawley rats for 3 days. Systolic blood pressures were measured (tail-cuff procedure) for 3 days before and each day during DAHP treatment. Blood pressure was significantly increased after DAHP treatment (122 +/- 2 vs. 154 +/- 3 mmHg before and after DAHP, respectively; P < 0.05). Endothelium-intact aortic segments from pentobarbital sodium-anesthetized rats were isolated and hung in organ chambers for measurement of isometric force generation. Aortas from DAHP-treated rats exhibited a decreased maximal relaxation to ACh compared with controls [% relaxation from phenylephrine (10-7 M)-induced contraction: DAHP 57 +/- 6% vs. control 79 +/- 4%; P < 0.05]. Relaxation responses to A-23187 were also decreased in aortas from DAHP-treated rats compared with controls. Incubation with sepiapterin (10-4 M, 1 h), which produces tetrahydrobiopterin via a salvage pathway, restored relaxation to ACh in aortas from DAHP-treated rats. Superoxide dismutase significantly increased ACh-induced relaxation in aortas from DAHP-treated rats, whereas catalase had no effect. Endothelium-independent relaxation to sodium nitroprusside in aortas from DAHP-treated rats was not different from control rats; however, nitric oxide synthase inhibition increased sensitivity to sodium nitroprusside in aortas from DAHP-treated rats. These results support the hypothesis that GTP cyclohydrolase 1 inhibition decreases relaxation and increases blood pressure in rats.

Animals↗

PubMed2003

GTP cyclohydrolase 1 downregulation contributes to glucocorticoid hypertension in rats.

NO, a potent vasodilator, has been implicated in the pathogenesis of glucocorticoid hypertension. NO synthase requires the cofactor tetrahydrobiopterin for the production of NO. Guanosine-triphosphate (GTP) cyclohydrolase 1 is the rate-limiting enzyme for the production of tetrahydrobiopterin, and in the presence of low levels of tetrahydrobiopterin, NO production is decreased. We have previously shown that tetrahydrobiopterin-dependent vasodilation is impaired in rats with glucocorticoid hypertension. However, the role GTP cyclohydrolase 1 plays in the pathogenesis of glucocorticoid hypertension has not been investigated. Therefore, we tested the hypothesis that downregulation of GTP cyclohydrolase 1 contributes to the development and maintenance of glucocorticoid hypertension in rats. Rats were implanted with dexamethasone (0.79 mg x kg(-1) x d(-1)) or sham-operated, and systolic blood pressures were measured at baseline and after 12 hours, 4 days, or 15 days. Blood pressure increased significantly after dexamethasone treatment. Isometric force generation was measured in endothelium-intact aortic ring segments. Aortas from dexamethasone-treated rats exhibited a significant time-dependent decrease in maximal relaxation to acetylcholine compared with control rats. Incubation with sepiapterin (10(-4) mol/L, 1 hour), which produces tetrahydrobiopterin via a salvage pathway, restored vasodilation to acetylcholine in aortas from 4- and 15-day dexamethasone-treated rats. GTP cyclohydrolase 1 mRNA expression levels also significantly decreased in a time-dependent manner. These results support the hypothesis that downregulation of GTP cyclohydrolase 1 contributes to increased blood pressure in glucocorticoid hypertensive rats.

Animals↗

PubMed2002

Impaired vasodilation and nitric oxide synthase activity in glucocorticoid-induced hypertension.

Synthetic glucocorticoids are among the most widely prescribed medications by physicians. Although they have a vast array of beneficial effects such as immunosuppression and anti-inflammation, excess glucocorticoids can lead to iatrogenic Cushing's syndrome, which includes hypertension and cardiovascular disease. The exact mechanism by which glucocorticoids elevate blood pressure is not completely understood, but it appears to be a complex pathology that involves increased responsiveness to vasoconstrictors and decreased vasodilator production. Nitric oxide is a vasodilator that plays a key role in blood pressure regulation, and previous studies have shown that a reduction in nitric oxide production or bioavailability contributes to hypertension. Tetrahydrobiopterin, a necessary cofactor for nitric oxide synthase activity, can affect nitric oxide production and bioavailability, with low levels causing decreased nitric oxide production. However, little is known about the interaction between glucocorticoids and tetrahydrobiopterin levels. In this review, the roles of nitric oxide and tetrahydrobiopterin in the pathogenesis of glucocorticoid hypertension will be discussed. Furthermore, the authors propose that glucocorticoids exert a genomic effect to decrease guanosine triphosphate cyclohydrolase I, the rate-limiting enzyme in the production of tetrahydrobiopterin. In the future, tetrahydrobiopterin supplementation in patients with iatrogenic Cushing's syndrome may prove to be beneficial and decrease mortality attributed to cardiovascular disease.

Antioxidants↗

PubMed2002

Left ventricular structure and function in obese adolescents: relations to cardiovascular fitness, percent body fat, and visceral adiposity, and effects of physical training.

OBJECTIVE: Little is known about the relations of fitness and fatness to left ventricular structure and function in obese adolescents. This project had 2 purposes: 1) to determine the correlations of cardiovascular fitness and adiposity to left ventricular parameters in obese adolescents; and 2) to see the effect of 8 months of physical training (PT) at low and high intensities. DESIGN: Obese 13- to 16-year-olds (N = 81) were tested at baseline and then randomly assigned to lifestyle education (LSE) alone, LSE plus moderate-intensity PT, or LSE plus high-intensity PT. Follow-up testing was conducted 8 months later. Because no significant differences were found between moderate-intensity and high-intensity PT, the groups were combined to form a LSE + PT group. INTERVENTION: Eight months of PT, offered 5 days per week with the target energy expenditure for all PT participants being 250 kcal/session, and LSE every 2 weeks. Outcome Measures. Left ventricular mass divided by height to the 2.7th power (LVM/Ht(2.7)), midwall fractional shortening (MFS), and relative wall thickness (RWT) were measured using M-mode echocardiography. Cardiovascular fitness was measured by a maximal multistage treadmill test; percent body fat (%BF) with dual-energy radiograph absorptiometry; and visceral adipose tissue (VAT) with magnetic resonance imaging. RESULTS: At baseline, high levels of VAT were associated with higher RWT (r = 0.30) and lesser MFS (r = -0.29). Compared with the LSE-alone group, the LSE + PT group significantly improved in cardiovascular fitness and decreased in %BF and VAT. However, there were no significant differences between groups on changes in LVM/Ht(2.7), MFS, or RWT. Individual changes in cardiovascular fitness, %BF, and VAT did not correlate significantly with interindividual changes in left ventricular structure and function. CONCLUSIONS: High levels of VAT were associated with unfavorable left ventricular structure and function. However, no evidence was provided that an 8-month PT program, which improved cardiovascular fitness and reduced general and visceral adiposity, improved left ventricular structure and function. Future studies consisting of longer training programs and/or greater weight reductions are needed to see whether the adverse left ventricular effects of obesity can be ameliorated by exercise training.

Adipose Tissue↗