Pike, Tasha L.

The augmented skeletal muscle vasodilation during hypoxic exercise is due, in part, to an intensity dependent contribution of beta‐receptor activation. We tested the hypothesis that an adenosine mediated vasodilation increases with hypoxic exercise intensity. Subjects (N=10) breathed hypoxic gas to titrate arterial O 2 saturation to 80% while remaining normocapnic (re‐breath system). Consecutive bouts of forearm exercise (10% and 20% of maximum) were performed under normoxia and hypoxia during phentolamine (alpha‐receptor antagonist) alone and the combination of phentolamine / aminophyline (adenosine receptor antagonist). Exogenous adenosine administered before and after aminophyline established effective receptor blockade. Forearm vascular conductance (FVC; ml/100mmHg/min) was calculated from blood flow (ml/min) and blood pressure (mmHg). During hypoxic exercise, the rise in FVC (Δ from baseline) during phentolamine was 314±30 and 470±37 (10% and 20% respectively). ΔFVC was similar at both 10% (349±45; P=0.3) and 20% (536±47; P=0.2) exercise during hypoxia with combined phentolamine / aminophyline. This occurred despite significant reduction in ΔFVC to exogenous adenosine following phentolamine / aminophyline (P<0.03). Our data suggests that in the absence of overlying vasoconstriction, adenosine does not contribute to the augmented hypoxic exercise hyperemia in humans.

The vascular effects of prostacyclin and contribution of endothelial derived nitric oxide (NO) to prostacyclin mediated dilation are unknown in aging. A pilot study was performed in healthy older subjects (n=6, 61–73 years old) and younger controls (n=6, 19–45 years old) that were matched for BMI. Subjects underwent brachial artery catheterization and received escalating doses of epoprostenol (PGI 2 2.5, 5, 10 ng/100ml forearm tissue/min) followed by sodium nitroprusside (SNP 0.25, 0.5, 1 mcg/100ml forearm tissue/min) after PGI 2 washout. SNP and PGI 2 were repeated after NO synthase inhibition with N G ‐Monomethyl‐L arginine acetate (L‐NMMA 1mg/min after 50mg load). Using venous occlusion plethysmography, forearm vascular conductance (FVC) was calculated using mean arterial pressure (MAP), as FVC= (FBF/MAP X 100). Percent change in FVC from baseline after PGI 2 was lower in the aging individuals (47, 160, 227 % change FVC) compared to younger controls (85, 218, 327 %change FVC) (p=0.039), L‐NMMA reduced baseline FVC similarly, and the dilator response to PGI 2 was no longer significant between groups. SNP effects were not significant between groups and unaffected by L‐NMMA. This data suggests a reduced effect to prostacyclin in the aging individual may be due to a reduction in the contribution of endothelial derived NO. Support provided by HL‐46493 and UL1‐RR24150.

The Gly allele of the Arg16/Gly β 2 ‐adrenergic receptor polymorphism has been associated with hypertension in a linkage analysis in Rochester, MN. Gly homozygotes have greater forearm β 2 ‐receptor mediated vasodilation than Arg after a normal Na + diet (150 mmol/day), and the difference is mediated by endothelial NO. To test the hypothesis that dietary Na + restriction affects β 2 ‐mediated dilation in these groups, we measured forearm blood flow (FBF, plethysmography) during brachial arterial infusion of isoproterenol (ISO) after 5 days of low dietary Na + (10 mmol/day), in healthy subjects homozygous for Arg (n=15, 8 women, 29 ± 8 yrs, mean ± SD) vs. Gly (n=17, 7 women, 31 ± 7 yrs). Baseline FBF did not differ between groups. ISO caused a significant increase in FBF that was not different based on genotype (P = 0.51, main effect of genotype; P = 0.72, genotype‐by‐ISO‐interaction). For example, the highest response to ISO was 10.3 ± 5.5 in Arg and 12.0 ± 4.4 ml/100 ml forearm vol/min in Gly (P t‐test = 0.33). NO inhibition with L‐NMMA decreased baseline FBF, and significantly blunted the response to ISO, but there was no evidence to suggest the responses were influenced by genotype (P = 0.89, genotype‐by‐ISO‐by‐L‐NMMA interaction). We conclude that greater NO‐mediated β 2 ‐receptor vasodilation in Gly homozygotes is no longer apparent following dietary Na + restriction, suggesting that greater dilator function in Gly homozygotes during normal Na + intake may be a protective vascular mechanism in a population where the Gly allele is associated with hypertension. Support: HL‐63328, GCRC RR‐00585, NCRR K23‐17520.

The forearm blood flow response to mental stress (MS) is due to circulating epinephrine (Epi), release of nitric oxide, and forearm sympathetic withdrawal. We recently demonstrated that forearm venous Epi predicts the vascular conductance (FVC) and HR response to MS. In a large, ongoing phenotyping study of sympathoexcitation and adrenergic receptor gene variation, we hypothesized that arterial Epi would predict the forearm vasodilator response to MS, while norepinephrine (NE) would predict the pressor response. In 54 healthy, normotensive young adults, FVC (plethysmography), HR (ECG), and blood pressure (brachial artery) were measured in a recumbent chair at rest and during 3 min of a computerized Stroop colored‐word test. During the final 30 sec of stress, arterial Epi and NE were assayed (HPLC). MS increased HR, BP, FVC, Epi, and NE (p < 0.05 for all). Unexpectedly, during MS the arterial Epi levels did not correlate with HR or FVC. However, a robust correlation existed for HR and FVC (r = 0.73, p < 0.001). Further, systolic pressure correlated with FVC (r = 0.36, p < 0.01) and NE (r = 0.46, p < 0.001). We conclude that the HR response to MS is a major contributor to FVC, independent of arterial Epi, suggestive of mechanical effects and potentially flow‐mediated dilation. This also confirms previous work that catecholamine spillover assays are more indicative of sympathoadrenal activation and hemodynamic responses. Support: K23 RR17520, HL 46493.

Background: Hypertensive patients have blunted arterial baroreflex sensitivity (BRS). In these patients, BRS is positively related to heart rate variability and inversely related to blood pressure (BP) variability. We hypothesized that this relationship would also be evident in healthy normotensives, and that individuals with higher BRS would have lower ambulatory 24‐hour BP. Methods: 24‐hour ambulatory BP and heart rate was recorded using Spacelabs recorders in 53 healthy, normotensive, non‐obese individuals (32 women, 21 men). Furthermore, BRS (baroreflex control of RR‐interval) was assessed with the modified Oxford technique (sequential bolus administration of sodium nitroprusside and phenylephrine). Results: BRS as well as heart rate and BP variabilities varied greatly among participants. Whereas no relation was observed between BRS and 24‐hour heart rate and BP variabilities, BRS was positively correlated to daytime heart rate variability (R=0.324, p=0.018) and inversely to 24‐hour average mean arterial pressure (R=0.400, p=0.003). Conclusion: In normotensive individuals, higher BRS is related to higher heart rate variability during daytime. Furthermore, BRS was inversely related to 24‐hour mean arterial pressure, consistent with the idea that the baroreflex may have more long‐term influences than previously thought. Supported by NIH grants K23 RR17520, HL 46493, DFG grant He 4605/1‐1.

We tested the hypothesis that adenosine contributes to augmented skeletal muscle vasodilation during hypoxic exercise. In separate protocols, subjects performed incremental rhythmic forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O2saturation). In protocol 1 ( n = 8), subjects received an intra-arterial administration of saline (control) and aminophylline (adenosine receptor antagonist). In protocol 2 ( n = 10), subjects received intra-arterial phentolamine (α-adrenoceptor antagonist) and combined phentolamine and aminophylline administration. Forearm vascular conductance (FVC; in ml·min−1·100 mmHg−1) was calculated from forearm blood flow (in ml/min) and blood pressure (in mmHg). In protocol 1, the change in FVC (ΔFVC; change from normoxic baseline) during hypoxic exercise with saline was 172 ± 29 and 314 ± 34 ml·min−1·100 mmHg−1(10% and 20%, respectively). Aminophylline administration did not affect ΔFVC during hypoxic exercise at 10% (190 ± 29 ml·min−1·100 mmHg−1, P = 0.4) or 20% (287 ± 48 ml·min−1·100 mmHg−1, P = 0.3). In protocol 2, ΔFVC due to hypoxic exercise with phentolamine infusion was 313 ± 30 and 453 ± 41 ml·min−1·100 mmHg−1(10% and 20% respectively). ΔFVC was similar at 10% (352 ± 39 ml·min−1·100 mmHg−1, P = 0.8) and 20% (528 ± 45 ml·min−1·100 mmHg−1, P = 0.2) hypoxic exercise with combined phentolamine and aminophylline. In contrast, ΔFVC to exogenous adenosine was reduced by aminophylline administration in both protocols ( P < 0.05 for both). These observations suggest that adenosine receptor activation is not obligatory for the augmented hyperemia during hypoxic exercise in humans.

Background Anesthetics administered to immature brains may cause histopathological changes and long-term behavioral abnormalities. The association between perinatal exposure to anesthetics during Cesarean delivery (CD) and development of learning disabilities (LD) was determined in a population-based birth cohort. Methods The educational and medical records of all children born to mothers residing in five townships of Olmsted County, Minnesota from 1976-1982 and remaining in the community at age 5 were reviewed to identify those with LDs. Cox proportional hazards regression was used to compare rates of LD between children delivered vaginally and via CD (with general or regional anesthesia). Results Of the 5,320 children in this cohort, 497 were delivered via CD (under general anesthesia n = 193, and regional anesthesia n = 304). The incidence of LD depended on mode of delivery (P = 0.050, adjusted for sex, birth weight, gestational age, exposure to anesthesia before age 4 yr, and maternal education). LD risk was similar in children delivered by vagina or CD with general anesthesia, but was reduced in children receiving CD with regional anesthesia (hazard ratio = 0.64, 95% confidence interval 0.44 to 0.92; P = 0.017 for comparison of CD under regional anesthesia compared to vaginal delivery). Conclusion Children exposed to general or regional anesthesia during CD are not more likely to develop LD compared to children delivered vaginally, suggesting that brief perinatal exposure to anesthetic drugs does not adversely affect long-term neurodevelopmental outcomes. The risk of LD may be lower in children delivered by CD whose mothers received regional anesthesia.