Johnson, Christopher P.

This study investigated the first multiomics data for association with tolerance to central hypovolemia in humans. Analyzing gene expression, proteins, and genetic variants in individuals with high and low tolerance to simulated hemorrhage, the findings show that severe blood loss causes widespread transcriptional changes, including the activation of innate immune system pathways and inhibition of gas transport processes. This research can help identify molecular factors that influence individuals’ tolerance levels for progressive blood loss.

Women who have experienced hypertensive pregnancy disorders (HPD) are at an increased risk for developing cardiovascular disease later in life, including fatal and non‐fatal stroke. Cerebrovascular reactivity is related to stroke in individuals with carotid artery disease, and it is possible that this measure may be altered in women with a history of HPD prior to overt cerebrovascular disease. It is unknown if cerebrovascular reactivity is altered in postmenopausal women decades after experiencing a hypertensive pregnancy. Therefore, the goal of this study was to determine if cerebral blood flow velocity and cerebrovascular reactivity are altered in women with a history of HPD in comparison to women with no history of HPD. We studied a cohort of postmenopausal women approximately 35 years after they experienced an HPD (n=27, age at testing: 58±1) and a group of age‐ and parity‐matched women with no history of HPD (n=30, age at testing: 59±1). We measured middle cerebral artery velocity (MCAv, via transcranial Doppler), continuous blood pressure (finger photoplethysmography), and end‐tidal CO 2 (nasal cannula) in these women at baseline (room air) and during stepped hypercapnia at 2, 4, and 6% inhaled CO 2 for 3 minutes at each condition. Women with a history of HPD had a higher body mass index than women without a history of HPD (29±1 vs. 26±1 kg/m 2 , respectively; p<0.05). At baseline and during 6% CO 2 , MCAv was lower in women with a history of HPD (baseline: 60±4 vs. 71±3 cm/s, respectively; 6% CO 2 : 82±6 vs. 99±5 cm/s, respectively; p<0.05 for both conditions) compared to women without a history of HPD. Cerebrovascular reactivity, the slope defining the association between MCAv and end‐tidal CO 2 across the entire breathing trial, was also lower in women with a history of HPD (2.0±0.2 vs. 2.7±0.2 cm/s/mmHg, respectively; p<0.05). Body mass index was not correlated with MCAv or cerebrovascular reactivity in either group (p>0.05). In conclusion, resting MCAv and cerebrovascular reactivity to CO 2 is lower in women with a history of HPD in comparison with women who have never experienced HPD. Our findings suggest that HPD may have long‐term effects on cerebrovascular regulation in women who have suffered from these conditions. Support or Funding Information NIH HL083947, NIA 1P50AG044170‐01, and CTSA UL1TR000135

The key vascular signals regulating muscle blood flow during exercise are unclear. We tested the hypothesis that in young adults, leg blood flow (LBF) during exercise would be reduced independently by pharmacological inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX). In 13 young adults, we measured heart rate (ECG), blood pressure (femoral artery and vein), blood gases, and venous oxygen saturation (indwelling oximeter) during steady‐state dynamic (60/min) knee extension exercise. LBF was determined by Doppler ultrasound of the femoral artery. Exercise (20W) increased leg vascular conductance (LVC) from 4± 1 to 33± 3 ml/min/100mmHg. The NOS inhibitor L‐NAME reduced LVC by ∼10% to 30± 1. Infusion of the COX inhibitor, ketoralac (n=9), increased LVC from 30± 1 to 34± 2. L‐NAME infusion reduced venous oxygen saturation from 48 to 38%, suggesting greater extraction to maintain oxygen consumption. Control intra‐arterial infusions of acetylcholine (ACH) and nitroprusside (NTP) tested inhibitor efficacy. The change in LVC to two doses of ACh was blunted 53 and 15%, by L‐NAME+ketorolac infusion. In contrast, the LVC responses to NTP were unaltered. These data implicate a modest role for NO‐mediated leg exercise hyperemia in adults and a potentially modest LBF restraint by vasoconstrictor prostaglandins. Funded by the NIH HL‐46493 and the Minnesota Obesity Center.

The ganglionic blocker trimethaphan (TMP) is no longer produced; alternatives are needed to inhibit baroreflex control of the circulation during systemic hemodynamic studies. We tested the hypothesis that combination anti‐cholinergic glycopyrrolate (Gly) and α2 receptor agonist dexmedetomidine (Dex) would inhibit baroreflex buffering in response to vasodilation to a similar degree as ganglionic blockade with TMP. In 2 separate trials, 5 males received an I.V. bolus and infusion of Gly‐Dex, and 11 males received TMP infusion. To offset the fall in blood pressure with TMP, phenylephrine (PE) was used to raise pressure to pre‐TMP baseline. Terbutaline was then infused for 15 minutes at 2 doses (33 and 67 ng/kg/min). Heart rate (HR), blood pressure (BP, oscillometric cuff for Gly‐Dex, brachial arterial line for TMP+PE), and cardiac output (CO, acetylene breathing) were recorded. Resting HR was higher with Gly‐Dex (mean ± SEM: 93±7mmHg) than TMP+PE (74±3mmHg, p<0.001) but resting BP, CO, stroke volume (SV), and total peripheral resistance (TPR) were similar between Gly‐Dex and TMP+PE. The cardiovascular responses to terbutaline were similar between Gly‐Dex and TMP+PE, except for the increase in CO which was significantly greater in the TMP + PE group. We conclude that Gly‐Dex is a viable pharmacologic alternative to TMP in physiologic measures of BP and TPR during vasodilator infusions.

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.

In men, muscle sympathetic nerve activity (MSNA) is positively related to total peripheral resistance (TPR) and inversely related to cardiac output (CO). However, this relationship was not observed in young women. We aimed to investigate whether simultaneous β ‐adrenergic stimulation offsets this balance in young women. We measured MSNA (peroneal microneurography), arterial pressure (brachial line), CO (open‐circuit acetylene) and TPR before and after systemic β ‐blockade with propranolol in 6 young normotensive women (age; 24 ± 2 yrs, body mass index; 23 ± 1 kg/m 2 ). There was no difference in CO (5.7 ± 0.3 L vs. 5.3 ± 0.4 L), mean arterial pressure (MAP; 95 ± 3 mmHg vs. 95 ± 2 mmHg) before and after beta‐blockade. However, there was significant reduction in heart rate (HR; 61 ± 3 beats/min vs. 55 ± 2 beats/min, P <0.05). β ‐blockade caused an increase in TPR (17.4 ± 1.2 mmHg/ml/min vs. 18.5 ± 1.3 mmHg/ml/min; P =0.07) and MSNA (28 ± 3 bursts/100hb vs. 33 ± 3 bursts/100hb, P =0.08). Before β ‐blockade there was no relationship of MSNA to TPR, CO or MAP. Following β ‐blockade, there was a positive relationship between TPR and MSNA (r=0.60). However, there was no relationship of MSNA to cardiac output (r = −0.12). Interestingly, MAP became related to MSNA (r = 0.56). In summary, the β ‐adrenergic receptors appear to play a key role in the sympatho‐hemodynamic balance in young women. AHA 09POST2170087