Hesse, Christiane

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 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.

β 2 ‐adrenergic receptor (ADRB2) gene polymorphisms influence vasodilation, but studies investigating regional or systemic responses conflict, possibly due to counter‐regulatory baroreflex action during systemic β 2 ‐agonist infusion. We tested the hypothesis that ADRB2 gene variation would influence the SVR response to ADRB2 agonist terbutaline (TERB) during baroreflex inhibition. 40 healthy young adults were recruited according to the double homozygous haplotypes: Arg16+Gln27 (n=13), Gly16+Gln27 (n=6), and Gly16+Glu27 (n=21). Arterial pressure was measured by brachial arterial catheter, cardiac output by acetylene breathing. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. Following baroreflex ablation with trimethaphan (3–7 mg/min), phenylephrine was titrated to restore blood pressure to baseline. TERB was infused i.v. at 33 and 67 ng/kg/min for 15 min/dose. There was partial evidence to suggest a main effect of haplotype on the change in SVR ( P = 0.06). For SNP position 16, the highest dose of TERB produced lower SVR in Gly16 vs Arg16 ( P = 0.03). Lymphocyte ADRB2 binding conformation was similar but receptor density was greater in Gly16 vs Arg16 ( P = 0.05). During baroreflex inhibition, the SVR response to systemic ADRB2 agonist is suggestive of augmented ADRB2 function in Gly16+Glu27 homozygotes, with greater influence from Gly16. Supported from NIH and DFG.

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.

Head up tilt (HUT) is a meaningful diagnostic tool for baroreflex dysfunction or autonomic failure. We sought to determine if baroreflex sensitivity (BRS), the rise in plasma catecholamines, or 24‐hr ambulatory HR variability (HRV) would correlate with HR and BP during HUT. We performed 60° HUT for 5 min followed by 2 modified Oxford trials in 46 young healthy males and females. Blood pressure (brachial artery) and HR (ECG) were recorded, while arterial epinephrine (Epi) and norepinephrine (NE) were assayed during the final 30 s of HUT. HUT increased HR (mean ± SD: 63 ± 9 to 79 ± 12), MAP (89 ± 7 to 93 ± 8), Epi (28 ± 13 to 61 ± 45), and NE (111 ± 57 to 242 ± 85) (p< 0.05 for all). Individuals with a high 24‐hr HRV had a greater increase in HR during HUT (r= 0.41, P<0.05). Interestingly, a negative correlation was observed between BRS and the NE response to HUT (r= −0.36, p<0.05), such that individuals with low NE response to tilt also had a high BRS. The Epi response was not correlated with any of the measures. These findings suggest that subjects with high vagal activity (high BRS) require a lower sympathetic response (NE) to maintain BP during orthostatic stress. Supported by: K23 RR17520, HL 46493, K12 RR023263 ‐03

Aging is associated with reduced endothelial function. There is indirect evidence for reduced prostacyclin (PGI 2 )-mediated vasodilation with aging, but it is unknown whether this is because of reduced dilation to PGI 2 or altered production. In addition, the contribution of endothelial NO to PGI 2 -mediated dilation is unknown. Using plethysmography to determine forearm blood flow, we studied the effect of PGI 2 in 10 older (61 to 73 years) and 10 younger (19 to 45 years) subjects using 3 escalating intra-arterial doses of PGI 2 (epoprostenol). PGI 2 was also administered after NO synthase inhibition with N G -monomethyl- l -arginine acetate. The percent of change in forearm vascular conductance (mean±SEM) from baseline after PGI 2 was significantly lower ( P =0.002) in the aging individuals (52±11%, 164±23%, and 221±27% versus 115±20%, 249±19%, and 370±35%). In addition, the group-by-dose interaction was also significant ( P =0.018). After NO synthase inhibition, the dose-response curve to PGI 2 was blunted in the young subjects but unchanged in the older subjects; the difference between the groups was no longer significant. Our data suggest that the reduced dilator effects of PGI 2 in older individuals are attributable to a reduction in the contribution of endothelial-derived NO versus alterations in the direct effects of PGI 2 on vascular smooth muscle.

Patients with hypertension have a blunted sensitivity of baroreflex control of heart period. In these patients, baroreflex sensitivity is positively related to heart rate variability and inversely related to blood pressure variability. We hypothesized that this relationship would also be evident in healthy normotensive subjects and that individuals with higher baroreflex sensitivity would have lower ambulatory 24-hour blood pressure. Twenty-four-hour ambulatory blood pressure and heart rate were recorded in 50 healthy, normotensive, nonobese individuals (31 women and 19 men). The baroreflex was assessed using sequential bolus administration of sodium nitroprusside and phenylephrine, and baroreflex sensitivity was calculated as the slope of the relation between systolic blood pressure and R-R interval during the resulting blood pressure transients. Baroreflex sensitivity was inversely correlated to 24-hour average mean arterial pressure ( R =0.49; P <0.001) and positively related to daytime heart rate variability ( R =0.33; P =0.02). In contrast, no relationship was found between baroreflex sensitivity and 24-hour heart rate or blood pressure variabilities. We conclude that the relationship between baroreflex sensitivity and daytime heart rate variability was similar to that reported previously in hypertensive subjects. Furthermore, the inverse relation between baroreflex sensitivity and mean arterial pressure supports the idea that the baroreflex may exert longer-term effects on blood pressure than thought previously.