Christiane Hesse

Aging Is Associated With Reduced Prostacyclin-Mediated Dilation in the Human Forearm

Aging is associated with reduced endothelial function. There is indirect evidence for reduced prostacyclin (PGI2)-mediated vasodilation with aging, but it is unknown whether this is because of reduced dilation to PGI2 or altered production. In addition, the contribution of endothelial NO to PGI2-mediated dilation is unknown. Using plethysmography to determine forearm blood flow, we studied the effect of PGI2 in 10 older (61 to 73 years) and 10 younger (19 to 45 years) subjects using 3 escalating intra-arterial doses of PGI2 (epoprostenol). PGI2 was also administered after NO synthase inhibition with NG-monomethyl-l-arginine acetate. The percent of change in forearm vascular conductance (mean±SEM) from baseline after PGI2 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 PGI2 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 PGI2 in older individuals are attributable to a reduction in the contribution of endothelial-derived NO versus alterations in the direct effects of PGI2 on vascular smooth muscle.

Baroreflex Sensitivity Inversely Correlates With Ambulatory Blood Pressure in Healthy Normotensive Humans

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.

Ambulatory arterial stiffness index is not correlated with the pressor response to laboratory stressors in normotensive humans

Background Ambulatory arterial stiffness index (AASI) is a novel estimate of arterial stiffness, which independently predicts cardiovascular mortality, even in normotensive individuals. Additionally, other markers derived from ambulatory blood pressure (BP) monitoring, including variability, pulse pressure, nocturnal dipping, and morning BP surge, have all been shown to be predictive of end-organ damage and cardiovascular disease. Exaggerated cardiovascular reactivity to sympathoexcitatory stimuli may also predict future incidence of hypertension. The purpose of this investigation was to test the hypothesis that AASI and other derivations of ambulatory BP, including pulse pressure, 24-h blood pressure variability, dipping, and morning surge, would be correlated with the pressor response to common physiological stress maneuvers. Method We measured continuous heart rate and arterial BP during head-up tilt, mental stress, cold pressor test, and isometric handgrip to fatigue in 67 healthy, normotensive, nonobese individuals (43 women, 24 men, mean age ± SD: 28 ± 6 years). Then, 24-h ambulatory BP was obtained, and AASI was defined as 1 minus the slope of diastolic on systolic BP in individual 24-h ambulatory BP recordings. Results Although all measures were widely variable among patients, there was no relationship between AASI, pulse pressure, blood pressure variability, dipping, and morning surge with the pressor responses. Conclusion We conclude that in the absence of aging, cardiovascular, or autonomic disease, the novel stiffness index (AASI) or other ambulatory BP indices are either poorly correlated with or mechanistically unrelated to the complex pressor response to common provocations of sympathoexcitation.

β2‐Adrenoceptor gene variation and systemic vasodilatation during ganglionic blockade

Regional infusions of β2‐adrenoceptor (ADRB2) agonist have generally shown that individuals homozygous for Gly16 produces greater vasodilatation than those homozygous for Arg16. Systemic infusions have shown an opposite effect on systemic vascular resistance (SVR), possibly confounded by baroreflexes or interactions between single nucleotide polymorphism (SNP) positions 16 and 27. We tested the hypothesis that ADRB2 gene variation would influence the SVR response to ADRB2 agonist terbutaline (Terb) during ganglionic blockade. Forty healthy young adults were recruited according to the double homozygous haplotypes: Arg16 + Gln27 (n= 13), the rare Gly16 + Gln27 (n= 6), and Gly16 + Glu27 (n= 21). Arterial pressure was measured by brachial arterial catheter, and 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−1), continuous phenylephrine was titrated to restore blood pressure to baseline. Terb was infused i.v. at 33 and 67 ng kg−1 min−1 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 (mean ±s.e.m.: 7.5 ± 0.4) vs. Arg16 (8.9 ± 0.7 units; P= 0.03). Lymphocyte ADRB2 binding conformation was similar but receptor density was greater in Gly16 vs. Arg16 (P= 0.05). We conclude that during ganglionic blockade, the SVR response to systemic ADRB2 agonist is suggestive of augmented ADRB2 function in Gly16 + Glu27 homozygotes, with greater influence from Gly16, providing further evidence that ADRB2 gene variation influences vasodilatation.

Genetic variation in the β2-adrenergic receptor: Impact on intermediate cardiovascular phenotypes

Genetic variation in drug targets (e.g. receptors) can have pronounced effects on clinical responses to endogenous and exogenous agonists. Polymorphisms in the gene encoding the β(2)-adrenergic receptor (β(2)-AR) have been associated with altered expression, down-regulation, and altered cell signaling in vitro. Because β(2)-ARs play a crucial role in the regulation of the cardiovascular system, the functional importance of genetic variation in the β(2)-AR on cardiovascular responses to physiological or pharmacological stimuli has gained widespread attention. The objective of this review is to characterize these intermediate cardiovascular phenotypes and their influence on cardiovascular disease and adrenergic drug responses.Two common single nucleotide polymorphisms, encoded at codon 46 (Gly(16)Arg) and 79 (Gln(27)Glu) of the β(2)-AR gene, have been studied intensively. They have been shown to be associated with altered vasodilator responses to regional and systemic administration of β(2)-agonists, altered cardiovascular responses to sympathoexcitatory maneuvers, and altered myocardial function. Importantly, these intermediate physiological patterns may influence the development of and the outcomes associated with hypertension and other cardiovascular diseases. As recently reported, β(2)-AR gene variation can risk-stratify patients receiving β-blocker therapy and may predict β-blocker efficacy in patients post acute coronary syndrome or in patients with heart failure.Further studies will advance our understanding of the link between β(2)-AR genotypes, intermediate cardiovascular phenotypes, and clinical phenotypes. In the long term, reassessment of the benefits of β-blocker-therapy within genotype groups should be carried out with the ultimate goal to design the optimal therapeutic regimen for the individual patient.

Autonomic Cardiovascular Control During a Novel Pharmacologic Alternative to Ganglionic Blockade

The purpose of this study was to compare ganglionic blockade with trimethaphan (TMP) and an alternative drug strategy using combined muscarinic antagonist (glycopyrrolate, GLY) and α‐2 agonist (dexmedetomidine, DEX). Protocol 1: incremental phenylephrine was administered during control and combined GLY‐DEX, or control and TMP on two control combined GLY and DEX or TMP infusion on two randomized days. Protocol 2: muscle sympathetic nerve activity (MSNA) and the baroreflex MSNA relationship was determined before and after GLY–DEX. Blood pressure was higher with GLY–DEX (99±3 mm Hg) and lower with TMP (78±3 mm Hg) relative to control (GLY–DEX: 90±2 mm Hg; TMP: 91±2 mm Hg;P<0.05). Incremental phenylephrine increased pressure during GLY–DEX (P<0.01 vs control) and TMP (P<0.01 vs control) to a similar degree. Both GLY–DEX and TMP infusion inhibited norepinephrine release (P<0.01 vs control). GLY–DEX inhibited baseline MSNA (P<0.05) and baroreflex changes in MSNA (P<0.01). We conclude that the GLY–DEX alternative drug strategy can be used as a reasonable alternative to pharmacologic ganglionic blockade to examine autonomic cardiovascular control.