Anna Mitchell

The angiotensin II receptor antagonist valsartan inhibits endothelin 1–induced vasoconstriction in the skin microcirculation in humans in vivo: Influence of the G‐protein β3 subunit (GNB3) C825T polymorphism

We investigated the influence of angiotensin II receptor blockade on angiotensin II–induced, endothelin 1 (ET‐1)–induced, and norepinephrine‐induced vasoconstriction to further characterize interactions of the 3 major pressor systems. ET‐1, angiotensin II, and norepinephrine act via G protein–coupled receptors with a possible involvement of the G‐protein β3 subunit (GNB3) C825T polymorphism. We studied the influence of this polymorphism on the responses to angiotensin II antagonism in the presence of ET‐1, norepinephrine, and angiotensin II.

Insulin‐mediated Venodilation is Impaired in Young, Healthy Carriers of the 825T Allele of the G‐protein β3 Subunit Gene (GNB3)

A C825T polymorphism has been identified for the gene encoding the G‐protein β3 subunit (GNB3). The 825T allele is associated with hypertension and obesity, which in turn are closely linked with resistance to the metabolic and vascular effects of insulin. We hypothesized that venodilation in response to insulin would be impaired in GNB3 825T‐allele carriers. Because vasodilatory properties of insulin are mainly mediated by nitric oxide, we also investigated the influence of the T−786C polymorphism of the gene for endothelial nitric oxide synthase (NOS3) on insulin‐mediated venous responses.

Endothelin-B-receptor-selective antagonist inhibits endothelin-1 induced potentiation on the vasoconstriction to noradrenaline and angiotensin II.

Objective Endothelin-A-receptor-antagonists inhibit angiotensin II- and noradrenaline-induced vasoconstriction. Whether functional constrictive endothelin-B-receptors play a role in the endothelin-1-mediated potentiation of vasoconstriction to angiotensin II and noradrenaline is thus far unknown. Methods We studied the effects of noradrenaline and angiotensin II (10−14,−16,−18 mol/l) in the presence of exogenous endothelin-1 (10−18 mol/l) with and without selective endothelin-B-receptor-blockade by BQ-788 (10−8 mol/l) and dual receptor blockade with BQ-788 and the endothelin-A-selective antagonist BQ-123 (10−8 mol/l) in 14 healthy male volunteers (aged 20–28). Studies were performed in the human skin microcirculation under in vivo conditions using laser-Doppler flowmetry and double injection technique. The area under the time-response curve of all doses was calculated. Results Endothelin-1 potentiated the effects of angiotensin II and noradrenaline (−944 ± 139 perfusion units (PU), P < 0.01; −926 ± 117 PU, P < 0.05, respectively). In the presence of BQ-788, the potentiating effect of endothelin-1 was significantly blunted (−624 ± 132 PU, P < 0.01; −549 ± 136 PU, P < 0.01, respectively). In the presence of BQ-123 and BQ-788 the vasoconstriction was fully inhibited (431 ± 108 PU, P < 0.001 and 421 ± 86 PU, P < 0.001, respectively). Conclusions These data suggest that functional vasoconstrictive endothelin-B receptors on vascular smooth muscle cells may contribute to the potentiating effects of high local concentrations of endothelin-1 on the vasoconstriction to noradrenaline and angiotensin II in human microcirculation.

Do saw palmetto extracts block human?1-adrenoceptor subtypes in vivo?

To test whether saw palmetto extracts, which act as α1‐adrenoceptor antagonists in vitro, also do so in vivo in man.

GNAQ TT(-695/-694)GC Polymorphism Is Associated with Increased Gq Expression, Vascular Reactivity, and Myocardial Injury after Coronary Artery Bypass Surgery

Background: Angiotensin II receptor type 1–mediated activation of the &agr;-subunit of the heterotrimeric Gq protein evokes increased vasoconstriction and may promote hypertrophy-induced myocardial damage. The authors recently identified a TT(-695/-694)GC polymorphism in the human Gq promoter, the GC allele being associated with an increased prevalence of cardiac hypertrophy. In this article, the authors tested whether the TT(-695/-694)GC polymorphism is associated with differences in (1) myocardial Gq protein expression, (2) vascular reactivity, and (3) myocardial damage after coronary artery bypass grafting. Methods: Gq protein expression was measured in right atrial muscle from 55 patients undergoing coronary artery bypass grafting as were skin perfusion changes (n = 18; laser Doppler imaging), saphenous vein ring vascular reactivity (n = 50, organ bath) in response to angiotensin II, and myocardial damage (227 patients undergoing coronary artery bypass grafting), as assessed by postoperative cardiac troponin I concentration. Results: Myocardial Gq expression was greater in GC/GC genotypes (GC/GC vs. TT/TT: 1.27-fold change; P = 0.006). Skin perfusion after intradermal angiotensin II injection decreased only in GC/GC genotypes (P = 0.0002). Saphenous vein rings exposed to increasing angiotensin II concentrations showed an almost doubled maximum contraction in GC/GC compared with individuals with the TT/TT genotype (P = 0.022). In patients undergoing coronary artery bypass grafting, baseline cardiac ejection fraction was different (GC/GC: 55 ± 13%; GC/TT: 54 ± 14%; TT/TT: 48 ± 15%; P = 0.037) and postoperative peak cardiac troponin I was greater in patients with the GC/GC (11.5 ± 13.8 ng/ml) than in patients with the GC/TT (9.2 ± 9.2 ng/ml) or patients with the TT/TT genotype (6.6 ± 4.8 ng/ml, P = 0.015). Conclusions: The GC/GC genotype of the TT(-695/-694)GC polymorphism is associated with increased Gq protein expression, augmented angiotensin II receptor type 1–related vasoconstriction, and increased myocardial injury after coronary artery bypass grafting, highlighting the impact of Gq genotype variation.

INFLUENCE OF AGE AND MENOPAUSE ON INTERACTIONS OF THE RENIN-ANGIOTENSIN-SYSTEM WITH THE ENDOTHELIN-SYSTEM IN THE HUMAN MICROCIRCULATION: PP.11.434

Objective: We have shown recently that angiotensin II (ANGII) type 1 receptor-antagonism inhibits endothelin (ET-1)-mediated vasoconstriction in young men and women. We now performed a study on the putative influence of age and menopause on ET-1-induced vascular responses and on the effect of ANGII-antagonism on these responses, respectively. Methods: 20 postmenopausal women (group 1: 56 ± 4 years) without hormone replacement and 21 premenopausal women (group 2: 24 ± 3 years, P < 0.001 vs. group 1) were included in a double blind, randomized, placebo controlled study. We used a Laser Doppler imager (moor LDI V 5.0, Axminister, UK) to evaluate changes in skin blood flow following intradermal injection of ET-1 (10–18, 10–16, 10–14, 10–12 mol) after oral intake of placebo (plac) or the ANGII-receptor antagonist valsartan (Vals, 80 mg). Oestradiol and progesterone serum levels were measured with enzyme immunoassay. Data were analyzed with ANOVA of the time-effect curves or t-test and are expressed as arbitrary perfusion units (PU, mean ± SD). Results: Following placebo postmenopausal women responded less to higher ET-1-doses (mean max. constriction plac + ET-1, group 1 vs. group 2: ET-12 -86 ± 79 PU vs. -234 ± 81 PU, P < 0.001; ET-14–44 ± 58 PU vs. -139 ± 128 PU, P < 0.001; ET-16 and ET-18, P > 0.05). In the presence of ANG II-antagonism mean max. vasoconstriction was significantly reduced in both groups (P < 0.001). In the presence of ANGII-antagonism the mean overall vascular response to ET-1 was vasodilation (ANGII + ET-1 group 1: + 23 ± 31 PU, P < 0.001 vs. baseline; group 2: +29 ± 77 PU, P < 0.05 vs. baseline) with no difference between groups (P > 0.05). Female sex hormone levels were similar in both groups (group 1 vs. 2: estradiol 10 ± 17pg/ml vs. 20 ± 35pg/ml; progesterone 0.5 ± 0.3ng/ml vs. 0.6 ± 0.3ng/ml; all P > 0.05). Conclusions: Age but not endogenous estradiol and progesterone seems to have influenced vascular responses to ET-1 in our study. Similar to our previous results obtained in healthy young men and women ANGII-antagonism not only inhibited ET-1-induced vasoconstriction but led to ET-1 mediated vasodilation. This effect of ANGII-antagonism seems to be independent of age and hormonal status in women. Figure 1. No caption available.

VASOCONSTRICTOR EFFECTS OF INSULIN IN THE HUMAN MICROCIRCULATION ARE MEDIATED VIA ENDOTHELIN-1-TYPE-B-RECEPTORS: 3D.04

Objective: In the vasculature insulin activates two distinct signaling pathways that result in secretion of nitric oxide (NO) and endothelin (ET-1), respectively. NO, stimulated by higher insulin doses, is thought to be the underlying agent in insulin-mediated, endothelium-dependent vasodilation. However, we have shown that at low doses insulin causes vasoconstriction in the human microcirculation. We postulated that ET-1 stimulated by insulin could be responsible for this vasoconstriction. In an earlier study we found, that insulin at a dose, that by itself caused vasoconstriction, inhibited vasodilation to an ET-1-type-A-receptor (ET-A)-antagonist, suggesting increased insulin-mediated ET-1-activity. The role of ET-1-type-B (ET-B)-receptors in this setting remained to be identified and was the focus of the present study. Methods: 18 healthy women and men (25 ± 4 years) were studied. We used a Laser-Doppler-Imager (moor LDI-V5.0, Axminister,UK) to measure changes in skin blood flow. 10-7 IU insulin (Insuman Rapid®, Sanofi,Germany) were injected intradermally alone or following injection of the ET-A-antagonist BQ123 10-8 mol, the ET-B-antagonist BQ788 10-8 mol (Bachem,Switzerland) and BQ123 10–8+BQ788 10–8 mol in combination. Effects of BQ123 10–8 mol and BQ788 (10–8 and 10–10 mol) were also recorded. Injection sites were scanned over 30 min. Data are presented as arbitrary perfusion units (PU) and are given as mean ± SD. Two-way ANOVA was used to analyze time-effect responses. Results: Again insulin led to mild but significant vasoconstriction (P < 0.0001 vs. baseline) and reduced BQ123-mediated vasodilation (BQ123 vs. BQ123+insulin: +177 ± 60 vs. +87 ± 39PU, P < 0.0001). ET-B-blockade with BQ788 at the lower dose (10–10 mol) produced vasoconstriction (−24 ± 8PU, P < 0.0001 vs. baseline), which at the higher dose (10–8 mol) was no longer present. In the presence of ET-B-blockade (BQ788 10–8 mol) insulin induced vasodilation (+104 ± 32PU, P < 0.0001 vs. baseline). Blockade of both ET-A and ET-B-receptors induced pronounced vasodilation that was not different from vasodilation to ET-A-blockade alone. However, in the presence of BQ788 insulin no longer affected vasodilation induced by BQ123. Conclusions: Vasoconstrictor effects of low insulin doses in the peripheral microcirculation of healthy humans seem to be mediated via ET-B-receptors. Figure 1. No caption available.