Hypoxia markedly impairs vascular endothelial function in the systemic circulation in HAPE-S subjects due to a decreased bioavailability of NO. Impairment of the NO pathway could contribute to the enhanced hypoxic pulmonary vasoconstriction that is central to the pathogenesis of HAPE.

Abstract-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 (meanϮSEM) from baseline after PGI 2 was significantly lower (Pϭ0.002) in the aging individuals (52Ϯ11%, 164Ϯ23%, and 221Ϯ27% versus 115Ϯ20%, 249Ϯ19%, and 370Ϯ35%). In addition, the group-by-dose interaction was also significant (Pϭ0.018). 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. A ging is associated with reduced endothelial function independent of disease. 1,2 Although much is known about how aging affects NO-mediated vasodilation, there is less information available about its influence on prostacyclin (PGI 2 )-mediated vasodilation. 3 In this context, indirect evidence obtained using cyclooxygenase (COX) inhibitors suggests that aging causes either reduced production of vasodilating prostanoids or perhaps reduced vasodilator responses to them. 4 However, COX is also involved in the production of several other prostaglandins (PGs), including PGE, PGF, PGD, and thromboxane, all with varying vascular effects, 5 and there is some evidence that aging causes an increase in the production of vasoconstricting prostanoids. 6 It is unknown whether the direct dilation caused by PGI 2 is maintained in older humans and how NO may contribute to this PGI 2 -mediated dilation.These questions are also clinically relevant in a general sense, because essential hypertension appears to cause changes in prostanoid-mediated endothelial vascular regulation similar to aging. In addition, suppression of PGI 2 caused by selective inhibition of COX-2 has been implicated in predisposing patients to myocardial infarction or thrombotic stroke. 7 It also appears that this risk is associated with older patients who receive COX-2 inhibitors. 8,9 This suggests that population differences in PGI 2 might influence these events.With this information as a background, we sought to test the hypothesis that forearm blood flow responses to PGI 2 in healthy older adults would be reduced compared with matched young adults and to determine whether age-related differences in...

The data suggest firstly that loss of body mass during space flight is rather a consequence of hypocaloric nutrition. Secondly, microG provokes a sodium retaining hormonal status and may lead to sodium storage without an accompanying fluid retention.

Abstract-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 (Rϭ0.49; PϽ0.001) and positively related to daytime heart rate variability (Rϭ0.33; Pϭ0.02). 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. Key Words: baroreflex Ⅲ ambulatory blood pressure monitoring Ⅲ heart rate variability Ⅲ blood pressure variability Ⅲ normotension T he arterial baroreflex is an important neural feedback mechanism by which blood pressure (BP) is regulated in humans. An acute rise in BP causes baroreceptor activation with afferent signaling to the nucleus tractus solitarii, eliciting reflex parasympathetic activation and sympathetic inhibition. The subsequent decreases in heart rate, cardiac contractility, vascular resistance, and venous return help maintain systemic BP homeostasis. 1 Whether the arterial baroreflex also plays a role in setting the long-term level of mean arterial pressure has been doubted for decades. 2 This is in part because the kidneys have an important role in long-term BP stability by regulating fluid volume 3 and particularly since McCubbin et al 4 demonstrated a marked resetting of the baroreflex in chronic hypertension. However, recent observations in conscious dogs have suggested that the baroreflexes do not completely reset and that baroreceptor afferent activity remains chronically elevated in hypertension. 5 Furthermore, prolonged baroreceptor afferent stimulation can lead to sustained reductions in mean arterial pressure (MAP). 6 Limited data from humans support the role of baroreceptors in long-term control of BP: patients with complete denervation of carotid baroreceptors (eg, from carotid glomus tumor resection, neck irradiation, or bilateral carotid endarterectomy) have a persis...

Riociguat (BAY 63-2521) is the first member of a novel class of compounds, the soluble guanylate cyclase (sGC) stimulators. Riociguat has a dual mode of action: it sensitizes sGC to endogenous nitric oxide (NO) and stimulates sGC independent of NO availability. To characterize the biopharmaceutical properties of riociguat, including absolute bioavailability, food interactions, and dose proportionality, riociguat (intravenous/oral) was administered to healthy male subjects in 3 open-label, randomized, crossover studies: absolute bioavailability (1 mg; [Formula: see text]), food effect (2.5 mg; [Formula: see text]), and dose proportionality (0.5-2.5 mg; [Formula: see text]). Absolute bioavailability was 94% (95% confidence interval [CI], 83%-107%). Riociguat absorption was delayed by a high-fat breakfast with little effect on the extent of absorption (area under the concentration-time curve [AUC]fed∶AUCfasted, 88% [90% CI, 82%-95%]). Exposure to riociguat was dose proportional over all doses (common slope of AUC, 1.09 [90% CI, 1.04-1.14]; maximum concentration, 0.98 [90% CI, 0.93-1.04]). Intraindividual variability was low; interindividual variability was moderate to high. Riociguat was well tolerated, and adverse events were consistent with the mode of action. In conclusion, riociguat shows complete oral absorption, no clinically relevant food effects, and a dose-proportional increase in systemic exposure (0.5-2.5 mg). These data support the suitability of the individualized dose adjustment scheme employed in the phase 3 clinical studies.

Abstract-We are studying a Turkish family with autosomal-dominant hypertension and brachydactyly; affected persons die of stroke before 50 years of age. With interphase fluorescence in situ hybridization, we found a chromosome 12p deletion, reinsertion, and inversion in affected persons. This finding suggested that the hypertension could be caused by one or more of 3 genes, the ATP-dependent potassium channel Kir6.1, its regulator the sulfonyl urea receptor SUR2, and the phosphodiesterase PDE3A. We further studied 6 affected and 4 nonaffected persons. Buttocks biopsies were done, small vessels were tested on a myograph, and mRNA was extracted. We performed forearm blood flow studies with intrabrachial artery diazoxide, isoproterenol, and milrinone infusions. Systemic pharmacological testing was done with intravenous diazoxide, nitroprusside, and isoproterenol. PDE3A mRNA was high in vessels from 3 affected subjects, but not high in 3 others. The vessels responded similarly to forskolin, with or without glibenclamide, and to cromakalim. However, there was a suggestion that the dilatation after milrinone might be exaggerated. The forearm infusion studies showed no differences in the responses to diazoxide, isoproterenol, or milrinone. Systemically, affected persons showed a greater blood pressure response to diazoxide and nitroprusside, and a greater heart rate response to isoproterenol than nonaffected persons. The results shed doubt on Kir6.1 and SUR2. The differences in PDE3A expression and responses may be the result of hypertension rather than the cause. Although our 3 candidate genes are no longer likely, the rearrangement we describe greatly enhances the perspectives of this project. Key words: hypertension Ⅲ genetics Ⅲ gene expression M endelian hypertension has revealed novel mechanisms, particularly as related to altered renal salt and water reabsorption. 1 Autosomal-dominant hypertension with brachydactyly is an exception. 2 We mapped the locus to chromosome 12p. 3 The renin-angiotensin-aldosterone responses were normal in affected persons, ruling out saltsensitive hypertension. 4 Blood pressure decreased equally well with 5 different drug classes. 5 We found some evidence for a possible central mechanism. Affected persons exhibited neurovascular contact from a looping posterior inferior cerebellar artery that may impinge on the brain stem at the area of the ventrolateral medulla. 6 Autonomic testing showed that affected subjects had reduced muscle sympathetic nerve activity and low-normal catecholamines; however, their capacity to buffer increases in blood pressure was markedly impaired. 7 We studied a Japanese child with type E brachydactyly and a 12p deletion and recruited more families, thereby narrowing our linkage interval. 8,9 Because the transcription factor L-SOX5 regulates collagen IIA1 gene expression in the digits of developing mice, we sequenced the entire 500 000 basepair gene and used single nucleotide polymorphisms (SNPs) for mapping. We found that the gene lies just outside our interval...

Prolonged microgravity alters the regulation of the peripheral vasculature. The influence of reduced food intake, as often observed in astronauts, on vascular function is unclear. In a randomized, four-phase, crossover study, the effect of simulated microgravity (13 days of bed rest), energetic restriction (-25%, fat reduced), and their combination on endothelium-dependent and -independent vasodilation was compared with ambulatory control conditions. Using venous occlusion plethysmography, cumulative intra-arterial dose-response curves to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilators were constructed in 10 healthy male volunteers before and on day 13 of each of the four intervention periods. Bed rest combined with normoenergetic nutrition impaired the dose-response to acetylcholine (ANOVA, P = 0.004) but not to sodium nitroprusside, whereas hypoenergetic diet under ambulatory conditions improved responses to acetylcholine (P = 0.044) and sodium nitroprusside (P < 0.001). When bed rest was combined with hypoenergetic diet, acetylcholine responses did not change. Similarly, under control conditions, no change was observed. Individual changes in the total cholesterol-to-HDL ratio were correlated with changes in endothelial and vascular smooth muscle relaxation. In conclusion, short-term bed rest impairs endothelium-dependent arterial relaxation in humans. A hypoenergetic, low-fat diet modulates serum lipids, improves endothelium-dependent and -independent relaxation, and may antagonize the unfavorable effects of simulated microgravity on endothelial function.

I The effects of intravenously administered propranolol 0.01 and 0.03, pindolol 0.001 and 0.003, practolol 0.12 and 0.36, atenolol 0.03 and 0.09, metoprolol 0.045 and 0.135 and acebutolol 0.12 and 0.36 mg/kg, on isoprenaline-induced changes in heart rate, blood pressure, plasma free fatty acids, immunoreactive insulin plasma levels and plasma renin activity were determined in six healthy human subjects. 2 Propranolol, atenolol and metoprolol had a stronger effect on resting heart rate than practolol, acebutolol and pindolol, probably reflecting differences in intrinsic f,-sympathomimetic activity.Antagonist potencies against isoprenaline-induced changes in heart rate and blood pressure suggested cardioselectivity for practolol, atenolol, metoprolol and the lower dose of acebutolol and noncardioselectivity for propranolol, pindolol and the higher dose of acebutolol. 3 All six f-adrenoceptor blocking agents were able, to a varying extent, to antagonize the isoprenaline-induced increases in plasma free fatty acids and plasma immunoreactive insulin levels. In general, the cardioselective agents were relatively less effective antagonists than the non-cardioselective agents.4 Resting plasma renin activity was reduced by all six fJ-adrenoceptor blocking agents, suggestive of the presence of fJ1-adrenoceptors mediating renin release, but the non-cardioselective agents propranolol and pindolol seemed relatively more effective in antagonizing isoprenaline-induced increases in plasma renin activity than the cardioselective agents, which indicates that 62-adrenoceptors might also be involved.5 The results are compatible with the hypothesis that both #,-and fJ2-adrenoceptors are involved in the regulation oflipolysis, insulin release and renin release.