Alberto Morganti

Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy

Abstract Sixty-nine pregnant women were studied sequentially throughout pregnancy and again four to six weeks postpartum. Average blood pressures were lower during pregnancy than postpartum, with diastolic pressures reduced more than systolic pressures. The lowest pressures occurred close to the 28th week of gestation and then tended to return towards nonpregnant levels. Increases in blood pressure that occurred during a change in position from the left lateral recumbent to the supine position did not predict subsequent hypertension in pregnancy; in 51 patients in whom diastolic blood pressure increased by 20 mm Hg or more with this maneuver, hypertension did not develop. Monthly plasma sampling in 19 patients revealed marked stimulation of the renin-aldosterone system, which became maximal in the third trimester. Plasma renin activity (PRA) increased sevenfold over nonpregnant levels. About 50 per cent of this increase could be attributed to an increase in plasma renin substrate. Mean plasma renin substrate increased by fourfold, plasma aldosterone by eightfold, whereas urinary aldosterone excretion increased even more. Both urine and plasma aldosterone correlated with increasing PRA. Plasma progesterone, estradiol and estriol also progressively increased throughout pregnancy and were correlated closely with each other. Altogether, these studies describe an early and sustained stimulation of the renin-aldosterone system in normal pregnancy that is independent of changes in sodium or potassium excretion. The increases observed in PRA are of lesser magnitude and are more consistent throughout pregnancy in individual subjects than previously reported, perhaps because inadvertent cryoactivation of inactive renin was avoided prior to renin measurement. Increases in the renin system activity in pregnancy very likely involve increased stimulation of renal renin secretion consequent to hemodynamic and fluid volume changes which tend to compromise effective arterial blood volume and pressure. These data provide base line patterns for study of the pathogenesis of hypertensions and toxemias of pregnancy.

Effects of chronic ACE inhibition on sympathetic nerve traffic and baroreflex control of circulation in heart failure

BACKGROUND In congestive heart failure ACE inhibitors chronically reduce plasma norepinephrine. No information exists, however, on whether and to what extent this reduction reflects a true chronic inhibition of sympathetic outflow and which mechanisms may be responsible. METHODS AND RESULTS In 24 patients aged 60.3+/-2.0 years (mean+/-SEM) affected by congestive heart failure (New York Heart Association class II) and treated with diuretics and digitalis, we measured mean arterial pressure (Finapres), plasma renin activity and angiotensin II levels (radioimmunoassay), plasma norepinephrine (high-performance liquid chromatography), and muscle sympathetic nerve activity (microneurography at a peroneal nerve) at rest and during baroreceptor stimulation and deactivation caused by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. In 12 patients measurements were repeated after a 2-month addition of the ACE inhibitor benazepril (10 mg/d P.O.), while in the remaining 12 patients they were performed again after 2 months without any treatment modifications. Benazepril did not alter mean arterial pressure, markedly increased plasma renin activity, reduced plasma angiotensin II, and caused a nonsignificant reduction in plasma norepinephrine. In contrast, muscle sympathetic nerve traffic was significantly reduced (-30.5+/-5.3%, P<.01). This reduction was accompanied by no change in the sympathoexcitatory responses to baroreceptor deactivation but by a marked enhancement of the sympathoinhibitory responses to baroreceptor stimulation (103.5+/-3.4%). CONCLUSIONS These results provide the first direct evidence that in congestive heart failure chronic ACE inhibitor treatment is accompanied by a marked reduction in central sympathetic outflow. This reduction may depend on a persistent restoration of baroreflex restraint on the sympathetic neural drive.

Increased Oxidative Stress and Platelet Activation in Patients With Hypertension and Renovascular Disease

Background—Hypertensive patients with renovascular disease (RVD) may be exposed to increased oxidative stress, possibly related to activation of the renin-angiotensin system. Methods and Results—We measured the urinary excretion of 8-iso-prostaglandin (PG) F2&agr; and 11-dehydro-thromboxane (TX) B2 as indexes of in vivo lipid peroxidation and platelet activation, respectively, in 25 patients with RVD, 25 patients with essential hypertension, and 25 healthy subjects. Plasma renin activity in peripheral and renal veins, angiotensin II in renal veins, cholesterol, glucose, triglycerides, homocysteine, and antioxidant vitamins A, C, and E were also determined. Patients were also studied 6 months after a technically successful angioplasty of the stenotic renal arteries. Urinary 8-iso-PGF2&agr; was significantly higher in patients with RVD (median, 305 pg/mg creatinine; range, 124 to 1224 pg/mg creatinine) than in patients with essential hypertension (median, 176 pg/mg creatinine; range, 48 to 384 pg/mg creatinine) or in healthy subjects (median, 123 pg/mg creatinine; range, 58 to 385 pg/mg creatinine). Urinary 11-dehydro-TXB2 was also significantly higher in RVD patients compared with healthy subjects. In RVD patients , urinary 8-iso-PGF2&agr; correlated with 11-dehydro-TXB2 (rs=0.48;P <0.05) and renal vein renin (rs=0.67;P <0.005) and angiotensin II (rs=0.65;P =0.005) ratios. A reduction in 8-iso-PGF2&agr; after angioplasty was observed in RVD patients with high baseline levels of lipid peroxidation. Changes in 8-iso-PGF2&agr; were related to baseline lipid peroxidation (rs=−0.73;P <0.001), renal vein angiotensin II (rs=−0.70;P <0.01) and renin (rs=−0.63;P <0.05) ratios. Conclusions—Lipid peroxidation is markedly enhanced in hypertensive patients with RVD and is related to activation of the renin-angiotensin system. Moreover, persistent platelet activation triggered or amplified by bioactive isoprostanes may contribute to the progression of cardiovascular and renal damage in this setting.

Angiotensin II AT2 receptor subtype: an uprising frontier in cardiovascular disease?

The renin–angiotensin system (RAS) plays a pivotal role in the regulation of fluid, electrolyte balance and blood pressure, and is a modulator of cellular growth and proliferation. Biological actions of RAS are linked to the binding of the effector molecule, angiotensin II (AngII), to specific membrane receptors, mostly the AT1 subtype and, to a lesser extent, other subtypes. Following the identification and characterization of the AT2 subtype receptor, it has been proposed that a complex interaction between AngII and its receptors may play an important role in the effects of RAS. In this paper current information on AngII subtype receptors – their structure, regulation and intracellular signalling – are reviewed, with a particular emphasis on the potential relevance for cardiovascular pathophysiology. In addition, we discuss modulation of expression of the AT2 receptor and its interaction with the AT1 receptor subtype, as well as the potential effects of this receptor on blood pressure regulation. A better understanding of the integrated effects of the AngII subtype receptors may help to elucidate the function of the RAS, as well as their participation in the mechanisms of cardiovascular disease and attendant therapeutic implications.

ACE inhibition attenuates sympathetic coronary vasoconstriction in patients with coronary artery disease.

BackgroundIn humans, angiotensin converting enzyme (ACE) inhibition attenuates the vasoconstriction induced by sympathetic stimulation in a number of peripheral districts. Whether this is also the case in the coronary circulation is unknown, however. Methods and ResultsIn nine normotensive patients with angiographically assessed coronary atherosclerosis, we measured the changes in mean arterial pressure (intra-arterial catheter), heart rate, rate-pressure product (RPP), coronary sinus blood flow (CBF, thermodilution method), and coronary vascular resistance (CVR, ratio between mean arterial pressure and CBF) induced by the cold pressor test (CPT, 2 minutes) and diving (30 seconds), i.e., two stimuli eliciting a sympathetic coronary vasoconstriction. The measurements were performed in the control condition and 30 minutes after captopril 25 mg p.o. In the control condition, CPI caused an increase in mean arterial pressure and heart rate. Despite the increase in RPP (+20.7±3.2%, p<0.01), CBF did not change and CVR increased (+12.2±4.0%, p<0.05); diving caused an increase in mean arterial pressure and a reduction in heart rate. RPP increased (+14.3±3.5%, p<0.01), but despite this increase, there was a reduction in CBF and a marked increase in CVR (+37.3±7.4%, p<0.01). Captopril did not modify the blood pressure and heart rate responses to both stimuli except for a slight accentuation of the bradycardia to diving. Despite the unchanged or only slightly reduced RPP response, the increase in CVR was markedly and significantly attenuated (p<0.01). ConclusionsACE inhibition attenuates sympathetic coronary vasoconstriction in patients with coronary artery disease. This is probably due to removal of the facilitating influence of angiotensin II on sympathetic modulation of coronary vasomotor tone.

Prevalence of left-ventricular hypertrophy in hypertension: an updated review of echocardiographic studies

Left-ventricular hypertrophy (LVH) is a cardinal manifestation of hypertensive organ damage associated with an increased cardiovascular (CV) risk. We reviewed recent literature on the prevalence of LVH, as assessed by echocardiography, in order to offer an updated information on the magnitude of subclinical alterations in LV structure in contemporary human hypertension. A MEDLINE search using key words ‘left ventricular hypertrophy’, ‘hypertension’, ‘echocardiography’ and ‘cardiac organ damage’ was performed in order to identify relevant papers. Full articles published in English language in the last decade, (1 January 2000–1 December 2010), reporting studies in adult or elderly individuals, were considered. A total of 30 studies, including 37 700 untreated and treated patients (80.3% Caucasian, 52.4% men, 9.6% diabetics, 2.6% with CV disease) were considered. LVH was defined by 23 criteria; its prevalence ranged from 36% (conservative criteria) to 41% (less conservative criteria) in the pooled population. LVH prevalence was not different between women and men (range 37.9–46.2 versus 36.0–43.5%, respectively). Eccentric LVH was more frequent than concentric hypertrophy (range 20.3–23.0 versus 14.8–15.8, respectively, P<0.05); concentric phenotype was found in a consistent fraction (20%) of both genders. Despite the improved management of hypertension in the last two decades, LVH remains a highly frequent biomarker of cardiac damage in the hypertensive population. Our analysis calls for a more aggressive treatment of hypertension and related CV risk factors leading to LVH.

Control of renin release: A review of experimental evidence and clinical implications

Present knowledge of the mechanisms regulating release of renin is reviewed with particular emphasis on neural factors. Evidence is given for a direct effect of renal innervation on beta adrenergic receptors in juxtaglomerular cells, and for the involvement of reflex release of renin in conditions such as tilting and acute salt depletion. Participation of neural and nonneural mechanisms of control is also shown to occur in other conditions, such as aortic constriction and hemorrhage. The view is held that neural sympathetic factors might explain some of the renin disturbances found in essential hypertension. First, in patients with high renin hypertension part of the hypertension is renin-dependent, and these pressor levels of renin seem to be neurally induced since they can commonly be suppressed by beta adrenoreceptor blocking agents. Second, the hypothesis is presented that patients with low renin hypertension, at least those who have no volume disturbance, have a blunted sympathetic control of renin release. Therefore a sufficiently precise test of sympathetic activity, and possibly of body fluid volumes, should be associated with renin profiles for a better understanding of the pathophysiology of arterial hypertension and as a better guide to therapeutic management. Indeed, most of the available antihypertensive drugs act on sympathetic activity, body fluid volume or renin, and this multifaceted profile would provide more rational guidelines for treatment.

Altered Release of Cytochrome P450 Metabolites of Arachidonic Acid in Renovascular Disease

The aim of the present cross-sectional study was to investigate whether activation of the renin-angiotensin system in renovascular disease affects the cytochrome P450 &ohgr;/&ohgr;-1 hydroxylase (20-hydroxyeicosatetraenoic acid [20-HETE]) and epoxygenase (epoxyeicosatrienoic acids [EETs]) pathways of arachidonic acid metabolism in vivo, each of which interacts with angiotensin II. Plasma concentration and urinary excretion of 20-HETE and EETs and their metabolites, dihydroxyeicosatrienoic acids, were measured in urine and plasma by mass spectrometry in 10 subjects with renovascular disease, 10 with essential hypertension, and 10 healthy normotensive subjects (control subjects), pair-matched for gender and age. Vascular and renal function were evaluated in all of the subjects. Plasma 20-HETE was highest in subjects with renovascular disease (median: 1.20 ng/mL; range: 0.42 to 1.92 ng/mL) compared with subjects with essential hypertension (median: 0.90 ng/mL; range: 0.40 to 2.17 ng/mL) and control subjects (median: 0.45 ng/mL; range: 0.14 to 1.70 ng/mL; P<0.05). Plasma 20-HETE significantly correlated with plasma renin activity in renovascular disease (rs=0.67; n=10; P<0.05). The urinary excretion of 20-HETE was significantly lower in subjects with renovascular disease (median: 12.9 &mgr;g/g of creatinine; range: 4.4 to 24.9 &mgr;g/g of creatinine) than in control subjects (median: 31.0 &mgr;g/g of creatinine; range: 11.9 to 102.8 &mgr;g/g of creatinine; P<0.01) and essential hypertensive subjects (median: 35.9 &mgr;g/g of creatinine; range: 14.0 to 72.5 &mgr;g/g of creatinine; P<0.05). Total plasma EETs were lowest, as was the ratio of plasma EETs to plasma dihydroxyeicosatrienoic acids, an index of epoxide hydrolase activity, in renovascular disease (ratio: 2.4; range: 1.2 to 6.1) compared with essential hypertension (ratio: 3.4; range: 1.5 to 5.6) and control subjects (ratio: 6.8; range: 1.4 to 18.8; P<0.01). In conclusion, circulating levels of 20-HETE are increased and those of EETs are decreased in renovascular disease, whereas the urinary excretion of 20-HETE is reduced. Altered cytochrome P450 arachidonic acid metabolism may contribute to the vascular and tubular abnormalities of renovascular disease.

European consensus on the diagnosis and management of fibromuscular dysplasia

The main objectives of this expert consensus are to raise awareness about fibromuscular dysplasia, which is more frequent and more often systemic than previously thought and can sometimes have devastating consequences; to provide up-to-date recommendations for the diagnosis, evaluation, and management of the disease; and to identify research priorities. The emphasis has been put on recommendations for daily practice. The main topics covered include definition, classification, diagnosis, and management of fibromuscular dysplasia in adult patients with symptomatic involvement of the renal arteries, supra-aortic trunks, and digestive and peripheral arteries.

Atrial Natriuretic Peptide and Hemodynamic Changes During Normal Human Pregnancy

We compared plasma atrial natriuretic peptide (ANP) and cGMP levels during normal pregnancy--a condition characterized by hypervolemia, high cardiac output, and decreased vascular resistance--with postpartum levels and assessed their relation to pregnancy-induced hemodynamic changes. Humoral and hemodynamic variables were measured in healthy women subjects in the supine and upright postures at each trimester of pregnancy and postpartum. Supine plasma ANP was increased throughout pregnancy (32 +/- 5, 21 +/- 3, and 19 +/- 2 versus 15 +/- 1 pmol.L-1, respectively, at each trimester versus postpartum), as was cGMP (8.6 +/- 1, 7.1 +/- 1, and 6.6 +/- 1 versus 5.6 +/- 1 nmol.L-1), and their increments were directly related (r = .68, P < .01). Both ANP and cGMP levels did not differ from postpartum levels after subjects stood. Supine stroke volume was initially increased but declined below postpartum levels in late pregnancy (69 +/- 4, 60 +/- 3, and 44 +/- 3 versus 58 +/- 4 mL.m-2), whereas after subjects stood it was always higher (56 +/- 3, 58 +/- 3, and 49 +/- 2 versus 44 +/- 2 mL.m-2); thus, stroke volume tended to increase in response to standing in late pregnancy. Supine cardiac index had a similar trend, which was opposite to that of total peripheral resistance (1213 +/- 62, 1265 +/- 79, and 1729 +/- 89 versus 1654 +/- 92 dyne.s-1.cm-5.m-2).(ABSTRACT TRUNCATED AT 250 WORDS)