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Biomedical subjects

Carlos M Ferrario

Publications and source records attributed to Carlos M Ferrario.

At least 19 recordsLinked to original sources
PubMed2003

Estrogen or the AT1 antagonist olmesartan reverses the development of profound hypertension in the congenic mRen2. Lewis rat.

The influence of estrogen on the regulation of cardiovascular function remains a controversial and complex area of investigation. We assessed the effects of estrogen depletion in the congenic mRen(2). Lewis rat, established from the back-cross of the original (mRen2)-27 transgenic onto the Lewis inbred strain. Ovariectomy of heterozygous mRen(2). Lewis at 4 to 5 weeks resulted in a progressive increase in blood pressure compared with the sham surgery congenics at weeks 6 to 11. At 11 weeks, the ovariectomized mRen(2). Lewis (OVX) systolic blood pressure averaged 195+/-3.7 mm Hg versus 141+/-4.0 mm Hg for sham. Plasma Angiotensin (Ang) II, serum ACE activity, plasma renin concentration, as well as urinary excretion of Ang II, 8-isoprostane F2alpha, and endothelin-1 were elevated; however, renal mRNA levels of eNOS were suppressed after ovariectomy. Estrogen replacement reduced blood pressure below both the sham and OVX by 11 weeks (125+/-2.9 mm Hg, n=7, P<0.01 versus OVX and sham). Moreover, the AT1 receptor antagonist olmesartan (CS866; week 12 to 16) essentially normalized blood pressure to 113+/-5.4 mm Hg (n=6, P<0.01 versus OVX and sham). The attenuation of the hypertension was still evident 7 weeks after complete withdrawal of treatment (124+/-4.1 mm Hg at week 23). In summary, the OVX mRen.2. Lewis exhibited a rapid and sustained increase in blood pressure. Estrogen or olmesartan lowered pressure by a similar extent. We conclude that the ovary exerts considerable influence on the regulation of the blood pressure in the mRen2. Lewis strain, possibly by limiting activation of the renin-angiotensin system.

Angiotensin Receptor Antagonists↗
PubMed2003

Enhanced renal immunocytochemical expression of ANG-(1-7) and ACE2 during pregnancy.

Previously we demonstrated that kidney concentration and urinary excretion of angiotensin-(1-7) are increased during normal pregnancy in rats. Since this finding may reflect local kidney production of angiotensin-(1-7), we determined the immunocytochemical distribution of angiotensin-(1-7) and its newly described processing enzyme, ACE2, in kidneys of virgin and 19-day-pregnant Sprague-Dawley rats. Sprague-Dawley rats were killed at the 19th day of pregnancy, and tissues were prepared for immunocytochemical by using a polyclonal antibody to angiotensin- (1-7) or a monoclonal antibody to ACE2. Angiotensin-(1-7) immunostaining was predominantly localized to the renal tubules traversing both the inner cortex and outer medulla. ACE2 immunostaining was localized throughout the cortex and outer medulla and was visualized in the renal tubules of both virgin and pregnant rats. The quantification of angiotensin-(1-7) and ACE2 immunocytochemical staining showed that in pregnant animals, the intensity of the staining increased by 56% and 117%, respectively (P<0.05). This first demonstration of the immunocytochemical distribution of angiotensin-(1-7) and ACE2 in kidneys of pregnant rats shows that pregnancy increases angiotensin-(1-7) immunocytochemical expression in association with increased ACE2 intensity of staining. The findings suggest that ACE2 may contribute to the local production and overexpression of angiotensin-(1-7) in the kidney during pregnancy.

Angiotensin I↗
PubMed2003

Contribution of angiotensin-(1-7) to cardiovascular physiology and pathology.

Increased understanding of the contribution of angiotensin peptides to the physiologic control of arterial pressure and cardiovascular regulation has been made possible with the introduction of agents that either inhibit the activity of angiotensins forming enzymes or block the action of the peptides at their specific receptor subtypes. This review highlights some of the lessons that have been learned from the study of the actions of angiotensin-(1-7) and its inter-relationship with other vasodilator mechanisms that modulate the control systems that determine blood pressure and tissue perfusion. The studies suggest that the renin-angiotensin system acts as a humoral mechanism for blood pressure control through the generation of several distinct forms of angiotensin peptides that may bind to diverse receptor subtypes.

Angiotensin I↗
PubMed2003

Characterization of angiotensin-(1-7) receptor subtype in mesenteric arteries.

Mesenteric arteries from male Sprague-Dawley rats were mounted in a pressurized myograph system. Ang-(1-7) concentration-dependent responses were determined in arteries preconstricted with endothelin-1 (10(-7)M). The receptor(s) mediating the Ang-(1-7) evoked dilation were investigated by pretreating the mesenteric arteries with specific antagonists of Ang-(1-7), AT(1) or AT(2) receptors. The effects of Ang-(3-8) and Ang-(3-7) were also determined. Ang-(1-7) caused a concentration-dependent dilation (EC(50): 0.95 nM) that was blocked by the selective Ang-(1-7) receptor antagonist D-[Ala(7)]-Ang-(1-7). Administration of a specific antagonist to the AT(2) receptor (PD123319) had no effect. On the other hand, losartan and CV-11974 attenuated the Ang-(1-7) effect. These results demonstrate that Ang-(1-7) elicits potent dilation of mesenteric resistance vessels mediated by a D-[Ala(7)]-Ang-(1-7) sensitive site that is also sensitive to losartan and CV-11974.

Angiotensin I↗
PubMed2003

The effect of methylenetetrahydrofolate reductase C677T common variant on hypertensive risk is not solely explained by increased plasma homocysteine values.

The C677T transition of methylenetetrahydrofolate reductase (MTHFR) gene causes a moderate increase in total plasma homocysteine (tHcy). We studied the effect of MTHFR TT homozygosity and mild hyperhomocysteinemia on arterial hypertension. Normotensive controls (n = 223) and hypertensive subjects (n = 235) were matched for age, gender, and history of cardiovascular disease. Homocysteine levels were measured by a polarization immunoassay method. Methylenetetrahydrofolate reductase we determined by polymerase chain reaction and restriction fragment analysis. Hypertensives showed elevated tHcy compared to normotensive group in men (P = 0.039). Homocysteine values higher than 15 micromol/L were associated with increased hypertensive risk in the male population [odds ratios (OR) = 1.63; 95% confidence interval (CI) = 1.06-2.52; P = 0.027]. In multivariate analysis, TT genotype was associated with an increased risk of hypertension in males (OR = 2.27; 95% CI = 1.12-4.60; P = 0.022) An increased hypertensive risk was observed in those TT males with tHcy levels higher than 15 micromol/L (OR = 2.78; 95% CI = 1.05-7.3; P = 0.032) but not in those non-TT males with tHcy levels higher than 15 micromol/L (P = 0.33). Our findings do not support the possibility that mild hyperhomocysteinemia my solely account for the hypertensive risk associated to the TT genotype.

Aged↗
PubMed2003

Angiotensin receptors contribute to blood pressure homeostasis in salt-depleted SHR.

This study evaluated the contribution of angiotensin peptides acting at various receptor subtypes to the arterial pressure and heart rate of adult 9-wk-old male conscious salt-depleted spontaneously hypertensive rats (SHR). Plasma ANG II and ANG I in salt-depleted SHR were elevated sevenfold compared with peptide levels measured in sodium-replete SHR, whereas plasma ANG-(1-7) was twofold greater in salt-depleted SHR compared with salt-replete SHR. Losartan (32.5 micromol/kg), PD-123319 (0.12 micromol. kg(-1). min(-1)), [d-Ala(7)]ANG-(1-7) (10 and 100 pmol/min), and a polyclonal ANG II antibody (0.08 mg/min) were infused intravenously alone or in combination. Combined blockade of AT(2) and AT((1-7)) receptors significantly increased the blood pressure of losartan-treated SHR (+15 +/- 1 mmHg; P < 0.01); this change did not differ from the blood pressure elevation produced by the sole blockade of AT((1-7)) receptors (15 +/- 4 mmHg). On the other hand, sole blockade of AT(2) receptors in losartan-treated SHR increased mean arterial pressure by 8 +/- 1 mmHg (P < 0.05 vs. 5% dextrose in water as vehicle), and this increase was less than the pressor response produced by blockade of AT((1-7)) receptors alone or combined blockade of AT((1-7)) and AT(2) receptors. The ANG II antibody increased blood pressure to the greatest extent in salt-depleted SHR pretreated with only losartan (+11 +/- 2 mmHg) and to the least extent in salt-depleted SHR previously treated with the combination of losartan, PD-123319, and [d-Ala(7)]ANG-(1-7) (+7 +/- 1 mmHg; P < 0.01). Losartan significantly increased heart rate, whereas other combinations of receptor antagonists or the ANG II antibody did not alter heart rate. Our results demonstrate that ANG II and ANG-(1-7) act through non-AT(1) receptors to oppose the vasoconstrictor actions of ANG II in salt-depleted SHR. Combined blockade of AT(2) and AT((1-7)) receptors and ANG II neutralization by the ANG II antibody reversed as much as 67% of the blood pressure-lowering effect of losartan.

Angiotensin I↗
PubMed2003

Pregnancy enhances the angiotensin (Ang)-(1-7) vasodilator response in mesenteric arteries and increases the renal concentration and urinary excretion of Ang-(1-7).

The vasoactive effect of angiotensin (Ang)-(1-7) in mesenteric resistance arteries together with its plasma and kidney concentration and urinary excretion was assessed in pregnant and virgin rats. Mesenteric arteries (230-290 microm) were mounted in a pressurized myograph system and Ang-(1-7) concentration-dependent response curves (10(-10)-10(-5) M) were determined in arteries preconstricted with endothelin-1 (10(-7) M). The Ang-(1-7) response was investigated in vessels with and without pretreatment with the Ang-(1-7) antagonist [D-[Ala(7)]-Ang-(1-7)] (10(-7) M). Ang-(1-7) caused a significantly enhanced, concentration-dependent dilation of mesenteric vessels (EC(50) = 2.7 nM) from pregnant compared with virgin female rats. D-[Ala(7)]-Ang-(1-7) eliminated the vasodilator effect of Ang-(1-7). There was no significant change in plasma concentration of Ang-(1-7) in pregnant animals. On the other hand, 24 h urinary excretion and kidney concentration of Ang-(1-7) were significantly higher in pregnant animals. The increased mesenteric dilation to Ang-(1-7) with enhanced kidney concentration and 24 h urinary excretion rate of Ang-(1-7) suggests an important role for this peptide in cardiovascular regulation during pregnancy.

Angiotensin I↗
PubMed2002

Hypertension-linked decrease in the expression of brain gamma-adducin.

Gene profiling data coupled with adducin polymorphism studies led us to hypothesize that decreased expression of this cytosolic protein in the brain could be a key event in the central control of hypertension. Thus, our objectives in the present study were to (1) determine which adducin subunit gene demonstrates altered expression in the hypothalamus and brainstem (two cardioregulatory-relevant brain areas) in two genetic strains of hypertensive rats and (2) analyze the role of adducins in neurotransmission at the cellular level. All three adducin subunits (alpha, beta, and gamma) were present in the hypothalamus and brainstem of Wistar Kyoto (WKY) and spontaneously hypertensive (SH) rats. However, only the gamma-adducin subunit expression was 40% to 60% lower in the SH rat compared with WKY rat. A similar decrease in gamma-adducin expression was observed in the hypothalamus and brainstem of the renin transgenic rat compared with its normotensive control. Losartan treatment of the SH rat failed to normalize gamma-adducin gene expression. A hypertension-linked decrease of gamma-adducin was confirmed by demonstrating a decrease in gamma-adducin expression in hypothalamic/brainstem neuronal cultures from prehypertensive SH rats. Neuronal firing rate was evaluated to analyze the role of this protein in neurotransmission. Perfusion of a gamma-adducin-specific antibody caused a 2-fold increase in the neuronal firing rate, an effect similar to that observed with angiotensin II. Finally, we observed that preincubation of neuronal cultures for 8 hours with 100 nmol/L angiotensin II caused a 60% decrease in endogenous gamma-adducin and was associated with a 2-fold increase in basal firing rate. These observations support our hypothesis that a decrease in gamma-adducin expression in cardioregulatory-relevant brain areas is linked to hypertension possibly by regulating the release of neurotransmitters.

Action Potentials↗
PubMed2002

Angiotensin-converting enzyme 2 is an essential regulator of heart function.

Cardiovascular diseases are predicted to be the most common cause of death worldwide by 2020. Here we show that angiotensin-converting enzyme 2 (ace2) maps to a defined quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension. In all hypertensive rat strains, ACE2 messenger RNA and protein expression were markedly reduced, suggesting that ace2 is a candidate gene for this QTL. Targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart. Genetic ablation of ACE on an ACE2 mutant background completely rescues the cardiac phenotype. But disruption of ACER, a Drosophila ACE2 homologue, results in a severe defect of heart morphogenesis. These genetic data for ACE2 show that it is an essential regulator of heart function in vivo.

Angiotensin II↗
PubMed2002

Use of angiotensin II receptor blockers in animal models of atherosclerosis.

Long considered independent risk factors for end-stage vascular disease, hypertension and atherosclerosis may be intimately linked through their effects on vascular endothelial dysfunction, which are mediated by the renin-angiotensin system (RAS). Angiotensin II, a potent vasoconstrictor and the principal active peptide of the RAS, can also produce structural changes in the vessel wall associated with atherosclerosis. The role of RAS in the pathogenesis of atherosclerosis is supported by several lines of evidence, including the presence and upregulation of angiotensin-converting enzyme (ACE) and angiotensin II in the walls of atherosclerotic arteries. This article reviews recent research showing that administration of the angiotensin II type 1-receptor blocking agents (ARB) losartan and olmesartan medoxomil to cynomolgus monkeys with diet-induced hyperlipidemia prevents the progression of atherosclerosis. Since these effects have been achieved without altering blood pressure or plasma cholesterol levels significantly, it is suggested that these novel effects of angiotensin II receptor blocker treatment may extend the therapeutic profile of this class of agents in the prevention of human vascular disease.

Angiotensin II↗
PubMed2002

Effects of omapatrilat on the renin-angiotensin system in salt-sensitive hypertension.

The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which omapatrilat induces an antihypertensive response in salt sensitive hypertension.

Adolescent↗
PubMed2002

The hypertension-lipid connection: insights into the relation between angiotensin II and cholesterol in atherogenesis.

Clinical data and experimental studies have established the important role of abnormal lipid metabolism in the causation of atherosclerosis and enthroned the hydroxymethylglutaryl coenzyme reductase inhibitors (statins) as a mainstay in management of patients with coronary heart disease. However, emerging experimental data underline the role of vascular renin-angiotensin systems in mediating the early stages of vascular endothelial dysfunction and inflammation as prerequisites for unleashing the cascade of cellular and molecular events that lead to the deposition of foam cells and their eventual progression to the atherosclerotic plaque. We discuss here the biological effects of statins and angiotensin II in the evolution of atherogenesis, underscoring possible links between statins and angiotensin receptor blockers. From the assessment of the commonality of effects resulting from the nonlipidic actions of statins and angiotensin II on the process of atherogenesis, we develop the argument that dyslipidemia may influence the ability to control blood pressure in hypertensive subjects and hypothesize that the combined use of statins and blockers of the renin-angiotensin system may have an additive effect in the management of hypertensive subjects.

Angiotensin II↗
PubMed2002

Mechanisms linking angiotensin II and atherogenesis.

PURPOSE OF REVIEW: The concept that angiotensin II plays a central role in early atherogenesis, progression to atherosclerotic plaque, and the most serious clinical sequelae of coronary artery disease is the subject of considerable current interest. Results from recent large clinical trials confirm that blunting of the renin-angiotensin system through either angiotensin converting enzyme inhibition or angiotensin II type 1 receptor blockade incurs significant beneficial outcomes in patients with coronary artery disease. The exact mechanisms for these effects are not yet clear, but are suggested by studies demonstrating that suppression of the renin-angiotensin system is associated with muted vascular oxidative stress. RECENT FINDINGS: As most of the biological effects of the renin-angiotensin system occur through stimulation of the angiotensin II type 1 receptor, the focus of this review is on changes in the vascular wall mediated by this receptor and primarily related to endothelial and vascular smooth muscle cells, monocyte/macrophages and platelets. The interactions between angiotensin II and nitric oxide exert particular demands on the vascular capacity to adapt to dyslipidemia, hypertension, estrogen deficiency and diabetes mellitus that appear to exacerbate atherogenesis. Associated with each of these conditions is angiotensin II-mediated stimulation of macrophages, platelet aggregation, plasminogen activator inhibitor 1, endothelial dysfunction, vascular smooth muscle cell proliferation and migration, apoptosis, leukocyte recruitment, fibrogenesis and thrombosis. SUMMARY: Inhibition of the actions of angiotensin II serves a dual purpose: indirectly through reduction of mechanical stress on the vascular wall, and directly by diminished stimulation for vascular restructuring and remodeling. Collectively, data from studies published over the last year confirm and extend the notion that angiotensin II is a true cytokine prevalent at all stages of atherogenesis.

Angiotensin II↗
PubMed2002

Vasopeptidase inhibition and Ang-(1-7) in the spontaneously hypertensive rat.

BACKGROUND: Omapatrilat, a new vasopeptidase inhibitor, inhibits the activity of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP). Because these two enzymes participate in the degradation of the vasodilator and natriuretic peptide, angiotensin-(1-7) [Ang-(1-7)], we assessed whether omapatrilat treatment is associated with changes in the plasma and urinary excretion rates of the angiotensins. METHODS: We investigated in spontaneously hypertensive rats (SHR) (0.24 kg body weight) the effect of omapatrilat on plasma and urinary concentrations of angiotensin (Ang) I, Ang II and Ang-(1-7) during 17 days of administration of either the drug (N = 15, 100 micromol/kg/day) or vehicle (N = 14) in the drinking water. Hemodynamic and renal excretory function studies were associated with histological examination of the expression of Ang-(1-7) in the kidneys of both vehicle and omapatrilat-treated SHRs. RESULTS: Omapatrilat induced a sustained lowering of systolic blood pressure (-68 mm Hg) without changes in cardiac rate. The mild positive water balance produced by omapatrilat did not cause natriuresis or kaliuresis, although it was associated with a significant decrease in urine osmolality. Blood pressure normalization was accompanied by increases in plasma Ang I (2969%), Ang II (57%), and Ang-(1-7) (163%) levels, paralleling pronounced increases in urinary excretion rates of Ang I and Ang-(1-7) but not Ang II. Detection of Ang-(1-7) immunostaining in the kidneys of five other SHR exposed either to vehicle (N = 3) or omapatrilat (N = 2) ascertained the source of the Ang-(1-7) found in the urine. Intense Ang-(1-7) staining, more pronounced in omapatrilat-treated SHR, was found in renal proximal tubules throughout the outer and inner regions of the renal cortex and the thick ascending loop of Henle, whereas no Ang-(1-7)-positive immunostaining was found in glomeruli and distal tubules. CONCLUSIONS: Omapatrilat antihypertensive effects caused significant activation of the renin-angiotensin system associated with increases in urinary excretion rates of Ang I and Ang-(1-7). Combined studies of Ang-(1-7) metabolism in urine and immunohistochemical studies in the kidney revealed the existence of an intrarenal source, which may account for the pronounced increase in the excretion rate of the vasodilator heptapeptide. These findings provide further evidence for a contribution of Ang-(1-7) to the regulation of renal function and blood pressure.

Angiotensin I↗
PubMed2002

Noninvasive ultrasound evaluation of the vertebral artery in hypertension.

BACKGROUND AND PURPOSE: Surgical decompression of the vascular loop of the vertebral artery (VA) at the left lateral medulla can reduce blood pressure (BP) in hypertension, and a larger diameter of the left VA has been found in hypertensive patients. Noninvasive evaluation of the VA in hypertension may assist selecting patients for more appropriate diagnosis and treatment. Duplex ultrasonography is used to study the relationship between VA diameter and BP. METHODS: A retrospective review of VA duplex ultrasonography was performed in 112 consecutive patients who were sent to the neurovascular laboratory at the Wake Forest University School of Medicine during a 2-month period. All measurements (BP, pulse rate, peak systolic velocity [PSV], end diastolic velocity [EDV], and diameters of both VAs) were determined according to standardized protocols. Left-right comparisons of VA diameters, PSV, and EDV between hypertensives and normotensives were performed by the matched-pairs analysis techniques. RESULTS: Fifty-five women and 57 men with a mean age of 64.8 years were studied. Hypertension was present in 65.2% of all patients. The age-adjusted mean left VA diameter was significantly higher than that of the right VA with an age-adjusted average differences of 0.2 mm (P = .03) for hypertensives compared to 0.04 mm (P = .75) for normotensives. No significant differences were observed in either PSV or EDV. CONCLUSIONS: Differences in left-right VA diameter in hypertensive subjects may be a previously unrecognized component of the vascular disturbances associated with the disease and represent an additional criterion for identifying those who may benefit from surgical and medical management.

Aged↗