PubMed Health⌕ Search

Biomedical subjects

C M Ferrario

Publications and source records attributed to C M Ferrario.

At least 37 records · Page 2Linked to original sources
PubMed2000

Angiotensin-converting enzyme expression in human carotid artery atherosclerosis.

Angiotensin-converting enzyme (ACE) inhibitors reduce the progression of atherosclerosis in animal models and reinfarction rates after myocardial infarction in humans. Although expression of components of the renin-angiotensin system has been reported in human coronary arteries, no data regarding their presence in carotid arteries, a frequent site for the occurrence of atherosclerosis plaques, are available. The following study sought to determine whether ACE mRNA and protein can be detected in human carotid atheromatous lesions. Twenty-four intact endarterectomy specimens were obtained from patients with severe carotid occlusive disease (17 males and 7 females, aged 68+/-1 years) and fixed within 30 minutes. Carotid artery specimens contained advanced Stary type V and VI lesions, and human ACE mRNA expression and protein were localized in cross sections by the combination of in situ hybridization and immunohistochemistry. Cell type-specific antibodies were used to colocalize ACE to smooth muscle cells, endothelial cells, macrophages, or lymphocytes. ACE protein was localized in the intima, whereas the overlying media was largely free of ACE staining. In less complicated lesions, ACE staining was modest and could be visualized in scattered clusters of macrophages and on the luminal side of carotid artery vascular endothelium. Smooth muscle cells were largely negative. ACE staining increased as lesions became more complex and was most prominent in macrophage-rich regions. The shoulder regions of plaques contained numerous ACE-positive macrophage foam cells and lymphocytes. In these areas, microvessels were positive for endothelial cell and smooth muscle cell ACE expression. However, microvessels in plaques free of inflammatory cells were stained only faintly for ACE expression. Labeling for ACE mRNA mirrored the pattern of protein expression, localizing ACE mRNA to macrophages and microvessels within the intima. In conclusion, atherosclerosis alters carotid artery ACE production, increasing transcription and translation within regions of plaque inflammation. These data provide another important mechanism by which inflammation associated with increased ACE expression may contribute to the progression of atherosclerosis.

Aged↗
PubMed2000

Contribution of angiotensin-(1-7) to blood pressure regulation in salt-depleted hypertensive rats.

We exposed 63 adult spontaneously hypertensive rats (SHR) and 10 (mRen-2)27 transgenic hypertensive rats to a 12-day regimen of either a normal diet (0.5%) or a low-salt diet (0.05%) to evaluate the hypothesis that the vasodepressor heptapeptide, angiotensin-(1-7) [Ang-(1-7)], buffers the pressor effects of angiotensin II during endogenous stimulation of the renin-angiotensin system. Catheters were inserted into a carotid artery and jugular vein under light anesthesia the day before the experiment. Separate groups of conscious instrumented SHR were given short-term infusions of an affinity-purified monoclonal Ang-(1-7) antibody or the neprilysin inhibitor SCH 39370. In addition, SHR and (mRen-2)27 rats were given the Ang-(1-7) receptor antagonist [D-Ala(7)]Ang-(1-7). Exposure to the low-salt diet increased plasma renin activity and elevated plasma levels of angiotensin I and angiotensin II in SHR by 81% and 68%, respectively, above values determined in SHR fed a normal salt diet. Concentrations of angiotensin I and angiotensin II were also higher in the kidney of salt-depleted SHR, whereas plasma and renal tissue levels of Ang-(1-7) were unchanged. Infusion of the Ang-(1-7) antibody produced dose-dependent pressor and tachycardic responses in salt-depleted SHR but no effect in SHR maintained on a normal-salt diet. A comparable cardiovascular response was produced in salt-depleted SHR given either SCH 39370 or [D-Ala(7)]Ang-(1-7). These agents had negligible effects on SHR fed a normal-salt diet. Blockade of Ang-(1-7) receptors produced a similar cardiovascular response in (mRen-2)27 transgenic hypertensive rats fed a low-salt diet. Injections of the heat-inactivated antibody or the subsequent infusion of the antibody to rats given [D-Ala(7)]Ang-(1-7) produced no additional effects. The data support the hypothesis that the hemodynamic effects of neurohormonal activation after salt restriction stimulate a tonic depressor action of Ang-(1-7).

Analysis of Variance↗
PubMed2000

Novel mechanisms linking angiotensin II and early atherogenesis.

We propose that Ang II exerts an as yet uncharacterized immunomodulatory effect on monocyte maturation, differentiation, or extravasation, which may depend on the myelomonocytic phenotype. Since the myelopoietic process originating at stem cells and culminating in release to the blood is at least 6 days, it is conceivable that the observation of reduced monocyte CD11b expression two weeks after completion of losartan treatment indicates a suppression of the CD11b phenotype in newly released CD14(+)/CD45(+) monocytes. Other studies employing suppression of AT(1)-receptors with deoxy-oligonucleotides have reported effects on blood pressure that surpass those predicted by the duration of the treatment.(87) These data would suggest that it is possible to interrupt a stimulatory signal by Ang II through a gene-related mechanism that in our experiments may reside in the mechanisms that regulate myelopoiesis. While our knowledge of the role of Ang II in the regulation of monocyte formation and function is incomplete, we have taken a first step in attempting to synthesize the data described above into a comprehensive hypothesis for further evaluation of the factors that initiate atherogenesis. Such effects may crucially contribute to the clinical benefit of AT(1)-receptor antagonists, independent of depressor effects, and may represent a paradigm for novel, anti-inflammatory actions by this class of drugs.

Angiotensin II↗
PubMed2000

Novel angiotensin II AT(1) receptor antagonist irbesartan prevents thromboxane A(2)-induced vasoconstriction in canine coronary arteries and human platelet aggregation.

This study was conducted to investigate whether the novel orally active nonpeptide angiotensin II (Ang II) AT(1) receptor antagonist irbesartan interacts with the thromboxane A(2)/prostaglandin endoperoxide H(2) (TxA(2)/PGH(2)) receptor in canine coronary arteries and human platelets. Coronary artery rings were isolated from male dog hearts (n = 18) and isometric tension of vascular rings was measured continuously at optimal basal tension in organ chambers. Autoradiographic binding of [(3)H]SQ29,548, a TxA(2) receptor antagonist, in canine coronary sections was determined. Blood for platelet aggregation studies was collected by venous puncture from healthy human volunteers (n = 6) who were free of aspirin-like agents for at least 2 weeks. Vascular reactivity and platelet aggregation in response to the TxA(2) analogs U46619 and autoradioagraphic receptor binding to the TxA(2) receptor antagonist [(3)H]SQ29,548 were studied with and without irbesartan. The TxA(2) analog U46619 produced dose-dependent vasoconstriction in coronary rings (EC(50) = 11.6 +/- 1.5 nM). Pretreatment with irbesartan inhibited U46619-induced vasoconstriction, and the dose-response curve was shifted to the right in a dose-dependent manner. The EC(50) of U46619 was increased 6- and 35-fold in the presence of 1 and 10 microM of irbesartan without a change of maximal contraction. At 1 microM, irbesartan is 2-fold more potent than the AT(1) receptor antagonist losartan in the inhibition of U46619-induced vasoconstriction in canine coronary arteries. In contrast, neither AT(1) receptor antagonists (CV11974 and valsartan), the AT(2) receptor antagonist PD123319, nor the angiotensin converting enzyme inhibitor lisinopril had any effect on U46619-induced coronary vasoconstriction. Irbesartan did not change potassium chloride-induced vasoconstriction; however, irbesartan did inhibit the vasoconstriction mediated by another TxA(2)/PGH(2) receptor agonist prostaglandin F(2alpha) (PGF(2alpha)). Neither the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester nor the cyclooxygenase inhibitor indomethacin had any effect on irbesartan's attenuation of U46619-induced vasoconstriction. Irbesartan specifically reversed U46619-preconstricted coronary artery rings with and without endothelium in a dose-dependent manner. Irbesartan at high concentrations significantly competed for [(3)H]SQ29,548 binding in canine coronary sections. U46619 stimulated dose-dependent human platelet aggregation of platelet-rich plasma. Preincubation with irbesartan significantly inhibited platelet aggregation in a concentration-dependent manner. In conclusion, the dual antagonistic actions of irbesartan by acting at both the AT(1) and TxA(2) receptors in blood vessels and platelets may overall enhance its therapeutic profile in the treatment of hypertension, atherosclerosis, and arterial thrombosis.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2000

Using angiotensin converting enzyme inhibitors in African-American hypertensives: a new approach to treating hypertension and preventing target-organ damage.

Angiotensin converting enzyme (ACE) inhibitors have been avoided as an initial therapeutic option in the treatment of hypertension in African-Americans. A major reason for this has been the widespread perception of clinicians that these agents have poor blood pressure (BP) lowering efficacy in this population. Remarkably uniform and pervasive interpretations of clinical trial data have formed the basis of this clinical perception and can be summarised as follows: (1) there has been a lesser BP lowering effect of ACE inhibitors in African-Americans compared to whites, particularly at low doses; and (2) short-acting ACE inhibitors like captopril prescribed at the midpoint of its maximal total daily dose lower BP less effectively than higher doses of calcium antagonists in African-Americans. A reinterpretation of published data from these same clinical trials suggests that: (1) the majority of African-Americans have meaningful BP responses to ACE inhibitors, albeit at a higher average dose than in whites; and (2) high levels of dietary sodium intake appear to explain a significant portion of the racial differences in BP response at the lower doses of ACE inhibitors. Thus, ACE inhibitors can effectively lower BP in African-Americans. These data suggest that the clinician should not avoid these agents in African-Americans because of a presumed lack of BP lowering efficacy. Rather, we should recognise the importance of adequate drug dosing and modest reductions in dietary sodium intake in augmenting the BP lowering effect of ACE inhibitors in hypertensive African-Americans.

Angiotensin II↗
PubMed1999

Role of AT1 receptors in area postrema on baroreceptor reflex in spontaneously hypertensive rats.

Intravenous injection of angiotensin II type 1 (AT1) receptor antagonist improves the baroreceptor reflex gain in spontaneously hypertensive rats (SHRs). To investigate the role of area postrema in the modulation of the baroreflex control by AT1 receptor, the effects of intravenous injection of CV-11974 (AT1 receptor antagonist) on the baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate (HR) were examined in sham and area postrema-lesioned SHRs. The baseline mean arterial pressure was similar in both groups. However, baseline heart rate was significantly lower (p < 0.01) in area postrema-lesioned SHR than in sham-lesioned SHR, 307 +/- 11 and 365 +/- 10 beats/min (bpm), respectively. Intravenous CV-11974 (0.05 mg/kg) significantly decreased mean arterial pressure; however, it did not change HR and RSNA in either group. Reflex changes in RSNA and HR were elicited by intravenous infusion of either phenylephrine or sodium nitroprusside before and after intravenous injection of CV-11974. Intravenous CV-11974 increased baroreflex control of RSNA (Gmax; -1.57 +/- 0.08 vs. -1.92 +/- 0.12%/mmHg, p < 0.05) and HR (Gmax; -0.54 +/- 0.12 vs. 1.25 +/- 0.24 bpm/mmHg, p < 0.05) in sham-lesioned SHRs. However, intravenous CV-11974 failed to alter the baroreflex sensitivities in area postrema-lesioned SHRs. These results suggest that the area postrema does not play a crucial role in maintenance of high blood pressure in adult SHRs, and that the improvement of baroreflex control of RSNA and HR by intravenous CV-11974 is mediated via the area postrema in SHRs.

Angiotensin Receptor Antagonists↗
PubMed1999

Differential response of angiotensin peptides in the urine of hypertensive animals.

Urinary excretion rates of angiotensin I (Ang I), angiotensin II (Ang II), and angiotensin-(1-7) [Ang-(1-7)] were determined in normotensive Sprague Dawley (SD), spontaneously hypertensive (SHR), and mRen-2 transgenic hypertensive animals before and following blockade of Ang II synthesis or activity for two weeks. This study was performed to determine for the first time whether inhibition of Ang II alters the excretion of angiotensin peptides in the urine. Rats were given either tap water or water medicated with lisinopril, losartan or both agents in combination. Blood pressure was monitored at regular intervals during the experiment by the tail-cuff method, and once again at the end of the study with a catheter implant into a carotid artery. Metabolic studies and 24 h urinary excretion variables and angiotensin peptides were determined before and during the procedures. While all three treatments normalized the blood pressure of hypertensive animals, therapy with either lisinopril or the combination of lisinopril and losartan had a greater antihypertensive effect in both SHR and [mRen-2]27 transgenic hypertensive rats. In the urine, the concentration of the angiotensins (normalized by 24-h creatinine excretion) was several-fold higher in the untreated hypertensive animals than in normotensive SD rats. In SD rats, lisinopril or lisinopril and losartan produced a sustained rise in urinary levels of Ang-(1-7) without changes in the excretion of Ang I and Ang II. In contrast, Ang I and Ang-(1-7) were significantly elevated in SHR medicated with lisinopril alone or in combination with losartan. Only losartan, however, augmented urinary levels of Ang II in the SHR. The antihypertensive effects of the three separate regimens had no effect on the urinary excretion of angiotensin peptides in [mRen-2]27 transgenic hypertensive rats. These data show that Ang I and Ang-(1-7) are excreted in large amounts in the urine of SD, SHR and [mRen-2]27 hypertensive rats. The unchanged Ang-(1-7) excretion in transgenic hypertensive (Tg+) rats after inhibition of the renin-angiotensin system agrees with the previous finding of a reduced plasma clearance of the peptide in this model of hypertension. The data suggest that this form of hypertension may be associated with increased activity of an endogenous converting enzyme inhibitor.

Administration, Oral↗
PubMed1999

Angiotensin II AT1-receptor blockade inhibits monocyte activation and adherence in transgenic (mRen2)27 rats.

This study investigated whether angiotensin II AT1-receptor blockade with losartan inhibits endothelium-monocyte interactions originating from long-term activation of the renin-angiotensin system in hypertensive transgenic rats [TGR(mRen2)27]. The number of circulating activated monocytes, monocytes adhered to thoracic aorta endothelium, and the extent of endothelial cell injury were compared in adult male transgenic (mRen2)27 and age-matched Hannover Sprague-Dawley (SD) rats after 12 days of continuous subcutaneous administration of saline (120 microl/24 h), losartan (10 mg/kg/24 h), or the vasodilator hydralazine (3 mg/kg/24 h). At the doses administered in this experiment, both losartan and hydralazine normalized mRen2 rat blood pressures equal to values in similarly treated SD rats. Compared with saline infusion, administration of either antihypertensive in mRen2 rats reduced (p<0.05) endothelial cell injury, but only losartan significantly (p<0.05) decreased the number of activated circulating and endothelium-adherent monocytes. Infusion of antihypertensives in SD rats had no effect on blood pressures, monocyte activity, or endothelial injury compared with saline administration. These findings suggest that the recruitment and infiltration of leukocytes into the subendothelium associated with renin-angiotensin system-induced hypertension is partly mediated by pressure-independent AT1-receptor pathways.

Angiotensin II↗
PubMed1999

Angiotensin-(1-7) reduces smooth muscle growth after vascular injury.

Regulation of vascular smooth muscle cell growth is critical to the maintenance of normal blood flow and vessel patency. Angiotensin-(1-7) [Ang-(1-7)] inhibits proliferation of vascular smooth muscle cells in vitro and opposes the mitogenic effects of angiotensin II. The present study investigated whether Ang-(1-7) inhibits vascular smooth muscle cell growth in vivo by determining its effect on neointimal formation and medial remodeling in balloon-injured carotid arteries. The carotid arteries of adult male Sprague-Dawley rats were injured with a balloon embolectomy catheter. Ang-(1-7) in saline (24 microg/kg per hour) or saline alone was infused intravenously for 12 days after injury. Pumps containing bromodeoxyuridine were implanted at the same time to determine DNA synthesis. Intravenous infusion increased plasma Ang-(1-7) to 166. 0+/-41.2 fmol/mL (n=6) compared with 46.9+/-4.2 fmol/mL (n=8) in saline-infused rats. Plasma concentrations of Ang II were not changed by Ang-(1-7) infusion. Elevation in circulating Ang-(1-7) had no effect on either blood pressure or heart rate compared with saline controls. Histomorphometric analysis of carotid arteries indicated that Ang-(1-7) infusion significantly reduced neointimal area compared with rats infused with saline (0.063+/-0.011 versus 0. 100+/-0.009 mm2; P<0.05). In contrast, Ang-(1-7) infusion had no effect on medial area of the injured or the contralateral uninjured artery compared with saline controls. Ang-(1-7) infusion also reduced the rate of DNA synthesis in both the neointima and the media of the injured vessels. Therefore, exogenous Ang-(1-7) inhibited vascular smooth muscle cell proliferation associated with balloon-catheter injury. Similar increases in endogenous plasma Ang-(1-7) and inhibition of neointimal growth were observed in rats after angiotensin-converting enzyme inhibitor or angiotensin type 1 receptor antagonist administration, suggesting that Ang-(1-7) may contribute to the in vivo antiproliferative effects of these agents on vascular smooth muscle.

Angiotensin I↗
PubMed1999

Increased central angiotensin and osmotic responses in the Ren-2 transgenic rat.

We previously demonstrated that the Ren-2 transgenic (TG) rat is sensitive to salt, showing a sodium-induced pressor response. The present studies determined the effect of central stimulation with hypertonic saline (HS) and angiotensin II (Ang II) on mean arterial pressure (MAP), heart rate (HR), and plasma vasopressin. HS (1 mol/L NaCl, 5 microL) or Ang II (100 ng, 5 microL) was injected into the lateral ventricle of conscious male TG and control rats. The pressor responses to HS and Ang were greater in TG than in control rats, increases of 42+/-4 and 41+/-4 mm Hg versus 25+/-3 and 18+/-2 mm Hg (HS and Ang II and TG and control rats, respectively). The TG rats also showed an increased vasopressin response to Ang II, peak levels of 14+/-3 versus 28+/-3 pg/mL (control versus TG rats). HS increased plasma vasopressin levels, although the group responses were not different. HR was not significantly altered by either stimulus. Results demonstrate an increased responsiveness to intraventricular HS and Ang II in Ren-2 transgenic rats, suggesting a relationship between the enhanced angiotensinergic drive and central cardiovascular and vasopressin responses.

Analysis of Variance↗
PubMed1999

State-of-the-Art lecture. Antiproliferative actions of angiotensin-(1-7) in vascular smooth muscle.

Hemodynamic factors, circulating hormones, paracrine factors, and intracrine factors influence vascular smooth muscle growth and plasticity. The well-characterized role of angiotensin II in the modulation of vascular tone and cell function may be critically involved in the mechanisms by which vascular smooth muscle responds to signals associated with vascular endothelial dysfunction and increases in oxidative stress. Studies from this laboratory suggest that the trophic actions of angiotensin II may be intrinsically regulated by angiotensin-(1-7), a separate product of the angiotensin system derived from the common substrate, angiotensin I. Exposure of cultured vascular smooth muscle cells to angiotensin-(1-7) inhibited the trophic actions of angiotensin II and reduced the expression of the mitogenic effects of both normal serum and platelet-derived growth factor. The growth-inhibitory actions of angiotensin-(1-7) were blocked by the selective D-alanine(7)-angiotensin-(1-7) antagonist and the nonselective angiotensin receptor blocker sarcosine(1)-threonine(8)-angiotensin II. In contrast, subtype-selective antagonists for the AT(1) and AT(2) receptors had no effect on the inhibitory actions of angiotensin-(1-7), a finding that is consistent with the pharmacological characterization of a high-affinity (125)I-labeled angiotensin-(1-7) binding site in the vasculature by use of selective and nonselective angiotensin II receptor antagonists. The relevance of these findings to the proliferative response of vascular smooth muscle cells after endothelial injury was confirmed by assessment of the effect of a 12-day infusion of angiotensin-(1-7) on neointimal formation. In these experiments, the proliferative response produced by injuring the carotid artery was inhibited by angiotensin-(1-7) through a mechanism that could not be explained by changes in arterial pressure. Because plasma angiotensin-(1-7) increased to levels comparable to those found in animals and human subjects given therapeutic doses of angiotensin-converting enzyme inhibitors, angiotensin-(1-7) may be one factor participating in the reversal of vascular proliferation during inhibition of angiotensin II formation or activity.

Angiotensin I↗
PubMed1999

Bi-directional actions of estrogen on the renin-angiotensin system.

Estrogen stimulates the renin-angiotensin system by augmenting both tissue and circulating levels of angiotensinogen and renin. We show, however, that angiotensin converting enzyme (ACE) activity in the circulation and in tissues is reduced in two animal models of postmenopausal chronic hormone replacement. We observed a reduction of ACE activity in association with a significant increase in plasma angiotensin I (Ang I) and hyperreninemia in ovariectomized monkeys treated with Premarin (conjugated equine estrogen) replacement for 30 months. Plasma angiotensin II (Ang II) levels were not increased in monkeys treated with estrogen, suggesting that the decrease in ACE curtailed the formation of the peptide. The Ang II/Ang I ratio, an in vivo index of ACE activity, was significantly reduced by estrogen treatment, further supporting the biochemical significance of estrogen's inhibition of ACE. In ovariectomized transgenic hypertensive (mRen2)27 rats submitted to estrogen replacement treatment for 3 weeks, ACE activity in plasma and tissue (aorta and kidney) and circulating Ang II levels were reduced, whereas circulating levels of angiotensin-(1-7) (Ang-(1-7)) were increased. Ang-(1-7), the N-terminal fragment of Ang II, is a novel vasodilator and antihypertensive peptide. Thus, the net balance of these effects of estrogen on the reninangiotensin vasoconstrictor/vasodilator system is to promote the anti-hypertensive effect.

Angiotensins↗
PubMed1998

Angiotensin-(1-7): a bioactive fragment of the renin-angiotensin system.

Accumulating evidence suggests that angiotensin-(1-7) [Ang-(1-7)] is an important component of the renin-angiotensin system. As the most pleiotropic metabolite of angiotensin I (Ang I) it manifest actions which are most often the opposite of those described for angiotensin II (Ang II). Ang-(1-7) is produced from Ang I bypassing the prerequisite formation of Ang II. The generation of Ang-(1-7) is under the control of at least three enzymes, which include neprilysin, thimet oligopeptidase, and prolyl oligopeptidase depending on the tissue compartment. Both neprilysin and thimet oligopeptidase are also involved in the metabolism of bradykinin and the atrial natriuretic peptide. Moreover, recent studies suggest that in addition to Ang I and bradykinin, Ang-(1-7) is an endogenous substrate for angiotensin converting enzyme. This suggests that there is a complex relationship between the enzymatic pathways forming angiotensin II and other various vasodepressor peptides from either the renin-angiotensin system or other peptide systems. The antihypertensive actions of angiotensin-(1-7) are mediated by an angiotensin receptor that is distinct from the pharmacologically characterized AT1 or AT2 receptor subtypes. Ang-(1-7) mediates it antihypertensive effects by stimulating synthesis and release of vasodilator prostaglandins, and nitric oxide and potentiating the hypotensive effects of bradykinin.

Angiotensin I↗
PubMed1998

Angiotensin-(1-7) immunoreactivity in the hypothalamus of the (mRen-2d)27 transgenic rat.

The distribution of angiotensin-(1-7) immunoreactive neurons was compared to those of vasopressin-(VP) and oxytocin-(OT) immunoreactive (IR) neurons in the hypothalamus of adult (mRen-2d)27 transgenic hypertensive and Sprague-Dawley rats. In both strains, angiotensin (Ang)-(1-7)-IR cells were found in the supraoptic nucleus (SON), and in the anterior (ap-), medial (mp-), and lateral (lp-) parvocellular, and posterior magnocellular (pm-) subdivisions of the paraventricular (PVN) nucleus. Three-dimensional reconstructions showed that cells immunoreactive to Ang-(1-7) and VP were specifically co-distributed in the SON and in the pmPVN. Double-labeling neurons for both peptides revealed that both Ang-(1-7) and VP were colocalized in a subpopulation of neurons in the pmPVN and SON. In combination with previous studies, our results suggest that Ang-(1-7) and VP are colocalized, co-released and may have a combined action at a common target. In addition, the introduction of the mouse submandibular renin (mRen-2d) transgene into Sprague-Dawley rats does not appear to have altered the fundamental organization of hypothalamic peptide systems involved in fluid homeostasis.

Angiotensin I↗
PubMed1998

Characterization of angiotensin-(1-7) in the urine of normal and essential hypertensive subjects.

A total of 31 healthy volunteers [39 +/- 7 (SD) years] and 18 untreated essential hypertensive subjects [43 +/- 9 years] collected urine for 24 h after a physical examination and laboratory tests. Radioimmunoassay measurements of angiotensin-(1-7) [Ang-(1-7)] in urine and plasma were done as described previously. Sitting systolic and diastolic blood pressures (+/- SD) averaged 118 +/- 11/74 +/- 7 mm Hg and 146 +/- 16/96 +/- 8 mm Hg in normal and essential hypertensive subjects, respectively (P < .001), whereas 24 h urinary volume was not different in normal and essential hypertensive subjects (P > .05). The concentration of Ang-(1-7) in the urine of normal subjects averaged 62.6 +/- 22.6 pmol/L corresponding to a urinary excretion rate of 98.9 +/- 44.7 pmol/24 h. Concurrent measurements of plasma Ang-(1-7) showed that the content of Ang-(1-7) in urine was 2.5-fold higher than that measured in the plasma. In contrast, untreated essential hypertensive subjects had lower concentrations and 24 h urinary excretion rates of Ang-(1-7) averaging 39.4 +/- 18.0 pmol/L and 60.2 +/- 14.6 pmol/24 h, respectively, (P < .001). Differences in the excretory rate of Ang-(1-7) between normal volunteers and essential hypertensive subjects were not modified by normalization of the data by urinary creatinine excretion rates. Urinary concentrations of Ang-(1-7) correlated inversely with systolic, diastolic and mean arterial pressures (r = -0.48, P < .001). Both urinary Ang-(1-7) [odds ratio of 0.92 (95% CI: 0.88-0.97)] and age were independent predictors of systolic blood pressure. These studies demonstrated the presence of Ang-(1-7) in urine and the existence of reduced levels of the heptapeptide in individuals with untreated essential hypertension. The relatively higher concentrations of Ang-(1-7) in urine compared to plasma agrees with data that showed that Ang-(1-7) may contribute to the regulation of blood pressure. The inverse association between Ang-(1-7) and arterial pressure provides a potential marker for the characterization of forms of essential hypertension associated with reduced production or activity of vasodilator hormones.

Adult↗