Biomedical subjects

C M Ferrario

Publications and source records attributed to C M Ferrario.

At least 55 records · Page 3Linked to original sources

PubMed1998

Depressor role of angiotensin AT2 receptors in the (mRen-2)27 transgenic rat.

The (mRen-2)27 transgenic rat (Tg+), a hypertensive model dependent on increased expression of the renin angiotensin system, was used to explore the role of angiotensin AT2 receptors in the control of cardiovascular and renal excretory function. Experiments tested the effect of blockade of AT2 receptors on basal blood pressure and the pressor, renal excretory, and vasopressin (VP) responses to intravenous hypertonic saline (HS). Chronically catheterized male Tg+ and normotensive Sprague-Dawley rats (Tg-) were housed in metabolic cages. PD123319 (AT2 antagonist) or 0.9% NaCl was given by intravenous bolus (3 mg/kg) followed by infusion (50 microg/kg/ min). Blockade of AT2 receptors both in Tg+ and Tg- rats produced no change in basal mean arterial pressure (MAP). The pressor response to intravenous HS (10% NaCl; 325 microL/100 g body weight) was significantly greater in Tg+ than in Tg- rats. PD123319 did not affect the peak rise in MAP but extended the time course of the response only in Tg+ rats. MAP was increased 39+/-4 and 36+/-3 mm Hg in Tg+ rats with and without the antagonist as compared to 20+/-2 and 24+/-2 mm Hg in Tg- rats. In the antagonist-treated Tg+ rats, MAP remained elevated for 60 min as compared to 5 min for Tg+ control or Tg- control or antagonist-treated rats. Hypertonic saline caused similar increases in plasma Na, VP, and in the natriuretic and diuretic responses in both Tg+ and Tg- rats, with no effect of antagonist treatment. These results demonstrate that Tg+ rats are sensitive to the effects of peripheral osmotic stimulation showing an increased pressor response, not attributed to greater secretion of VP or diminished natriuresis. These data also suggest that angiotensin AT2 receptors play a depressor role in the sodium-induced pressor response in this model.

Angiotensin Receptor Antagonists↗

PubMed1998

Differential actions of angiotensin-(1-7) in the kidney.

Angiotensin-(1-7) is a bioactive component of the renin-angiotensin system that is endogenously formed in the circulation and various tissues by several enzymatic pathways from either angiotensin (Ang) I or Ang II. Initial studies indicated that Ang-(1-7) mimicked some of the effects of Ang II, including stimulation of release of prostanoids and vasopressin. However, Ang-(1-7) is devoid of the vasoconstrictor, central pressor, or thirst-stimulating actions associated with Ang II. In fact, new findings reveal depressor, vasodilator, and antihypertensive actions that may be more apparent in hypertensive animals or humans. Thus, increasing evidence suggests that Ang-(1-7) may oppose the actions of Ang II directly or as a result of increasing prostaglandins or nitric oxide. In this review, we examine recent studies to address whether the kidney is a target organ for antihypertensive actions of Ang-(1-7).

Angiotensin I↗

PubMed1998

Role of AT1 and AT2 receptors in the plasma clearance of angiotensin II.

This study assessed the role of angiotensin (Ang) AT1 and AT2 receptors as modulators of the plasma clearance of Ang II. Groups of male spontaneously hypertensive rats (SHRs; n = 25) were given an intravenous injection of either saline, losartan, PD123319, losartan in combination with PD123319, or Sar1-Thr8-Ang II. One hour later, Ang II (0.5 microg/kg) was infused for 15 min into a vein. Immediately thereafter, arterial blood samples were collected at regular intervals for the assay of plasma Ang II levels by radioimmunoassay. The infusion of Ang II significantly increased baseline mean arterial pressure (MAP) in rats pretreated with either saline or PD123319 but not in those receiving losartan, losartan combined with PD123319, or Sar1-Thr8-Ang II. The plasma clearance of Ang II was significantly greater in rats injected with either PD123319, losartan combined with PD123319, or Sar1-Thr8-Ang II compared to those injected either saline or losartan. Furthermore, the half-life of Ang II in rats pretreated with saline or losartan was significantly greater than that measured in the other three groups. These results suggest that plasma clearance of Ang II in the SHRs is independent of an AT1 receptor, but plasma levels of the peptide are unexpectedly protected by an AT2 receptor-dependent mechanism.

Angiotensin II↗

PubMed1998

Losartan inhibits thromboxane A2-induced platelet aggregation and vascular constriction in spontaneously hypertensive rats.

Our recent studies have shown that the nonpeptide angiotensin II (Ang II) antagonist losartan interacts with thromboxane A2/prostaglandin H2 receptors and inhibits the thromboxane A2 (TxA2) analog U46619-induced vasoconstriction in canine coronary arteries. In this study, we further investigated whether losartan prevents TxA2-induced platelet aggregation and vasoconstriction in spontaneously hypertensive rats (SHRs). Pretreatment with losartan (10 microM) significantly reduced U46619-induced, concentration-dependent washed platelet aggregation. The inhibition is specific for losartan, because another Ang II AT1-receptor antagonist, CV11974 (10 microM), an active metabolite of TCV116, did not block the platelet aggregation caused by U46619. In addition, losartan (10 microM) augmented acetylcholine (ACH)-induced nitric oxide (NO)-dependent vasodilation and abolished the ACH-induced endothelium-derived contracting factor (EDCF)-mediated vasoconstriction in the aortic rings from adult SHRs. U46619 produced dose-dependent vasoconstriction in aortic vessels of SHRs, which was demonstrated to be blocked by the potent, selective TxA2/PGH2 receptor antagonist SQ29,548. Pretreatment with losartan (10(-6)-10(-5) M) inhibited the contractile response of U46619 and shifted the concentration-response curve to the right in a dose-dependent manner. The effective concentration at half maximal contraction (EC50) of U46619 was increased 2.5- and 7.6-fold in the presence of 1 and 10 microM losartan, respectively, without changes in maximal contraction. The active metabolite of losartan, EXP3174, at 1 microM also competitively inhibited U46619-induced contractions in aortic rings of SHRs. In contrast, neither the AT1-receptor antagonist CV11974, the AT2 antagonist PD123319, nor the angiotensin-converting enzyme inhibitor lisinopril, each at concentrations of 1 microM, had any effect on the U46619-induced constriction in aortic rings. In conclusion, losartan, acting as both AT1- and TxA2/PGH2-receptor antagonists, may enhance its therapeutic profile in the treatment of hypertension and cardiovascular disease.

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

PubMed1998

Cardiovascular, endocrine, and body fluid-electrolyte responses to salt loading in mRen-2 transgenic rats.

We previously demonstrated that mRen-2 transgenic [Tg(+)] rats are sensitive to chronic high NaCl intake, showing increased arterial pressure and vasopressin (VP) secretion. In this study, we determined the effect of a chronic osmotic challenge, 4 days of drinking 2% NaCl, on direct arterial blood pressure, heart rate, fluid-electrolyte balance, circadian rhythm of mean arterial pressure (MAP), and changes in plasma VP and catecholamines. Under baseline conditions, male Tg(+) rats showed a significant shift in the peak in circadian MAP into the light portion of the day-night cycle. Substitution of 2% NaCl for drinking water caused a rapid increase in MAP, 20 +/- 5 mmHg in Tg(+) rats within 6 h. Whereas the amplitude of circadian MAP fluctuations increased in salt-loaded Tg(+) rats, there was no significant change in the circadian timing of peak MAP with salt loading. Tg(+) rats showed exaggerated osmotic-induced increases in plasma VP, norepinephrine (NE), and epinephrine (Epi) compared with Tg(-) rats. Plasma NE and Epi were increased two- and fourfold, respectively, in the hypertensive rats with no significant change in the Tg(-) rats. Intravenous administration of a VP antagonist did not alter arterial pressure in either Tg(+) or Tg(-) rats. Tg(+) and Tg(-) rats showed a positive sodium balance with no significant difference observed between the groups. Tg(+) rats showed a significant increase in salt consumption, plasma sodium, osmolality, and hematocrit, accompanied by a negative water balance. We conclude that Tg(+) rats are sensitive to acute and chronic osmotic stimuli in terms of blood pressure, fluid-electrolyte balance, and plasma VP and catecholamines. Whereas elevated plasma VP does not contribute to the hypertensive response, increased sympathetic drive may mediate the salt-induced blood pressure changes in this model.

Animals↗

PubMed1998

Angiotensin II acts at AT1 receptors in the nucleus of the solitary tract to attenuate the baroreceptor reflex.

The object of the current study was to determine if ANG II acts at type 1 (AT1) or type 2 (AT2) receptors in the nucleus of the solitary tract (NTS) to reduce baroreceptor reflex control of renal sympathetic nerve activity (RSNA) and heart rate (HR). Experiments were carried out in urethan-anesthetized Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Reflex changes in RSNA and HR were elicited by intravenous infusion of either phenylephrine or sodium nitroprusside before and after bilateral microinjection of CV-11974 (AT1 receptor antagonist, 10 pmol), PD-123319 (AT2 receptor antagonist, 100 pmol), or artificial cerebrospinal fluid (aCSF, 50 nl) in the NTS. Mean arterial pressure (MAP)-RSNA and MAP-HR data were fit to logistic functions to analyze the baroreceptor reflex. Baroreceptor reflex sensitivities for RSNA and HR were attenuated in SHR compared with those in WKY rats. Bilateral injection of CV-11974, PD-123319, or aCSF in the NTS of either strain had no effect on baseline arterial pressure, HR, or RSNA. However, CV-11974 injected in the NTS increased significantly (P < 0.01) the sensitivities for baroreceptor reflex control of RSNA and HR in SHR and WKY rats. Neither PD-123319 nor aCSF altered baroreceptor reflex control of RSNA and HR in either SHR or WKY rats. These results demonstrate that endogenous ANG II acts at AT1 receptors of the NTS to attenuate the baroreceptor reflex in SHR as well as in WKY rats.

Angiotensin Receptor Antagonists↗

PubMed1998

Angiotensin-(1-7) contributes to the antihypertensive effects of blockade of the renin-angiotensin system.

Angiotensin-converting enzyme (ACE) inhibition alone or in combination with the angiotensin type-I receptor (AT1) antagonist losartan augments circulating levels of the bioactive peptide angiotensin-(1-7) [Ang-(1-7)]. Hence, we determined whether Ang-(1-7) contributes to the hypotensive effects produced by the combined administration of lisinopril and losartan in spontaneously hypertensive rats by blocking the peptide's synthesis with either of two structurally different neprilysin inhibitors. Intravenous administration of CGS 24592 (30 mg/kg) to rats in which blood pressure was normalized by 9 days of therapy with lisinopril and losartan elicited an elevation of mean arterial pressure that was sustained throughout the infusion period and for 20 minutes thereafter. The hypertensive response was associated with a 62% reduction in circulating levels of Ang-(1-7) and no change in plasma angiotensin II (Ang II). Intravenous infusion of one other neprilysin inhibitor (SCH 39370, 30 mg/kg) produced an increase in mean blood pressure of a magnitude similar to that found with CGS 24592. Pretreatment with the nonselective antagonist [Sar1,Thr8]-Ang II abolished any additional pressor effects of either neprilysin inhibitor in spontaneously hypertensive rats treated with lisinopril or losartan. However, neither the endothelin A antagonist BQ123 nor the kinin B2 antagonist HOE 140 had an effect on basal blood pressure or altered the pressor or heart rate effects of the neprilysin inhibitors. These data suggest that inhibition of Ang-(1-7) formation in rats exposed to the combined blockade of Ang II production and activity is associated with a reversal of the antihypertensive actions produced by these therapies. Thus, endogenous Ang-(1-7) functions as a vasodilator hormone in this form of genetic hypertension.

Angiotensin I↗

PubMed1998

Metabolism of angiotensin-(1-7) by angiotensin-converting enzyme.

Angiotensin converting enzyme (ACE) inhibitors augment circulating levels of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] in man and animals. Increased concentrations of the peptide may contribute to the antihypertensive effects associated with ACE inhibitors. The rise in Ang-(1-7) following ACE inhibition may result from increased production of the peptide or inhibition of the metabolism of Ang-(1-7)-similar to that observed for bradykinin. To address the latter possibility, we determined whether Ang-(1-7) is a substrate for ACE in vitro. In a pulmonary membrane preparation, the ACE inhibitor lisinopril attenuated the metabolism of low concentrations of 125I-Ang-(1-7). The primary product of 125I-Ang-(1-7) metabolism was identified as Ang-(1-5). Using affinity-purified ACE from canine lung, HPLC separation and amino acid analysis revealed that ACE functioned as a dipeptidyl carboxypeptidase cleaving Ang-(1-7) to the pentapeptide Ang-(1-5). The ACE inhibitors lisinopril and enalaprilat (1 micromol/L), as well as the chelating agents EDTA, o-phenanthroline, and DTT (0.1-1 mmol/L) abolished the generation of Ang-(1-5) and did not yield other metabolic products. Ang-(1-5) was not further hydrolyzed by ACE. Kinetic analysis of the hydrolysis of Ang-(1-7) by ACE revealed a substrate affinity of 0.81 micromol/L and maximal velocity of 0.65 micromols min(-1) mg(-1). The calculated turnover constant for the peptide was 1.8 sec(-1) with a catalytic efficiency (Kcat/Km) of 2200 sec(-1) mmol/L(-1). These findings suggest that increased levels of Ang-(1-7) following ACE inhibition may be due, in part, to decreased metabolism of the peptide.

Angiotensin I↗

PubMed1998

Vasodepressor actions of angiotensin-(1-7) unmasked during combined treatment with lisinopril and losartan.

Blockade of angiotensin II (Ang II) function during 8 days of oral therapy with lisinopril (20 mg/kg) and losartan (10 mg/kg) normalized the arterial pressure (112+/-3/70+/-3 mm Hg) and raised the plasma concentrations of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] of 21 male spontaneously hypertensive rats (SHR). Treated animals were then given a 15-minute infusion of either mouse immunoglobulin G1 or a specific monoclonal Ang-(1-7) antibody while their blood pressure and heart rate were recorded continuously in the awake state. The concentrations of Ang II and Ang-(1-7) in arterial blood were determined by radioimmunoassay. Infusion of the Ang-(1-7) antibody caused significant elevations in mean arterial pressure that were sustained for the duration of the infusion and were accompanied by transient bradycardia. Although the hemodynamic effects produced by infusion of the Ang-(1-7) antibody had no effect on plasma levels of Ang II, they caused a twofold rise in the plasma concentrations of Ang-(1-7). A pressor response of similar magnitude and characteristics was obtained in a separate group of SHR treated with the combination of lisinopril and losartan for 8 days during an infusion of [Sar1-Thr8]Ang II. The pressor response induced by the administration of this competitive, non-subtype-selective Ang II receptor blocker was not modified by pretreatment of the rats with an angiotensin type-2 (AT2) receptor blocker (PD123319). Plasma concentrations of Ang II and Ang-(1-7) were not changed by the administration of [Sar1-Thr8]Ang II either in the absence or in the presence of PD123319 pretreatment. These results are the first to indicate an important contribution of Ang-(1-7) in mediating the vasodilator effects caused by combined inhibition of angiotensin-converting enzyme and AT1 receptors. The comparable results obtained by administration of [Sar1-Thr8]Ang II suggest that the vasodepressor effects of Ang-(1-7) during the combined treatment is modulated by a non-AT1/AT2 angiotensin subtype receptor.

Angiotensin I↗

PubMed1998

Converting enzyme determines plasma clearance of angiotensin-(1-7).

We determined the mechanism accounting for the removal and metabolism of angiotensin-(1-7) [Ang-(1-7)] in 21 anesthetized spontaneously hypertensive (SHR), 18 age-matched normotensive Sprague-Dawley (SD), and 36 mRen-2 transgenic (TG+) rats. Animals of all 3 strains were provided with tap water or tap water containing losartan, lisinopril, or a combination of lisinopril and losartan for 2 weeks. On the day of the experiment, Ang-(1-7) was infused for a period of 15 minutes at a rate of 278 nmol . kg-1 . min-1. After this time, samples of arterial blood were collected rapidly at regular intervals for the assay of plasma Ang-(1-7) levels by radioimmunoassay. Infusion of Ang-(1-7) had a minimal effect on vehicle-treated SD rats but elicited a biphasic pressor/depressor response in vehicle-treated SHR and TG+ rats. In lisinopril-treated rats, Ang-(1-7) infusion increased blood pressure, whereas losartan treatment abolished the pressor component of the response without altering the secondary fall in arterial pressure. Combined treatment with lisinopril and losartan abolished the cardiovascular response to Ang-(1-7) in all 3 strains. In vehicle-treated SD, SHR and TG+ the half-life (t1/2) of Ang-(1-7) averaged 10+/-1, 10+/-1, and 9+/-1 seconds, respectively. Lisinopril alone or in combination with losartan produced a statistically significant rise in the half-life of Ang-(1-7) in all 3 strains of rats. Plasma clearance of Ang-(1-7) was significantly greater in the untreated SD rats compared with either the SHR or TG+ rat. Lisinopril treatment was associated with reduced clearance of Ang-(1-7) in all 3 strains. Concurrent experiments in pulmonary membranes from SD and SHR showed a statistically significant inhibition of 125I-Ang-(1-7) metabolism in the presence of lisinopril. These studies showed for the first time that the very short half-life of Ang-(1-7) in the circulation is primarily accounted for peptide metabolism by ACE. These findings suggest a novel role of ACE in the regulation of the production and metabolism of the two primary active hormones of the renin angiotensin system.

Administration, Oral↗

PubMed1998

Role of nitric oxide in the evolution of renal ischemia in two-kidney, one-clip renovascular hypertension.

To clarify the role of nitric oxide (NO) in the pathogenesis of renovascular hypertension, we examined the effects of long-term oral administration of either the precursor substrate L-arginine or the NO synthesis inhibitor Nomega-nitro-L-arginine (L-NA) on systemic and renal hemodynamics in dogs with chronic two-kidney, one-clip (2K-1C) renovascular hypertension. Furthermore, the importance of NO in maintaining kidney function in chronic renal ischemia was evaluated. Chronic inhibition of NO production aggravated the rise in blood pressure (L-NA 117.7+/-6.8 vs. control 107.2 3.3 mmHg, p < 0.05 on day 1) and stimulated marked bradycardia (L-NA 84.9+/-3.2 vs. control 94.6+/-2.6 beats/min, p < 0.05 on day 1). These changes were associated with significant reductions in renal plasma flow (RPF, L-NA 0.03+/-0.02 vs. control 0.85+/-0.20 ml/min/kg, p < 0.01) and glomerular filtration rate (GFR, L-NA 0.02+/-0.01 vs. 0.22+/-0.05 ml/min/kg, p < 0.01) in the ischemic kidney. In contrast, in the contralateral non-clipped kidney, chronic inhibition of NO production induced a significant reduction in RPF with no significant change in GFR. Oral administration of L-arginine had no effect on the magnitude of hypertension. L-arginine significantly improved RPF (2.76+/-0.49 ml/min/kg) and GFR (0.61+/-0.08 ml/min/kg) in the ischemic kidney, whereas the elevation of RPF and GFR in the non-clipped kidney was not significant. Unilateral renal artery occlusion in these hypertensive dogs resulted in diffuse atrophic tubulointerstitial changes in the ischemic kidney. These changes were markedly aggravated by NO synthesis inhibition. On the other hand, L-arginine treatment significantly protected against the morphological changes of renal ischemia. These data show that NO plays a key role in the maintenance of renal function during the evolution of hypertension induced by chronic renal ischemia. In addition, these data demonstrate that renovascular hypertension is associated with a compensatory increase in the vasodilator function of the vascular endothelium.

Animals↗

PubMed1998

Antihypertensive effects of angiotensin-(1-7).

Accumulating evidence suggests that angiotensin-(1-7)(Ang-(1-7)) is an important component of the renin-angiotensin system and that the actions of the peptide may either contribute to or oppose those of Ang II. Ang-(1-7) can be converted directly from Ang I bypassing prerequisite formation of Ang II. Formation of Ang-(1-7) is under the control of at least three endopeptidases depending on the tissue compartment and include neprilysin, thimet oligopeptidase and prolyl oligopeptidase. 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. These enzymatic pathways may contribute to a complex relationship between the hypertensive actions of Ang II and various vasodepressor peptides from either the renin-angiotensin system or other peptide systems. Ang-(1-7) is devoid of the vasoconstrictor, central pressor, or thirst-stimulating actions associated with Ang II. In fact, new findings reveal depressor, vasodilator, and antihypertensive actions that may be more apparent in hypertensive animals or humans. Thus, Ang-(1-7) may oppose the actions of Ang II directly or as a result of increasing prostaglandins or nitric oxide. In this review, we examine the mechanisms by which Ang-(1-7) may contribute to cardiovascular regulation.

Angiotensin I↗

PubMed1998

Novel angiotensin peptides regulate blood pressure, endothelial function, and natriuresis.

Accumulating evidence suggests that angiotensin-(1-7) is an important component of the renin-angiotensin system, having actions that are either identical to or opposite that of angiotensin II. Angiotensin I can be directly converted to angiotensin-(1-7), bypassing formation of angiotensin II. This pathway is under the control of three enzymes: neutral endopeptidases 24.11 (neprilysin) and 24.15 and prolyl-endopeptidase 24.26. Two of the three angiotensin-forming enzymes (neprilysin and endopeptidase 24.15) also contribute to the breakdown of bradykinin and the atrial natriuretic peptide. Furthermore, angiotensin-(1-7) is a major substrate for angiotensin-converting enzyme. These observations suggest that the process of biotransformation between the various Ang peptides of the renin-angiotensin system and other vasodepressor peptides are intertwined through this enzymatic pathway. Substantial evidence suggests that angiotensin-(1-7) stimulates the synthesis and release of vasodilator prostaglandins, and nitric oxide, while also augmenting the metabolic actions of bradykinin. In addition, angiotensin-(1-7) alters tubular sodium and bicarbonate reabsorption, decreases Na+-K+-ATPase activity, induces diuresis, and exerts a vasodilator effect. These physiologic effects of angiotensin-(1-7) favor a blood pressure-lowering effect. The majority of the data currently available suggest that angiotensin-(1-7) mediates its effects through a novel non-AT1/AT2 receptor subtype.

Angiotensin II↗

PubMed1998

Angiotensin-(1-7): a novel vasodilator of the coronary circulation.

Angiotensin-(1-7) [Ang-(1-7)] possesses novel biological functions that are distinct from angiotensin II (Ang II). In coronary arteries, the octapeptide Ang II and the heptapeptide Ang-(1-7) exert opposing actions. Ang II elicits vasoconstriction and Ang-(1-7) is a vasodilator. Ang-(1-7) elicits vasodilation by an endothelium-dependent release of nitric oxide. Further, the vasorelaxant activity is markedly attenuated by the bradykinin (BK) B2 receptor antagonist icatibant and does not appear to be associated with the synthesis and release of prostaglandins. Ang-(1-7) vasodilation is mediated by a non-AT1/AT2 receptor, since [Sar1Thr8]-Ang II, but neither candesartan, an AT1 receptor antagonist, nor PD123319, an AT2 receptor antagonist, blocked the response. Specific and high affinity binding of 125I-Ang-(1-7) to the endothelial layer of canine coronary arteries was demonstrated using in vitro emulsion autoradiography. Binding was effectively competed for by either unlabeled Ang-(1-7) or the specific Ang-(1-7) antagonist [D-Ala7]-Ang-(1-7). Additionally, Ang-(1-7) potentiated synergistically BK-induced vasodilation. The EC50 of BK vasodilation (2.45 +/- 0.51 nmol/L vs 0.37 +/- 0.08 nmol/L) was shifted 6.6-fold left-ward in the presence of 2 mumol/L concentration of Ang-(1-7). The potentiated response was specific for BK, since Ang-(1-7) did not augment the vasodilation produced by either acetylcholine or sodium nitroprusside; further, it was specific for Ang-(1-7), since neither Ang I nor Ang II augmented the BK response. In contrast to the vasodilator actions of Ang-(1-7), the potentiated response was not blocked by candesartan, PD123319 or [Sar1Thr8]-Ang II. Novel studies from our group demonstrate that Ang-(1-7) is both a substrate and inhibitor for angiotensin converting enzyme (ACE). Ang-(1-7) was shown to retard the degradation of 125I-[Tyr0]-BK in coronary rings. These studies describe novel actions of Ang-(1-7) as a vasodilator and a local synergistic modulator of kinin-induced vasodilation in coronary arteries.

Angiotensin I↗

PubMed1997

Endothelial injury in transgenic (mRen-2)27 hypertensive rats.

Transgenic [(mRen-2)27] rats develop severe hypertension as the result of transfection with the mouse Ren-2 gene. This study tested the hypothesis that hypertensive [(mRen-2)27] rats have increased endothelial dysfunction by examining the extent of vascular endothelial cell injury and turnover within the thoracic aorta of age-matched female transgene positive [Tg(+)] and transgene negative [Tg(-)] littermates. Transgenic hypertensive rats had arterial pressures significantly higher than Tg(-) animals, but no differences in heart rate or body weight. The extent of endothelial cell injury was estimated in Haütchen preparations of thoracic aorta endothelium by counting cells immunostained for the presence of cytoplasmic immunoglobulin G (IgG) at sites with or without intercostal artery branches. Both Tg(+) and Tg(-) littermates had a greater percentage of injured endothelial cells at branch sites than at nonbranch aorta (P < .01). However, the number of vascular endothelial cells staining positively for IgG was significantly higher in hypertensive rats both at sites away from (P < .05) and in the immediate vicinity of (P < .1) the orifices of intercostal arteries. En face preparations of the thoracic aorta were also examined for cells incorporating 5-bromo-2 '-deoxyuridine (BrdU) to estimate the percentage of endothelial cells undergoing replication. There was no difference in endothelial cell replication at either branch or nonbranch sites between hypertensive and normotensive rats. However, the percentage of endothelial cells undergoing replication at branch sites in both Tg(+) and Tg(-) rats was significantly greater than at nonbranch sites (P < .01). These data provide the first demonstration for the effects of high blood pressure on the vascular endothelium of a monogenetic model of hypertension produced by increased activity of the renin-angiotensin system. The divergent effects of this form of hypertension on vascular endothelial injury and endothelial turnover suggest that the decrease in the reparative capacity of the vascular endothelium induced by the combination of hypertension and associated angiotensinemia may contribute to the endothelial dysfunction accompanying vascular remodeling.

Animals↗

PubMed1997

Chronic estrogen treatment in female transgenic (mRen2)27 hypertensive rats augments endothelium-derived nitric oxide release.

Postmenopausal estrogen replacement therapy is associated with a reduction in cardiovascular events in women, but the mechanisms for this protection are unclear, especially in hypertensive subjects. In this study we investigated the effects of 17beta-estradiol (E2) treatment on blood pressure and endothelial function of transgenic [(mRen2)27] hypertensive and normotensive rats. Thirty female transgenic negative [Tg(-)] and hypertensive positive [Tg(+)] rats were ovariectomized and received either E2 (1.5 mg/rat, subcutaneously, for 3 weeks) or placebo. Chronic 17beta-estradiol treatment lowered mean blood pressure in both Tg hypertensive (159 +/- 4 v 145 +/- 4 mm Hg, P < .05, placebo v E2) and normotensive rats (119 +/- 4 v 108 +/- 2 mm Hg, P < .05, placebo v E2). Pressor responses to intravenous injection of phenylephrine were augmented in the Tg(+) as compared with Tg(-) rats. With chronic E2 treatment the pressor responses to phenylephrine were attenuated in both groups. Isometric tension of aortic rings was measured in vitro in organ chambers. The acetylcholine (Ach)-induced endothelium-dependent vascular relaxation was less potent in Tg(+) versus Tg(-) rats. E2 treatment significantly enhanced the Ach-induced relaxation of both Tg(+) and Tg(-) groups (ED50: 55.5 +/- 11.7 v 10.3 +/- 2.6; 23.8 +/- 6.5 v 5.1 +/- 1.2 nmol/L, placebo v E2 in Tg(+) and Tg(-), respectively). After E2 treatment the ED50 response in Tg(+) rats was no different from Tg(-) rats. However, the maximum vasodilation elicited by Ach was attenuated in Tg(+) as compared with Tg(-) rats. The calcium ionophore (A23187)-induced endothelium-dependent relaxation was less potent in Tg(+) as compared to Tg(-) rats and was enhanced by E2 treatment only in Tg(+) animals. There were no differences in the vasodilator responses elicited by sodium nitroprusside. Removal of endothelium and blockade of NO production abolished the endothelium-dependent vasodilation. The selective NO synthase inhibitor, N(G)-monomethyl-L-arginine (LMMNA), was used to evaluate indirectly the basal contribution of NO in vascular rings. The response to LMMNA was attenuated in untreated Tg(+) as compared to Tg(-) rats. E2 treatment augmented the contraction response to NOS inhibition in both Tg(+) and Tg(-) rats, resulting in a response in Tg(+) rats that was no different from Tg(-) rats. These results indicate that untreated, surgically ovariectomized hypertensive rats show deficiencies in endothelial function, which can be improved by estrogen replacement.

Animals↗

PubMed1997

Hypertension-related morbidity and mortality in the southeastern United States.

Stroke mortality is higher in the Southeast compared with other regions of the United States. The prevalence of hypertension is also higher (black men = 35%, black women = 37.7%, white men = 26.5%, white women = 21.5%), and the proportion of patients whose hypertension is being controlled is poor, especially in white and black men. The prevalence of hypertension-related complications other than stroke is also higher in the Southeast. The five states with the highest death rates for congestive heart failure are all in the southern region. Of the 15 states with the highest rates of end-stage renal disease, 10 are in the Southeast. Obesity is very prevalent (24% to 28%) in the Southeast. Although Michigan tops the ranking for all states, 6 of the top 15 states are in the Southeast, as are 7 of the 10 states with the highest reported prevalence regarding no leisure-time physical activity. Similar to other areas of the United States, dietary sodium and saturated fat intake are high in the Southeast; dietary potassium intake appears to be relatively low. Other factors that may be associated with the high prevalence, poor control, and excess morbidity and mortality of hypertension-related complications in the Southeast include misperceptions of the seriousness of the problem, the severity of the hypertension, lack of adequate follow-up, reduced access to health care, the cost of treatment, and possibly, low birth weights. The Consortium of Southeastern Hypertension Control (COSEHC) is a nonprofit organization created in 1992 in response to a compelling need to improve the disproportionate hypertension-related morbidity and mortality throughout this region. The purpose of this position paper is to summarize the data that document the problem, the consequences, and possible causative factors.

Adult↗

PubMed1997

Effects of chronic hormone replacement on the renin-angiotensin system in cynomolgus monkeys.

OBJECTIVE: To characterize the effects of estrogen, estrogen combined with progestin, and no treatment in ovariectomized cynomolgus monkeys during long-term reproductive hormone replacement. METHODS: Forty-five surgically postmenopausal cynomolgus monkeys fed a lipid-lowering diet were administered a conjugated equine estrogen (Premarin, 7.2 micrograms/day for the first 8 months, then 166 micrograms/day for the remaining 22 months), alone or in combination with 650 micrograms/day medroxyprogesterone acetate (Cycrin) for 30 months, or left with no hormone replacement therapy. Animals were anesthetized with ketamine-pentobarbital, and samples were taken for measurements of plasma renin activity, angiotensin converting enzyme activity, and angiotensin peptides, angiotensin I (Ang I), angiotensin II (Ang II), and angiotensin-(1-7) [Ang-(1-7)]. RESULTS: Chronic replacement therapy with estrogen resulted in a significant elevation of the plasma renin activity [11.7 +/- 2.0 ng/ml per h control versus 22.8 +/- 4.6 ng/ml per h with estrogen (P < 0.05) versus 32.8 +/- 4.9 ng/ml per h with combination therapy (P < 0.01)], whereas estrogen or combination therapy caused a significant reduction in angiotensin converting enzyme activity [229 +/- 8 nmol/ml per min control versus 189 +/- 10 nmol/ml per min with estrogen (P < 0.05) versus 196 +/- 11 nmol/ml per min with combination therapy (P < 0.05)]. Both of these changes in angiotensin processing enzymes observed during replacement therapy resulted in significant increases in plasma Ang I levels [46.7 +/- 12.5 pg/ml control versus 175.5 +/- 65.9 pg/ml with estrogen (P < 0.05) and 561.7 +/- 373.6 pg/ml with combination therapy (P < 0.05)]. Plasma Ang II and Ang-(1-7) levels were not significantly changed. The mean blood pressure did not change with either treatment. CONCLUSION: These studies reveal that, although chronic estrogen replacement activates renin activity and Ang I, it causes a shift in the processing of angiotensin peptides such that the concurrent reduction in angiotensin converting enzyme activity leads to unchanged plasma Ang II levels. Thus, the potentially harmful effects of estrogen-induced hyperreninemia are balanced by its actions interfering with the formation of the vasoactive product Ang II.

Angiotensin I↗