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Biomedical subjects

E L Schiffrin

Publications and source records attributed to E L Schiffrin.

At least 19 recordsLinked to original sources
PubMed1999

Mitogen-activated protein/extracellular signal-regulated kinase inhibition attenuates angiotensin II-mediated signaling and contraction in spontaneously hypertensive rat vascular smooth muscle cells.

This study investigates the role of extracellular signal-regulated kinases (ERKs) in angiotensin II (Ang II)-generated intracellular second messengers (cytosolic free Ca2+ concentration, ie, [Ca2+]i, and pHi) and in contraction in isolated vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats (WKY) using the selective mitogen-activated protein (MAP)/ERK inhibitor, PD98059. VSMCs from mesenteric arteries were cultured on Matrigel basement membrane matrix. These cells, which exhibit a contractile phenotype, were used to measure [Ca2+]i, pHi, and contractile responses to Ang II (10(-12) to 10(-6) mol/L) in the absence and presence of PD98059 (10(-5) mol/L). [Ca2+]i and pHi were measured by fura-2 and BCECF methodology, respectively, and contraction was determined by photomicroscopy. Ang II-stimulated ERK activity was measured by Western blot analysis using a phospho-specific ERK-1/ERK-2 antibody and by an MAPK enzyme assay. Ang II increased [Ca2+]i and pHi and contracted cells in a dose-dependent manner. Maximum Ang II-elicited contraction was greater (P<0.05) in SHR (41.9+/-5.1% reduction in cell length relative to basal length) than in WKY (28.1+/-3.0% reduction in cell length relative to basal length). Basal [Ca2+]i, but not basal pHi, was higher in SHR compared with WKY. [Ca2+]i and pHi effects of Ang II were enhanced (P<0.05) in SHR compared with WKY (maximum Ang II-induced response [Emax] of [Ca2+]i, 576+/-24 versus 413+/-43 nmol/L; Emax of pHi, 7.33+/-0.01 versus 7.27+/-0.03, SHR versus WKY). PD98059 decreased the magnitude of contraction and attenuated the augmented Ang II-elicited contractile responses in SHR (Emax,19. 3+/-3% reduction in cell length relative to basal length). Ang II-stimulated [Ca2+]i (Emax, 294+/-55 nmol/L) and pHi (Emax, 7. 27+/-0.04) effects were significantly reduced by PD98059 in SHR. Ang II-induced ERK activity was significantly greater (P<0.05) in SHR than in WKY. In conclusion, Ang II-stimulated signal transduction and associated VSMC contraction are enhanced in SHR. MAP/ERK inhibition abrogated sustained contraction and normalized Ang II effects in SHR. These data suggest that ERK-dependent signaling pathways influence contraction and that they play a role in vascular hyperresponsiveness in SHR.

Angiotensin II↗
PubMed1999

Role of extracellular signal-regulated kinases in angiotensin II-stimulated contraction of smooth muscle cells from human resistance arteries.

BACKGROUND: We assessed the role of extracellular signal-regulated kinases (ERKs) in Ang II-stimulated contraction and associated signaling pathways in vascular smooth muscle cells (VSMCs) from human small arteries. METHODS AND RESULTS: VSMCs derived from resistance arteries (<300 microm in diameter) from subcutaneous gluteal biopsies of healthy subjects (n=8) were used to assess Ang II-stimulated [Ca2+]i, pHi, and contractile responses. [Ca2+]i and pHi were measured with fura 2-AM and BCECF-AM, respectively, and contraction was measured photomicroscopically in cells grown on Matrigel matrix. To determine whether tyrosine kinases and ERKs influence Ang II-stimulated responses, cells were pretreated with 10(-5) mol/L tyrphostin A-23 (tyrosine kinase inhibitor) and PD98059 (MEK inhibitor). Ang II-stimulated MEK activity was determined by tyrosine phosphorylation of ERKs. The angiotensin receptor subtypes (AT1 and AT2) were assessed with [Sar1,Ile8]Ang II (a nonselective subtype antagonist), losartan (a selective AT1 antagonist), and PD123319 (a selective AT2 antagonist). Ang II dose-dependently increased [Ca2+]i (pD2=8.4+/-0.36, Emax=541+/-55 nmol/L), pHi (pD2=9. 4+/-0.29, Emax=7.19+/-0.01), and contraction (pD2=9.2+/-0.21, Emax=36+/-2.2%). Ang II induced rapid tyrosine phosphorylation of ERKs, which was inhibited by PD98059. Tyrphostin A-23 and PD98059 attenuated (P<0.05) Ang II-stimulated second messengers, and PD98059 reduced Ang II-induced contraction by >50%. [Sar1,Ile8]Ang II and losartan, but not PD123319, blocked Ang II-stimulated responses. CONCLUSIONS: These data demonstrate that in VSMCs from human peripheral resistance arteries, functional Ang II receptors of the AT1 subtype are coupled to signaling cascades involving Ca2+ and pHi pathways that are partially dependent on tyrosine kinases and ERKs. ERKs, the signaling cascades characteristically associated with cell growth, may play an important role in Ang II-stimulated contraction of human VSMCs.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1999

Relationship between small-artery structure and systolic, diastolic and pulse pressure in essential hypertension.

OBJECTIVE: Studies of cerebral arterioles have suggested that pulse pressure may be a more important determinant of small-artery structure than systolic, diastolic or mean blood pressure in stroke-prone spontaneously hypertensive rats and in rats with an arterio-venous shunt. A study of small arteries has suggested that this is not the case in human essential hypertension. We therefore investigated the role of hemodynamic determinants on small-artery structure in hypertensive patients. DESIGN AND METHODS: To determine whether pulse pressure contributes to structural alterations in human essential hypertension, small arteries (lumen < 300 microns) were obtained from gluteal subcutaneous biopsies of 40 normotensive subjects aged 40.7 +/- 1.2 years and 45 untreated essential hypertensive humans aged 46.5 +/- 1.3 years. The relationship between the media: lumen ratio of the small arteries and levels of systolic, diastolic and mean blood pressure and pulse pressure was investigated. RESULTS: The media: lumen ratio (5.33 +/- 0.001%) of small gluteal subcutaneous arteries of normotensive subjects was significantly smaller and the lumen diameter (306 +/- 13 microns) significantly larger than in untreated hypertensive patients (7.42 +/- 0.001% and 244 +/- 9.7 microns respectively, P < 0.001). The media: lumen ratio of both groups examined together correlated with systolic blood pressure (r = 0.45, P < 0.001), diastolic blood pressure (r = 0.56, P < 0.001) and mean arterial pressure (r = 0.55, P < 0.001). The media: lumen ratio of vessels from hypertensive patients correlated with diastolic blood pressure (r = 0.22, P < 0.01) but not with systolic or mean blood pressure. There was no correlation between the media: lumen ratio of small gluteal subcutaneous arteries and pulse pressure in this population of normotensive and hypertensive subjects, examined together or separately. CONCLUSION: These results suggest that in 30- to 65-year-old humans with systolodiastolic essential hypertension, pulse pressure does not appear to be an important determinant of small-artery structure.

Adult↗
PubMed1999

Role of AT2 receptors in angiotensin II-stimulated contraction of small mesenteric arteries in young SHR.

This study assesses the receptor subtype (AT1 and AT2) through which angiotensin II (Ang II) mediates contraction in small arteries of young and adult spontaneously hypertensive rats (SHR). Segments of third-order mesenteric arteries ( approximately 200 microm in lumen diameter) were mounted in a pressurized system. Systolic blood pressure and media:lumen ratio of small arteries were significantly greater (P<0.001) in young SHR and adult SHR than in age-matched Wistar-Kyoto rats (WKY). Ang II-induced contractile effects were significantly increased (P<0.05) in young SHR compared with age-matched WKY. AT1 blockade with losartan, and combined AT1 and AT2 blockade with losartan and PD123319, abolished Ang II-stimulated contraction in young and adult rats. AT2 blockade (PD123319) significantly reduced (P<0.01) Ang II-elicited contraction in young SHR but had no effect in WKY or adult SHR, indicating that AT2 receptors may contribute to Ang II-induced contraction in young SHR. To determine the Ang receptor status in rat mesenteric vessels, AT1 and AT2 receptor mRNA expression was determined by reverse transcription-polymerase chain reaction. AT1 and AT2 receptor protein expression were detected by Western blot analysis. AT1 receptor mRNA was equally expressed in age-matched rats, but expression was significantly lower in young rats compared with adult rats. AT2 receptor mRNA was weakly expressed in WKY and adult SHR. In vessels from young SHR, AT2 receptor mRNA expression was significantly increased compared with the other groups. AT1 receptor protein was equally expressed in adult rats of both strains but was undetectable in young rats. AT2 receptor protein was only detectable in young rats, with the magnitude of expression greater in SHR than WKY. In conclusion, Ang II-stimulated contractile responses are augmented in vessels from young SHR. These effects are reduced by selective AT2 blockade and abolished by AT1 blockade, indicating that both Ang receptor subtypes are involved in contraction in young SHR. In WKY and adult SHR, losartan, but not PD123319, inhibited Ang II-induced contraction, indicating the exclusive involvement of AT1 receptors. Thus, in SHR, in the phase of developing hypertension, enhanced Ang II-stimulated vascular contraction may be associated with changes in Ang II receptor status, as evidenced pharmacologically and by increased vascular AT2 receptor mRNA and protein expression.

Aging↗
PubMed1999

Mechanics and composition of human subcutaneous resistance arteries in essential hypertension.

Mechanical properties of arteries are altered in some rat models of hypertension, and this may influence peripheral resistance and blood pressure as well as some of the complications of hypertension. It has usually been assumed that arterial wall stiffness is increased in hypertension, although recent studies suggest that this may not necessarily be the case in large arteries. We determined whether the mechanics of human resistance arteries are altered in hypertension. Subcutaneous resistance arteries (lumen diameter<300 microm) were isolated from hypertensive and normotensive subjects of similar ages (46+/-3 and 43+/-4 years, respectively). Vessels were mounted in a pressurized myograph, deactivated, and exposed to intraluminal pressures ranging from 3 to 140 mm Hg. At each pressure, lumen and media dimensions were measured. Media-to-lumen ratio and media width were greater in hypertensive vessels, reducing wall stress (P<0.01), whereas media cross section was similar in vessels from both groups. Isobaric elastic modulus (which is influenced by vessel geometry and by wall component stiffness) was lower in hypertensive vessels (P<0. 01). Stiffness of wall components (slope of incremental elastic modulus versus stress, which is geometry-independent) was significantly lower in hypertensive vessels (8.2+/-0.7) versus normotensive vessels (11.0+/-1.0, P<0.05), whereas distensibility was unchanged. Electron microscopic analysis of the media of the small arteries showed a greater collagen to elastin ratio (P<0.05) in the media of vessels from hypertensive patients. In conclusion, the stiffness of wall components (slope of elastic modulus versus stress) is not increased but is in fact decreased in subcutaneous resistance arteries from patients with mild essential hypertension. Reduced stiffness of resistance arteries from hypertensive patients does not appear to relate to changes in volume density of extracellular matrix components but may be the result of changes in extracellular matrix architecture or cell-matrix attachment, which remains to be established.

Adult↗
PubMed1998

Effect of chronic treatment with two different ET(A) selective endothelin receptor antagonists on blood pressure and small artery structure of deoxycorticosterone acetate (DOCA)-salt hypertensive rats.

Chronic treatment with a combined ET(A) and ET(B) endothelin receptor antagonist blunts hypertension development and small artery hypertrophy in deoxycorticosterone acetate (DOCA)-salt treated rats, in which endothelin-1 is overexpressed in endothelial cells of blood vessels. To determine whether ET(A) receptor antagonism played a predominant role in these findings, in this study the effects of two orally active ET(A) selective endothelin receptor antagonists, A-127722.5 and LU 135252, were evaluated on blood pressure and small artery structure in DOCA-salt hypertensive rats. Rats received A-127722.5 (30 mg/kg/day) or LU 135252 (50 mg/kg/day) in their drinking water since induction of hypertension. Whereas three of 10 untreated DOCA-salt hypertensive rats died, in the two treated groups none died and all appeared healthier. Systolic blood pressure of treated DOCA-salt hypertensive rats, measured with the tail cuff method, was lower than that of untreated DOCA-salt hypertensive rats by a mean of 20 mm Hg (P < .01) after 4 weeks of treatment with A-127722.5 and by 14 mm Hg (P < .01) with LU 135252. Cardiac and aortic relative weights were unaffected by treatment with either agent. Small arteries of the mesenteric, coronary, renal, and femoral vasculature, examined under standardized conditions after mounting on a wire myograph, were found to exhibit significant inward hypertrophic remodeling in DOCA-salt hypertensive rats. DOCA-salt hypertensive rats treated with A-127722.5 had a significantly smaller media width and media-to-lumen ratio in the four vascular beds examined, and rats treated with LU 135252 showed these findings in mesenteric and renal small arteries. These results demonstrate that chronic ET(A) selective antagonism induces similar effects to those of combined ET(A)/ET(B) receptor antagonists in DOCA-salt hypertensive rats; namely, mild reduction in development of hypertension and blunting of small artery morphological changes, and also appears to improve survival. These results suggest a role of ET(A) receptors in the endothelin dependent component of blood pressure elevation in DOCA-salt hypertensive rats, and in the small artery morphological changes present in this model of experimental hypertension.

Animals↗
PubMed1998

Apoptosis in vasculature of spontaneously hypertensive rats: effect of an angiotensin converting enzyme inhibitor and a calcium channel antagonist.

Increased apoptosis has been demonstrated in various forms of human and experimental cardiovascular disease. The role of this phenomenon in the vasculature in different models of hypertension is unclear. In hypertension, regression of vessel wall hypertrophy/hyperplasia or remodeling in response to various antihypertensive drugs may be mediated in part by apoptosis. This study examined vascular smooth muscle apoptosis in spontaneously hypertensive rats (SHR), in which it may presumably counterbalance vascular wall growth. Angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers induce regression of the vascular wall in hypertension. Therefore, we investigated the effect of the ACE inhibitor enalapril and the dihydropyridine calcium channel blocker amlodipine on apoptosis in blood vessels of SHR to determine whether part of the growth inhibitory effect of these drugs is mediated by apoptosis. This was performed by detection and measurement of DNA fragmentation using DNA laddering and examining aortic histologic sections with in situ end-labeling (terminal deoxynucleotide transferase-mediated dUTP-nick labeling [TUNEL]). Ten-week-old SHR were treated for 12 weeks with 10 mg/kg per day of enalapril and 20 mg/kg per day of amlodipine. Blood pressure was significantly reduced by enalapril and amlodipine (P < .01). Cross-sectional area of aorta was significantly increased (3.34+/-0.15 mm2) in SHR compared to that of Wistar-Kyoto (WKY) control rats (1.17+/-0.07 mm2, P < .01). The cross-sectional area of the aorta was significantly smaller in enalapril-treated SHR (2.42+/-0.12 mm2, P < .05) compared to untreated SHR, and almost normalized by amlodipine (1.65+/-0.31 mm2, P < .01). Apoptosis characterized using terminal deoxynucleotidyl transferase to radiolabel 3'-OH ends of fragmented DNA extracted from aorta, showed presence of fragmented labeled DNA as "DNA laddering," a hallmark of apoptosis. SHR had increased apoptosis (341+/-25 pixels/microg DNA) compared to WKY controls (206+/-13 pixels/microg DNA, P < .01). Apoptosis was six- to eightfold greater in aorta of enalapril and amlodipine-treated SHR (P < .01). These results were confirmed by in situ end-labeling of fragmented DNA in aortic histologic sections. Western blot quantification of Bax and Bcl-2 (pro- and antiapoptotic gene products, respectively) showed higher Bax and lower Bcl-2 expression, and accordingly increased the Bax-to-Bcl-2 ratio in aorta from SHR treated with enalapril or amlodipine in comparison to untreated SHR. In conclusion, enhanced apoptosis is present in aorta of SHR, possibly as a homeostatic mechanism counterbalancing growth. Antihypertensive agents such as the ACE inhibitor enalapril and the calcium antagonist amlodipine may cause regression or inhibition of vascular wall growth in SHR partly through enhanced apoptosis, which may contribute to the antihypertensive effects of these drugs.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Vascular remodeling and endothelial function in hypertensive patients: effects of antihypertensive therapy.

OBJECTIVE: To review studies of effects of antihypertensive agents on alterations in structure and function of small (resistance-size) arteries in hypertensive patients and in experimental hypertensive models, since these vessels may contribute to blood pressure elevation or to the complications of hypertension. MAIN OUTCOME MEASURES: The structure and endothelium-dependent relaxation of small arteries obtained in hypertensive humans from gluteal subcutaneous biopsies, and from different vascular beds in hypertensive rats, without and after antihypertensive treatment, and studied on a wire-myograph or as pressurized arteries, are described as reported in different studies. RESULTS: Treatment of spontaneously hypertensive rats (SHR) with angiotensin converting enzyme (ACE) inhibitors, calcium channel antagonists, angiotensin receptor antagonists and novel beta blockers such as carvedilol, has been shown to result in regression of the altered structure of small arteries in different vascular beds, in addition to improved endothelium-dependent relaxation. Several studies in hypertensive patients have now shown that treatment with some ACE inhibitors (cilazapril and perindopril) or extended release calcium channel antagonists (nifedipine GITS) induces similar effects in small arteries obtained from gluteal subcutaneous biopsies: both structure and endothelium-dependent relaxation improve under treatment. In contrast, hypertensive patients with equally well-controlled blood pressure but treated with the beta blocker atenolol did not in any of three studies exhibit any improvement in the structure of small arteries or in endothelial function. CONCLUSION: Although treatment for at least one year with some ACE inhibitors and extended release calcium channel antagonists corrects the structure and endothelium-dependent relaxation of gluteal subcutaneous small arteries, it still remains to be determined whether this apparently beneficial effect beyond blood pressure lowering of these and other agents with vascular protective properties will result in reduced morbidity and mortality in hypertensive patients.

Adrenergic beta-Antagonists↗
PubMed1998

Effects of enalapril and amlodipine on small-artery structure and composition, and on endothelial dysfunction in spontaneously hypertensive rats.

OBJECTIVES: To determine whether an angiotensin converting enzyme inhibitor, enalapril, and a dihydropyridine calcium channel antagonist, amlodipine, regress the altered structure, media composition, and vascular relaxation of small arteries of spontaneously hypertensive rats. METHODS: Spontaneously hypertensive rats aged 10 weeks were treated for 12 weeks with 10 mg/kg per day enalapril or 10-20 mg/kg per day amlodipine and compared with age-matched untreated spontaneously hypertensive rats. Small coronary, renal, mesenteric, and femoral arteries (lumen diameter 200-250 microm) were studied isometrically on a wire myograph, and mesenteric arteries isobarically as pressurized vessels. The composition of the vascular media of the latter was studied by electron microscopy. RESULTS: Blood pressure, and cardiac and aortic hypertrophy were reduced in treated spontaneously hypertensive rats. Treatment significantly decreased media thickness and media: lumen ratio of coronary, renal, mesenteric, and femoral small arteries studied isometrically and of pressurized mesenteric small arteries. Media cross-sectional area was smaller for coronary arteries studied isometrically and mesenteric arteries studied isobarically. Electron microscopic analysis revealed an increase in collagen: elastin ratio in the media of spontaneously hypertensive rat vessels, and a decrease under treatment to levels found in Wistar-Kyoto rats, with no significant changes detected in smooth muscle cells. The amplitude of contractions induced by acetylcholine on wire-myograph-mounted mesenteric arteries from spontaneously hypertensive rats were decreased by treatment, and relaxation of pressurized arteries induced by acetylcholine was normalized. CONCLUSION: Treatment of spontaneously hypertensive rats with enalapril or with amlodipine resulted in regression of cardiovascular hypertrophy and amelioration of endothelial dysfunction. Morphometric results obtained using an isometric myograph and a pressurized preparation to study rat small arteries were closely correlated. Regression of structural remodeling in small arteries was outward hypotrophic, with a reduction in the collagen: elastin ratio, and without net change in the absolute and relative volumes of smooth muscle and number of smooth muscle layers.

Amlodipine↗
PubMed1998

Endothelin and endothelin antagonists in hypertension.

The endothelins (ET) are potent 21-amino-acid vasoconstrictor peptides produced in many different tissues, particularly in the endothelium of blood vessels. ET-1 is the main endothelin secreted by the endothelium, and acts in a paracrine or autocrine fashion on blood vessels by interacting with ETA or ETB receptors on smooth muscle to stimulate contraction or on ETB receptors on endothelial cells to induce the release of vasorelaxants (nitric oxide and prostacyclin). Production of ET-1 is enhanced in several experimental models of hypertension in the rat, such as sodium-sensitive forms, e.g. deoxycorticosterone acetate (DOCA)-salt hypertensive, DOCA-salt-treated spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats, as well as other models such as stroke-prone SHR, angiotensin II-infused rats and fructose-fed rats, and possibly 1-K 1C Goldblatt hypertensive rats. In contrast, SHR, 2-K 1C Goldblatt hypertensive rats and nitric oxide-deficient (L-NAME-treated) hypertensive rats do not exhibit an ET-1 component. Endothelin dependency is manifested by excessive vascular growth, particularly in small arteries, and blood pressure lowering and regression of vascular growth after treatment with endothelin antagonists. The latter may be combined ETA/ETB or selective ETA antagonists, of which several are orally active and already in clinical development. In humans, endothelin-dependent vascular tone has been shown in studies of forearm blood flow. Enhanced expression of ET-1 mRNA has been demonstrated in the endothelium of small arteries of patients with moderate to severe hypertension. In a 4-week trial the combined ETA/ETB antagonist bosentan reduced the blood pressure of essential hypertensive patients equally to enalapril. Bosentan improved hemodynamics in patients with heart failure in acute and 2-week-long studies. Endothelin antagonists also offer promise in a rapidly fatal condition, primary pulmonary hypertension. Thus, the endothelin system appears to be involved in different forms of cardiovascular disease in experimental animals and humans, and its interruption offers great promise as a new therapeutic intervention in hypertension, heart failure and other diseases.

Animals↗
PubMed1998

Mechanical properties of mesenteric resistance arteries from Dahl salt-resistant and salt-sensitive rats: role of endothelin-1.

OBJECTIVE: Hypertension has been associated with altered structure and mechanics of resistance arteries. This study assessed whether the passive mechanics of mesenteric small arteries are altered in hypertensive Dahl salt-sensitive rats (Dahl-SS) vs normotensive Dahl salt-resistant rats (Dahl-SR). The role of endothelin-1 in determining small artery mechanics was also studied. DESIGN: Male Dahl-SR and Dahl-SS were treated with high sodium (4% NaCl) for 10 weeks. Subgroups of each strain were treated with the ETA-endothelin receptor antagonist, A-127722 (30 mg/kg/d), concomitantly. Third-order branches of mesenteric arteries were mounted in a pressure myograph and exposed to intraluminal pressures ranging up to 140 mmHg. Media thickness and lumen diameter were measured at each pressure, from which wall mechanics were calculated. RESULTS: Tail-cuff systolic blood pressure was elevated with high sodium in Dahl-SS vs Dahl-SR. At the given dose, A-127722 decreased blood pressure in Dahl-SS slightly but significantly. Lumen diameter was lesser and media-lumen ratios were greater in vessels from Dahl-SS. Under isobaric conditions, vessels from Dahl-SS exhibited decreased wall stress and incremental elastic modulus. However, there were no changes in isobaric incremental distensibility or elastic modulus in relation to wall stress. A-127722 attenuated the changes in media:lumen ratio and isobaric stress observed in Dahl-SS. CONCLUSIONS: Dahl salt-sensitive hypertension was associated with altered structure of mesenteric resistance arteries, which decreased wall stress. Endothelin-1 may be involved in these changes. These arteries exhibit decreased isobaric stiffness and no difference in geometry-independent stiffness, indicating that the decreased lumen diameter is a result of eutrophic remodeling.

Animals↗
PubMed1998

Endothelin-1 signaling is altered in cardiac cells from deoxycorticosterone acetate-salt hypertensive rats.

The cardiac cellular effects of endothelin-1 (ET-1) on intracellular free Ca2+ concentration ([Ca2+]i) were investigated in deoxycorticosterone acetate (DOCA)-salt rats with severe cardiac hypertrophy. [Ca2+]i was measured by fura-2 methodology in ventricular cardiomyocytes and fibroblasts of DOCA-salt hypertensive and control unilaterally nephrectomized rats (Uni-Nx). Blood pressure and heart weight were increased (p < 0.01) in DOCA-salt rats compared to control rats. ET-1 (10(-12)-10(-6) M) increased [Ca2+]i in a dose-dependent manner in both cell types from control and hypertensive rats. However, ET-1-induced [Ca2+]i responses were significantly attenuated (p < 0.01) in cardiomyocytes and fibroblasts of DOCA-salt rats. Sarafotoxin S6c (S6c) increased [Ca2+]i in fibroblasts but not in cardiomyocytes. In conclusion, ET-1 dose-dependently increased [Ca2+]i in cardiomyocytes (primarily via ETA receptors) and fibroblasts (via ETA and ETB receptors). Cardiac cell ET-1 signaling pathways are blunted in DOCA-salt hypertensive rats. ET-1 may not play a critical role in the pathophysiology of the severe concentric cardiac hypertrophy present in DOCA-salt hypertensive rats.

Animals↗
PubMed1998

Vascular endothelin-1 expression and effect of an endothelin ETA antagonist on structure and function of small arteries from stroke-prone spontaneously hypertensive rats.

There is some evidence that the endothelin (ET) system may participate in blood pressure elevation and in vascular hypertrophy in stroke-prone spontaneously hypertensive rats (SHR-SP). To further understand the involvement of the ET system in this hypertensive model, we examined preproendothelin-1 (preproET-1) mRNA abundance in blood vessels of 5-week and 18-week SHR-SP in comparison to SHR, and treated 12-week old SHR-SP with the ETA-selective receptor antagonist A-127722.5 (30 mg/kg/day in the drinking water) for 10 weeks. Abundance of preproET-1 mRNA by Northern blot analysis was increased more than twofold in aorta and mesenteric arteries of SHR-SP relative to SHR at 18 weeks but not at 5 weeks of age. SHR-SP treated with A-127722.5 had a tail-cuff systolic blood pressure at 22 weeks of age of 241 +/- 2 mm Hg vs. 251 +/- 3 mm Hg in untreated SHR-SP (p < 0.05). Heart:body weight ratio was no different in both groups, but aortic segment:body weight ratio was slightly but significantly smaller in treated SHR-SP (p < 0.05). Pressurized mesenteric small arteries from treated SHR-SP had a smaller media width (12.6 +/- 0.6 microns vs. 14.9 +/- 0.5 microns; p < 0.05) and media:lumen ratio (5.8 +/- 0.2% vs. 7.3 +/- 0.3%; p < 0.01), whereas media cross-sectional area and lumen diameter tended to decrease and increase, respectively, without achieving statistical significance. Acetylcholine-induced relaxation was improved in treated SHR-SP (99.6 +/- 0.6% vs. 90.0 +/- 3.6%; p < 0.05), whereas relaxation responses to sodium nitroprusside were similar in both groups. These results show increases of preproET-1 expression in blood vessels that appear to be secondary to blood pressure elevation. There is a small ET-dependent component in blood pressure elevation and in conduit and resistance artery changes in adult stroke-prone SHR.

Animals↗
PubMed1998

Endothelin-1 gene expression in blood vessels and kidney of spontaneously hypertensive rats (SHR), L-NAME-treated SHR, and renovascular hypertensive rats.

Spontaneously hypertensive rats (SHR), renovascular hypertensive rats [two-kidney one clip Goldblatt (2-K 1C) and 1-K 1C], and SHR treated with the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), do not respond to endothelin (ET) receptor antagonists with a decrease in blood pressure. However, treatment with ET receptor antagonists has shown some beneficial renal and coronary effects in SHR. In this study we examined tissues from SHR, L-NAME-treated SHR, 2-K 1C, and 1-K 1C, using in situ hybridization with a specific rat preproET-1 cRNA probe to evaluate preproET-1 mRNA abundance in blood vessels, heart, and kidneys. Grain density was similar in SHR and Wistar-Kyoto (WKY) rats in all tissues examined. L-NAME-treated SHR showed increased grain density vs. SHR in endothelium of aorta and of small coronary arteries and in kidney glomeruli, but not in renal or mesenteric arteries. 2-K 1C presented increased grain density in coronary arteries and in glomeruli of the unclipped but not the clipped kidney vs. glomeruli of control rats. 1-K 1C rats exhibited increases in preproET-1 mRNA relative to unilaterally nephrectomized control rats in endothelium of aorta and in mesenteric and coronary arteries, but not in renal arteries or glomeruli. None of the hypertensive models studied showed detectable evidence of myocardial overexpression of preproET-1 mRNA. Therefore, tissue-specific enhancement of ET-1 expression may underlie ET-dependent functional alterations and may explain the beneficial effects of ET receptor antagonists in the coronary circulation or in the kidney in some hypertensive models, but not in SHR.

Animals↗
PubMed1998

Effects of AT1 and AT2 angiotensin receptor antagonists in angiotensin II-infused rats.

Angiotensin II (Ang II) appears to exert its contractile and growth-promoting effects through the AT1 receptor subtype, whereas the AT2 subtype may have growth-inhibitory and proapoptotic properties. Recently, some data have challenged this emerging concept. To clarify the role of AT1 and AT2 receptors, we treated Wistar rats that were infused with Ang II (120 ng/kg/min subcutaneously by osmotic minipump), with the AT1 antagonist losartan (10 mg/kg/d in the drinking water) and the AT2 antagonist PD123319 (30 mg/kg/d subcutaneously by osmotic minipump) for 21 days. At the end of the study, tail-cuff systolic blood pressure was 106+/-2.8 mm Hg in untreated rats and 108+/-2.0 mm Hg in rats infused with Ang II that received losartan, whereas it rose to 158+/-4.9 mm Hg in Ang II-infused rats and 158+/-3.0 mm Hg in rats infused with Ang II rats and PD123319 (the two latter groups P<.01 versus the two other groups). Heart weight, and aorta cross-section/body weight ratio were higher in Ang II-infused rats than in controls and were significantly reduced in Ang II-infused rats that received losartan (P<.05). Wire-myograph-mounted coronary, renal, mesenteric, and femoral small arteries from Ang II-infused rats and Ang II-infused rats receiving PD123319 had a greater media, media cross-section, and media/lumen ratio than vessels from untreated or Ang II-infused rats treated with losartan. These results support the concept that in Wistar normotensive rats infused for 3 weeks with angiotensin II, growth in the heart, aorta, and coronary, renal, mesenteric, and femoral small arteries is mediated by the AT1 receptor; the results show little evidence of a role of AT2 receptors in mediating angiotensin II effects in this experimental paradigm.

Administration, Oral↗
PubMed1998

Effect of vasopressin antagonism on structure and mechanics of small arteries and vascular expression of endothelin-1 in deoxycorticosterone acetate salt hypertensive rats.

The structural and mechanical properties of small arteries are altered in rat models of hypertension. The precise role of humoral factors in these changes has not been determined. In deoxycorticosterone acetate (DOCA) salt hypertension, endothelin-1 (ET-1) peptide content and gene expression are enhanced in mesenteric resistance arteries. These vessels also present augmented vasoconstrictor responsiveness to vasopressin versus control uninephrectomized rats. To determine whether an interaction exists between vasopressin and ET-1 in the pathogenesis of small-artery structural alterations in DOCA-salt rats, we examined the effect of chronic V1 vasopressin receptor antagonism (OPC-21268, 30 mg/kg BID) on the structure and mechanical properties of mesenteric resistance arteries using a pressure myograph and the effect on preproendothelin-1 (preproET-1) gene expression, determined by Northern blot analysis of preproET-1 mRNA. Tail-cuff systolic pressures were elevated in DOCA-salt (200+/-11 mm Hg) versus uninephrectomized rats (109+/-4 mm Hg) and decreased slightly but significantly by OPC-21268 to 187+/-7 mm Hg (P<0.01). Treatment with DOCA-salt increased vascular media-lumen ratios and media cross-sectional areas and reduced both stress and incremental elastic modulus for a given pressure. However, there was no change in distensibility or incremental elastic modulus versus media stress. OPC-21268 partially attenuated the vascular growth in DOCA-salt rats. PreproET-1 mRNA was increased 2-fold in mesenteric arteries of DOCA-salt rats versus uninephrectomized rats, an effect abrogated by OPC-21268. Thus, DOCA-salt hypertension is associated with altered morphology of the small-arterial wall, without altering stiffness of the arterial wall components. OPC-21268 regressed in part these changes, suggesting the involvement of vasopressin. The concomitant attenuation of enhanced ET-1 expression by OPC-21268 suggests that ET-1 may be involved in mediating in part the vascular effects of vasopressin in DOCA-salt hypertensive rats.

Animals↗
PubMed1998

Effect of magnesium on calcium responses to vasopressin in vascular smooth muscle cells of spontaneously hypertensive rats.

This study investigated the modulatory effect of magnesium (Mg++) on basal and agonist-stimulated intracellular free calcium (Ca++) concentration ([Ca++]i) in vascular smooth muscle cells from spontaneously hypertensive rats (SHR). Effects of increasing extracellular Mg++ concentration ([Mg++]e) on vasopressin (AVP)-induced [Ca++]i responses were determined in primary cultured unpassaged vascular smooth muscle cells from mesenteric and aortic vessels (representing resistance and conduit arteries, respectively) of Wistar Kyoto rats (WKY) and SHR. [Ca++]i was measured by fura-2 methodology. Underlying mechanisms for Mg++ actions were determined in Ca(++)-free buffer and in the presence of diltiazem (10(-6) M), an L-type Ca++ channel blocker. Basal and AVP-stimulated [Ca++]i responses were significantly increased (p < .05) in SHR (pD2 = 8.3 +/- 0.1, Emax = 532 +/- 14 nM for SHR; pD2 = 8.0 +/- 0.04, Emax = 480 +/- 15 nM for WKY). [Mg++]e dose-dependently reduced basal and agonist-induced [Ca++]i responses. High [Mg++]e (4.8 mM) attenuated [Ca++]i responses to AVP in WKY (Emax = 328 +/- 30 nM) and SHR (Emax = 265 +/- 27 nM) and normalized AVP-elicited hyper-responsiveness in SHR (pD2 in high [Mg++]e, 8.1 +/- 0.3 for SHR, 7.8 +/- 0.6 for WKY). Extracellular Ca++ withdrawal and diltiazem abolished the attenuating effects of high [Mg++]e in WKY but not in SHR. These findings demonstrate that Mg++ dose-dependently reduces [Ca++]i and that high [Mg++]e attenuates AVP-stimulated [Ca++]i responses and normalizes sensitivity to AVP in SHR. In WKY, Mg++ actions are dependent primarily on Ca++ influx through L-type Ca++ channels, whereas in SHR, the modulatory effects of [Mg++]e are mediated both by Ca++ influx through Ca++ channels and by intracellular Ca++ release.

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