Li Yuan Deng

Effects of a beta-blocker or a converting enzyme inhibitor on resistance arteries in essential hypertension.

Seventeen male untreated mild essential hypertensive patients aged 41 +/- 2 years agreed to participate in a double-blind randomized trial to test the effects of antihypertensive treatment on the structure and function of subcutaneous resistance arteries. Patients were treated with either 50 to 100 mg/d atenolol or 2.5 to 5 mg/d cilazapril. Blood pressure before treatment was 148 +/- 6/99 +/- 1 and 147 +/- 2/99 +/- 1 mm Hg, respectively. At 1 year of treatment blood pressure was 131 +/- 4/85 +/- 2 and 132 +/- 2/87 +/- 1 mm Hg, respectively. Resistance arteries (200 to 400 microns lumen diameter) dissected from subcutaneous gluteal biopsies obtained before treatment and at 1 year showed that the media-lumen ratio of arteries from patients treated with cilazapril was reduced to 6.31 +/- 0.21% from 7.54 +/- 0.31% before treatment (P < .05), still slightly but significantly larger (P < .05) than the media-lumen ratio of resistance arteries of normotensive control subjects (5.15 +/- 0.30%). In contrast, in arteries from patients treated with atenolol there was no significant change with treatment (7.97 +/- 0.60% before and 8.07 +/- 0.45% after 1 year of treatment). Active wall tension responses to endothelin-1 were blunted in hypertensive patients and normalized in the cilazapril-treated patients. Depressed active media stress responses to norepinephrine, arginine vasopressin, and endothelin-1 were accordingly normalized in the patients receiving cilazapril as the media width became thinner but were unchanged in those taking atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure and function of resistance arteries of hypertensive patients treated with a beta-blocker or a calcium channel antagonist.

Objective To investigate the effects on resistance artery structure and function of monotherapy with the β-blocker atenolol or the calcium channel antagonist nifedipine in its once a day form or gastrointestinal therapeutic system (GITS). Subjects Twenty well-controlled essential hypertensive patients matched for age, body mass index, duration and severity of hypertension. Normotensive subjects and untreated hypertensives served as the reference groups. Methods Resistance-size small arteries (standardized lumen diameter 247 ± 8µ m) were dissected from a gluteal subcutaneous biopsy, and studied both on a wire myograph and as pressurized vessels. Results The media width:lumen diameter ratio of arteries was 5.37 ± 0.09% in normotensive subjects, 5.38 ± 0.18% in patients treated with nifedipine GITS, 6.81 ± 0.18% in patients treated with atenolol and 7.08 ± 0.12% in untreated hypertensives (for each of the latter two groups P<0.001, versus each of the two former groups). The media stress developed in response to noradrenaline and the endothelium- dependent relaxation induced by acetylcholine were significantly smaller in small arteries from untreated or atenolol-treated patients than they were in those from normotensive subjects or nifedipine GITS-treated patients. Conclusion Hypertensive patients with well-controlled blood pressures under treatment for more than 1 year with the once-a-day calcium channel antagonist nifedipine GITS exhibit normal structure and function of gluteal subcutaneous small arteries, whereas similar patients with blood pressure equally well controlled by the β-blocker atenolol present thicker small arteries with abnormal endothelium- dependent relaxation and altered contractility. Whether this finding applies also to other vascular beds, and whether it is associated with a better outcome in relation to morbidity and mortality resulting from elevated blood pressure, remain to be established.

Enhanced expression of endothelin-1 gene in resistance arteries in severe human essential hypertension.

Background Endothelins are potent vasoconstrictors, and may also act as mitogens and hypertrophic agents. Expression of a member of this family of peptides, endothelin-1, is enhanced in the endothelium of blood vessels of rats with severe forms of hypertension, even in the absence of elevated plasma endothelin levels. In some of these hypertensive models enhanced endothelin-1 gene expression may contribute to vascular hypertrophy of small arteries and to elevation of blood pressure. Objective To establish whether endothelin-1 may play a role in essential hypertension in humans, in whom plasma levels are known to be usually within normal limits, by examining the expression of the endothelin-1 gene in resistance-size arteries of normotensive subjects, and in humans with mild and severe hypertension. Methods Using in-situ hybridization, the abundance of endothelin-1 messenger RNA transcripts was evaluated in small arteries of subcutaneous gluteal fat obtained by biopsy in normotensive and hypertensive patients. Results Vessels from five normotensive subjects and four untreated mild essential hypertensive patients did not exhibit topographically localized specific labeling with the antisense human endothelin-1 probe. Biopsies from four untreated hypertensive patients with moderate-to- severe blood pressure elevation, in contrast, showed a heavy density of grains on endothelial cells of small arteries of gluteal subcutaneous fat, corresponding to hybridization of the antisense human endothelin-1 complementary RNA probe with endothelin-1 messenger RNA. Conclusion Some patients with moderate-to-severe essential hypertension, similar to some experimental rat models with severe blood pressure elevation, exhibit enhanced endothelial expression of the endothelin-1 gene. This is the first demonstration that overexpression of the endothelin-1 gene may occur in the vascular wall in a small sample of this subset of hypertensive patients. This pathophysiologic phenomenon could play a role in blood pressure elevation and perhaps in the pathogenesis of vascular hypertrophy. Treatment with endothelin receptor antagonists may offer a novel therapy for these moderate-to-severe hypertensive patients.

Progressive improvement in the structure of resistance arteries of hypertensive patients after 2 years of treatment with an angiotensin i-converting enzyme inhibitor Comparison with effects of a β-blocker

To investigate the effects of antihypertensive drugs on resistance artery structure, 17 essential hypertensive patients were randomly assigned to be treated with an angiotensin I-converting enzyme inhibitor, cilazapril, or a beta-blocker, atenolol, for 2 years. Blood pressure was well controlled throughout the 2 years. Before starting treatment, at the end of the first year and at the end of the second year, patients were subjected to gluteal subcutaneous fat biopsies, from which resistance-size arteries were dissected to be studied. The media width to lumen diameter ratio of arteries from patients in the cilazapril group was 7.5 +/- 0.3% before starting treatment, and decreased significantly (P < .05) to 6.3 +/- 0.2% at the end of the first year, and to 5.8 +/- 0.2% at the end of the second year, at which time it was not different from that of arteries from normotensive subjects (5.2 +/- 0.2%). In patients treated with atenolol, resistance arteries exhibited a media-to-lumen ratio of 8.0 +/- 0.6% before treatment, 8.1 +/- 0.5% after 1 year of treatment, and 7.9 +/- 0.3% at the end of the second year of treatment, all significantly higher (P < .01) than that of arteries from normotensive subjects. Thus, treatment for 2 years with the angiotensin I-converting enzyme inhibitor cilazapril resulted in progressive normalization of the structure (media-to-lumen ratio) of gluteal subcutaneous fat resistance arteries of essential hypertensive patients, whereas there was no change in patients treated with the beta-blocker atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Blunted effects of endothelin upon small subcutaneous resistance arteries of mild essential hypertensive patients.

OBJECTIVE In experimental models of hypertension in the rat, resistance arteries present a blunted response to endothelin, a potent vasoconstrictor peptide. The primary objective of this study was to investigate whether, as in hypertensive rat blood vessels, the response of human resistance arteries to endothelin was altered in essential hypertensive patients, in order to further understand the possible physiopathological involvement of this peptide in human hypertension. DESIGN Normotensive male subjects and sex- and age-matched mild essential hypertensive patients who had not received antihypertensive drugs for more than 6 months were investigated. METHODS Small arteries were dissected from gluteal subcutaneous biopsies and mounted on a wire-myograph. Blood vessels were measured and dose-response curves to different agents tested. RESULTS The external diameter of blood vessels of the hypertensive patients tended to be smaller and the width of their media tended to be thicker, but the cross-sectional area of the wall was similar in both groups. Lumen diameters were significantly smaller in hypertensives and the media:lumen ratio was significantly increased in hypertensive patients. Active tension responses and sensitivity to norepinephrine, arginine vasopressin and angiotensin II were similar in both groups, but calculated active pressure responses were enhanced in hypertensives due to the smaller blood vessel lumen. Tension responses to endothelin-1 at increasing concentrations of 0.1 to 100 nmol/l were lower in hypertensive patients, but the calculated transmural active pressure developed was not significantly different at or above 10 nmol/l. CONCLUSION These results suggest that gluteal subcutaneous small resistance arteries of male essential hypertensive patients exhibit a decrement in responsiveness to endothelin-1. The altered design of the hypertensive blood vessels enhanced calculated pressure responses, which may contribute to the maintenance of elevated blood pressure.

Increased endothelium-1 gene expression in the endothelium of coronary arteries and endocardium in the DOCA-salt hypertensive rat

Endothelin-1 (ET-1) is a potent vasoconstrictor and inotropic agent which may also induce cell hypertrophy. The role of ET-1 in ventricular hypertrophy in hypertension is unknown. We investigated ET-1 gene expression and immunoreactive ET-1 (ir-ET-1) concentration in the heart of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. To identify the cellular sites of ET-1 production in the heart, we performed in situ hybridization histochemistry. DOCA-treated rats which underwent unilateral nephrectomy (Uni-Nx) or not, exhibited mild systolic blood pressure elevation and ventricular hypertrophy. Blood pressure elevation and cardiac hypertrophy were more severe in DOCA-salt hypertensive rats. Ventricular ET-1 mRNA was similar in Uni-Nx control and DOCA-treated rats by Northern blot analysis, whereas in DOCA-salt hypertensive rats it was significantly increased. Ir-ET-1 concentration was also enhanced in ventricles from DOCA-salt hypertensive rats compared with Uni-Nx control rats. In situ hybridization histochemistry using a 35S-labelled complementary RNA ET-1 probe demonstrated that the level of ET-1 mRNA transcripts was increased exclusively in endothelial cells of large epicardial and small intramyocardial coronary arteries and in areas of the endocardium, but not significantly in myocardial cells of either the atria or ventricles. Enhanced ET-1 production may contribute to vascular changes, both structural and functional, in the heart in this model of hypertension in the rat, but probably does not contribute to the severe cardiac hypertrophy found in DOCA-salt hypertensive rats.

Effect of hypertension induced by nitric oxide synthase inhibition on structure and function of resistance arteries in the rat

To determine whether inhibition of generation of endothelium-derived relaxing factor or nitric oxide (NO) resulted in elevated blood pressure and its effect on resistance arteries, rats were offered NG-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthase, in their drinking water. Blood pressure (BP) rose slightly from 100 +/- 2 mmHg in controls to 130 +/- 5 mmHg with 25 mg/Kg L-NAME per day and to 173 +/- 9 mmHg with 100 mg/Kg per day for 2 1/2 to 4 weeks. Rats were studied after 1-2 weeks of hypertension (BP > 150 mmHg). The concentration of cyclic guanosine monophosphate, the intracellular second messenger of NO, was significantly depressed in aorta and in the mesenteric vascular bed in L-NAME-treated rats. Mesenteric resistance arteries studied on a wire-myograph exhibited similar external and lumen diameters, whereas media width and media/lumen ratio were greater (p < 0.01). Cross-sectional area of the media was similar. Active wall tension in response to norepinephrine tended to be greater in blood vessels from L-NAME-treated rats, while responses to vasopressin and endothelin-1 were unaltered. Sensitivity to norepinephrine was significantly enhanced in L-NAME-treated rats (p < 0.001), while that to endothelin-1 and arginine8 vasopressin was similar. In conclusion, administration of an NO synthase inhibitor produces hypertension, with exaggerated media/lumen ratio in resistance arteries and enhancement of response to norepinephrine, which together with decreased NO generation may contribute to elevation of blood pressure.

Effect of antihypertensive treatment on response to endothelin of resistance arteries of hypertensive rats

In other studies, we noted decreased reactivity of resistance arteries to endothelin-1 (ET-1) in hypertensive rats and humans. To determine whether these changes are reversible with antihypertensive treatment, we examined a hypertensive model exquisitely sensitive to angiotensin I-converting enzyme (ACE) inhibition, the two-kidney, one-clip (2K, 1C) Goldblatt hypertensive rat. Rats were allowed to become hypertensive for 6 weeks. At this point, either the clip was removed, or rats were treated with 5–10 mg/kg/day cilazapril, 100–150 mg/kg/ day metoprolol, or 25 mg/kg/day hydralazine, or were left untreated. After 8 weeks more, mesenteric resistance arteries were examined after mounting on a wire-myograph. Blood pressure (BP) and heart/body weight ratio were normalized in undipped and cilazapril-treated rats. Plasma renin activity (PRA) was normalized only in the undipped group. Media width, media/lumen ratio, and media cross-sectional area were similar in control normotensive, undipped, and cilazapril-treated rats and increased in untreated hypertensive, metoprolol, and hydralazine groups. Dose-response curves of resistance arteries to ET-1 were significantly blunted in untreated hypertensive rats (maximum active tension = 2.3 ± 0.3 vs 3.4 ± 0.1 N/m in control, p < 0.01), metoprolol-treated (2.2 ± 0.4 N/m), and hydralazine-treated rats (2.1 ± 0.5 N/m), and were normalized in cilazapril (3.3 ± 0.1 N/m) and undipped rats (3.2 ± 0.1 N/m). Similar effects were noted in response to norepinephrine (NE) and arginine vasopressin (AVP). We conclude that effective blood pressure (BP) reduction results in regression of the morphologic changes of resistance arteries of 2-K, 1 C hypertensive rats and normalizes blunted responses to endothelin-1 and other agents in these blood vessels. Whether these effects are only a result of BP reduction or of other phenomena remains to be established.

Endothelin subtype B receptor-mediated calcium and contractile responses in small arteries of hypertensive rats.

Endothelin-1 elicits vasoconstrictor responses through endothelin subtype A receptors, which are located on vascular smooth muscle cells, and vasodilator responses through endothelin subtype B receptors, which occur predominantly on endothelial cells. Endothelin subtype B receptors also may be present on vascular smooth muscle cells, in which they may mediate vasoconstriction. The aims of this study were to determine the presence of vascular smooth muscle vasoconstrictor endothelin subtype B receptors in mesenteric resistance arteries and to assess whether endothelin subtype B receptor-mediated responses differ between spontaneously hypertensive rats and Wistar-Kyoto rats. Contractile responses to the endothelin subtype B receptor agonist sarafotoxin S6c and endothelin-1 were measured simultaneously with [Ca2+]i in endothelium-denuded mesenteric resistance arteries from adult spontaneously hypertensive rats and Wistar-Kyoto rats. To simulate in vivo conditions matched as closely as possible to in vitro conditions, vessels were mounted in a vessel flow chamber in which intraluminal pressure was maintained at 60 mm Hg. Contraction was determined by video imaging to record lumen diameter, and [Ca2+]i was measured by the fura 2 method. Basal [Ca2+]i was significantly higher (P < .01) in hypertensive (170 +/- 4 nmol/L) compared with normotensive rats (134 +/- nmol/L). The endothelin subtype B receptor agonist sarafotoxin S6c increased [Ca2+]i in a concentration-dependent manner. Sarafotoxin S6c-induced [Ca2+]i and contractile responses were significantly lower in hypertensive compared with normotensive rats. These data demonstrate that endothelin subtype B receptors are present in vascular smooth muscle of small arteries and that endothelin subtype B receptor-mediated vasoconstriction occurs through intracellular calcium signaling pathways.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of antihypertensive treatment on vascular remodeling in essential hypertensive patients

Summary Resistance arteries may play a critical role in hypertension, and correcting their structural abnormalities may improve the clinical outcome of hypertensive patients. There have been several studies of the effects of antihypertensive treatment on the structure of resistance vessels in hypertension. These studies have yielded inconclusive results regarding the ability of individual drugs to induce regression of the changes occurring in blood vessels in hypertension, both in experimental models and in humans. This article reviews the results of studies of antihypertensive treatment on resistance vessel structure and function, and in particular those of a recent study in which the effects of treatment with the angiotensin-converting enzyme inhibitor cilazapril and the β-blocker atenolol on the structure and function of subcutaneous resistance arteries were evaluated in a double-blind randomized trial in patients with mild essential hypertension. In this study, patients were randomly assigned to receive either cilazapril or atenolol, and blood pressure was effectively controlled for I year. Treatment for 1 year with cilazapril resulted in a significant reduction in the media-to-lumen ratio of resistance arteries dissected from subcutaneous gluteal fat biopsy samples, although the ratio was still slightly but significantly larger than that of resistance arteries of normotensive controls. In arteries from patients treated with atenolol there was no significant change in media-to-lumen ratio with treatment. Contractile responses to several vasoconstrictors, particularly endothelin-1, which were blunted in hypertensive patients, were normalized in the cilazapril-treated patients, but were unchanged in those taking atenolol. These results suggest that in humans it is possible to correct in part the vascular remodeling present in hypertension. Treatment with drugs such as cilazapril and possibly other converting-enzyme inhibitors may provide better clinical outcomes in the treatment of hypertension by improving resistance vessel structure and function.