Endothelial factors and microvascular hypertensive disease.

This paper discusses the role of endothelial dysfunction in human hypertension, especially in relation to small resistance artery structure, as well as the effects of anti-hypertensive drugs on endothelial function of small arteries in human and experimental hypertension. A significant impairment of endothelial function was observed in human essential hypertension as well as in secondary forms of hypertension. No correlation was observed with vascular structure. In animal models of genetic hypertension there is substantial evidence for a beneficial effect of anti-hypertensive treatment with angiotensin converting enzyme (ACE) inhibitors, calcium entry blockers and angiotensin II receptor blockers on endothelial function in small resistance arteries. A significant improvement in endothelial dysfunction may be observed in hypertensive patients after prolonged treatment with ACE inhibitors (cilazapril, lisinopril), calcium entry blockers (nifedipine), and angiotensin II receptor blockers (losartan), while atenolol and hydrochlorotiazide proved to be ineffective in this regard despite similar blood pressure reductions. We conclude that: (i) the development of hypertension is usually associated with the presence of endothelial dysfunction in small resistance arteries of essential hypertensive patients; (ii) vascular structure does not seem to be the major determinant of endothelial function, at least in subcutaneous small resistance arteries; (iii) anti-hypertensive therapy with ACE inhibitors, angiotensin II receptor blockers and calcium entry blockers may improve endothelial function; (iv) a decrease in blood pressure seems to be necessary but not sufficient to obtain a beneficial effect on the endothelium in humans.

Effect of treatment on flow-dependent vasodilation of the brachial artery in essential hypertension.

off aim of our study was to evaluate the effect of antihypertensive treatment on flow-mediated dilation (FMD)of a large artery, a noninvasive estimate of endothelial function, in hypertensive patients. In 78 consecutive hypertensive patients (40%men; age range, 42 to 67 years) we measured by a high-resolution ultrasound system the changes of brachial artery diameter during reactive hyperemia and after sublingual glyceryl trinitrate (400 microg); brachial artery flow velocity was measured by pulsed Doppler. The results of 2 studies are reported. In the first study, this procedure was repeated in 58 patients after 6 and 12 months of treatment with a combination of antihypertensive drugs; in a second study, the FMD was assessed in 20 patients after 2 months of monotherapy with either nifedipine or hydrochlorothiazide. In the first study, FMD was significantly increased after treatment compared with baseline (from 3.1+/-3% at baseline to 6.5+/-4.5% at 6 months and to 8.12+/-4. 6% at 12 months; P<0.001 by ANOVA), concomitant with blood pressure reduction (from 162+/-24/102+/-13 mm Hg to 141+/-12/89+/-6 mm Hg and to 141+/-9/89+/-6 mm Hg; P<0.001 by ANOVA); significant changes of endothelium-independent dilation were also observed, but only after 12 months of treatment (from 14.2+/-4.8 at baseline to 15.5+/-4.7 at 6 months and 16.8+/-5.9% at 12 months; P=0.03 by ANOVA). In the second study, FMD was significantly increased during nifedipine treatment as compared with baseline (from 5+/-6.18% at baseline to 9. 45+/-3.94%, P<0.001), while it did not change in patients receiving hydrochlorothiazide (from 5.15+/-5.28% at baseline to 4.69+/-4.34%, NS). No significant changes of endothelium-independent dilation were observed with both drugs (from 17.10+/-2.4% to 18.14+/-3.76% and from 18.73+/-4.07% to 17.46+/-4.27% during nifedipine and hydrochlorothiazide, respectively, NS). Thus, in essential hypertensive patients an improvement of the impaired FMD of the brachial artery, evaluated by noninvasive ultrasound, may be observed after long-term, effective blood pressure reduction, suggesting a beneficial effect of antihypertensive treatment on endothelial function. It seems that beyond blood pressure control, a calcium antagonist may be more effective than a diuretic in this respect.

Reduction of cardiovascular structural changes by nifedipine GITS in essential hypertensive patients.

The aim of this study was to evaluate the effect of the calcium antagonist Nifedipine GITS in a double-blind, randomized comparison with the diuretic hydrochlorothiazide (HCTZ) on reduction of left ventricular (LV) mass and minimal vascular resistance in a group of essential hypertensives with left ventricular hypertrophy (LVH). The effects on blood pressure and on echocardiographic LV functional parameters were also analysed. After two months of randomized treatment with Nifedipine GITS or HCTZ, if diastolic blood pressure was > 90 mmHg, a combination of the two drugs was given and was continued for 24 weeks. M-mode, 2D-guided echocardiography was used to measure LV mass index (LVMI) according to the "Penn convention". Minimal vascular resistance was measured in the forearm, from arterial pressure and maximal blood flow, using a strain gauge plethysmography. All examinations were performed before and after 8 and 24 weeks of treatment. Changes in LVMI were analysed at 8 weeks and at 24 weeks in patients receiving monotherapy ("according to protocol" analysis), and also at the end of treatment in patients taking Nifedipine or HCTZ monotherapy or the combination of the two drugs ("intention to treat" analysis). Both Nifedipine and HCTZ significantly reduced systolic and diastolic blood pressure (p < 0.001), without any significant difference between the two drug treatments. Heart rate was not significantly modified by either treatment. A progressive decrease in LVMI was observed after 8 and 24 weeks of treatment with Nifedipine monotherapy (ANOVA, p = 0.03), while the decrease in LVMI during HCTZ treatment did not progress further at 24 weeks (ANOVA, p = 0.49). A significant reduction of minimal vascular resistance was observed in patients treated with Nifedipine GITS monotherapy (ANOVA, p = 0.001), but not in the HCTZ group (ANOVA, p = 0.06). Comparison of changes of forearm minimal vascular resistance, considering baseline values, could demonstrate a greater effect during Nifedipine monotherapy as compared to HCTZ monotherapy. In conclusion, in a group of hypertensive patients with LVH, treatment for 24 weeks with Nifedipine GITS alone or in combination with HCTZ induced a significant reduction in LVMI and of forearm vascular structural changes, as evaluated by minimal vascular resistance. The decrease of minimal vascular resistance was significantly greater in patients treated with Nifedipine monotherapy, as compared to those given HCTZ.

Effects of losartan and enalapril on small artery structure in hypertensive rats.

We evaluated the effects on cardiovascular structure of the angiotensin-converting enzyme (ACE) inhibitor enalapril and of the angiotensin II receptor blocker losartan, administered either at hypotensive or nonhypotensive dosage in spontaneously hypertensive rats (SHR). SHR were treated from ages 4 to 12 weeks with low-dose (1 mg x kg(-1) x d(-1)) enalapril, low-dose (0.5 mg x kg(-1) x d(-1)) losartan, high-dose (25 mg x kg(-1) x d(-1)) enalapril, or high-dose (15 mg x kg(-1) x d(-1)) losartan. Untreated WKY and SHR were also studied. Rats were killed at 13 weeks of age, and the heart was weighed. Mesenteric small arteries were dissected and mounted on a micromyograph for determination of media thickness and lumen diameter. In fixed arteries, cell volume, number of cells per segment length, and number of cell layers were measured using the unbiased "disector" method. Systolic blood pressure was significantly reduced by the high doses of both drugs, but the hypotensive effect was greater with enalapril than with losartan (P<0.05). In the high-dose enalapril and losartan groups, there were similar reductions in relative left ventricular mass, media/lumen ratio, and number of cell layers of resistance arteries; however, there were no differences in the cell volume or number of cells per segment length of resistance arteries. Low-dose enalapril did not affect systolic blood pressure or any of the structural parameters. The results show that the hypotensive effects of both losartan and enalapril were associated with outward remodeling of resistance arteries at the cellular level. The effect of losartan on resistance artery structure was equal to that of enalapril, despite the smaller hypotensive effect.

Effects of hypotensive and non-hypotensive doses of manidipine on structure, responses to endothelin-1 and ICAM-1 production in mesenteric small resistance arteries of spontaneously hypertensive rats.

OBJECTIVE: We have evaluated the effects of a new calcium channel blocker, manidipine, given at both high, hypotensive and low, non-hypotensive doses, on vascular morphology, response to endothelin-1 and ICAM-1 production in mesenteric small resistance arteries of spontaneously hypertensive rats (SHR). METHODS: Ten SHR were treated with manidipine 3 mg/kg per day (high dose) and 10 with manidipine 0.3 mg/kg/per day (low dose). The drug was administered by gavage from the 4th to 12th weeks of age. Eighteen Wistar-Kyoto (WKY) rats and 18 SHR were kept untreated as controls. Rats were killed at 13 weeks. Mesenteric small arteries were dissected and mounted on a micromyograph for determination of indexes of vascular structure (media thickness, wall thickness, media/lumen ratio). RESULTS: Systolic blood pressure was significantly reduced by the high dose of the drug, while no effect was observed with low-dose manidipine. A reduction in the media/lumen ratio was observed only in SHR treated with high-dose manidipine. The response to endothelin-1 in untreated SHR was significantly lower in comparison with WKY; a significant reduction was observed in SHR treated with high-dose manidipine. ICAM-1 vascular concentrations were higher in untreated SHR than in WKY controls. Both high- and low-dose manidipine reduced ICAM-1 concentrations toward normalization. CONCLUSIONS: Manidipine at high, hypotensive, but not at low, non-hypotensive doses has been proven to reduce structural alterations in mesenteric small resistance arteries, and to normalize vascular responses to endothelin-1. In addition, manidipine, at both low and high doses, may reduce ICAM-1 vascular production, thus suggesting a possible anti-atherogenic effect.

Effects of low and high doses of fosinopril on the structure and function of resistance arteries.

It has been suggested that angiotensin-converting enzyme inhibitors may induce a significant regression of cardiovascular hypertrophy not only through blood pressure reduction but also as a possible consequence of growth factor inhibition. The aim of this study was to evaluate the effects of the angiotensin-converting enzyme inhibitor fosinopril, given either at a hypotensive high dose or a nonhypotensive low dose, on structural and functional alterations of mesenteric resistance arteries and on cardiac mass in spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats. Fosinopril was administered in the drinking water from 6 to 12 weeks of age. Rats were killed at 12 weeks, and the ratio of heart weight to body weight was measured. Mesenteric arterioles were dissected and mounted on a micromyograph (Mulvany's technique). Vascular morphology (media-lumen ratio, media thickness) and endothelial function (response to acetylcholine) were then assessed. During the 6 weeks of treatment, systolic pressure in SHR treated with high-dose fosinopril was significantly lower compared with that in untreated SHR, whereas no difference was observed with low-dose fosinopril. In SHR treated with both high-dose and low-dose fosinopril, a statistically significant reduction of vascular structural alterations, in terms of both media-lumen ratio and media thickness, was observed. The ratio of heart weight to body weight was reduced only in SHR treated with high-dose fosinopril. An improvement in the endothelium-dependent relaxation to acetylcholine was observed in SHR treated with high-dose fosinopril compared with untreated SHR, whereas in SHR treated with low-dose fosinopril no improvement in endothelial function was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Delayed development of hypertension after short-term nitrendipine treatment.

In this study we evaluated the delayed effects of a calcium entry blocker on blood pressure and on vascular structural and functional alterations in mesenteric resistance arteries of spontaneously hypertensive rats (SHR). The calcium entry blocker nitrendipine was administered (30 mg/kg per day) according to three different schedules: in one group of SHR from 4 to 8 weeks of age (n = 12), in a second group from 8 to 12 weeks of age (n = 12), and in a third group from 4 to 12 weeks of age (n = 12). Twelve untreated SHR and 12 untreated Wistar-Kyoto rats served as controls. Half the animals of each group were killed at 13 weeks, and the remaining were killed at 38 weeks. After death, relative left ventricular mass was calculated. Vascular morphology and function (responses to norepinephrine and acetylcholine) in mesenteric small arteries were then assessed using a micromyographic technique. Nitrendipine treatment delayed the development of hypertension and determined the regression of structural alterations of mesenteric resistance arteries in SHR. These favorable effects were maintained for several weeks after treatment withdrawal, provided that treatment was started at 4 weeks of age. Considering the functional alterations of mesenteric arteries in SHR (responses to norepinephrine and acetylcholine), nitrendipine treatment determined an improvement of both these dysfunctions as long as reductions of the media-to-lumen ratio and blood pressure, respectively, were maintained.

Improved left ventricular systolic and diastolic function after regression of cardiac hypertrophy, treatment withdrawal, and redevelopment of hypertension.

The aim of this study was to differentiate the effects of changes of arterial pressure from those of regression of left ventricular hypertrophy (LVH) on systolic and diastolic function at rest and during a rapid increase in afterload, induced by handgrip and cold pressor tests. An additional purpose was to assess the hemodynamic mechanisms responsible for the increase in arterial pressure after treatment withdrawal. Therefore, we evaluated the cardiac anatomy and function (TM echo) at rest and during handgrip and cold pressor tests in 23 hypertensive patients, before therapy and 20-30 days after withdrawal of treatment, which had lasted 6-12 months, when left ventricular mass index (LVMI) was significantly reduced (from 140 +/- 44 to 113 +/- 13 g/m2, p less than 0.001) but the arterial pressure had increased again to pretreatment values (166 +/- 19/105 +/- 7 mm Hg before treatment vs. 162 +/- 15/100 +/- 12 mm Hg). The LVMI reduction was due to a decrease in LV wall thickness, whereas the LV internal dimensions did not change. Systolic function was evaluated by the relationship between LV end-systolic stress (ESS) and fractional shortening (FS): at rest as well as at the peak of handgrip and cold pressor tests, highly significant negative correlations between ESS and FS (range of -0.71 to -0.96) were found. Considering each point of relation between ESS and FS in hypertensive patients, in comparison with 95% prediction limits of the correlation obtained in normal subjects, a "supernormal" systolic function at rest was observed in 10 of 23 patients and a reduced systolic function was not present after treatment withdrawal and redevelopment of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Regression of cardiovascular structural changes after long-term antihypertensive treatment with the calcium antagonist nitrendipine.

Regression of cardiovascular structural changes is a main goal of antihypertensive treatment. Nitrendipine is a calcium antagonist of the dihydropiridine group that may be given once daily. In different animal models of experimental hypertension, nitrendipine was shown to reduce blood pressure (BP) and left ventricular (LV) mass, to prevent early mortality, and to limit the development of vascular lesions. It has also been proposed that nitrendipine is able to preserve tissue integrity and increase life span in malignant hypertension, because it prevents a deleterious calcium overload in the heart and arterial vessels. In humans, the effect of nitrendipine on LV mass has been evaluated in a limited number of studies with conflicting results. It has been shown that nitrendipine is able to increase the compliance of large arteries; its effect on vascular structural changes has never been reported. In this study, nitrendipine (20 mg o.d.) was given to 10 hypertensive patients. BP, (ambulatory BP monitoring) heart rate (HR), LV mass and function (TM echo, 2D guided), forearm minimal vascular resistance (min VR = BP/max blood flow--venous occlusion plethysmography--taken as an index of vascular STC), plasma renin activity (PRA), plasma catecholamines (NE and E), and aldosterone (ALD) were measured during placebo, after 2 and 6 months of treatment. BP was significantly reduced and HR was slightly increased. After 6 months of treatment a significant reduction of LV mass index (p less than 0.001) and of min VR (p less than 0.002) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)