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M P Schlaich

Publications and source records attributed to M P Schlaich.

At least 19 recordsLinked to original sources
PubMed2006

Impaired basal NO activity in patients with glomerular disease and the influence of oxidative stress.

Endothelial dysfunction has been found to be linked to and predictive of cardiovascular events. Whether endothelial function of the renal vasculature is impaired in patients with chronic glomerular disease and whether oxidative stress is of importance in this setting has not yet been determined. In this study, endothelial function of the renal vasculature was investigated in 25 patients with chronic glomerular disease and 50 control subjects matched for age and blood pressure. Renal plasma flow (RPF) and glomerular filtration rate were measured by constant infusion input clearance technique at baseline and following infusions of the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 4.25 mg/kg), the substrate of NOS L-arginine (100 mg/kg) and the antioxidant vitamin C (3 g co-infused with L-arginine 100 mg/kg). At baseline, RPF was similar in the two groups. The reduction in RPF in response to L-NMMA was less pronounced in patients with chronic glomerular disease compared to control subjects (-4.6+/-12 vs -9.8+/-9%; P=0.040), indicating reduced basal nitric oxide (NO) activity in chronic glomerular disease. Co-infusion of the antioxidant vitamin C on top of L-arginine induced a more pronounced increase in RPF in patients with chronic glomerular disease than in control subjects (21.7+/-17 vs 10.9+/-22%; P=0.036). Our findings suggest that basal NO activity of the renal vasculature is reduced in patients with chronic glomerular disease compared to age- and blood pressure-matched control subjects. This might be in part related to increased oxidative stress.

Adult↗
PubMed2001

Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks.

OBJECTIVES: We investigated whether improvement of endothelial dysfunction in hypercholesterolemia can be achieved with short-term lipid-lowering therapy. BACKGROUND: Impaired endothelium-dependent vasodilation plays a pivotal role in the pathogenesis of atherosclerosis and acute coronary syndromes. METHODS: In a randomized, double-blind, placebo-controlled trial, we studied 37 patients (52 +/- 11 yrs) with low density lipoprotein cholesterol > or = 160 mg/dl (196 +/- 44 mg/dl) randomly assigned to either cerivastatin (0.4 mg/d) or placebo. Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh 12, 48 microg/min) and endothelium-independent vasodilation by intra-arterial infusion of nitroprusside (3.2, 12.8 microg/min). RESULTS: Low density lipoprotein cholesterol decreased after two weeks of treatment (cerivastatin -33 +/- 4% vs. placebo + 2 +/- 4%, x +/- SEM, p < 0.001). Endothelium-dependent vasodilation improved after two weeks of therapy with cerivastatin compared with baseline (ACh 12 microg/min: + 22.3 +/- 5.2 vs. + 11.2 +/- 1.9 ml/min/100 ml, p < 0.01; ACh 48 microg/min: +31.2 +/- 6.3 vs. +19.1 +/- 3.1 ml/min/100 ml, p < 0.05). In contrast, changes in forearm blood flow to ACh were similar before and after therapy in the placebo group (ACh 12 microg/min: + 12.9 +/- 3.6 vs. + 9.0 +/- 1.9 ml/min/100 ml, NS; ACh 48 microg/min: +20.7 +/- 3.7 vs. 19.4 +/- 2.9 ml/min/100 ml, NS). Endothelium-dependent vasodilation improved in comparison with placebo (ACh 48 microg/min: +203 +/- 85% [cerivastatin] vs. -26 +/- 71% [placebo], p < 0.05). This improvement in endothelium-dependent vasodilation was no longer observed when the nitric oxide-synthase inhibitor N(G)-monomethyl-L-arginine was coinfused (ACh 48 microg/min + N(G)-monomethyl-L-arginine 4 micromol/min -48 +/- 85% [cerivastatin]). CONCLUSIONS: Short-term lipid-lowering therapy with cerivastatin can improve endothelial function and NO bioavailability after two weeks in patients with hypercholesterolemia.

Adult↗
PubMed2001

Impaired sodium excretion during mental stress in mild essential hypertension.

In hypertensive rats, environmental stress causes sodium retention by an exaggerated increase in renal sympathetic nerve activity, which is modulated by angiotensin II. We tested whether similar effects can be observed in humans. In 66 normotensive subjects (half of them with a family history of hypertension) and 36 subjects with mild essential hypertension, urinary sodium excretion and renal hemodynamics were examined at rest and during mental stress treated either with placebo or ACE inhibition in a double-blind, randomized, cross-over design. Despite a marked increase in glomerular filtration rate in response to mental stress (Deltaglomerular filtration rate, 4.3+/-7.7 mL/min in normotensives without versus 5.6+/-8.4 mL/min in normotensives with a family history versus 10.1+/-5.7 mL/min in patients with mild essential hypertension; P:<0.002), the increase in urinary sodium excretion was blunted in patients with mild essential hypertension (Deltaurinary sodium excretion, 0.12+/-0.17 mmol/min versus 0.10+/-0.14 mmol/min versus 0.05+/-0.14 mmol/min; P:<0.05). ACE inhibition corrected the natriuretic response to mental stress in subjects with mild essential hypertension (Deltaurinary sodium excretion, 0.05+/-0.14 mmol/min with placebo versus 0.13+/-0.19 mmol/min with ACE inhibition; P:<0.01); thus, after ACE inhibition, urinary sodium excretion increased similarly in all 3 groups. In conclusion, impaired sodium excretion occurs during mental stress in human essential hypertension but not in subjects with positive family history of hypertension. This abnormality in sodium handling during activation of the sympathetic nervous system appears to be mediated by angiotensin II.

Adolescent↗
PubMed2000

Prospective analysis of the value of 24-hour ambulatory blood pressure on renal function after kidney transplantation.

BACKGROUND: No prospective study has been performed to determine the prognostic value of 24-hr ambulatory blood pressure (24-hr ABP) versus casual blood pressure (CBP) in patients after kidney transplantation. We have addressed this issue by analyzing renal graft function in patients for the first 5 years after transplantation. METHODS: The 24-hr ABP (SpaceLabs 90207) was monitored 6 and 18 months after transplantation in 46 renal transplant recipients without any acute episodes of rejection. Combined study endpoints were death of patients, need for dialysis, second transplantation, and doubling of serum creatinine. RESULTS: Six months after transplantation systolic and diastolic 24-hr ABP correlated with serum creatinine (r=0.41, P=0.005 and r=0.37, P<0.01, respectively) although CBP did not. Divided into tertiles according to average 24-hr ABP (lower tertile: < or =91 mmHg; middle tertile: 92-97 mmHg; upper tertile: > or =98 mmHg) serum creatinine significantly differed between the three groups (1.26 +/- 0.38 vs. 1.32 +/- 0.25 vs. 1.65 +/- 0.39 mg/dl, respectively; analysis of variance, P< 0.01). Confounding factors of renal function such as age, body weight, cold and warm ischemic time, cytomegaly virus status, methylprednisone and cyclosporine dosages, cyclosporine concentrations, as well as concomitant antihypertensive medication did not differ among the three groups. In the long-term follow-up (5 years), combined endpoints were reached in 3 of 15 of the lower tertile group, in 3 of 15 of the median tertile group, and in 8 of 16 of the upper tertile group (log-rank test, P<0.01). No relation to long-term out come was found when patients were stratified according to their CBP. CONCLUSION: In our small but homogenous study cohort 24-hr ABP was more closely related to renal function in patients after transplantation than CBP suggesting that 24-hr ABP is superior for evaluation of hypertension-related renal graft dysfunction.

Adult↗
PubMed2000

Impact of aldosterone on left ventricular structure and function in young normotensive and mildly hypertensive subjects.

Left ventricular (LV) hypertrophy is an independent risk factor for cardiovascular morbidity and mortality. Experimental data revealed that elevated circulating aldosterone is associated with increased collagen accumulation resulting in myocardial fibrosis. To analyze whether aldosterone is also associated with cardiac structural and functional changes in humans, we examined the effects of aldosterone on LV structure and function before and after suppression of aldosterone by increasing oral salt intake. The study group comprised 26 normotensive male white healthy control subjects (age 26 +/- 3 years) and 31 male white subjects (age 25 +/- 3 years) with mild essential hypertension (World Health Organization stages I to II). Two-dimensional-guided M-mode echocardiography and 24-hour ambulatory blood pressure (BP) monitoring was performed in each subject. Simultaneously, we measured 24-hour urinary sodium excretion, 24-hour urinary aldosterone, and serum aldosterone concentration at baseline and after increasing oral salt intake to suppress aldosterone secretion. In all subjects LV mass correlated with body mass index (r = 0.42, p <0.001) and both 24-hour ambulatory systolic (r = 0.28, p <0.05) and diastolic (r = 0.25, p <0.05) BP. Changes in urinary sodium excretion correlated inversely with changes in serum aldosterone concentration (r = -0.28; p <0.05). Urinary aldosterone concentration after salt loading decreased in normotensive (10.98 vs 7.44 microg/24 hours; p <0.02) but not in hypertensive (9.34 vs 10.51 microg/24 hours; p = NS) subjects. Serum and urinary aldosterone levels at baseline were not related to LV structure or function. In contrast, after increasing oral salt intake, urinary aldosterone concentration was related to LV mass (r = 0.43; p <0.01) and impaired midwall fractional fiber shortening (r = -0.33; p <0.02) in all subjects, independent of 24-hour ambulatory BP. Subgroup analysis revealed that this was significant only in hypertensive (r = 0.46; p <0.01 and r = -0.44; p <0.02, respectively) but not in normotensive (r = 0.28 and -0.16; p = NS for both, respectively) subjects. Consistently, the greater serum aldosterone remained after increasing oral salt intake, the greater was LV mass (r = 0.35; p <0.01). The latter was found in hypertensive subjects (r = 0.44; p <0.02), independent of 24-hour ambulatory BP, but not in normotensive subjects (r = 0.025; p = NS). Inadequate suppression of aldosterone in response to an increase in oral salt intake is related to LV structural and functional changes in hypertensive subjects. Thus, our results support experimental data indicating that aldosterone affects LV structure and function in humans and that this effect is BP independent.

Adult↗
PubMed2000

Mildly elevated homocysteine concentrations impair endothelium dependent vasodilation in hypercholesterolemic patients.

BACKGROUND: Elevated low density lipoproteins (LDL)-cholesterol and homocysteine levels have both been found to be associated with an increased risk for atherosclerotic vascular disease. To assess the effects of elevated homocysteine levels in hypercholesterolemic subjects on endothelial function, we examined basal and stimulated nitric oxide (NO) mediated vasodilation in the forearm vascular bed in hypercholesterolemic subjects with normal or elevated homocysteine levels. METHODS: Twenty-seven white subjects (age: 48 +/- 12 years) with elevated LDL-cholesterol (> or = 160 mg/dl) were divided into two groups with normal (n = 11) or mildly elevated (n = 16) homocysteine plasma concentration. We used strain gauge plethysmography to measure changes in forearm blood flow in response to intraarterial administration of increasing doses of acetylcholine (3, 12, 24, 48 microg/min), sodium nitroprusside (200, 800, 3200 ng/min), and N-monomethyl L-arginine (L-NMMA) (1, 2, 4 micromol/min). Total homocysteine plasma concentrations were determined by high performance liquid chromatography fluorimetry. RESULTS: Endothelium independent vascular relaxation tested by i.a. sodium nitroprusside and changes in forearm blood flow after i.a. L-NMMA indicating basal production and release of nitric oxide were similar between the two groups with normal or elevated homocysteine levels. In contrast, endothelium dependent vasodilation as assessed by the administration of i.a. acetylcholine differed between the groups with normal or elevated homocysteine levels for all doses tested (MANOVA P < 0.01: ACH 48 microg/min: 480 +/- 237% with normal vs 234 +/- 130% with elevated homocysteine; P < 0.002). This was significant even after taking possible covariates such as age, blood pressure, body mass index, LDL-, high density lipoproteins (HDL)-cholesterol, and trigylcerides into account (MANOVA P < 0.02). CONCLUSIONS: From our study we conclude that homocysteine impairs endothelium dependent vasodilation in subjects with elevated LDL-cholesterol levels. The most intriguing finding is that even mildly elevated homocysteine levels seem to be of crucial importance for deterioration of endothelial function, especially if other cardiovascular risk factors such as hypercholesterolemia preexist.

Adult↗
PubMed2000

Effects of oral contraceptives on vascular endothelium in premenopausal women.

OBJECTIVE: Premenopausal women are protected against atherosclerosis by high plasma estrogen levels, which have been suggested to augment endothelial nitric oxide synthesis and to improve endothelial function. In contrast, premenopausal use of oral contraceptives is associated with an increased cardiovascular risk. We investigated the influence of oral contraception on endothelial function. STUDY DESIGN: Sixteen healthy premenopausal women with a mean age (+/-SD) of 27 +/- 3 years, 8 of whom used oral contraceptives and 8 of whom did not, were examined in a case-control study. Forearm plethysmography was used to measure changes of forearm blood flow in response to intra-arterial infusion of increasing doses of acetylcholine, sodium nitroprusside, and N (G)-monomethyl-L -arginine. RESULTS: Endothelium-dependent vasodilatation (change from baseline after acetylcholine 48 microg/min) was similar between women with (828% +/- 137%) and without oral contraception (701% +/- 114%; P not significant), as was endothelium-independent vasodilatation (change from baseline after sodium nitroprusside 3200 ng/min, 271% +/- 38% vs 289% +/- 23%; P not significant). In contrast, inhibition of nitric oxide synthase with N (G)-monomethyl-L -arginine induced a significantly more marked decrease in blood flow among women with oral contraception than among those without at all dosages (change from baseline after 4-micromol/min N (G)-monomethyl-L -arginine, -26% +/- 3% vs -14% +/- 5%; P =.009 by analysis of variance). CONCLUSION: Stimulated nitric oxide bioavailability remained unaffected in a group of premenopausal women receiving oral contraceptives. In contrast, basal nitric oxide production and release appeared to be enhanced by oral contraceptive use.

Acetylcholine↗
PubMed2000

Plasma soluble adhesion molecules and endothelium-dependent vasodilation in early human atherosclerosis.

Levels of soluble cellular adhesion molecules are increased in patients with atherosclerosis, and have been found to predict coronary heart disease. Therefore these molecules have been suggested to represent laboratory markers for inflammation and activation of endothelial cells. Impaired endothelium-dependent vasodilation has been demonstrated to be an early marker of atherosclerosis. We hypothesized that soluble adhesion molecules are related to impaired endothelium-dependent vasodilation and may serve as an early marker of atherosclerosis. Patients (n=52) with moderate and uncomplicated hypercholesterolaemia [low-density lipoprotein (LDL)-cholesterol 4.89+/-1.26 mmol/l] were compared with healthy controls (n=43; LDL-cholesterol 2.44+/-0.79 mmol/l). Endothelium-dependent vasodilation of the forearm vasculature was assessed by intra-arterial infusion of acetylcholine (12 and 48 microg/min). Forearm blood flow was measured by venous occlusion plethysmography. Plasma concentrations of the soluble forms of ICAM-1 (intercellular cell adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1) and E-selectin were measured by ELISA. Hypercholesterolaemic patients had impaired endothelium-dependent vasodilation in comparison with healthy controls (forearm blood flow after 48 microg/min acetylcholine: 21.3+/-10.6 and 30.4+/-16.3 ml. min(-1).100 ml(-1) respectively; P=0.002). Plasma concentrations of soluble adhesion molecules were not different between hypercholesterolaemic patients and controls (ICAM-1, 196+/-56 and 180+/-38 ng/ml respectively; VCAM-1, 431+/-137 and 405+/-65 ng/ml respectively; E-selectin, 39+/-17 and 37+/-12 ng/ml respectively). Moreover, levels of soluble adhesion molecules were not correlated with endothelium-dependent vasodilation. Thus, in hypercholesterolaemic patients without clinical atherosclerosis, levels of soluble adhesion molecules were not elevated in comparison with healthy controls. In addition, these markers of endothelial inflammation were not related to impaired endothelium-dependent vasodilation. Our data indicate that measurement of levels of soluble adhesion molecules cannot replace assessment of endothelium-dependent vasodilation in detection of early hypercholesterolaemic atherosclerosis.

Adolescent↗
PubMed2000

Is l-arginine infusion an adequate tool to assess endothelium-dependent vasodilation of the human renal vasculature?

Systemic administration of L-arginine alters renal haemodynamics in humans. We examined whether L-arginine-induced vasodilation of the renal vasculature is related to an increased production and release of NO by comparing the effects of L- and D-arginine on renal endothelium-dependent vasodilation. In a double-blind randomized cross-over study including 20 young, healthy male white subjects (age 26+/-2 years), we determined the effects of intravenous administration of L-arginine or its enantiomer D-arginine, at doses of 100 mg/kg body weight for 30 min or 500 mg/kg for 30 min, on renal haemodynamics. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by a constant-infusion input-clearance technique (using p-aminohippuric acid and inulin respectively). In addition, changes in blood pressure, heart rate, urinary sodium excretion (U(Na)) and urinary cGMP were measured. HPLC was used to determine L- and D-arginine concentrations. Intravenous infusion of L-arginine at 100 mg/kg for 30 min increased RPF from 641+/-87 to 677+/-98 ml/min (P=0.019), whereas infusion of D-arginine did not (from 642+/-74 to 657+/-86 ml/min; not significant). The change in RPF was more marked during the infusion of L-arginine than during the infusion of D-arginine (+36+/-61 versus +16+/-57 ml/min; P=0.037). Infusion of both L- and D-arginine at doses of 500 mg/kg for 30 min increased RPF from baseline [from 641+/-87 to 762+/-133 ml/min (P<0.001) and from 642+/-74 to 713+/-120 ml/min (P=0.004) respectively], but the change in RPF again was greater in response to L-arginine infusion than to infusion with D-arginine (+121+/-97 versus +71+/-94 ml/min; P=0.018). In accordance, changes in renal vascular resistance (RVR) were higher in response to L-arginine compared with D-arginine for both doses (P<0.05 and P<0.001 respectively). U(Na) increased only with L-arginine (change in U(Na), +0.33+/-0.26 mmol/min; P<0.01) but not with D-arginine (change in U(Na), +0.11+/-0.17 mmol/min; not significant). The change in U(Na) was more pronounced during infusion of L-arginine compared with infusion of D-arginine (P=0.023). In parallel, urinary excretion of cGMP only increased in response to L-arginine (+676+/-272 pmol/l; P=0.038) and not during D-arginine infusion (+185+/-153 pmol/l; not significant). L-Arginine-induced changes in RPF, RVR, U(Na) and cGMP excretion differed significantly from those induced by D-arginine. Thus although no direct measurements of NO synthesis were performed, putative markers of NO synthesis suggest that the renal vasodilatory response to L-arginine, at least in part, was due to increased production and release of NO. The dose of L-arginine at 100 mg/kg for 30 min emerged as the most suitable, because of the absence of systemic haemodynamic changes. The effects of infusion of L-arginine at 500 mg/kg for 30 min on renal endothelium-dependent vasodilation need to be corrected for the effects of D-arginine before conclusions can be drawn.

Adult↗
PubMed1999

Relation between the renin-angiotensin-aldosterone system and left ventricular structure and function in young normotensive and mildly hypertensive subjects.

BACKGROUND: High angiotensin II levels in relation to the corresponding urinary sodium excretion have been found to modulate left ventricular (LV) structure in middle-aged hypertensive patients. To analyze whether such a relation between the renin-angiotensin-aldosterone system and left ventricular structure is already present in young individuals, we examined the changes of angiotensin II and aldosterone in response to increased salt intake and their relations to LV structure and function. METHODS: In 119 young (aged 26 +/- 3 years) patients with normal or mildly elevated blood pressure, we determined LV structure and function (2-dimensional guided M-mode echocardiography and pulse wave Doppler sonography) and 24-hour ambulatory blood pressure (SpaceLabs 90207). Dietary sodium intake as estimated by 24-hour urinary sodium excretion, plasma renin activity, angiotensin II, and aldosterone concentrations were measured first on a normal diet and second at high salt intake to determine the extent of the resulting suppression of the renin-angiotensin-aldosterone system. RESULTS: Body mass index (r = 0.43, P <.001) and both systolic (r = 0.24, P <. 01) and diastolic (r = 0.19, P <.05) 24-hour ambulatory blood pressure correlated with LV mass. No straightforward relation was found between LV structure and baseline angiotensin II or aldosterone concentration. The increase of sodium excretion at high salt intake was related to a physiologically expected decrease of angiotensin II and aldosterone levels in normotensive (r = -0.36, P <.01 and r = -0.32; P =.016, respectively) but not in hypertensive patients. Changes in angiotensin II or aldosterone concentration were not related to LV structure in either hypertensive or normotensive young individuals. However, changes in aldosterone secretion correlated with diastolic filling parameters in hypertensive patients (velocity-time integrals of the A over E wave: r = 0.32, P =.03; atrial contribution of LV filling: r = 0.33, P =. 025) but not in normotensive individuals. CONCLUSION: In contrast to middle-aged hypertensive patients, neither angiotensin II, aldosterone, nor their suppression in response to high salt intake were related to LV structure in young hypertensive patients. However, inadequate suppression of aldosterone after salt intake was associated with diastolic filling abnormalities in our young hypertensive patients, which may represent early changes in hypertensive heart disease and precede potential structural alterations.

Adult↗
PubMed1999

825T allele of the G-protein beta3 subunit gene (GNB3) is associated with impaired left ventricular diastolic filling in essential hypertension.

OBJECTIVE: Recently, a novel C825T polymorphism in the gene (GNB3) encoding for the G-protein beta3 subunit was identified. The 825T allele is associated with the generation of a novel splice variant, enhanced intracellular signal transduction, and arterial hypertension. In this study, we investigated the impact of the 825T allele on left ventricular structure and function in mild to moderate essential hypertensive subjects. METHODS: In 34 white patients with established mild to moderate essential hypertension (World Health Organization stage I or II, mean age 52 +/- 9 years) genotype analysis of GNB3 C825T polymorphism, insertion/deletion polymorphism of the ACE gene and 1166 A/C polymorphism of the AT1 receptor gene was performed. In each patient, 24 h ambulatory blood pressure measurement (SpaceLabs 90207) and two-dimensional guided M-mode echocardiography combined with Doppler sonography were performed. RESULTS: In our homogenous study group, the GNB3 825T allele was not associated with casual and 24 h ambulatory blood pressure (CC versus TC/TT: 144 +/- 13/92 +/- 8 versus 151 +/- 14/97 +/- 7 and 143 +/- 11/92 +/- 7 versus 150 +/- 16/ 96 +/- 9 mmHg, respectively) or parameters of left ventricular structure (relative wall thickness: CC versus TC/TT, 0.48 +/- 0.1 versus 0.46 +/- 0.1; left ventricular mass: CC versus TC/TT, 281 +/- 65 versus 299 +/- 80 g). However, transmitral flow variables reflecting left ventricular diastolic filling were impaired in patients expressing the TC/TT genotype (ratio of peak late (A) to early (E) velocities: CC versus TC/TT, 0.95 +/- 0.24 versus 1.2 +/- 0.26, P< 0.02; velocity time integrals A/E: CC versus TC/TT, 0.57 +/- 0.16 versus 0.76 +/- 0.23, P< 0.01) while all co-variables such as age, body mass index, ambulatory blood pressure, heart rate and end-diastolic volume were similar between the two groups. If patients were stratified according to the I/D polymorphism of the ACE gene and the A1166C polymorphism of the AT1 receptor gene, no differences in blood pressure, left ventricular structure or systolic and diastolic function of the left ventricle were found between different genotypes. CONCLUSION: The GNB3 825T allele was associated with impaired left ventricular diastolic filling in hypertensive subjects in this study. Since alterations in left ventricular filling have been identified as an early marker of hypertensive heart disease, the GNB3 C825T polymorphism may influence cardiac adaptation to increased afterload.

Adult↗
PubMed1999

Low-density lipoprotein-cholesterol determines vascular responsiveness to angiotensin II in normocholesterolaemic humans.

OBJECTIVE: Both LDL-cholesterol and angiotensin II have been shown to increase the risk for and severity of cardiovascular disease. In hypercholesterolaemia, experimental studies have demonstrated an increased angiotensin type 1 (AT1) receptor expression on vascular smooth muscle cells and an increased vascular responsiveness to vasopressors has been documented in humans. We investigated in a normocholesterolaemic young population whether vascular responsiveness to angiotensin II (Ang II) infusion depends on LDL-cholesterol serum levels in the systemic and renal circulation. DESIGN AND METHODS: Changes in systolic and diastolic blood pressure (deltaBP) to Ang II infusion (0.5 and 3.0 ng/kg per min) were investigated in 103 normocholesterolaemic (LDL-cholesterol < 160 mg/dl) young white men (26+/-3 years; 24 h BP: 128+/-10/75+/-7 mmHg) without cardiovascular disease. According to their LDL-cholesterol levels, participants were classified into tertiles (lower tertile < 85 mg/dl, middle tertile 85-111 mg/dl, upper tertile > 111 mg/dl). RESULTS: Blood pressure (BP) responses to Ang II infusion 3.0 ng/kg per min were enhanced in the group with the highest LDL-cholesterol levels (delta systolic BP: +12.8+/-6.7, +13.2+/-8.6, +17.9+/-9.6, P < 0.02; delta diastolic BP: +11.1+/-5.8, +11.5+/-6.5, +16.5+/-8.3, P < 0.01, for the lower, middle and upper tertiles, respectively). This holds true when baseline BP was taken into account as a confounding covariable (P < 0.015). BP responses to Ang II infusion were related to LDL-cholesterol serum levels (delta systolic BP: r = 0.26, P = 0.01; delta diastolic BP: r = 0.32, P = 0.001). In multiple stepwise regression analysis, LDL-cholesterol emerged as the strongest determinant of vascular responsiveness to Ang II (delta systolic BP: P < 0.01; delta diastolic BP: P < 0.001). CONCLUSION: In young male subjects, responsiveness to Ang II is determined by the LDL-cholesterol serum level even in the normal range of LDL-cholesterol, thereby potentially contributing to the cardiovascular risk of LDL-cholesterol even within the so-called normal range.

Adult↗
PubMed1999

Angiotensin II stimulates left ventricular hypertrophy in hypertensive patients independently of blood pressure.

Angiotensin II (AII) is known to be a growth stimulating factor for myocardial cells. We examined whether an exaggerated responsiveness to AII might aggravate left ventricular (LV) hypertrophy in human essential hypertension. To determine the responsiveness to AII in humans, we examined changes in mean arterial pressure (MAP), renal blood flow (RBF), and glomerular filtration rate (GFR) (steady state input clearance technique with para-aminohippurate and inulin, respectively) and aldosterone secretion to AII infusions (0.5 and 3.0 ng/kg/min) in 71 normotensive male and 48 hypertensive male subjects (age: 26 +/- 3 years; 24-h ambulatory blood pressure: 121 +/- 5/71 +/- 4 mmHg v 138 +/- 7/82 +/- 7 mmHg, P < .001). In addition, each patient underwent two-dimensional guided M-mode echocardiography at rest to assess cardiac structure and function. When given AII 3.0, a greater increase of MAP (13 +/- 7 v 17 +/- 8 mm Hg, P < .022) and a more marked decrease of RBF (-203 +/- 123 mL/min v -270 +/- 137 mL/min, P < .007) were found in hypertensives than in normotensives, whereas changes in GFR and aldosterone concentration were similar in both groups. Most important, changes in GFR to AII correlated with echocardiographically determined LV mass (normotensives: AII 0.5: r = 0.33, P < .006, AII 3.0: r = 0.28, P < .05; hypertensives: AII 0.5: r = 0.41, P < .006, AII 3.0: r = 0.32, P < .05). After taking baseline MAP and body mass index into account, the increase in GFR to AII 0.5 in hypertensives still correlated with LV mass (partial r = 0.37, P < .01). Inasmuch as the increase of GFR is a marker of the responsiveness to AII (related to vasoconstriction at the postglomerular site), our data suggest that increased sensitivity to AII is linked to LV hypertrophy in early essential hypertension, independently of the level of blood pressure.

Adult↗
PubMed1998

Does lipoprotein(a) impair endothelial function?

OBJECTIVES: This study was undertaken to test the hypothesis that lipoprotein(a) [Lp(a)] impairs endothelial function. BACKGROUND: Elevated Lp(a) plasma levels have been demonstrated to be associated with an increased risk of coronary heart disease. In atherosclerosis, endothelial dysfunction is known to be an early indicator of vascular changes. However, the effect of Lp(a) on nitric oxide (NO)-dependent vasodilator response has not yet been determined. We therefore examined the influence of Lp(a) on basal and stimulated NO-mediated vasodilator response in the forearm vascular bed. METHODS: Strain gauge plethysmography was used to measure changes in forearm blood flow produced by intraarterial infusion of increasing doses of acetylcholine (3, 12, 24 and 48 microg/min), sodium nitroprusside (200, 800 and 3,200 ng/min) and N-monomethyl L-arginine (L-NMMA) (1, 2 and 4 micromol/min) in 57 white subjects (mean age +/- SD 37 +/- 14 years). Lp(a) plasma concentrations were determined by rocket immunoelectrophoresis. RESULTS: Endothelium-dependent vasodilation tested by intraarterial acetylcholine and endothelium-independent vascular relaxation tested by intraarterial sodium nitroprusside were not correlated with Lp(a). Similarly, no significant differences in forearm blood flow changes were observed when patients were classified into tertiles according to their individual Lp(a) concentration. In contrast, changes in forearm blood flow after intraarterial L-NMMA indicating basal production and release of NO differed significantly among tertiles. Patients in the highest Lp(a) tertile (49.2 +/- 20.3 mg/dl) had a much greater vasoconstrictive response to L-NMMA than patients in the lowest Lp(a) tertile (4.8 +/- 2.5 mg/dl): 2 micromol/min of L-NMMA, -23.6 +/- 22.5% vs. -10.4 +/- 9.1% (p < 0.02); 4 micromol/min of L-NMMA, -27.8 +/- 10.3% vs. -17.6 +/- 9.9% (p < 0.03). Lp(a) plasma level consistently correlated negatively with the forearm blood flow responses to 4 micromol/min of intraarterial L-NMMA (r = -0.38, p < 0.01). Multiple stepwise regression analysis of variables, including total and high and low density lipoprotein cholesterol, further confirmed that plasma Lp(a) remained a significant independent determinant of forearm blood flow changes in response to L-NMMA (p < 0.02). CONCLUSIONS: The endothelium-dependent vasoconstrictive response to L-NMMA was enhanced in subjects with relatively high Lp(a) plasma levels, suggesting an increased basal production and release of NO. This response seemed to reflect a compensatory mechanism of the endothelium to yet unknown Lp(a)-induced atherosclerotic effects.

Acetylcholine↗
PubMed1998

Left ventricular hypertrophy and its regression: pathophysiology and therapeutic approach: focus on treatment by antihypertensive agents.

In numerous studies, left ventricular hypertrophy (LVH) has been clearly established to be a strong blood pressure (BP) independent risk factor for cardiovascular morbidity and mortality. In fact, increased echocardiographic left ventricular mass (LVM) has been shown to predict cardiovascular complications not only in patients with arterial hypertension, but also in the general population. Preliminary data revealed that regression of LVH reduced cardiovascular complications. As a consequence, regression of LVH emerged as a desirable goal in patients with echocardiographically determined LVH. These findings raised the question of whether certain antihypertensive drugs differ in their ability to reduce LVM. To resolve this issue, several comparative studies and some metaanalyses have been carried out. Regarding the available data until the end of 1996 including only double-blind, randomized, controlled clinical studies with parallel group design, we found that angiotensin converting enzyme (ACE) inhibitors reduced LVM by 12% (95% CI, 9.0-14.5%), calcium channel blockers by 11% (95% CI, 7.8-13.7%), beta-blockers by 5% (95% CI, 1.2-7.3%), and diuretics by 8% (95% CI, 3.9-11.1%) (overall: P < .01). A similar reduction was found for posterior and septal wall thickness. Thus, ACE inhibitors and calcium channel blockers seemed to be more potent than beta-blockers in their ability to reduce LVH, with diuretics in the intermediate range. The role of new antihypertensive agents such as AT-receptor antagonists cannot be conclusively answered, because the available data source is too small at this time. In addition to the drug class, reduction of LVH seems to be determined by pretreatment LVM, decline in BP, and duration of drug treatment. Further prospective controlled trials will be required to finally evaluate whether the excellent reduction of LVH with ACE inhibitors and calcium channel blockers can be transferred into improved cardiovascular prognosis.

Antihypertensive Agents↗
PubMed1998

Update on reversal of left ventricular hypertrophy in essential hypertension (a meta-analysis of all randomized double-blind studies until December 1996).

OBJECTIVE: To provide an update on the ability of different antihypertensive drugs to reduce left ventricular hypertrophy in essential hypertension. DATA SOURCES: Relevant medical databases including MEDLINE, BIOSIS PREVIEWS, EMBASE, and SCISEARCH as well as review articles to December 1996. STUDY SELECTION: Meta-analysis of all published articles including only double-blind, randomized, controlled clinical studies with parallel-group design. DATA EXTRACTION: Literature search and data extraction according to a prefixed scheme performed independently by two investigators. The primary parameter was reduction of left ventricular mass by antihypertensive therapy with placebo, diuretics, beta-blockers, calcium channel blockers, or ACE-inhibitors. DATA SYNTHESIS: Fifty studies published till the end of December 1996 were identified. They comprised a total of 1715 patients in 13 placebo (n=165, age: 50+/-3 years) and 89 active treatment arms (n=1550, age: 56+/-10 years) respectively. Overall, for active treatment left ventricular mass index was the more reduced the greater the decrease in systolic blood pressure, (r=0.27; P<0.05), the longer the duration of therapy (r=0.36; P<0.001), and the higher the pretreatment value of left ventricular mass index (r= 0.53; P<0.001). Left ventricular mass index was decreased by 12% with ACE-inhibitors (95% CI: 9.0-14.5%), by 11% with calcium channel blockers (95% CI: 7.8-13.7%), by 5% with beta-blockers (95% CI: 1.2-7.3%) and by 8% with diuretics (95% CI: 3.9-11.1%) (overall P<0.01). Subsequent tests revealed that ACE-inhibitors and calcium channel blockers were more effective than beta-blockers in reducing left ventricular mass index (P<0.05). Similar differences between drug classes were found with regard to effect on left ventricular wall thickness (P<0.05). CONCLUSIONS: Decrease in systolic blood pressure, duration of antihypertensive therapy, degree of pretreatment left ventricular hypertrophy and antihypertensive drug class determined the reduction of left ventricular hypertrophy. ACE-inhibitors and calcium channel blockers were more potent in reducing left ventricular mass than beta-blockers, with diuretics in the intermediate range.

Adrenergic beta-Antagonists↗
PubMed1998

Inadequate suppression of angiotensin II modulates left ventricular structure in humans.

BACKGROUND: In a previous study we found that high angiotensin II levels in relation to the corresponding urinary sodium excretion aggravate left ventricular hypertrophy in hypertensive patients. To analyze whether a dysregulation of the renin angiotensin aldosterone system determines left ventricular structure in young individuals, we examined whether the response of angiotensin II after increasing salt intake is related to left ventricular structure. METHODS: In 51 young, male Caucasians with normal or mildly elevated blood pressure, left ventricular structure, 24-hour ambulatory blood pressure and dietary sodium intake (as estimated by 24-hour sodium excretion) were determined in parallel with plasma renin activity, angiotensin II, and aldosterone concentrations. Angiotensin II concentration and 24-hour sodium excretion were measured twice: firstly on a normal Bavarian diet and secondly at high salt intake to determine the resulting suppression of the renin-angiotensin-aldosterone system. RESULTS: Body mass index (r = 0.42, p < 0.001) and both systolic (r = 0.28, p < 0.05) and diastolic (r = 0.25, p < 0.05) 24-hour ambulatory blood pressure correlated with left ventricular mass. No direct relationship was found between left ventricular structure and baseline angiotensin II concentration. The lower the physiological decrease of angiotensin II after high oral salt intake, i.e. the higher the angiotensin II level after salt intake remained, the greater was left ventricular mass (r = 0.38; p < 0.006) even after taking 24-hour ambulatory blood pressure into account (partial correlation; r = 0.43, p < 0.005). Consistently, angiotensin II concentration at high salt intake correlated with left ventricular mass independently of ambulatory blood pressure (partial correlation: r = 0.29, p < 0.05). Subgroup analysis revealed that the increase in sodium excretion at high salt intake was related to the decrease in angiotensin II levels in normotensive (r = -0.43, p < 0.05), but not in hypertensive subjects (r = 0.16, n.s.). The changes in angiotensin II concentration at high salt intake were related to left ventricular mass in hypertensive (r = 0.43, p < 0.02), but not in normotensive individuals (r = 0.21, n.s.). CONCLUSION: Our finding that angiotensin II concentration at high salt intake correlated with left ventricular mass independently of ambulatory blood pressure suggests that inadequate suppression of angiotensin II after high salt intake contributes to left ventricular hypertrophy already in young hypertensive individuals independently of blood pressure.

Adult↗