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Johannes Jacobi

Publications and source records attributed to Johannes Jacobi.

16 recordsLinked to original sources
PubMed2006

Microenvironmental VEGF distribution is critical for stable and functional vessel growth in ischemia.

The critical role of vascular endothelial growth factor (VEGF) expression levels in developmental angiogenesis is well established. Nonetheless, the effects of different local (microenvironmental) VEGF concentrations in ischemia have not been studied in the adult organism, and VEGF delivery to patients has been disappointing. Here, we demonstrate the existence of both lower and upper threshold levels of microenvironmental VEGF concentrations for the induction of therapeutic vessel growth in ischemia. In the ischemic hind limb, implantation of myoblasts transduced to express VEGF164 at different levels per cell increased blood flow only moderately, and vascular leakage and aberrant preangiomatous vessels were always induced. When the same total dose was uniformly distributed by implanting a monoclonal population derived from a single VEGF-expressing myoblast, blood flow was fully restored to nonischemic levels, collateral growth was induced, and ischemic damage was prevented. Hemangiomas were avoided and only normal, pericyte-covered vessels were induced persisting over 15 mo. Surprisingly, clones uniformly expressing either lower or higher VEGF levels failed to provide any functional benefit. A biphasic effect of VEGF dose on vessel number and diameter was found. Blood flow was only improved if vessels were increased both in size and in number. Microenvironmental VEGF concentrations determine efficacy and safety in a therapeutic setting.

Animals↗
PubMed2005

Dimethylarginine dimethylaminohydrolase overexpression suppresses graft coronary artery disease.

BACKGROUND: Graft coronary artery disease (GCAD) is the leading cause of death after the first year of heart transplantation. The reduced bioavailability of endothelium-derived nitric oxide (NO) may play a role in endothelial vasodilator dysfunction and the structural changes that are characteristic of GCAD. A potential contributor to endothelial pathobiology is asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor. We hypothesized that lowering ADMA concentrations by dimethylarginine dimethylaminohydrolase (DDAH) overexpression in the recipient might suppress GCAD and long-term immune responses in murine cardiac allografts. METHODS AND RESULTS: In one series, donor hearts of C-H-2(bm12)KhEg (H-2(bm12)) wild-type (WT) mice were heterotopically transplanted into C57BL/6 (H-2b) transgenic mice overexpressing human DDAH-I or WT littermates and procured after 4 hours of reperfusion (WT and DDAH-I recipients, n=6 each). In a second series, donor hearts were transplanted into DDAH-I-transgenic or WT mice and procured 30 days after transplantation (n=7 each). In DDAH-I recipients, plasma ADMA concentrations were lower, in association with reduced myocardial generation of superoxide anion (WT versus DDAH-I, 465.7+/-79.8 versus 173.4+/-32.3 micromol.L(-1).mg(-1).h(-1); P=0.02), inflammatory cytokines, adhesion molecules, and chemokines. GCAD was markedly reduced in cardiac allografts of DDAH-I-transgenic recipients as assessed by luminal narrowing (WT versus DDAH, 79+/-2% versus 33+/-7%; P<0.01), intima-media ratio (WT versus DDAH, 1.1+/-0.1 versus 0.5+/-0.1; P<0.01), and the percentage of diseased vessels (WT versus DDAH, 100+/-0% versus 62+/-10%; P<0.01). CONCLUSIONS: Overexpression of DDAH-I attenuated oxidative stress, inflammatory cytokines, and GCAD in murine cardiac allografts. The effect of DDAH overexpression may be mediated by its reduction of plasma and tissue ADMA concentrations.

Amidohydrolases↗
PubMed2005

Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis.

BACKGROUND: This study was designed to determine whether overexpression of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) could enhance angiogenesis by reducing levels of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). METHODS AND RESULTS: In DDAH1 transgenic (TG) and wild-type mice (each n=42), the role of DDAH overexpression on angiogenesis was studied by use of the disk angiogenesis system and a murine model of hindlimb ischemia (each n=21). After surgery, animals were treated with either PBS or the NOS inhibitors ADMA or N(omega)-nitro-L-arginine methyl ester (L-NAME; each 250 micromol x kg(-1) x d(-1)) by use of osmotic minipumps (each n=7). L-NAME was chosen to study an inhibitor that is not degraded by DDAH. Neovascularization in the disk angiogenesis system was impaired by both NOS inhibitors; however, TG animals were resistant to the effects of ADMA on neovascularization. Similarly, TG mice were more resistant to the inhibitory effect of ADMA on angioadaptation (angiogenesis and arteriogenesis) after hindlimb ischemia, as assessed by fluorescent microsphere studies and postmortem microangiograms. Enhanced neovascularization and limb perfusion in TG mice were associated with reduced plasma and tissue ADMA levels and enhanced tissue NOS enzyme activity. CONCLUSIONS: We describe a novel mechanism by which DDAH regulates postnatal neovascularization. Therapeutic manipulation of DDAH expression or activity may represent a novel approach to restore tissue perfusion.

Amidohydrolases↗
PubMed2005

Lipid-independent effects of statins on endothelial function and bioavailability of nitric oxide in hypercholesterolemic patients.

BACKGROUND: Experimental evidence suggests a lipid-independent effect of statins on endothelial function and nitric oxide (NO) availability in humans. We investigated whether improvement in NO availability in hypercholesterolemia can be achieved rapidly with statins before lipid-lowering therapy is complete. METHODS: We studied 41 patients (52 +/- 11 years) with low-density lipoprotein (LDL) cholesterol > or = 130 mg/dL (179 +/- 45 mg/dL) randomly assigned to treatment either with atorvastatin (20 mg/day) or cerivastatin (0.4 mg/day). Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh) after 3 days (n = 18) and 14 days (n = 39) of treatment. NO availability and oxidative stress were assessed by coinfusion of l-NMMA and vitamin C. RESULTS: After 3 days of treatment, LDL-cholesterol decreased by 11.9% with a further decrease to 29.6% after 14 days ( P < .001). Endothelium-dependent vasodilation improved by +46.7% after 3 days of statin therapy compared with before therapy (ACh 48 microg/min: +15.7 +/- 10.6 vs +10.7 +/- 10.8 mL/min per 100 mL, P < .05). No further improvement in endothelium-dependent vasodilation (+42.7% compared with before therapy) could be demonstrated after 14 days of treatment (ACh 48 microg/min: +17.7 +/- 10.3 vs +12.4 +/- 9.3 mL/min per 100 mL before therapy, P < .001). Coinfusion of ACh plus vitamin C was able to improve endothelium-dependent vasodilation before but not after 3 or 14 days of statin therapy either. The improvement in endothelium-dependent vasodilation after therapy was no longer observed when the NO-synthase inhibitor l-NMMA was coinfused together with ACh. CONCLUSIONS: Short-term lipid-lowering therapy with statins is able to improve endothelial function and NO availability almost completely after 3 days in hypercholesterolemic patients probably by decreasing oxidative stress. This improvement seems to be more rapid than the accompanying decline in LDL-cholesterol and not related to these lipid changes. This finding can support the concept of lipid-independent effects of statins in humans.

Acetylcholine↗
PubMed2005

CYP3A5 genotype is associated with elevated blood pressure.

The present study aimed to determine whether a polymorphism in CYP3A5, encoding the major CYP3A enzyme in the human kidney, is associated with blood pressure in Caucasians. A homogenous group of 115 young, white male students with normal or mildly elevated, but untreated blood pressure was included. Blood pressure was recorded by ambulatory 24-h blood pressure-monitoring and compared between individuals with high (*1/*3) and low CYP3A5 expression (*3/*3). Moreover, genotype-dependent differences in parameters associated with the renin-angiotensin-aldosterone system were evaluated. Twenty-four hour diastolic blood pressure values were not significantly different between the two groups. However, individuals with the CYP3A5*3/*3 genotype had significantly higher 24-h ambulatory systolic blood pressure values compared to subjects with the CYP3A5*1/*3 genotype (129+/-10 versus 124+/-9, P < 0.05). There was no association of CYP3A5 genotype with angiotensin II plasma concentrations, renal plasma flow, glomerular filtration rate, urinary sodium excretion and parameters determined by echocardiography, but the *3/*3 group had significantly lower serum aldosterone concentrations compared to the individuals with the *1/*3 genotype (101+/-29 versus 117+/-29 pg/ml, P < 0.05). These data, as generated with a homogenous population of young Caucasians, indicate that the CYP3A5 genotype affects blood pressure in humans possibly by genotype-dependent differences in renal, CYP3A5-mediated metabolism of cortisol and/or aldosterone. We interpret the lower serum aldosterone concentration in the genotype group with the elevated systolic blood pressure as a counter-regulatory mechanism to attenuate the increased blood pressure associated with the CYP3A5*3/*3 genotype.

Adult↗
PubMed2004

Adenoviral gene transfer with soluble vascular endothelial growth factor receptors impairs angiogenesis and perfusion in a murine model of hindlimb ischemia.

BACKGROUND: The purpose of the current study was to examine the contribution of endogenous vascular endothelial growth factor (VEGF) to ischemia-induced angiogenesis and perfusion. METHODS AND RESULTS: C57BL/6J mice (n=28) were subjected to unilateral hindlimb ischemia after intravenous injection of recombinant adenoviruses (10(9) plaque-forming units) encoding the ligand-binding ectodomain of VEGF receptor 1 (VEGFR1/Ad Flt1), VEGF receptor 2 (VEGFR2/Ad Flk1-Fc), a control murine IgG2alpha Fc fragment (Ad Fc), or vehicle (phosphate-buffered saline). Hindlimb perfusion was assessed by both laser Doppler and fluorescent microsphere injection 10 days after surgery. The role of endogenous VEGF in ischemia-induced angiogenesis and arteriogenesis was measured by capillary density and microangiography, respectively. Adenoviral gene transfer with soluble VEGFRs significantly attenuated hindlimb perfusion as assessed by laser Doppler and microsphere analysis (P<0.05). Furthermore, soluble VEGFRs significantly reduced ischemia-induced angiogenesis and collateral growth and inhibited histological recovery of muscle tissue. Adverse events consistent with ongoing vascular insufficiency such as limb necrosis or gangrene were observed only in animals expressing soluble VEGFRs and not in control animals. CONCLUSIONS: Systemic, soluble receptor-mediated VEGF inhibition indicates an essential role for endogenous VEGF during postischemic angiogenesis and hindlimb perfusion.

Adenoviridae↗
PubMed2004

Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis.

Soluble receptors to vascular endothelial growth factor (VEGF) can inhibit its angiogenic effect. Since angiogenesis is involved in wound repair, we hypothesized that adenovirus-mediated gene transfer of a soluble form of VEGF receptor 2 (Flk-1) would attenuate wound healing in mice. C57Bl/6J and genetically diabetic (db/db) mice (each n=20) received intravenous (i.v.) injections of recombinant adenoviruses (10(9) PFU) encoding the ligand-binding ectodomain of VEGF receptor 2 (Flk-1) or cDNA encoding the murine IgG2alpha Fc fragment (each n=10). At 4 days after gene transfer, two full-thickness skin wounds (0.8 cm) were created on the dorsum of each animal. Wound closure was measured over 9-14 days after which wounds were resected for histological analysis. Prior to killing, fluorescent microspheres were systemically injected for quantitation of wound vascularity. Single i.v. injections of adenoviruses encoding soluble Flk-1 significantly decreased wound angiogenesis in both wild-type and diabetic mice. Fluorescence microscopy revealed a 2.0-fold (wild type) and 2.9-fold (diabetic) reduction in wound vascularity in Flk-1-treated animals (p<0.05). Impairment of angiogenesis was confirmed by CD31 immunohistochemistry. Interestingly, despite significant reductions in wound vascularity, wound closure was not grossly delayed. Our data indicates that while VEGF function is essential for optimal wound angiogenesis, it is not required for wound closure.

Adenoviridae↗
PubMed2003

Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence.

BACKGROUND: NO is a major regulator of cardiovascular physiology that reduces vascular and cardiac contractility. Accumulating evidence indicates that endogenous inhibitors may regulate NOS. The NOS inhibitors asymmetric dimethylarginine (ADMA) and N-monomethylarginine are metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). This study was designed to determine if increased expression of DDAH could reduce tissue and plasma levels of the NOS inhibitors and thereby increase NO synthesis. METHODS AND RESULTS: We used gene transfer and transgenic approaches to overexpress human DDAH I in vitro and in vivo. The overexpression of DDAH in cultured endothelial cells in vitro induced a 2-fold increase in NOS activity and NO production. In the hDDAH-1 transgenic mice, we observed approximately 2-fold increases in tissue NOS activity and urinary nitrogen oxides, associated with a 2-fold reduction in plasma ADMA. The systolic blood pressure of transgenic mice was 13 mm Hg lower than that of wild-type controls (P<0.05). The systemic vascular resistance and cardiac contractility were decreased in response to the increase in NO production. CONCLUSIONS: DDAH I overexpression increases NOS activity in vitro and in vivo. The hDDAH-1 transgenic animal exhibits a reduced systolic blood pressure, systemic vascular resistance, and cardiac stroke volume. This study provides compelling evidence that the elaboration and metabolism of endogenous ADMA plays an important role in regulation of NOS activity.

Amidohydrolases↗
PubMed2003

Effect of AT1 receptor blockade on endothelial function in essential hypertension.

BACKGROUND: Angiotensin II adversely affects endothelial function and NO availability. We analyzed the effect of AT(1) receptor blockade on endothelium-dependent vasodilation and basal nitric oxide (NO) production and release in hypertensive patients. METHODS AND RESULTS: Sixty patients (53 +/- 10 years) with essential hypertension were randomized to 6 weeks of double-blind therapy with either valsartan (80 mg), hydrochlorothiazide (HCTZ) (25 mg), or placebo once daily. Basal NO production and release was assessed by measuring forearm blood flow (FBF) in response to intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA), and endothelium-dependent vasodilation by measuring FBF in response to intra-arterial administration of acetylcholine, respectively. Intra-arterial infusion of noradrenaline and sodium nitroprusside was used to assess endothelium-independent changes in FBF. Blood pressure (BP) similarly decreased with active treatments (P < .001). After valsartan treatment, the decrease of FBF in response to L-NMMA was augmented (4 micromol/min L-NMMA, -1.3 +/- 1.2 after v -0.5 +/- 1.1 mL/min/100 mL before therapy, P < .02; 8 micromol/min L-NMMA: -1.7 +/- 1.3 after v -1.1 +/- 1.2 mL/min 100 mL before therapy, P < .05). No improvement was found after placebo or HCTZ treatment. Changes in L-NMMA-induced decrease of FBF with valsartan treatment were not related to BP changes. Neither drug substantially modified the response of FBF induced by intra-arterial infusion of acetylcholine, noradrenaline, and sodium nitroprusside. CONCLUSIONS: The AT(1) receptor blockade with valsartan improved basal NO production and release. The effect seems to be BP independent, as BP reduction with HCTZ failed to increase NO availability.

Acetylcholine↗
PubMed2002

Nicotine accelerates angiogenesis and wound healing in genetically diabetic mice.

Recently, we have discovered an endogenous cholinergic pathway for angiogenesis mediated by endothelial nicotinic acetylcholine receptors (nAChRs). Since angiogenesis plays a major role in wound repair, we hypothesized that activation of nAChRs with nicotine would accelerate wound healing in a murine excisional wound model. In genetically diabetic and control mice full-thickness skin wounds (0.8 cm) were created on the dorsum and topically treated over 7 days with either vehicle (phosphate-buffered saline, PBS) or nicotine (10(-8) mol/L, 10(-9) mol/L; each, n = 5). Wound size was measured over 14 days followed by resection, histological analysis, and quantitation of vascularity. In diabetic animals an agonist (epibatidine, 10(-10) mol/L) or antagonist (hexamethonium, 10(-4) mol/L) of nAChRs as well as the positive control basic fibroblast growth factor (bFGF, 25 microg/kg) were also tested. To further study the role of endothelial nAChRs in angiogenesis, we used an ex vivo vascular explant model. In diabetic mice wound healing was markedly impaired. Nicotine significantly accelerated wound healing as assessed by closure rate and histological score. The effects of nicotine were equal to bFGF and were mimicked by epibatidine and blocked by hexamethonium. Histomorphometry revealed increased neovascularization in animals treated with nicotine. Furthermore, capillary-like sprouting from vascular explants was significantly enhanced by nicotine. In conclusion, agonist-induced stimulation of nAChRs accelerates wound healing in diabetic mice by promoting angiogenesis. We have discovered a cholinergic pathway for angiogenesis that is involved in wound healing, and which is a potential target for therapeutic angiogenesis.

Animals↗
PubMed2002

Assessment of endothelial function of the renal vasculature in human subjects.

BACKGROUND: L-Arginine, the substrate of nitric oxide (NO) synthase, and N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of endothelial NO synthase, are used to analyze endothelial function of the renal vasculature. However, little is known about the appropriate dose of L-arginine to be used and the duration of action of L-arginine and L-NMMA. METHODS: Twenty-nine healthy male subjects (age, 27+/-1 years) were examined. In protocol 1 (N = 17), L-arginine at low (100 mg/kg) and high dose (250 mg/kg), and high-dose L-arginine combined either with L-NMMA (total dose, 4.25 mg/kg; N = 9) or placebo (N = 8) were given. In protocol 2 (N = 12), L-NMMA was given before L-arginine infusion (100 mg/kg). Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured at rest and at the end of each infusion step. RESULTS: In protocol 1, L-arginine dose dependently increased RPF and GFR (RPF: 599+/-19 v 630+/-18 v 690+/-24 mL/min, P <.05; GFR: 111+/-3 v 115+/-3 v 121+/-3 mL/min, P <.01; for baseline, L-arginine 100 mg/kg and 250 mg/kg, respectively). However, these changes could not be antagonized by coinfusion of L-NMMA to L-arginine 250 mg/kg: RPF and GFR remained unchanged in both the placebo and the L-NMMA group. In protocol 2, L-NMMA decreased RPF (492+/-18 v 567+/-27 mL/min, P <.01) and increased GFR (122+/-4 v 118+/-3 mL/min, P <.05). These changes could only be partially reversed by subsequent infusion of L-arginine (RPF: 533+/-15 mL/min; GFR: 121+/-4 mL/min; both parameters P = NS v L-NMMA and v baseline). CONCLUSIONS: L-arginine at a dose of 100 mg/kg is sufficient to analyze endothelial function of the renal vasculature. The prolonged effect of L-NMMA and L-arginine must be taken into account in study protocols using both substances. Thus, stimulation and blockade of NO synthase cannot be examined in the same protocol.

Adult↗
PubMed2002

Effects of enalapril and eprosartan on the renal vascular nitric oxide system in human essential hypertension.

BACKGROUND: Experimental data in humans on the contribution of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers to the nitric oxide system of the renal vasculature are inconsistent. Enalapril and eprosartan, alone and in combination, were used to determine their short-term effects on the renal nitric oxide system and renal hemodynamics of human subjects with essential hypertension. METHODS: Twenty male, white patients (27 +/- 1 years) with mild essential hypertension (143 +/- 11/95 +/- 6 mm Hg) were included in a double-blind, randomized, placebo-controlled, fourfold cross-over study with placebo, enalapril (20 mg/day), eprosartan (600 mg/day), or combination of both drugs (10 and 300 mg/day, respectively) each over a one week period followed by a two-week washout phase. After each study phase the glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined. Basal nitric oxide synthesis of the renal vasculature was assessed by the decrease in RPF after inhibition of nitric oxide synthase with NG-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg). RESULTS: After one week of therapy, the combination therapy decreased casual blood pressure by 5 +/- 2/3 +/- 1 mm Hg versus placebo (P < 0.01). Neither enalapril alone (-2 +/- 2/1 +/- 2 mm Hg, NS vs. placebo) nor eprosartan alone (-1 +/- 1/0 +/- 2 mm Hg, NS vs. placebo) had a clear-cut significant effect on casual blood pressure. In the combination phase, RPF increased by 123 +/- 36 mL/min (P < 0.01). Neither enalapril alone (+59 +/- 46 mL/min, P = 0.21) nor eprosartan alone (+113 +/- 51 mL/min, P = 0.06) had a clear-cut significant effect on RPF. Changes of RPF induced by treatment correlated with the L-NMMA induced decrease in RPF in the combination (r = 0.70, P < 0.01) and eprosartan phase (r = 0.86, P < 0.001), but not in the enalapril phase (r = -0.44, P = 0.10). Renal vascular resistance was reduced by each active treatment with the most prominent reduction in the combination phase. GFR was unaffected by any treatment. CONCLUSIONS: In contrast to the effects of either substance alone, a combination of half the dose of eprosartan with half the dose of enalapril had a prominent effect on renal perfusion. The effects of eprosartan on RPF are mediated, at least in part, by an increased bioavailability of nitric oxide in the renal vasculature.

Acrylates↗
PubMed2002

Altered aldosterone response to salt intake and angiotensin II infusion in young normotensive men with parental history of arterial hypertension.

OBJECTIVE: An increased sensitivity to angiotensin II (Ang II) has been observed in patients with established hypertension. In the current study we tested whether young normotensive subjects with positive family history of arterial hypertension exhibit an increased sensitivity to Ang II, thereby potentially contributing to the pathogenesis of essential hypertension in these subjects. METHODS AND DESIGN: Normotensive young men (25 +/- 2 years) with positive family history (PFH) (n = 28) and negative family history (NFH) (n = 60) of arterial hypertension were investigated to study aldosterone response, and systemic and renal haemodynamic changes (p-aminohippurate- and inulin-clearance) to Ang II infusion (0.5 and 3.0 ng/min per kg). In addition, aldosterone response to salt loading (5 g/day for 1 week) was analysed. RESULTS: Ambulatory blood pressure (ABP) (mean: 84 +/- 4 versus 83 +/- 4 mmHg; NS), body mass index (23.5 +/- 2.5 versus 24.1 +/- 2.4 kg/m(2); NS), and urinary sodium excretion (191 +/- 55 versus 170 +/- 73 mmol/24 h; NS) did not differ between PFH and NFH at baseline. Changes in BP, urinary sodium and potassium excretion were similar between PFH and NFH in response to salt loading. However, salt loading did not result in an adequate suppression of aldosterone in PFH compared with NFH (8 +/- 62 versus -32 +/- 39 pg/ml; P < 0.001). Baseline values and changes in mean arterial BP (NFH: +13.4 +/- 7.6; PFH: +14.4 +/- 5.3 mmHg; NS), renal plasma flow (NFH: - 113 +/- 68; PFH: - 122 +/- 64 ml/min; NS) and glomerular filtration rate (NFH: +5.0 +/- 5.3; PFH: +4.2 +/- 8.3 ml/min; NS) in response to Ang II (3.0 ng/min per kg) were similar between the two groups. In contrast, the increases in serum aldosterone (PFH: 63.6 +/- 70.1 versus NFH: 37.7 +/- 46.8 pg/ml; P < 0.05) and urinary potassium excretion (PFH: 0.05 +/- 0.1 versus NFH: -0.01 +/- 0.07 mmol/min; P < 0.05) 30 min after stopping Ang II infusion were more pronounced and prolonged in PFH than in NFH. CONCLUSIONS: Our findings suggest that young normotensive subjects with parental history of arterial hypertension are characterized by an inadequate suppression of aldosterone production in response to salt loading and an exaggerated and prolonged hyper-responsiveness of aldosterone secretion in response to Ang II. This might contribute to the increased risk for the development of essential hypertension in subjects with positive family history of arterial hypertension.

Adult↗
PubMed2002

Impact of NO-synthase inhibition on renal hemodynamics in normotensive and hypertensive subjects.

OBJECTIVE: To examine the acute effects of NO-synthase inhibition on renal hemodynamics in normotensive and hypertensive subjects. METHODS: Changes of renal plasma flow (RPF) and glomerular filtration rate (GFR) in response to intravenous infusions of NG-monomethyl-l-arginine (l-NMMA) (3 mg/kg per 30 min) were measured in 32 normotensive and in 39 essential hypertensive patients by use of clearance technique. RESULTS: l-NMMA significantly decreased RPF in normotensive and hypertensive individuals (P < 0.001), while GFR was preserved. Changes of renal hemodynamic parameters were similar in hypertensive and normotensive subjects (deltaRPF: -88 +/- 89 versus -81 +/- 105 ml/min, P = NS; deltaGFR 1.6 +/- 8.2 versus 4.3 +/- 8.9 ml/min, P = NS) Furthermore, l-NMMA increased mean arterial pressure (deltaMAP 5.3 +/- 6.3 versus 6.0 +/- 6.1 mmHg, P = NS) and decreased heart rate (deltaHR -5.8 +/- 3.9 versus -4.1 +/- 3.8 beats/min, P = NS) to a similar extent in both groups. CONCLUSION: Basal NO synthesis of the renal vasculature is not impaired in patients with established essential hypertension.

Adult↗
PubMed2002

AT1-receptor blockade improves augmentation index: a double-blind, randomized, controlled study.

OBJECTIVE: Arterial hypertension leads to vascular structural and functional adaptive processes that are influenced by angiotensin II. To analyze the effects of AT receptor blockade on vascular function we determined augmentation index. METHODS AND DESIGN: A total of 60 patients (53 +/- 10 years) with essential hypertension mean [blood pressure (BP) 173 +/- 9/102 +/- 3 mmHg] were randomized to 6 weeks double-blind therapy with either valsartan 80 mg, hydrochlorothiazide (HCTZ) 25 mg or placebo once daily. Radial artery pressure wave was determined by applanation tonometry before and after therapy. The central aortic pressure wave and augmentation index were derived by a generalized transfer function. RESULTS: Active therapy similarly reduced systolic and diastolic blood pressure (SBP, DBP) (valsartan: -22 +/- 18/-11 +/- 11 mmHg, HCTZ: -22 +/- 23/-14 +/- 14 mmHg, all P < 0.001). However, only valsartan, but no HCTZ reduced the augmentation index (valsartan: from 148 +/- 18 to 126 +/- 24, < 0.001; HCTZ: from 145 +/- 19 to 142 +/- 18, NS). Augmentation index reduction was greater with valsartan (-22 +/- 11) than with HCTZ (-3 +/- 11) and placebo (0 +/- 13) (P < 0.01 for pairwise comparison of valsartan versus HCTZ and placebo after Bonferroni correction). Differences remained significant after taking changes in supine BP into account (covariance, P < 0.01). CONCLUSIONS: Blood pressure reduction with the AT receptor antagonist valsartan but not with hydrochlorothiazide reduced the augmentation index in essential hypertension.

Adult↗