Matthias Schmitt

Basal NO Locally Modulates Human Iliac Artery Function In Vivo

We demonstrated previously that endogenous NO influences large-artery distensibility in the ovine hindlimb. However, the role of basal NO in larger human conduit arteries is controversial. The aim of this study was to investigate whether basal production of NO, acting locally, influences iliac artery distensibility in humans. Distensibility was assessed by intra-arterial measurement of the pulse wave velocity. Eighteen subjects, free of significant coronary or iliac artery disease, were studied after diagnostic cardiac catheterization. Simultaneous pressure waveforms were recorded with a high-fidelity dual-pressure sensing catheter, placed in the common iliac artery during intra-arterial infusion of saline (baseline), glyceryl trinitrate (4 nmol/min), or NG-monomethyl-l-arginine (8 and 16 &mgr;mol/min). Drugs were infused proximally, via the catheter to perfuse the segment of artery under study, or distally, via the sheath, to control for any reflex changes in flow or sympathetic activation. Velocity was calculated using the foot-to-foot methodology. Six subjects received glyceryl trinitrate and 12 NG-monomethyl-l-arginine. There was no change in velocity after infusion of glyceryl trinitrate or NG-monomethyl-l-arginine via the sheath. However, infusion of glyceryl trinitrate via the catheter significantly reduced velocity by 31.43±5.80% (mean±SEM; P<0.01; P=0.02 for comparison). Likewise, infusion of the highest dose of NG-monomethyl-l-arginine via the catheter significantly increased velocity by 27.25±8.20% (P=0.001; P=0.02 for comparison). Importantly, there was no change in mean arterial blood pressure throughout the studies. These data indicate that under resting conditions, local NO production modulates human iliac artery distensibility and that exogenous NO increases arterial distensibility.

Nebivolol Increases Arterial Distensibility In Vivo

Arterial stiffness is a key determinant of cardiovascular risk in hypertensive patients. &bgr;-Blockers appear to be less effective than other drugs in improving outcome in hypertensive patients, and a potential explanation may be that &bgr;-blockers are less effective in reducing arterial stiffness. The aim of this study was to assess the direct effect of &bgr;-blockade on pulse wave velocity (PWV), a robust measure of arterial distensibility, using a local, ovine, hind-limb model. In addition, we hypothesized that the vasodilating &bgr;-blocker nebivolol, but not atenolol, would increase arterial distensibility in vivo. All studies were conducted in anesthetized sheep. PWV was recorded in vivo using a dual pressure-sensing catheter placed in the common iliac artery. Intraarterial infusion of nebivolol reduced PWV by 6±3% at the higher dose (P<0.001), but did not alter mean arterial pressure (change of −1±3 mm Hg, P=0.1). In contrast, atenolol had no effect on PWV (P=0.11) despite a small drop in mean pressure (change of −5±3 mm Hg, P<0.01). Infusion of glyceryl trinitrate led to a dose-dependent fall in PWV, and 2 nmol/min produced a similar reduction in PWV to the higher dose of nebivolol (500 nmol/min). The effect of nebivolol on PWV was significantly attenuated during coinfusion of NG-monomethyl-l-arginine (P=0.003) and also during coinfusion of butoxamine (P=0.02). These results demonstrate that nebivolol, but not atenolol, increases arterial distensibility. This effect of nebivolol is mediated through the release of NO via a &bgr;2 adrenoceptor–dependent mechanism. Thus, nebivolol may be of benefit in conditions of increased large artery stiffness, such as isolated systolic hypertension.

Role of nitric oxide and oxidative stress in baroreceptor dysfunction in patients with chronic heart failure

Abnormalities of autonomic control of the cardiovascular system are seen in chronic heart failure (CHF) and confer a poor prognosis. Nitric oxide appears to be important in the regulation of baroreflex control in health and in disease states. The antioxidant vitamin C increases nitric oxide bioavailability in CHF. We evaluated the effects of vitamin C on baroreceptor sensitivity (BRS) by sequence analysis in 100 CHF patients and 44 control subjects. Groups of 55 CHF patients and 22 controls were randomly allocated to receive a single intravenous injection of vitamin C (2 g) or placebo. In addition, 45 CHF patients were randomly allocated to receive a 4-week course of oral vitamin C (4 g/day) or placebo. An age-related reference range for BRS was developed in 22 healthy controls matched for age and gender to the CHF group. BRS was significantly impaired in the CHF group compared with age-matched older controls and young controls (6.9 +/- 3.1, 12.5 +/- 4.9 and 21.7 +/- 9.1 mmHg/ms respectively; P < 0.001 between groups). Intravenous vitamin C acutely improved BRS in CHF patients by 24% (by 1.8 +/- 4.1 mmHg/ms; P < 0.05), but not in controls. There was no improvement in BRS in CHF patients given chronic oral vitamin C. Thus acute intravenous, but not chronic oral, vitamin C improved BRS in CHF patients. There was no effect of intravenous vitamin C in healthy subjects, suggesting that the mechanism was either by free radical scavenging or due to central effects.

Lack of rapid aldosterone effects on forearm resistance vasculature in health

Objectives Systemic infusions of aldosterone cause an acute increase in systemic vascular resistance (SVR) in healthy subjects. It is not clear whether this is due to a direct effect on the vasculature or the result of increased sympathetic tone. We investigated the short-term effects of locally infused aldosterone on the forearm resistance bed. Methods In this dose response study, we assessed the effects of incremental doses (10, 50, 100 ng/minute) of intrabrachial aldosterone on forearm blood flow (FBF), using conventional strain gauge plethysmography. Arterial blood pressure was monitored continuously, using finger photo-plethysmography. Forearm vascular resistance (FVR) was calculated. FBF and FVR were also measured in the non-infused arm. Changes in FBF and FVR in the infused arm were corrected for those occurring in the control arm. Results Plasma aldosterone levels in the venous effluent of the infused arm increased in a dose-dependent fashion, from 113.3±17.9 pg/ml at baseline to 297.8±51.8 pg/ml at 10 ng/minute (p=<0.01), 743.9±105.9 pg/ml at 50 ng/min (p=<0.001 vs. baseline) and 1230.6±73.7 pg/ml at 100 ng/min (p=<0.0005 vs. baseline). Plasma concentrations of aldosterone in the control arm did not change significantly vs. baseline. The corrected FBF (+4.1±10.3%) and corrected FVR (+4.3±11.3%) did not change significantly even at peak infusion rates. Conclusions Local intra-arterial infusion of aldosterone had no acute effect on forearm resistance vessels in healthy male volunteers.

Supine rest reduces platelet activation and aggregation

Platelet activation and aggregation are central processes in acute coronary syndromes and myocardial infarction, and are stimulated by physical and mental stress. However, it is not known if and to what extent the ordinary stress inherent in a persons daily routine contributes to platelet activation and aggregation. We measured platelet activation and aggregation in 12 healthy non-smokers, before and after 45 min supine rest in a calm environment. This simple manouver resulted in a highly significant fall in platelet aggregation (7.9-4.4 ohms, p <0.001) and in plasma epinephrine (35.6-22.5 ng/ml, p = 0.037), norepinephrine (392.8-202.7 ng/ml, p <0.001) and soluble P-selectin (51.9-44.7 ng/ml, p <0.001). Von Willebrand factor (86.2-80.9 IU/ml) and beta-thromboglobulin (279.1-262.4 IU/ml) did not change significantly. Our findings show that a persons ordinary daily routine contributes to platelet activation and aggregation, and that these can be reduced by supine rest. This has methodological implications for studies involving measures of platelet activation and aggregation, and also suggests a mechanism by which bed rest in a calm environment may contribute, however slightly, to the management of acute coronary syndromes.

Effects of exogenous and endogenous natriuretic peptides on forearm vascular function in chronic heart failure

Objective—Natriuretic peptides (NPs) reduce central venous pressure in patients with chronic heart failure (cHF) despite attenuation of arterial, renal, and humoral effects. This suggests a preserved venodilator response. This study had 4 aims: to compare the venodilator effects of human NPs in patients with cHF; to assess the contribution of basal ANP and BNP levels to regulation of forearm vascular volume (FVV); to test the hypothesis that venous ANP responsiveness is preserved in cHF; and to assess the involvement of endothelial nitric oxide-synthase (eNOS) in NP-induced vascular effects. Methods and Results—Venous and arterial forearm vascular responses to incremental intra-arterial doses of ANP, Urodilatin, BNP, CNP, or the ANP receptor antagonist A71915 were studied in 53 patients and 11 controls. ANP receptor antagonism reduced FVV by 4.4%±1.2% (P<0.05). The forearm blood flow (FBF) response to ANP was significantly blunted in patients versus controls (P<0.01), whereas FVV increased similarly in both groups (maximum 14.7% and 13.4%, both P<0.001). The eNOS blockade reduced ANP-induced FBF changes in controls but not in patients (P<0.05), whereas similar reductions in FVV changes were seen in groups (both P<0.001). Conclusions—In cHF venous, but not arterial, ANP responsiveness is preserved. Arterial endothelial dysfunction may contribute to NP resistance.

Modulation of the natriuretic peptide system in heart failure: from bench to bedside?

Since the discovery of atrial natriuretic peptide, the unravelling of the natriuretic peptide system has been a story of scientific success. However, bridging the gap between bench and bedside has proved difficult, and as yet has not provided any major clinical progress. In this review we will first give a detailed outline of the key elements constituting the natriuretic peptide system. Secondly, we will briefly explain the underlying rationale, basic concepts and evidence behind currently pursued strategies to potentiate the natriuretic peptide system. Thirdly, we will highlight some of the problems that have so far hindered successful translation of these theoretically viable treatment options into tangible clinical progress.

Preservation of venous endothelial function in the forearm venous capacitance bed of patients with chronic heart failure despite arterial endothelial dysfunction

OBJECTIVESnThe goal of this study was to assess whether endothelial dysfunction occurs in the forearm venous capacitance bed of patients with chronic heart failure (CHF) and to determine the role of nitric oxide (NO) in modulating venous tone.nnnBACKGROUNDnControl of venous tone is crucially important in CHF. More than 70% of blood volume lies in the venous capacitance beds. Therefore, small changes in venous tone may markedly affect cardiac filling pressures and cardiac output.nnnMETHODSnVenous tone was measured using radionuclide forearm venous plethysmography in 24 patients with CHF and 16 age-matched controls. The effect of basal NO activity on venous tone was assessed by infusing N-monomethyl-L-arginine 12 mg/min and stimulated NO using carbachol 15 microg/min. Brachial artery flow-mediated dilation was assessed by ultrasonic wall-tracking.nnnRESULTSnBlockade of basal NO release caused a significant and similar venoconstriction in patients (9.6 +/- 1.8%, p < 0.01) and controls (6.6 +/- 1.7%, p < 0.01). Carbachol-induced venodilation was significant and similar in patients (36.8 +/- 3.9%, p < 0.001) and controls (40.7 +/- 3.9%, p < 0.001). Brachial artery flow-mediated dilation was impaired in patients compared with controls (2.0 +/- 0.6% vs. 7.5 +/- 2.5%, p < 0.01).nnnCONCLUSIONSnOur data indicate that, despite marked impairment of the function of the arterial endothelium, there is preservation of both basal and stimulated NO release in the forearm venous capacitance bed. This may provide important insights into mechanisms of endothelial dysfunction in CHF and the potential for novel therapy.

Atrial Natriuretic Peptide Regulates Regional Vascular Volume and Venous Tone in Humans

Objective—To date, the contribution of basal atrial natriuretic peptide (ANP) levels to resting vascular function in humans is unknown. In the present study we sought to investigate the role of ANP in regulating regional vascular volume and venous tone in healthy subjects. Methods and Results—We used radionuclide plethysmography to examine the effects of ANP and the ANP-receptor antagonist A71915 on forearm vascular volume. Creating pressure/volume relations, we determined changes in vascular volume, compliance, and tone. Performing dose-ranging studies, we additionally assessed the potency and specificity of A71915 in the forearm resistance vasculature. Equilibrium blood pool scintigraphy was then used to assess the effects of systemic administration of A71915 on regional intestinal vascular volume. Infusion of ANP increased forearm vascular volume in a dose-dependent manner (maximum 20%; P <0.001), exerting a maximum venodilating effect at plasma levels similar to that seen in heart failure. A71915 increased venous tone, thereby decreasing vascular volume by 9.6±1.1%, P <0.001 (forearm), and 2.6±0.5%, P =0.01 (intestinal beds). At an infusion ratio of 50:1, A71915 almost completely abolished the effects of ANP on forearm blood flow. Conclusions—ANP locally regulates regional vascular volume and tone without affecting compliance.

Effects of bradykinin on venous capacitance in health and treated chronic heart failure.

In the present study, we investigated the effects of basal and intra-arterial infusion of bradykinin on unstressed forearm vascular volume (a measure of venous tone) and blood flow in healthy volunteers (n=20) and in chronic heart failure patients treated with ACEIs [ACE (angiotensin-converting enzyme) inhibitors] (n=16) and ARBs (angiotensin receptor blockers) (n=14). We used radionuclide plethysmography to examine the effects of bradykinin and of the bradykinin antagonists B9340 [B1 (type 1)/B2 (type 2) receptor antagonist] and HOE140 (B2 antagonist). Bradykinin infusion increased unstressed forearm vascular volume in a similar dose-dependent manner in healthy volunteers and ARB-treated CHF patients (healthy volunteers maximum 12.3±2.1%, P<0.001 compared with baseline; ARB-treated CHF patients maximum 9.3±3.3%, P<0.05 compared with baseline; P=not significant for difference between groups), but the increase in unstressed volume in ACEI-treated CHF patients was higher (maximum 28.8±7.8%, P<0.001 compared with baseline; P<0.05 for the difference between groups). In contrast, while the increase in blood flow in healthy volunteers (maximum 362±9%, P<0.001) and in ACEI-treated CHF patients (maximum 376±12%, P<0.001) was similar (P=not significant for the difference between groups), the increase in ARB-treated CHF patients was less (maximum 335±7%, P<0.001; P<0.05 for the difference between groups). Infusion of each receptor antagonist alone similarly reduced basal unstressed volume and blood flow in ACEI-treated CHF patients, but not in healthy volunteers or ARB-treated CHF patients. In conclusion, bradykinin does not contribute to basal venous tone in health, but in ACEI-treated chronic heart failure it does. In ARB-treated heart failure, venous responses to bradykinin are preserved but arterial responses are reduced compared with healthy controls. Bradykinin-mediated vascular responses in both health and heart failure are mediated by the B2, rather than the B1, receptor.