James M. Ritter

Vasoactive Drugs Influence Aortic Augmentation Index Independently of Pulse-Wave Velocity in Healthy Men

Aortic augmentation index, a measure of central systolic blood pressure augmentation arising mainly from pressure-wave reflection, increases with vascular aging. The augmentation index is influenced by aortic pulse-wave velocity (related to aortic stiffness) and by the site and extent of wave reflection. To clarify the relative influence of pulse-wave velocity and wave reflection on the augmentation index, we studied the association between augmentation index, pulse-wave velocity, and age and examined the effects of vasoactive drugs to determine whether altering vascular tone has differential effects on pulse-wave velocity and the augmentation index. We made simultaneous measurements of the augmentation index and carotid-to-femoral pulse-wave velocity in 50 asymptomatic men aged 19 to 74 years at baseline and, in a subset, during the administration of nitroglycerin, angiotensin II, and saline vehicle. The aortic augmentation index was obtained by radial tonometry (Sphygmocor device, PWV Medical) with the use of an inbuilt radial to aortic transfer function. In multiple regression analysis, the aortic augmentation index was independently correlated only with age (R =0.58, P <0.0001). Nitroglycerin (3 to 300 &mgr;g/min IV) reduced the aortic augmentation index from 4.8±2.3% to −11.9±5.3% (n=10, P <0.002). Angiotensin II (75 to 300 ng/min IV) increased the aortic augmentation index from 9.3±2.4% to 18.3±2.9% (n=12, P <0.001). These drugs had small effects on aortic pulse-wave velocity, producing mean changes from baseline of <1 m/s (each P <0.05). In healthy men, vasoactive drugs may change aortic augmentation index independently from aortic pulse-wave velocity.

Photoplethysmographic assessment of pulse wave reflection: Blunted response to endothelium-dependent beta2-adrenergic vasodilation in type II diabetes mellitus☆

OBJECTIVES We sought to determine whether a simple index of pressure wave reflection may be derived from the digital volume pulse (DVP) and used to examine endothelium-dependent vasodilation in patients with type II diabetes mellitus. BACKGROUND The DVP exhibits a characteristic notch or inflection point that can be expressed as percent maximal DVP amplitude (IP(DVP)). Nitrates lower IP(DVP), possibly by reducing pressure wave reflection. Response of IP(DVP) to endothelium-dependent vasodilators may provide a measure of endothelial function. METHODS The DVP was recorded by photoplethysmography. Albuterol (salbutamol) and glyceryl trinitrate (GTN) were administered locally by brachial artery infusion or systemically. Aortic pulse wave transit time from the root of the subclavian artery to aortic bifurcation (T(Ao)) was measured by simultaneous Doppler velocimetry. RESULTS Brachial artery infusion of drugs producing a greater than threefold increase in forearm blood flow within the infused limb was without effect on IP(DVP), whereas systemic administration of albuterol and GTN produced dose-dependent reductions in IP(DVP). The time between the first and second peak of the DVP correlated with T(Ao) (r = 0.75, n = 20, p < 0.0001). The effects of albuterol but not GTN on IP(DVP) were attenuated by N(G)-monomethyl-L-arginine. The IP(DVP) response to albuterol (400 microg by inhalation) was blunted in patients with type II diabetes mellitus as compared with control subjects (fall 5.9 +/- 1.8% vs. 11.8 +/- 1.8%, n = 20, p < 0.02), but that to GTN (500 microg sublingually) was preserved (fall 18.3 +/- 1.2% vs. 18.6 +/- 1.9%, p = 0.88). CONCLUSIONS The IP(DVP) is influenced by pressure wave reflection. The effects of albuterol on IP(DVP) are mediated in part through the nitric oxide pathway and are impaired in patients with type II diabetes.

Preserved Endothelium-Dependent Vasodilatation in Patients with Essential Hypertension

BACKGROUND Previous studies suggest that vascular endothelial function may be impaired in essential hypertension. Although muscarinic agonists dilate blood vessels by releasing an endothelium-derived relaxing factor closely related to nitric oxide, nitroprusside dilates vessels by a mechanism that is independent of the endothelium. The finding of an impaired response to muscarinic agonists but a normal response to nitroprusside in patients with hypertension has suggested that endothelial function is abnormal in hypertension. METHODS We reassessed this issue by measuring forearm blood flow by plethysmography during the infusion of vasodilators into the brachial arteries of 95 subjects: 37 normotensive controls (mean [+/- SE] arterial blood pressure, 92 +/- 1 mm Hg) and 58 patients with essential hypertension (mean arterial blood pressure, 121 +/- 1 mm Hg). RESULTS In an initial study, vascular responses to the vasodilators carbachol and nitroprusside were similar in normotensive controls (n = 19) and hypertensive patients (n = 17). We wondered whether this might be attributable to the use of previously untreated patients or to the choice of carbachol as the muscarinic agonist. However, we found that the vasodilator responses to nitroprusside, acetylcholine, carbachol, and isoproterenol were also similar in separate groups of normotensive controls (n = 18) and hypertensive subjects, whether the subjects had never been treated for hypertension (n = 24) or had had therapy withheld for two weeks (n = 17). The 95 percent confidence intervals for the difference between the controls and hypertensive patients in the ratio of endothelium-dependent vasodilatation induced by acetylcholine or carbachol to endothelium-independent vasodilatation induced by nitroprusside were -14 to +23 percent for acetylcholine and -13 to +12 percent for carbachol. CONCLUSIONS In contrast to previous studies, our findings suggest that selective impairment of the responsiveness of the forearm vasculature to muscarinic agonists is not universal in patients with essential hypertension.

Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature.

OBJECTIVES The goal of this study was to investigate the mechanism of reduced vasoconstrictor sensitivity to norepinephrine in women compared with men. BACKGROUND beta2-adrenergic agonists such as albuterol dilate forearm resistance vessels, partly by activating the L-arginine/nitric oxide pathway. Norepinephrine (which acts as beta- as well as alpha-adrenergic receptors) causes less forearm vasoconstriction in women than it does in men. This could be explained by a greater sensitivity to beta2-receptor stimulation in women than in men. METHODS Forearm blood flow was measured by venous occlusion plethysmography in healthy women (days 10 to 14 of the menstrual cycle) and in men. Drugs were administered via the brachial artery in three separate protocols: albuterol +/- NG-monomethyl-L-arginine (an inhibitor of nitric oxide synthase); substance P, nitroprusside and verapamil (control vasodilators); norepinephrine (+/- propranolol, a beta-adrenergic receptor antagonist). RESULTS Vasodilator responses to albuterol were greater in women than they were in men (p = 0.02 by analysis of variance). NG-monomethyl-L-arginine reduced these similarly in men and women. Responses to control vasodilators were less in women than they were in men (each p < 0.05). Norepinephrine caused less vasoconstriction in women than it did in men (p = 0.02). Propranolol did not influence basal flow in either gender nor responses of men to norepinephrine but increased vasoconstriction to each dose of norepinephrine in women (p < 0.0001 for interaction between gender and propranolol). Responses to norepinephrine coinfused with propranolol were similar in men and women. CONCLUSIONS Stimulation of beta2-adrenergic receptors causes greater forearm vasodilation in premenopausal women, at midmenstrual cycle, than it does in men. This is sufficient to explain why vasoconstriction to brachial artery norepinephrine is attenuated in such women.

Contour analysis of the photoplethysmographic pulse measured at the finger

Analysis of the contour of the peripheral pulse to assess arterial properties was first described in the nineteenth century. With the recognition of the importance of arterial stiffness there has been a resurgence of interest in pulse wave analysis, particularly the analysis of the radial pressure pulse acquired using a tonometer. An alternative technique utilizes a volume pulse. This may conveniently be acquired optically from a finger (digital volume pulse). Although less widely used, this technique deserves further consideration because of its simplicity and ease of use. As with the pressure pulse, the contour of the digital volume pulse is sensitive to changes in arterial tone induced by vasoactive drugs and is influenced by ageing and large artery stiffness. Measurements taken directly from the digital volume pulse or from its second derivative can be used to assess these properties. This review describes the background to digital volume pulse contour analysis, how the technique relates to contour analysis of the pressure pulse, and current and future applications.

Noninvasive Assessment of the Digital Volume Pulse Comparison With the Peripheral Pressure Pulse

The digital volume pulse can be recorded simply and noninvasively by photoplethysmography. The objective of the present study was to determine whether a generalized transfer function can be used to relate the digital volume pulse to the peripheral pressure pulse and, hence, to determine whether both volume and pressure pulse waveforms are influenced by the same mechanism. The digital volume pulse was recorded by photoplethysmography in 60 subjects (10 women, aged 24 to 80 years), including 20 subjects with previously diagnosed hypertension. Simultaneous recordings of the peripheral radial pulse and digital artery pulse were obtained by applanation tonometry and a servocontrolled pressure cuff (Finapres), respectively. In 20 normotensive subjects, measurements were obtained after the administration of nitroglycerin (NTG, 500 &mgr;g sublingually). Transfer functions obtained by Fourier analysis of the waveforms were similar in normotensive and hypertensive subjects. In normotensive subjects, transfer functions were similar before and after NTG. By use of a single generalized transfer function for all subjects, the radial and digital artery pressure waveforms could be predicted from the volume pulse with an average root mean square error of 4.4±2.0 and 4.3±1.9 mm Hg (mean±SD) for radial and digital artery waveforms, respectively, similar to the error between the 2 pressure waveforms (4.4±1.4 mm Hg). The peripheral pressure pulse is related to the digital volume pulse by a transfer function, which is not influenced by effects of hypertension or NTG. Effects of NTG on the volume pulse and pressure pulse are likely to be determined by a similar mechanism.

Effects of Inhibition of the l-Arginine/Nitric Oxide Pathway on Vasodilation Caused by β-Adrenergic Agonists in Human Forearm

BACKGROUND We examined whether vasodilator responses to beta-agonists in human forearm vasculature are mediated in part through the nitric oxide pathway. METHODS AND RESULTS We measured forearm blood flow responses to brachial artery infusions of beta-adrenergic agonists in healthy men. Salbutamol was more than 100 times as potent as dobutamine. Cumulative doses of salbutamol (0.3 to 3.5 nmol.min-1) did not cause tachyphylaxis to an identical repeated infusion after a 24-minute recovery period. Vasodilators were infused with this sequence during coinfusion of saline and NG-monomethyl-L-arginine (L-NMMA, 4 mumol.min-1), an inhibitor of nitric oxide synthase. L-NMMA coinfusion inhibited responses (area under the dose-response curve) to isoproterenol (0.01 to 0.1 nmol.min-1) by 59 +/- 7% (n = 5) and inhibited those to salbutamol (0.3 to 3.5 nmol.min-1) by 52 +/- 6% (n = 8). L-NMMA had no significant effect on vasodilator responses to nitroprusside (2.7 to 11.0 nmol.min-1, n = 8), verapamil (20 to 80 nmol.min-1, n = 8), or prostacyclin (0.08 to 0.24 nmol.min-1, n = 8). CONCLUSIONS These results suggest that beta-adrenergic vasodilator responses in human forearm vasculature are mediated predominantly through beta 2-adrenergic receptors and are dependent on nitric oxide synthesis.

The Phytoestrogen Genistein Produces Acute Nitric Oxide–Dependent Dilation of Human Forearm Vasculature With Similar Potency to 17β-Estradiol

BackgroundGenistein, a phytoestrogen, may have estrogenic cardioprotective actions. We investigated whether genistein influences endothelium-dependent vasodilation in forearm vasculature of healthy human subjects and compared the effects of genistein with those of 17&bgr;-estradiol. Methods and ResultsThe brachial arterial was cannulated with a 27-gauge needle for drug infusion. Forearm blood flow responses were measured with strain-gauge plethysmography. Genistein (10 to 300 nmol/min, each dose for 6 minutes) produced a dose-dependent increase in forearm blood flow from 3.4±0.3 to 9.6±1.3 mL · min−1 · 100 mL forearm−1 (mean±SEM) in men (n=9, P <0.0001 by ANOVA). The mean forearm venous concentration of genistein during infusion of the highest dose was 1.8±0.3 &mgr;mol/L in 6 additional men. Genistein produced a similar increase in blood flow in premenopausal women. Daidzein, another phytoestrogen, was ineffective, but equimolar concentrations of 17&bgr;-estradiol caused similar vasodilation to genistein. Responses to genistein and 17&bgr;-estradiol were inhibited to the same degree by the NO synthase inhibitor NG-monomethyl-l-arginine. A threshold dose of genistein potentiated the endothelium-dependent vasodilator acetylcholine but not the endothelium-independent vasodilator nitroprusside. ConclusionsGenistein causes l-arginine/NO-dependent vasodilation in forearm vasculature of human subjects with similar potency to 17&bgr;-estradiol and potentiates endothelium-dependent vasodilation to acetylcholine.

Pressure Wave Reflection Assessed From the Peripheral Pulse Is a Transfer Function Necessary

Abstract—Synthesis of the aortic pressure waveform by application of a transfer function to the radial pulse allows the estimation of aortic systolic blood pressure and aortic augmentation index, an index of pressure wave reflection derived from the early systolic component of the waveform. The accuracy of this approach for determining the aortic augmentation index has been questioned, however, and it may be possible to derive similar information without using a transfer function. We compared aortic systolic blood pressure and the aortic augmentation index obtained from carotid and radial arteries with the use of transfer functions. We examined the correlation between the aortic augmentation index and a radial augmentation index obtained without use of a transfer function. Arterial tonometry (Sphygmocor) was performed in 84 subjects including healthy volunteers (n=30), subjects with essential hypertension (n=30), and patients with coronary artery disease (n=24). Effects of nitroglycerine and norepinephrine on aortic and radial augmentation index were examined in 12 healthy volunteers. Values of aortic systolic pressure obtained from radial and carotid arteries by using transfer functions were in acceptable agreement (R =0.98, difference=−0.9±4.6 mm Hg; mean±SD, n=84), but those of aortic augmentation index differed especially in control subjects (R =0.47, difference=−3.8±12.4%). Aortic augmentation index was, however, closely correlated with radial augmentation index (R =0.96, n=84). Nitroglycerine and norepinephrine produced parallel changes in the aortic and radial augmentation index. Our findings question the use of a transfer function to obtain the aortic augmentation index but suggest that similar information on central pressure wave reflection can be obtained directly from the radial pulse.

Evidence for a Difference in Nitric Oxide Biosynthesis Between Healthy Women and Men

There is indirect evidence for a gender difference in nitric oxide (NO) synthesis from vascular endothelium. The aim of the present study was to determine NO production more directly in healthy women and men by the measurement of 15N nitrate excreted in urine after the intravenous administration of L-[15N]2-guanidino arginine. Twenty-four healthy volunteers (13 men aged 22 to 40 years and 11 women aged 23 to 42 years) participated in this study. No subjects were receiving any medication. Women were studied between the 7th and 14th days of their menstrual cycles. Arterial blood pressure was measured oscillometrically, and 1.13 micromol L-[15N]2 arginine was administered intravenously after an overnight fast. Urine was collected for the next 36 hours in separate 12-hour periods. Urinary 15N/14N nitrate ratio was assessed by dry combustion in an isotope ratio mass spectrometer. Mean 36-hour urinary 15N nitrate excretion was greater in women than in men (2111+/-139 versus 1682+/-87 etamol; P<0.05). Furthermore, total urinary 15N nitrate excretion was associated inversely with the mean arterial blood pressure in the whole group of subjects (coefficient of correlation, 0.47; P=0.022). The present data show that whole-body production of NO is greater in healthy premenopausal women than in men under ambulatory conditions. The cellular origin of NO measured in this study is unknown, but differences in endothelial production could underlie differences in vascular function between men and women.