Effects of Intravenous PD 123319 on Haemodynamic and Arterial Stiffness Indices in Healthy Volunteers

Brillante, D.; Johnstone, Martina T; Howes, L. G.

doi:10.3317/jraas.2005.007

Cited by 11 publications

(9 citation statements)

References 20 publications

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“…In support of this hypothesis, our previous studies on the intravenous infusion of the highly selective AT 2 R blocker PD123319 (10 µg/min for 3 min) [16] did not produce any significant haemodynamic or arterial stiffness changes compared with placebo infusion in 16 healthy volunteers [17]. In contrast, infusion of the same dose of PD123319 in ten age-and sex-matched otherwise healthy individuals with HOMA-IR [HOMA (homeostasis model assessment) of insulin resistance] > 2 produced a significant increase in the stiffness of small-to-medium-sized arteries with a concurrent rise in SVRI (systemic vascular resistance index), but no other haemodynamic changes [18].…”

Section: Introductionsupporting

confidence: 51%

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Arterial stiffness and haemodynamic response to vasoactive medication in subjects with insulin-resistance syndrome

et al. 2007

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INSR (insulin-resistance syndrome) affects 25% of the Australian population and is associated with increased cardiovascular risk. In the present study, we postulated that early cardiovascular changes in these individuals may be associated with an activated RAS (renin-angiotensin system). We studied 26 subjects: 13 with INSR [waist circumference, 99+/-6 cm; HOMA (homoeostasis model assessment) score, 2.5+/-0.3] and 13 NCs (normals controls; waist circumference, 77+/-2 cm; HOMA score, 1.4+/-0.2). All received intravenous GTN (glyceryl trinitrate; 10, 20 and 40 microg/min), L-NMMA (N(G)-monomethyl-L-arginine; 3 mg/kg of body weight), AngII (angiotensin II; 8 and 16 ng/min), the selective AT(2)R (AngII type 2 receptor) inhibitor PD123319 (10 and 20 microg/min) and AngII (16 ng/min)+PD123319 (20 microg/min). At the end of each infusion, arterial stiffness indices [SI (stiffness index) and RI (reflection index)] and haemodynamic parameters were measured. There was a significantly higher RI response to AngII (P=0.0004 for both 8 and 16 ng/min doses) and to PD123319 (P=0.004 and P=0.03 for 10 and 20 microg/min doses respectively) in subjects with INSR compared with NCs. Co-infusion of AngII and PD123319 did not lead to additive changes in RI. RI responses to L-NMMA and GTN were not significantly different in both groups. No significant differences in SI and haemodynamic responses were detected. In conclusion, AT(1)R (AngII type 1 receptor) and AT(2)R activity produce arterial stiffness changes in subjects with INSR. Evidence of increased AT(1)R- and AT(2)R-mediated responses in small-to-medium-sized arteries in INSR was found, and may play an early role in the pathogenesis of vascular changes in INSR before haemodynamic changes become apparent.

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Section: Introductionsupporting

confidence: 51%

“…Power calculation for n = 13 in each group had an 80 % statistical power to detect a difference of > 10 % in responsiveness (two-tailed α of P < 0.05), based on the between-person variability observed from previous studies [17,18].…”

Section: Discussionmentioning

confidence: 99%

Arterial stiffness and haemodynamic response to vasoactive medication in subjects with insulin-resistance syndrome

et al. 2007

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“…AT 2 −/− mice exhibit enhanced blood pressure increase as a result of peripheral or central administration of Ang II (Li et al, 2003), indication of increased AT 1 receptor activation. However, administration of PD123319 to normal animals and to humans does not significantly affect blood pressure (Welch et al, 2007; Chappellaz and Smith, 2007; Brillante et al, 2005; Duke et al, 2005). This suggests a differential influence of AT 2 receptor activity on blood pressure control when comparing the mouse AT 2 −/− model and pharmacological blockade of AT 2 receptors in adult subjects.…”

Section: Discussionmentioning

confidence: 97%

A peripherally administered, centrally acting angiotensin II AT2 antagonist selectively increases brain AT1 receptors and decreases brain tyrosine hydroxylase transcription, pituitary vasopressin and ACTH

Macova¹,

Pavel²,

Saavedra³

2009

Brain Research

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The physiological actions of brain Angiotensin II AT 2 receptors and their relationship to Angiotensin II AT 1 receptors remain controversial. To further clarify their role, we determined to what extent systemic administration of an AT 2 receptor antagonist affected AT 2 receptor binding within the brain and the expression of AT 1 receptors. For this purpose, we subcutaneously administered the AT 2 receptor antagonist PD123319 (1 mg/kg/day) to adult male rats for two weeks via osmotic minipumps. We also studied the content of pituitary adrenocorticotropic hormone and vasopressin, representative of hypothalamic-pituitary-adrenal axis activation, and the tyrosine hydroxylase gene expression in the locus coeruleus as a measure of central norepinephrine function. We found significant decreases in AT 2 receptor binding in brain areas inside the blood brain barrier, the inferior olive and the locus coeruleus. AT 2 receptor blockade increased AT 1 receptor binding and mRNA expression not only in the subfornical organ and the median eminence, situated outside the blood brain barrier, but also in the hypothalamic paraventricular nucleus, located inside the blood brain barrier. These changes paralleled decreased expression of tyrosine hydroxylase mRNA in the locus coeruleus and decreased pituitary adrenocorticotropic and vasopressin content. Our results demonstrate that sustained peripheral administration of an AT 2 antagonist decreases binding to brain AT 2 receptors, indicating that this drug is a useful tool for the study of their central role. AT 2 receptor activity inhibition up-regulates AT 1 receptor expression in specific brain areas. Blockade of brain AT 2 receptors is compatible with enhanced hypothalamic-pituitary-adrenal axis and decreased central sympathetic system activity.

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“…Cardiac output was measured at rest and during handgrip exercise by thoracic electrical bioimpedance (BioZ; CardioDynamics, San Diego, CA) as previously described (2,25). Stroke volume was derived from change in impedance/time measured during electrical systole.…”

Section: Methodsmentioning

confidence: 99%

Differential effects of nebivolol vs. metoprolol on microvascular function in hypertensive humans

Velasco

Solow

Price

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Use of ␤-adrenergic receptor (AR) blocker is associated with increased risk of fatigue and exercise intolerance. Nebivolol is a newer generation ␤-blocker, which is thought to avoid this side effect via its vasodilating property. However, the effects of nebivolol on skeletal muscle perfusion during exercise have not been determined in hypertensive patients. Accordingly, we performed contrast-enhanced ultrasound perfusion imaging of the forearm muscles in 25 untreated stage I hypertensive patients at rest and during handgrip exercise at baseline or after 12 wk of treatment with nebivolol (5-20 mg/day) or metoprolol succinate (100 -300 mg/day), with a subsequent double crossover for 12 wk. Metoprolol and nebivolol each induced a reduction in the resting blood pressure and heart rate (130.9 Ϯ 2.6/81.7 Ϯ 1.8 vs. 131.6 Ϯ 2.7/80.8 Ϯ 1.5 mmHg and 63 Ϯ 2 vs. 64 Ϯ 2 beats/min) compared with baseline (142.1 Ϯ 2.0/88.7 Ϯ 1.4 mmHg and 75 Ϯ 2 beats/min, respectively, both P Ͻ 0.01). Metoprolol significantly attenuated the increase in microvascular blood volume (MBV) during handgrip at 12 and 20 repetitions/min by 50% compared with baseline (mixed-model P Ͻ 0.05), which was not observed with nebivolol. Neither metoprolol nor nebivolol affected microvascular flow velocity (MFV). Similarly, metoprolol and nebivolol had no effect on the increase in the conduit brachial artery flow as determined by duplex Doppler ultrasound. Thus our study demonstrated a first direct evidence for metoprolol-induced impairment in the recruitment of microvascular units during exercise in hypertensive humans, which was avoided by nebivolol. This selective reduction in MBV without alteration in MFV by metoprolol suggested impaired vasodilation at the precapillary arteriolar level.exercise; sympathetic nervous system; muscle blood flow; hypertension NEW & NOTEWORTHYWe identified a deleterious effect of chronic administration of metoprolol on microvascular function during handgrip in hypertensive patients, which was not observed with nebivolol. The impaired muscle capillary recruitment during exercise may predispose to development of exercise intolerance.PREVIOUS STUDIES DEMONSTRATED impaired muscle capillary recruitment in hypertension (8, 12), possibly related to impaired microvascular function or capillary rarefaction (27,28). In hypertensive patients, both metoprolol and propranolol can further impair microvascular function by acutely reducing resting capillary blood flow in the skeletal muscle (22, 23), which may predispose to development of exercise intolerance or fatigue. Nebivolol is a third-generation ␤-adrenergic receptor (AR) blocker that also possesses vasodilator properties (35). The vasodilator effect is attributed to partly due to the antioxidant effect via inhibition of NADPH oxidase activity or reduced expression of the NADPH oxidase subunits p47 phox (18,20, 35). However, the chronic effect of either older or newer generation ␤-AR blockers on microvascular function during exercise and endothelial cell (EC) expression of the p47 phox N...

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Effects of Intravenous PD 123319 on Haemodynamic and Arterial Stiffness Indices in Healthy Volunteers

Cited by 11 publications

References 20 publications

Arterial stiffness and haemodynamic response to vasoactive medication in subjects with insulin-resistance syndrome

Arterial stiffness and haemodynamic response to vasoactive medication in subjects with insulin-resistance syndrome

A peripherally administered, centrally acting angiotensin II AT2 antagonist selectively increases brain AT1 receptors and decreases brain tyrosine hydroxylase transcription, pituitary vasopressin and ACTH

Differential effects of nebivolol vs. metoprolol on microvascular function in hypertensive humans

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