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Effects of a fixed-dose ACE inhibitor-diuretic combination on ambulatory blood pressure and arterial properties in isolated systolic hypertension.
Ferguson, JM, Minas, J, Siapantas, S, Komesaroff, PA, Sudhir, K
Journal of cardiovascular pharmacology. 2008;(6):590-5
Abstract
The ideal therapy for patients with isolated systolic hypertension remains unclear; diuretics, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors are all used in clinical practice. The aim of this study was to determine whether a fixed-dose ACE inhibitor/diuretic combination would reduce ambulatory blood pressures (BP) and arterial stiffness in isolated systolic hypertension more than antihypertensive monotherapy. In this randomized, double-blind study, 8 weeks of fosinopril/hydrochlorothiazide combination (10/12.5 mg titrated up to 20/12.5 mg) was compared with the calcium channel blocker (amlodipine, 5 mg titrated up to 10 mg) and diuretic (indapamide, 2.5 mg) monotherapy in 28 patients with isolated systolic hypertension. Each patient received all 3 therapies. Assessments included 24-hour ambulatory BP, clinic BP, and applanation tonometry-derived augmentation index. At 8 weeks, the fall in average 24-hour systolic BP and night time systolic BP were significantly greater in the fosinopril-hydrochlorothiazide group, compared to amlodipine and indapamide. The decrease in augmentation index and central aortic systolic BP was also greater in the fosinopril-hydrochlorothiazide group, compared to either amlodipine or indapamide. There was no difference between therapies in decrease in clinic systolic or diastolic BP, or diastolic ABP (average 24-h, diurnal, or nocturnal). Compared with either calcium channel blocker or diuretic therapy, a fixed-dose ACE inhibitor-diuretic combination induces greater reductions in systolic ABP, particularly at night, favorable effects that may be related to a decrease in the intensity of or delay in arterial wave reflections. ACE inhibitor-diuretic combination therapy is a useful approach to cardiovascular risk reduction in isolated systolic hypertension.
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Progesterone does not influence vascular function in postmenopausal women.
Honisett, SY, Pang, B, Stojanovska, L, Sudhir, K, Komesaroff, PA
Journal of hypertension. 2003;(6):1145-9
Abstract
BACKGROUND The protective functions of oestrogen therapy alone on cardiovascular risk parameters are well established; however, the action of progesterone on vascular parameters in an oestrogen-deprived environment is less clear. OBJECTIVES To examine the effects of progesterone alone on vascular function and hormone levels in postmenopausal women. DESIGN In a randomized, double-blind, cross-over design study, 20 healthy postmenopausal women were tested before and after 6 weeks of treatment with micronized progesterone (100 mg/daily) and matching placebo. METHODS Tests included measurement of sex hormones and gonadatropin levels, lipids and measures of surrogate markers of vascular function including, blood pressure, flow-mediated dilation of the brachial artery, systemic arterial compliance and cutaneous vascular reactivity. RESULTS The mean (+/- SEM) age of subjects was 56.4 +/- 2.7 years and the average body mass index at the baseline visit was 27.1 +/- 1.0 kg/m2. Progesterone levels increased as a result of progesterone treatment (0.9 +/- 0.2 to 9.5 +/- 2.3 nmol/l, P = 0.001), whereas follicle-stimulating hormone levels decreased (75.1 +/- 11.4 to 67.6 +/- 10.0, P = 0.001). Systemic arterial compliance, flow mediated dilation, cutaneous vascular reactivity, blood pressure, body mass index, plasma levels of cholesterol, lipids and oestrogen were unchanged. CONCLUSIONS We conclude that progesterone given without oestrogen does not adversely affect vascular function in postmenopausal women.
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3.
Rapid potentiation of endothelium-dependent vasodilation by estradiol in postmenopausal women is mediated via cyclooxygenase 2.
Calkin, AC, Sudhir, K, Honisett, S, Williams, MR, Dawood, T, Komesaroff, PA
The Journal of clinical endocrinology and metabolism. 2002;(11):5072-5
Abstract
Estrogens influence cardiovascular function through direct and indirect effects and via genomic and nongenomic mechanisms. The pathways underlying the nongenomic mechanisms are not completely understood. Estrogen-induced responses in vascular cells have been shown to influence prostaglandins and cyclooxygenase (COX), a key enzyme in the production of prostaglandins, with two isoforms, COX-1 and COX-2. We investigated the effects of prostaglandins on the acute potentiation by 17beta-estradiol (E) of acetylcholine (ACh)-mediated vasodilation in the cutaneous vasculature. Using a double-blind placebo-controlled design, we assessed skin blood flow in 32 healthy, postmenopausal women by laser Doppler velocimetry with direct current iontophoresis of ACh and sodium nitroprusside before and after 6-wk treatment periods with aspirin (a nonspecific COX-1 and COX-2 inhibitor), diclofenac (predominantly a COX-2 inhibitor, which also inhibits COX-1), celecoxib (a specific COX-2 inhibitor), given at anti-inflammatory doses, or placebo. Blood flux values before iontophoresis of ACh did not differ between the treatment groups or after E administration, excluding a direct cutaneous vasodilator effect of the treatments or of E. Acute E administration enhanced the response to ACh after aspirin, diclofenac, and placebo; however, this effect was completely abolished with celecoxib treatment (P < 0.05). E had no effect on sodium nitroprusside-mediated vasodilation after any of the treatments. We conclude that the COX-2 pathway plays a specific role in the rapid E-induced potentiation of cholinergic vasodilation in postmenopausal women.
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4.
Effects of wild yam extract on menopausal symptoms, lipids and sex hormones in healthy menopausal women.
Komesaroff, PA, Black, CV, Cable, V, Sudhir, K
Climacteric : the journal of the International Menopause Society. 2001;(2):144-50
Abstract
OBJECTIVES Many women seek alternatives to hormonal therapies for the management of menopausal symptoms. Among the treatments currently popular are extracts of wild yam (Dioscorea villosa), which are applied topically in the form of a cream. These preparations are known to contain steroidal saponins, including diosgenin, which has been claimed to influence endogenous steroidogenesis. However, there have been no studies of the safety or efficacy of these preparations in the management of menopausal symptoms. METHODS We therefore conducted a double-blind, placebo-controlled, cross-over study of the effects of a wild yam cream in 23 healthy women suffering from troublesome symptoms of the menopause. After a 4-week baseline period, each woman was given active cream and matching placebo for 3 months in random order. Diaries were completed over the baseline period and for 1 week each month thereafter, and blood and saliva samples were collected at baseline and at 3 and 6 months, for measurement of lipids and hormones. RESULTS The average age of the subjects was 53.3 +/- 1.1 (SEM) years and average time since last period 4.3 +/- 0.9 years. At baseline, the average body mass index was 27.3 +/- 0.8, cholesterol level 5.7 +/- 0.2 mmol/l and follicle stimulating hormone (FSH) level 74.2 +/- 5.1 IU/l; estradiol levels were undetectable in the majority of cases. After 3 months of treatment, no significant side-effects were reported with either active treatment or placebo, and there were no changes in weight, systolic or diastolic blood pressure, or levels of total serum cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, FSH, glucose, estradiol, or serum or salivary progesterone. Symptom scores showed a minor effect of both placebo and active treatment on diurnal flushing number and severity and total non-flushing symptom scores, and on nocturnal sweating after placebo, but no statistical difference between placebo and active creams. CONCLUSIONS This study suggests that short-term treatment with topical wild yam extract in women suffering from menopausal symptoms is free of side-effects, but appears to have little effect on menopausal symptoms. It emphasizes the importance of careful study of treatments for menopausal symptoms if women are to be adequately informed about the choices available to them.
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5.
Low-dose estrogen supplementation improves vascular function in hypogonadal men.
Komesaroff, PA, Fullerton, M, Esler, MD, Dart, A, Jennings, G, Sudhir, K
Hypertension (Dallas, Tex. : 1979). 2001;(5):1011-6
Abstract
It is widely accepted that in women, estrogens provide protection against the development of cardiovascular disease. However, the cardiovascular role of estrogens in men remains uncertain, despite preliminary evidence that endogenous estrogens produced by aromatization of androgenic precursors are of physiological importance. Hypogonadal men have very low levels of circulating estrogen. We studied the responsiveness of forearm resistance arteries to vasoconstrictor and vasodilator agents in 12 men (mean+/-SEM age, 68.7+/-2.6 years) rendered hypogonadal as a result of treatment for prostatic cancer, before and after 8 weeks of estrogen supplementation (estradiol valerate 1 mg daily; n=7) or placebo (n=5). Forearm blood flow was measured by venous occlusion plethysmography, and vasoactive agents were infused through a brachial artery cannula in doses that did not affect blood pressure or heart rate. Estrogen supplementation was well tolerated, with no adverse effects. After estrogen treatment, mean estradiol levels increased from <30 to 308+/-65 pmol/L, and both systolic and diastolic blood pressures were reduced. HDL cholesterol levels increased significantly, and vasoconstrictor responses to the NO synthase inhibitor N(G)-monomethyl-L-arginine (1, 2, 4 micromol/min) were enhanced. Vasoconstrictor responses to angiotensin II (8, 16, 32 ng/min) were markedly attenuated by estrogen treatment, as were vasoconstrictor responses to norepinephrine (25, 50, 100 ng/min). Estrogen did not alter the vasodilator responses to acetylcholine (9.25, 18.5, 37 microgram/min) or to the endothelium-independent agent sodium nitroprusside (1.6 microgram/min). Responses to all vasoactive agents were unchanged after administration of placebo. We conclude that low-dose estrogen supplementation in hypogonadal men is well tolerated, lowers blood pressure, and may affect vascular reactivity in a manner that is potentially beneficial, through several mechanisms, including enhancement of basal NO release and attenuation of vasoconstrictor responses to angiotensin II and norepinephrine. These findings suggest the need to consider a possible clinical role for estrogenic compounds in cardiovascular risk reduction in some groups of men.