Helena Gustafsson

Interaction Between Na+/K+-Pump and Na+/Ca2+-Exchanger Modulates Intercellular Communication

Ouabain, a specific inhibitor of the Na+/K+-pump, has previously been shown to interfere with intercellular communication. Here we test the hypothesis that the communication between vascular smooth muscle cells is regulated through an interaction between the Na+/K+-pump and the Na+/Ca2+-exchanger leading to an increase in the intracellular calcium concentration ([Ca2+]i) in discrete areas near the plasma membrane. [Ca2+]i in smooth muscle cells was imaged in cultured rat aortic smooth muscle cell pairs (A7r5) and in rat mesenteric small artery segments simultaneously with force. In A7r5 coupling between cells was estimated by measuring membrane capacitance. Smooth muscle cells were uncoupled when the Na+/K+-pump was inhibited either by a low concentration of ouabain, which also caused a localized increase of [Ca2+]i near the membrane, or by ATP depletion. Reduction of Na+/K+-pump activity by removal of extracellular potassium ([K+]o) also uncoupled cells, but only after inhibition of KATP channels. Inhibition of the Na+/Ca2+-exchange activity by SEA0400 or by a reduction of the equilibrium potential (making it more negative) also uncoupled the cells. Depletion of intracellular Na+ and clamping of [Ca2+]i at low concentrations prevented the uncoupling. The experiments suggest that the Na+/K+-pump may affect gap junction conductivity via localized changes in [Ca2+]i through modulation of Na+/Ca2+-exchanger activity.

Reduced anti-contractile effect of perivascular adipose tissue on mesenteric small arteries from spontaneously hypertensive rats: role of Kv7 channels.

Perivascular adipose tissue (PVAT) has been shown to produce vasoactive substances and regulate vascular tone. This function of PVAT has been reported to be altered in hypertension. However, the underlying mechanisms are not fully understood. In this study we used age-matched normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) as well as Sprague-Dawley rats and tested effects of PVAT on mesenteric small arteries. Vessels were mounted in a Mulvany-Halpern myograph and cumulative concentration-response relations to noradrenaline were determined in the presence or absence of PVAT. We found that PVAT has an anti-contractile effect on mesenteric small vessels, irrespective of strains. A reduced effect of PVAT was observed in SHR compared to WKY rats; the difference between strains was eliminated by 10 μM XE991, a blocker of Kv7 (KCNQ) voltage-dependent potassium channels. The anti-contractile effect of PVAT was not affected by depolarizing smooth muscle cells with high K(+) solution. Sensitivities to exogenous vasodilators acetylcholine or sodium nitroprusside were not potentiated but reduced in vessels with PVAT. Our results suggest that the reduced anti-contractile effect of PVAT in SHR correlates with a deficiency in Kv7 channels. Diffusion hindrance of PVAT is also a factor that should be considered in investigations on rat mesenteric small arteries.

Cardiovascular and metabolic characteristics 40 years after hypertensive pregnancies: a long-term follow-up study of mothers.

Objectives: Maternal cardiovascular morbidity is increased after hypertensive pregnancies (HTP). The pathways from complicated pregnancies to future cardiovascular disease are complex. The aim of the present study was to test the hypothesis that different cardiovascular mechanisms are changed in women who experienced HTP four decades earlier in comparison to women with normotensive pregnancies. Methods: One hundred and five women (50 with hypertensive and 55 with normal pregnancies) were examined with anthropometric measurements; office blood pressure, ambulatory blood pressure and central blood pressure, pulse wave velocity, augmentation index, intimal–media thickness, echocardiography and laboratory measurements. In addition another 204 women were followed-up by a questionnaire regarding their pregnancy 40 years ago, as well as their present health status and medications. Results: Women with HTP had more often diagnosed hypertension when compared with women with normal pregnancies (50 vs. 31%, respectively; P = 0.046), but the groups did not differ in any blood pressure levels. HTP were associated with higher pulse wave velocity (8.8 m/s vs. 7.8 m/s, P = 0.021), and higher levels of P-glucose (5.7 mmol/l vs. 5.2 mmol/l, P = 0.022), P-HbA1c (4.4% vs. 4.2%, P = 0.010) and noradrenaline (2.45 mmol/l vs. 2.11 mmol/l, P = 0.040) when compared with normotensive pregnancies. Women followed up with a questionnaire reported deteriorated cardiovascular health compared to women attending the clinical investigations of the study. Conclusion: HTP are associated with impairment in vascular function and metabolic status 40 years postpartum despite well controlled blood pressure levels.

Effects of estrogen plus progesterone on hemodynamic and vascular reactivity in hypertensive postmenopausal women

Abstract Aims. To investigate the medium-term effects of estrogen plus progesterone therapy (EPT) on vascular reactivity, endothelial function and hemodynamic responses in 20 hypertensive postmenopausal women. Methods. This randomized, double-blind, cross-over, placebo-controlled study investigates the effect of 6 months of EPT (conjugated equine estrogen plus medroxyprogesterone). Blood pressure (office and ambulatory), heart rate and heart rate variability (HRV) were measured at baseline and following EPT/placebo treatment. In eight women, we used a wire-myograph to assess endothelial function and contractile response of subcutaneous arteries to transmural nerve stimulation (TNS) and exogenous noradrenaline. Results. EPT decreased vascular reactivity to cumulative TNS compared with baseline (p<0.01) and placebo (p<0.05). Moreover, EPT diminished sensitivity to exogenous noradrenaline (p<0.05). Although EPT reinforced response to acetylcholine, we observed no difference in maximal relaxation induced by substance P or acetylcholine. EPT did not affect ambulatory blood pressure, heart rate or HRV. Conclusions. Oral combined medium-term EPT reduces adrenergic reactivity in subcutaneous arteries from treated hypertensive postmenopausal women. EPT might act postjunctionally at the adrenergic vascular receptor level. In the present study, EPT neither reduces sympathetic activity nor increases vagal tone, and thus does not support an effect on the central hemodynamic system.

Influence of chronic hormone replacement therapy on left ventricular mass and serum-ACE activity.

Abstract Aims. The aim of this investigation was to study the effects of hormone replacement therapy (HRT) on left ventricular mass (LVM) and serum-angiotensin-converting enzyme (ACE) activity (S-ACE) in well controlled hypertensive postmenopausal women. Methods. In this prospective, randomized, crossover, double-blind trial we studied 20 well controlled hypertensive postmenopausal women who received 6 months of HRT and 6 months of placebo on top of antihypertensive treatment. Two-dimensional M-mode, office blood pressure, 24-h ambulatory blood pressure (ABPM), S-estradiol and S-ACE activity were investigated at baseline, after 6 and 12 months. Results. LVM was significantly influenced by HRT (analysis of variance, ANOVA, p<0.01). However, the order in randomization of HRT and placebo had an impact on the analysis of LVM reduction (baseline – HRT – placebo: ns; baseline – placebo – HRT: p<0.01 ANOVA). Only the women lacking blockade of the renin–angiotensin–aldosterone system (RAAS) as antihypertensive treatment (n=10) experienced a reduction in LVM and a tendency of decreased S-ACE activity in response to HRT compared with baseline (p< 0.05 and p= 0.06 respectively). Conclusions. Six months of HRT resulted in significant reduction of LVM without any change in ABPM. HRT may reduce LVM through interaction with the RAAS, since hypertensive women without RAAS blockade exhibited an effect of HRT on LVM and S-ACE activity, which was not seen in women on RAAS blockade.

Aldosterone to Renin Ratio as a Screening Instrument for Primary Aldosteronism in a Middle-Aged Population with Atrial Fibrillation

Atrial fibrillation seems to be overrepresented among patients with primary aldosteronism. The aim of this study was to determine the usefulness of aldosterone to renin ratio as a screening instrument for primary aldosteronism in an atrial fibrillation population with relatively low cardiovascular risk profile. A total of 149 patients <65 years and with history of AF were screened for primary aldosteronism using aldosterone to renin ratio. Pathologically increased aldosterone to renin ratio (>65 pmol/mIU) was found in 15 participants (10.1%). Further investigation of the positive screened participants and confirmatory saline infusion test resulted in a diagnosis of primary aldosteronism in four individuals out of 149 (2.6%). Three out of the four individuals with primary aldosteronism had previously been diagnosed with hypertension, but only one out of the four had uncontrolled blood pressure, that is, >140/90 mmHg. All participants had normal potassium levels. Individuals with increased aldosterone to renin ratio had significantly higher mean systolic and diastolic blood pressure in comparison to participants with normal aldosterone to renin ratio (136 vs. 126 mmHg, p=0.02 and 84 vs. 78 mmHg, p=0.02). These findings suggest that assessment of aldosterone to renin ratio can be useful for identification of underlying primary aldosteronism in patients with diagnosed atrial fibrillation and hypertension in spite of well controlled blood pressure and normokalemia.

Bestrophin-3 is differently expressed in normal and injured mouse glomerular podocytes

Bestrophins are putative calcium‐activated chloride channels. Recently, cell‐protective functions for Bestrophin‐3 (Best3) were proposed. Best3 exists in different splice variants. We have here examined expression, alternative splicing and localization of Best3 in mouse podocytes under normal conditions and during endoplasmic reticulum (ER) stress.

Cardiac structure and function is related to current blood pressure rather than to previous hypertensive pregnancy.

Cardiac structure and function is related to current blood pressure rather than to previous hypertensive pregnancy

Acute Effects of Transdermal 17β-Estradiol on Hemostatic Variables after 24-hour Treatment

The aim of this study was to investigate the acute effects of transdermal 17β-estradiol (Estraderm®) on plasma levels of coagulatory and fibrinolytic factors in postmenopausal normotensive and hypertensive women. Eleven normotensive and 13 hypertensive women were included in this placebo-controlled crossover study. In a randomized order each subject was treated with a patch of 100 yig 17β-estradiol or placebo for 24 hours. Serum levels of tissue type plasminogen activator (tPA) activity, plasminogen activator inhibitor I (PAI-1) activity, tPA antigen, PAI-I antigen, FVII, FX, and fibrinogen were assayed after both treatments. There was no significant difference in serum levels of hemostatic variables after treatment with estrogen compared to levels after placebo treatment in either of the groups. Nor was there any measurable difference when comparing hypertensive and normotensive subjects.

Cardiovascular response to stress and perceived stress is not altered 40 years after hypertensive pregnancies

Objective: Women experiencing hypertensive pregnancies have an increased risk for cardiovascular disease. Whether stress increase the risk is unknown. The objective was to test if cardiovascular response to stress and/or perceived stress differed in relation to blood pressure status during pregnancy 40 years earlier. Methods: Cardiovascular response was examined with mental stress test, and perceived stress was evaluated with a questionnaire in 105 women. Results: Resting heart rate was higher, and pulse reactivity was lower in women with previous hypertensive pregnancies. Neither blood pressure nor perceived stress differed. Conclusion: Response to physical or psychological stress is not affected many years after pregnancy.