Posterior leukoencephalopathy following, intrathecal chemotherapy with MRA-documented vasospasm

Posterior leukoencephalopathy syndromes have been reported with hypertension, and immunosuppressive and chemotherapy agents. Cerebral vasospasm on MR angiography (MRA) has been noted in cases due to eclampsia. The authors report a case of Balint syndrome with irreversible posterior leukoencephalopathy on MRI following intrathecal methotrexate and cytarabine. Hypertension was not present. Diffuse, reversible arterial irregularities consistent with vasospasm were present on MRA during the acute illness.

Elevated plasma membrane and sarcoplasmic reticulum Ca2+ pump mRNA levels in cultured aortic smooth muscle cells from spontaneously hypertensive rats

We have observed previously that Ca2+ pump-mediated Ca2+ efflux is elevated in cultured aortic smooth muscle cells from spontaneously hypertensive rats compared to those from Wistar-Kyoto rat controls. The objective of this work was to determine if these strains differ in mRNA levels for the PMCA1 isoform of the plasma membrane Ca2+-ATPase and the SERCA2 isoform of the sarcoplasmic reticulum Ca2+-ATPase. mRNA levels were compared in cultured aortic smooth muscle cells from 10-week-old male rats. PMCA1 and SERCA2 mRNA levels were elevated in SHR compared to WKY. Angiotensin II increased the level of PMCA1 and SERCA2 mRNA in both strains. These studies provide further evidence for alterered Ca2+ homeostasis in hypertension at the level of Ca2+ transporting ATPases in the spontaneously hypertensive rat model. These data are also consistent with the hypothesis that the expression of these two Ca2+ pumps may be linked. (C) 1997 Academic Press

Intracellular free Ca2+ and basal Mn2+ influx in cultured aortic smooth muscle cells from spontaneously hypertensive and normotensive Wistar-Kyoto rats.

Numerous studies investigating the possible role of altered Ca2+ homeostasis in hypertension have compared resting and agonist-stimulated intracellular free Ca2+ ([Ca2+](i)) in cultured aortic smooth muscle cells from spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. However, such studies have not given consistent results. Differences in the method used to load cells with the Ca2+-sensitive indicator fura-2 have been investigated here as a possible source of variability between studies. We also describe the adaptation of a fluorescence technique for the assessment of basal Ca2+ permeability in SHR and WKY through the measurement of Mn2+ influx. The results are consistent with the hypothesis that basal Ca2+ influx is elevated in cultured aortic smooth muscle cells from SHR compared to those from WKY. However, this was not reflected as a significant difference between the two strains in basal or angiotensin II (200 nmol/L)stimulated [Ca2+](i). Furthermore, this result was not dependent on the protocol used to load cells with fura-2. Hence, measurement of bulk [Ca2+](i) does not appear to be the most sensitive parameter for altered Ca2+ homeostasis in SHR. Other compartments of the cell may better reflect altered Ca2+ fluxes in hypertension and are discussed in this work.

Selective down-regulation of the astrocyte glutamate transporters GLT-1 and GLAST within the medial thalamus in experimental wernicke's encephalopathy

Although earlier studies on thiamine deficiency have reported increases in extracellular glutamate concentration in the thalamus, a vulnerable region of the brain in this disorder, the mechanism by which this occurs has remained unresolved. Treatment with pyrithiamine, a central thiamine antagonist, resulted in a 71 and 55% decrease in protein levels of the astrocyte glutamate transporters GLT-1 and GLAST, respectively, by immunoblotting in the medial thalamus of day 14 symptomatic rats at loss of righting reflexes. These changes occurred prior to the onset of convulsions and pannecrosis. Loss of both GLT-1 and GLAST transporter sites was also confirmed in this region of the thalamus at the symptomatic stage using immunohistochemical methods. In contrast, no change in either transporter protein was detected in the non-vulnerable frontal parietal cortex. These effects are selective; protein levels of the astrocyte GABA transporter GAT-3 were unaffected in the medial thalamus. In addition, astrocyte-specific glial fibrillary acidic protein (GFAP) content was unchanged in this brain region, suggesting that astrocytes are spared in this disorder. Loss of GLT-1 or GLAST protein was not observed on day 12 of treatment, indicating that down-regulation of these transporters occurs within 48 h prior to loss of righting reflexes. Finally, GLT-1 content was positively correlated with levels of the neurofilament protein alpha -internexin, suggesting that early neuronal drop-out may contribute to the down-regulation of this glutamate transporter and subsequent pannecrosis. A selective, focal loss of GLT-1 and GLAST transporter proteins provides a rational explanation for the increase in interstitial glutamate levels, and may play a major role in the selective vulnerability of thalamic structures to thiamine deficiency-induced cell death.

Prediction of outcomes in hypertensive patients with suspected coronary disease

Stress echocardiography has been shown to improve the diagnosis of coronary artery disease in the presence of hypertension, but its value in prognostic evaluation is unclear. We sought to determine whether stress echocardiography could be used to predict mortality in 2363 patients with hypertension, who were followed for up to 10 years (mean 4.0+/-1.8) for death and revascularization. Stress echocardiograms were normal in 1483 patients (63%), 16% had resting left ventricular (LV) dysfunction alone, and 21% had ischemia. Abnormalities were confined to one territory in 489 patients (21%) and to multiple territories in 365 patients (15%). Cardiac death was less frequent among the patients able to exercise than among those undergoing dobutamine echocardiography (4% versus 7%, P<0.001). The risk of death in patients with a negative stress echocardiogram was <1% per year. Ischemia identified by stress echocardiography was an independent predictor of mortality in those able to exercise (hazard ratio 2.21, 95% confidence intervals 1.10 to 4.43, P=0.0001) as well as those undergoing dobutamine echo (hazard ratio 2.39, 95% confidence intervals 1.53 to 3.75, P=0.0001); other predictors were age, heart failure, resting LV dysfunction, and the Duke treadmill score. In stepwise models replicating the sequence of clinical evaluation, the results of stress echocardiography added prognostic power to models based on clinical and stress-testing variables. Thus, the results of stress echocardiography are an independent predictor of cardiac death in hypertensive patients with known or suspected coronary artery disease, incremental to clinical risks and exercise results.

Myocardial abnormalities in hypertensive patients with normal and abnormal left ventricular filling: a study of ultrasound tissue characterization and strain

Abnormal left ventricular (LV) filling is common, but not universal, in hypertensive LV hypertrophy (LVH). We sought to elucidate the relative contributions of myocardial structural changes, loading and hypertrophy to LV dysfunction in 113 patients: 85 with hypertensive LVH and 28 controls without LVH and with normal filling. Patients with normal dobutamine stress echocardiography and no history of coronary artery disease were selected, in order to exclude a contribution from ischaemia or scar. Abnormal LV filling was identified in 65 LVH patients, based on Doppler measurement of transmitral filling and annular velocities. All patients underwent grey-scale and colour tissue Doppler imaging from three apical views, which were stored and analysed off line. Integrated backscatter (113) and strain rate imaging were used to detect changes in structure and function; average cyclic variation of 113, strain rate and peak systolic strain were calculated by averaging each segment. Calibrated 113 intensity, corrected for pericardial 113 intensity, was measured in the septum and posterior wall from the parasternal long-axis view. Patients with LVH differed significantly from controls with respect to all backscatter and strain parameters, irrespective of the presence or absence of abnormal LV filling. LVH patients with and without abnormal LV filling differed with regard to age, LV mass and incidence of diabetes mellitus, but also showed significant differences in cyclic variation (P < 0.01), calibrated 113 in the posterior wall (P < 0.05) and strain rate (P < 0.01), although blood pressure, heart rate and LV systolic function were similar. Multivariate logistic regression analysis demonstrated that age, LV mass index and calibrated IB in the posterior wall were independent determinants of abnormal LV filling in patients with LVH. Thus structural and functional abnormalities can be detected in hypertensive patients with LVH with and without abnormal LV filling. In addition to age and LVH, structural (not functional) abnormalities are likely to contribute to abnormal LV filling, and may be an early sign of LV damage. 113 is useful for the detection of myocardial abnormalities in patients with hypertensive LVH.

Endogenous endothelin-1 limits exercise-induced vasodilation in hypertensive humans

Essential hypertension is a common disorder, associated with increased endothelin-l-mediated vasoconstrictor tone at rest. We hypothesized that increased vasoconstrictor activity of endothelin-1 might explain why the normal decrease in peripheral vascular resistance in response to exercise is attenuated in hypertensive patients. Therefore, we investigated the effect of endothelin A (ETA) receptor blockade on the vasodilator response to handgrip exercise. Forearm blood flow responses to handgrip exercise (15%, 30%, and 45% of maximum voluntary contraction) were assessed in hypertensive patients and matched normotensive subjects, before and after intra-arterial infusions of the ETA receptor antagonist BQ-123; a control dilator, hydralazine; and placebo (saline). Preinfusion (baseline) vasodilation in response to exercise was significantly attenuated at each workload in hypertensive patients compared with normotensive subjects. Intra-arterial infusions of hydralazine and saline did not increase the vasodilator response to exercise in either hypertensives or normotensives at any workload. The vasodilator response to exercise was markedly enhanced after BQ-123 at the 2 higher workloads in hypertensives (157 +/- 48%, P < 0.01; 203 &PLUSMN; 58%, P < 0.01) but not in normotensives. This suggests that the impaired vasodilator response to exercise in hypertensive patients is, at least in part, a functional limitation caused by endogenous ETA receptor-mediated vasoconstriction. Treatment with endothelin receptor antagonists may, therefore, increase exercise capacity in essential hypertension.

Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats

1 This study has administered pirfenidone (5-methyl-l-phenyl-2-[1H]-pyridone) or amiloride to attenuate the remodelling and associated functional changes, especially an increased cardiac stiffness, in DOCA-salt hypertensive rats. 2 In control rats, the elimination half-life of pirfenidone following a single intravenous dose of 200 mg kg(-1) was 37 min while oral bioavailability at this dose was 25.7%. Plasma pirfenidone concentrations in control rats averaged 1.9 +/- 0.1 mug ml(-1) over 24 It after 14 days' administration as a 0.4% mixture in food. 3 Pirfenidone (approximately 250-300 mg kg(-1) day(-1) as 0.4% in food) and amiloride (I mg kg-1 day(-1) sc) were administered for 2 weeks starting 2 weeks post-surgery. Pirfenidone but not amiloride attenuated ventricular hypertrophy (2.69 +/- 0.09, UNX 2.01 +/- 0.05. DOCA-salt 3.11 +/- 0.09 mg kg(-1) body wt) without lowering systolic blood pressure. 4 Collagen deposition was significantly increased in the interstitium after 2 weeks and further increased with scarring of the left ventricle after 4 weeks; pirfenidone and amiloride reversed the increases and prevented further increases. This accumulation of collagen was accompanied by an increase in diastolic stiffness constant; both amiloride and pirfenidone, reversed this increase. 5 Noradrenaline potency (positive chronotropy) was decreased in right atria (neg log EC50: control 6.92 +/- 0.06; DOCA-salt 6.64 +/- 0.08); pirfenidone but not amiloride reversed this change. Noradrenaline was a more potent vasoconstrictor in thoracic aortic rings (neg log EC50: control 6.91 +/- 0.10; DOCA-salt 7.90 +/- 0.07); pirfenidone treatment did not change noradrenaline potency. 6 Thus, pirfenidone and amiloride reverse and prevent cardiac remodelling and the increased cardiac stiffness without reversing the increased vascular responses to noradrenaline.

Responsiveness, affinity constants and beta-adrenoceptor reserves for isoprenaline on aortae from normo-, pre and hypertensive rats

The objective of this study was to determine the responsiveness, affinity constants and beta-adrenoceptor reserves for isoprenaline on the isolated aorta in the maturation of normotensive and hypertensive rats. The effects of a very slowly reversible antagonist, bromoacetylalprenololmenthane (BAAM), on the relaxant responses of the aortae of 5- and 14-week-old Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs) to isoprenaline were determined. Five-week-old SHRs are pre-hypertensive and the aortic rings are less responsive to isoprenaline than age-matched WKY (pD(2) values: WKY, 8.40; SHRs, 8.03). Similar relaxant responses to forskolin were obtained on the aortae of 5- and 14-week-old WKY and SHRs. The K-A value for isoprenaline at the aortic beta(2)-adrenoceptors of the 5-week-old WKY was 2.1 x 10(-7) M, and similar values were obtained on the aortae of 5-week-old SHR and 14-week-old WKY and SHRs. In the maturation of the WKY aortae from 5 to 14 weeks, there was a reduction in the maximum response, a major loss of sensitivity and a loss of 2-adrenoceptor reserve for isoprenaline. On 5-week-old SHR aorta, the sensitivity to isoprenaline was 2.5-fold lower, and the beta(2)-adrenoceptor reserve was less than on age-matched WKY. In the development of hypertension on the SHR aorta from 5 to 14 weeks, there was a reduction in the maximum response to isoprenaline. At 14 weeks, the sensitivity and the 2-adrenoceptor reserve to isoprenaline were similar, but the maximum responses were lower on the SHR than WKY. As there are differences in pre-hypertensive SHR and age-matched WKY aortic responses to isoprenaline, it is no longer valid to consider that the loss of responsiveness to isoprenaline in hypertension is solely owing to the hypertension. There are no changes in affinity, but major changes in the sensitivity, maximum responses and aortic beta(2)-adrenoceptor reserves to isoprenaline in the maturation of normotensive and pre-hypertensive aortae.

Effects of BDF 9198 on left ventricular contractility in advanced spontaneously hypertensive rats with heart failure

In the first part of this study, we characterized 24-month-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs), their heart weights, and the responses of the isolated left ventricles to electrical stimulation. In the main part of the study, we tested whether the positive inotropic effects of BDF 9198, which prevents the closure of the cardiac sodium channel, were present in senescence and heart failure. Thus, we studied the effects of BDF 9198 on the left ventricle strips of 24-month-old WKY rats (senescence) and SHRs using contractility methods. In comparison with WKY rats, the left ventricles of 24-month-old SHRs were hypertrophied and had prolonged times to peak contraction. BDF 9198 (10(-8) to 10(-6) m) was a positive inotrope on the left ventricles of WKY rats, with a maximum augmenting effect of 122% with BDF 9198 at 10(-7) m. The magnitude of the augmenting effects of BDF 9198 were reduced in SHR heart failure, with a maximum augmenting effect of 26% at 10(-7) m. BDF 9198 at 10(-6) m attenuated the responses of the SHR left ventricle to electrical stimulation. In conclusion, the potential of drugs that prevent closure of the sodium channel as positive inotropes in the treatment of heart failure should be further considered.

Effects of dofetilide on cardiovascular tissues from normo- and hypertensive rats

The aim was to test whether dofetilide has some potential for use in the treatment of heart failure. Dofetilide at less than or equal to 3 x 10(-5) m had no effect on the quiescent Wistar Kyoto (WKY) rat aorta, mesenteric and intralobar arteries, or the spontaneous contractions of the WKY rat portal vein. Dofetilide at 10(-6) to 3 x 10(-5) m relaxed the KCl-contracted aorta. Dofetilide at 10(-9)-10(-7) m augmented the force of contraction of left ventricle strips from 12- and 18-month-old WKY rats at 2 Hz. Spontaneously hypertensive rats (SHRs) at 12 and 17-21 months of age are models of cardiac hypertrophy and failure, respectively. The augmentation of force at 2 Hz with dofetilide was similar on 12- and 18-month-old WKY rats and 12-month-old SHRs but reduced on the 18-month-old SHR left ventricle. At a higher more physiological frequency, 4 Hz, the threshold concentration of dofetilide required to augment the force responses of 21-month-old SHR left ventricles was markedly increased and the maximum augmenting effect was decreased. Dofetilide at 10(-7)-10(-5) m reduced the rate of the 17-month-old WKY rat right atrium, and had a similar effect on age-matched SHR right atrium. In summary, dofetilide is a positive inotrope and negative chronotrope in the rat. However, as the positive inotropic effect is not observed with clinically relevant concentrations at a physiological rate in heart failure, dofetilide is unlikely to be useful as a positive inotrope in the treatment of heart failure.