Long-term administration of amlodipine prevents decompensation to diastolic heart failure in hypertensive rats.

UNLABELLED: OBJECTIVES; We assessed the effects of long-term amlodipine administration in a diastolic heart failure (DHF) rat model with preserved systolic function as well as the relationship between changes in left ventricular (LV) myocardial stiffening and alterations in extracellular matrix. BACKGROUND: Although the effect of long-term administration of amlodipine has been shown to be disappointing in patients with systolic failure, the effect is unknown in those with DHF. METHODS: Dahl salt-sensitive rats fed a high-salt diet for seven weeks were divided into three groups: eight untreated rats (DHF group), eight rats given high-dose amlodipine (10 mg/kg/day; HDA group) and seven rats given low-dose amlodipine (1 mg/kg/day; LDA group). RESULTS: High-dose administration of amlodipine decreased systolic blood pressure and controlled excessive hypertrophy, without a decrease in the collagen content, and prevented the elevation of LV end-diastolic pressure at 19 weeks. Low-dose administration of amlodipine with subdeppressive effects did not control either hypertrophy or fibrosis; however, it prevented myocardial stiffening and, hence, the elevation of LV end-diastolic pressure. The ratio of type I to type III collagen messenger ribonucleic acid levels was significantly lower in both the HDA and LDA groups than in the DHF group. CONCLUSIONS: Long-term administration of amlodipine prevented the transition to DHF both at the depressor and subdepressor doses. Amlodipine did not decrease the collagen content, but attenuated myocardial stiffness, with inhibition of the phenotype shift from type III to type I collagen. Thus, amlodipine may exert beneficial effects through amelioration of collagen remodeling in the treatment of DHF.

Increased urinary phosphate excretion in pseudohypoparathyroidism type II with long-term treatment with phosphodiesterase inhibitor.

A 58-year-old woman was diagnosed to have pseudohypoparathyroidism (PHP) type II because of the absence of an increase of urinary phosphate secretion, despite a marked increase in urinary cAMP excretion on the Ellsworth-Howard test. We treated the patient with a cyclic-nucleotide phosphodiesterase inhibitor, theophylline, resulting in increased urinary phosphate and cAMP excretions. Dibutyl cAMP administration induced the increase in the urinary phosphate excretion. In this case, the unresponsiveness of the urinary phosphate secretion to cAMP was recovered by a high dose of cAMP or long-term administration of a phosphodiesterase inhibitor. These data imply that cAMP responsiveness to renal tubular phosphate reabsorption should be more strictly elucidated in the patient with PHP type II.

Reversal of GATA-6 downregulation promotes smooth muscle differentiation and inhibits intimal hyperplasia in balloon-injured rat carotid artery.

The GATA-6 transcription factor is expressed in quiescent vascular smooth muscle cells (VSMCs) in culture, and levels of its transcript are rapidly downregulated on mitogen stimulation. In this study, we demonstrate that the GATA-6 transcript, protein, and DNA-binding activity are downregulated in rat carotid arteries on balloon injury. Downregulation was detected at 1 and 3 days after injury and recovered by 7 days. To assess the role of GATA-6 downregulation in injury-induced vascular lesion formation, adenoviral vectors were used to express wild-type human GATA-6 cDNA (Ad-GATA6) or an inactive mutant cDNA that lacks a portion of the zinc-finger domain (Ad-GATA6DeltaZF). Adenovirus-mediated GATA-6 gene transfer to the vessel wall after balloon injury partially restored the levels of GATA-6 protein and DNA-binding activity to before injury levels. The local delivery of Ad-GATA6 but not Ad-GATA6DeltaZF inhibited lesion formation by 46% relative to saline control and 50% relative to a control adenovirus that expressed lacZ. Local delivery of Ad-GATA6 also reversed changes in the expression patterns of smooth muscle myosin heavy chain, smooth muscle alpha-actin, calponin, vinculin, metavinculin, and proliferating cell nuclear antigen that are associated with injury-induced VSMC phenotypic modulation. These data indicate that the injury-induced downregulation of GATA-6 is an essential feature of VSMC phenotypic modulation that contributes to vessel lesion formation.

Changes in muscle sympathetic nerve activity and effect of breathing maneuvers during microgravity induced by parabolic flight in humans.

UNLABELLED: This study aimed to clarify how muscle sympathetic nerve activity (MSNA) in humans, which plays an important role in blood pressure control against gravity, is altered under microgravity (microG) conditions, and how the MSNA change is modified by breathing maneuvers. Ten subjects seated themselves in a jet aircraft with their knees extended. MSNA was recorded microneurographically from the left tibial nerve with simultaneous monitoring of ECG, blood pressure, respiration, and intrathoracic blood volume estimated by the impedance method during parabolic flight in a jet aircraft. In half of the parabolas, their respiration was controlled at 0.25 Hz by a metronome. RESULTS: MSNA was enhanced under hypergravity just before microG entry, and immediately suppressed by microG induced by parabolic flight. The suppression was more marked with controlled than with uncontrolled respiration (51.6 +/- 7.2 vs 82.8 +/- 2.5%, mean +/- SE, 1G=100%). MSNA changes during microG correlated significantly to changes in blood pressure and intrathoracic blood volume. The blood pressure fall 10 to 15 sec after microG entry was less prominent with controlled than with uncontrolled respiration. We conclude that changes in arterial blood pressure and intrathoracic blood volume modulate MSNA during microG induced by parabolic flight, depending largely on breathing maneuvers.

[Outcome of initial treatment with high-dose vitamin B6, valproate sodium or clonazepam in West syndrome].

We reviewed the outcome (seizures and development) of 25 cases with West syndrome in which antiepileptic drugs (valproate sodium, clonazepam) or high doses of vitamin B6, instead of ACTH therapy, were administered for the initial treatment. Five of 9 cryptogenic cases (56%) and 4 of 16 symptomatic cases (25%) showed complete cessation of spasms. In cryptogenic cases, response to vitamin B6, valproate sodium or clonazepam was not predicted by clinical features (age of onset, seizure type, initial EEG finding or treatment lag). On the other hand, response to these drugs was correlated with some clinical findings in symptomatic cases; all infants with neurocutaneous syndrome (tuberous sclerosis, neurofibromatosis type 1) had controlled infantile spasms, while none of patients with severe neonatal asphyxia or with prior other seizures responded. Twenty of 25 patients have been followed-up. The average age at follow-up was 5 years and 8 months. Prognosis of both cryptogenic and symptomatic "responders" was favorable; all had seizures controlled, and 50% had normal psychomotor development or only mild impairment (DQ > 70). Symptomatic "nonresponders" had the worst prognosis. Our results suggest that choice of drug in the initial treatment of West syndrome should be determined by clinical features (especially etiology).

Transient increase in human muscle sympathetic nerve activity during manual acupuncture.

To clarify the effects of manual acupuncture on the autonomic nervous system, we measured efferent muscle sympathetic nerve activity (MSNA) from the right peroneal nerve while simultaneously recording blood pressure and heart rate both during the resting period and after manual acupuncture applied to the Tsusanli acupoint of the same limb. The needle was rotated intermittently for 30 s at 5-min intervals. MSNA increased transiently with the suppression of heart rate during rotation of the acupuncture needle. No consistent change in blood pressure was found throughout the acupuncture session. After removal of the needle, both the MSNA and heart rate returned to the initial control values, and the mean blood pressure showed an increase over the resting value. MSNA showed a negative correlation with heart rate in four out of five subjects who received acupuncture. These results suggest that the coactivation of cardiac vagal and muscle sympathetic nerves is evoked by the acupuncture maneuver.

Sleep-related changes in human muscle and skin sympathetic nerve activities.

To characterize the features of sympathetic nerve activity during non-REM sleep, we measured the muscle and skin sympathetic nerve activities (MSNA and SSNA, respectively) using a double recording microneurographic technique. Eight healthy volunteers were monitored by polysomnography (including EEG, EOG, EMG, and ECG) and received acoustic stimuli (880 Hz, 125 ms) during sleep stage 2. The specific discharge properties of MSNA during wakefulness included pulse-synchronicity, short burst duration and a non-responsiveness to arousal stimuli. These were considered to be generated by an inhibitory input from the baroreceptors to the cardiovascular center. In contrast, SSNA lacked pulse-synchronicity, had longer bursts, and was responsive to a variety of stimuli. Burst rates of MSNA and SSNA were reduced during sleep stages 1 and 2 (light sleep) vs. during a wakefulness. Both MSNA and SSNA appeared to be related to spontaneously occurring K-complexes. The baroreflex latency (from the ECG R-wave to the integrated MSNA burst peak) was constant at approximately 1.20 s during sleep, suggesting that pulse-synchronicity was maintained. The MSNA burst evolution time (interval between initiation of the burst and its peak) became longer with a transition to deeper non-REM sleep stages, whereas the SSNA burst evolution times remained constant. K-complexes induced by acoustic stimuli were frequently accompanied by MSNA and/or SSNA. MSNA responded to acoustic stimuli during light sleep, but some bursts lacked a close relation in time to cardiac rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)

Muscle sympathetic nerve responsiveness to static contraction is not altered under hypoxia.

The purpose of this study was to determine if response in muscle sympathetic nerve activity (MSNA) to static muscle contraction alters or not during peripheral chemoreceptor stimulation with hypoxia. MSNA was recorded from the tibial nerve using a microneurographic technique in seven healthy subjects in a sitting position. They performed a static handgrip exercise (SHG) for 2 min under normobaric normoxia and hypobaric hypoxic conditions corresponding to an altitude of 4,000 m (460 mmHg). MSNA represented as burst rate and total sympathetic nerve activity (TSNA) (burst rate X mean burst amplitude) at rest increased by 7.7 bursts/min and by 60%, respectively, compared to those under normoxia. During the exercise, MSNA increased over control values before exercise both under normoxia and hypoxia. TSNA increased during the first and second minute of SHG by 19% (p greater than 0.05) and 35% (p less than 0.05) in normoxia and by 15 (p greater than 0.05) and 34% (p less than 0.05) in hypoxia over the control value, respectively, while the absolute intensity of MSNA during SHG was higher under hypoxia. The response of MSNA to SHG which showed algebraic sums was the same under normoxia and hypoxia, that might relate to consist of afferent pathways independent from carotid chemoreflex.