The actions of the calcium-channel blocker D-600 on cardiac noradrenaline stores were investigated by giving rats the drug systemically and then using a high-performance liquid chromatograph equipped with an electrochemical detector to determine the noradrenaline content of their hearts. A single 5-mg/kg dose of D-600 caused a significant depletion of noradrenaline content of the ventricles (approximately 31%) but not of the auricles. However, when multiple doses of D-600 were given at 12-h intervals, the depletion of cardiac noradrenaline content was more marked and both the auricular and ventricular contents were significantly decreased. Depletion of noradrenaline content was maximal 4 h after administration of D-600. A partial recovery of noradrenaline content occurred 16 h after administration of D-600, indicating that this effect of D-600 is reversible. In in vitro studies, D-600 (10(-7) to 10(-3) M) evoked a dose-related increase in the basal outflow of tritium from the rat isolated atria preloaded with [3H]noradrenaline ([3H]NA), indicating that depletion of cardiac noradrenaline stores by D-600 may be due to a direct action on sympathetic nerves rather than to increased reflex sympathetic activity secondary to profound vasodilation caused by the drug. The metabolic profile of tissue 3H content and of D-600-evoked 3H overflow was also examined. Whereas greater than 90% of tissue 3H content consisted of unchanged [3H]NA, 60-70% of the D-600-evoked overflow consisted of [3,4-3H]dihydroxyphenylglycol, and approximately 5% was unchanged NA, thus indicating that D-600 causes release of [3H]NA intraneuronally.(ABSTRACT TRUNCATED AT 250 WORDS)
Pulmonary hypertension (PH) is a devastating condition that without proper management can deteriorate progressively. Elevated pulmonary artery pressure without an identifiable etiology is called IPAH. PH resulting from a specific disease is referred to as secondary PH; left-sided cardiac disease can lead to an increase in pulmonary artery pressure resulting in increased vascular resistance and subsequent structural remodeling. If left-sided failure progresses to right-sided failure with high pulmonary artery pressure, the outcome is ominous. It has been clearly proven that early diagnosis and effective medical therapy can markedly decrease morbidity and mortality. In this review, we discuss the current treatment modalities and their limitations for PH secondary to heart failure. Conventional therapy in patients with pulmonary arterial hypertension as well as recent advances in the medical management of PH in general, are also described. Last, the surgical management of these patients and other promising interventional modalities are reviewed.
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