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Caracasanamide, one of the hypotensive agents isolated from Verbesina caracasana, is a mixture of (Z)-1a and (E)-1b forms of 1-[(3,4-dimethoxycinnamoyl)amino]-4- [(3-methyl-2-butenyl)-guanidino]butane. The structure of (E)-caracasanamide (1b) was confirmed by high-yielding synthesis starting from N,N'-bis(tert-butoxycarbonyl)-S-methylisothiourea. The water-soluble Z-form of 1a, assayed by i.v. route in anesthetized rats at doses ranging from 50 to 1600 micrograms/kg body weight, was found to decrease blood pressure, to increase cardiac inotropism, respiratory frequency, and tidal volume, and to induce a very slight and not significant tachycardia. Higher doses determined respiratory depression and, in some cases, consequent cardiac arrest. The compound was shown to affect cardiovascular function by acting at the vascular level in inducing arterial vasodilation, by determining sympathetic hypotone through central neurogenic mechanisms, and by interacting with the cardiac beta 1-adrenoreceptors. The respiratory effects were independent of the cardiovascular ones. In lowering blood pressure, the compound was more potent than guanethidine and not less potent than reserpine and papaverine. (Z)-Caracasanamide may therefore be useful in the treatment of arterial hypertension of moderate degree.

Cadmium, a widespread toxic pollutant of occupational and environmental concern, is a known human carcinogen. The prostate is a potential target for cadmium carcinogenesis, although the underlying mechanisms are still unclear. Furthermore, cadmium may induce cell death by apoptosis in various cell types, and it has been hypothesized that a key factor in cadmium-induced malignant transformation is acquisition of apoptotic resistance. We investigated the in vitro effects produced by cadmium exposure in normal or tumor cells derived from human prostate epithelium, including RWPE-1 and its cadmium-transformed derivative CTPE, the primary adenocarcinoma 22Rv1 and CWR-R1 cells and LNCaP, PC-3 and DU145 metastatic cancer cell lines. Cells were treated for 24 hours with different concentrations of CdCl2 and apoptosis, cell cycle distribution and expression of tumor suppressor proteins were analyzed. Subsequently, cellular response to cadmium was evaluated after siRNA-mediated p53 silencing in wild type p53-expressing RWPE-1 and LNCaP cells, and after adenoviral p53 overexpression in p53-deficient DU145 and PC-3 cell lines. The cell lines exhibited different sensitivity to cadmium, and 24-hour exposure to different CdCl2 concentrations induced dose- and cell type-dependent apoptotic response and inhibition of cell proliferation that correlated with accumulation of functional p53 and overexpression of p21 in wild type p53-expressing cell lines. On the other hand, p53 silencing was able to suppress cadmium-induced apoptosis. Our results demonstrate that cadmium can induce p53-dependent apoptosis in human prostate epithelial cells and suggest p53 mutation as a possible contributing factor for the acquisition of apoptotic resistance in cadmium prostatic carcinogenesis.

The integrity of caveolin-1-containing membrane microdomains is prerequisite for arachidonic acid recruitment and EDHF signaling in porcine arteries.

Previous human studies demonstrated that lead exposure may modify the metabolism of catecholamines and of hormones controlled by the hypothalamo-pituitary axis and may affect the kallikrein-kinin system. This paper reports unpublished data on the plasma renin activity of lead-exposed workers; these results are in agreement with those of previous human and experimental studies suggesting that the synthesis or release of renin is increased after short and moderate exposure to inorganic lead and reduced whenever the exposure is prolonged. Previous experimental investigations demonstrated that lead may act on the cardiovascular system, with effects on the renin-angiotensin system, on the reactivity to stimulation of peripheral catecholaminergic receptors, on sympathetic and vagal tone, and on reactivity to the stimulation of baroreceptors. This paper reports the results of a study on male Sprague-Dawley rats that received 0, 15, 30, and 60 micrograms/mL of lead in drinking water for 18 months. Blood pressure was increased in the rats receiving 30 and 60 ppm of lead; cardiac inotropism was augmented only in those receiving the higher dose of the metal, and heart rate was not modified. Cardiovascular responses to agonists indicated that lead exposure affects the renin-angiotensin system and induces sympathetic hyperactivity by acting on central and peripheral sympathetic junctions increasing the responsiveness to stimulation of alpha 2-adrenoreceptors and by increasing the reactivity to stimulation of cardiac and vascular beta-adrenergic and dopaminergic receptors. The cAMP-dependent availability of Ca2+ for contractile mechanisms of the cardiovascular muscle cells was affected by lead.

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