Skin pigmentation is an important human phenotypic trait whose regulation, in spite of recent advances, has not yet been fully understood. The pigment melanin is produced in melanosomes by melanocytes in a complex process called melanogenesis. The melanocyte interacts with endocrine, immune, inflammatory and central nervous systems, and its activity is also regulated by extrinsic factors such as ultraviolet radiation and drugs. We have carried out a review of the current understanding of intrinsic and extrinsic factors regulating skin pigmentation, the melanogenesis stages and related gene defects. We focused on melanocyte-keratinocyte interaction, activation of melanocortin type 1 receptor (MC1-R) by peptides (melanocyte-stimulating hormone and adrenocorticotropic hormone) resulting from proopiomelanocortin (POMC) cleavage, and mechanisms of ultraviolet-induced skin pigmentation. The identification and comprehension of the melanogenesis mechanism facilitate the understanding of the pathogenesis of pigmentation disorders and the development of potential therapeutic options.

Imidazolines bind with high affinity not only to alpha-adrenoceptors but also to specific imidazoline binding sites (IBS) labelled by either [3H]clonidine or [3H]idazoxan and termed I1- and I2-IBS, respectively. Since bovine adrenal chromaffin cells lack alpha 2-adrenoceptors, we investigated the pharmacological characteristics of [3H]clonidine binding sites in the bovine adrenal medulla. The binding of [3H]clonidine was rapid, reversible, partly specific (as defined by naphazoline 0.1 mmol/l; 55% specific binding at [3H]clonidine 10 nmol/l), saturable and of high affinity. The specific binding of [3H]clonidine to bovine adrenal medullary membranes was concentration-dependently inhibited by various imidazolines, guanidines and an oxazoline derivative but not, or with negligible affinity, by rauwolscine and (-)-adrenaline. In most cases, the competition curves were best fitted to a two-site model. The rank order of affinity for the high affinity site (in a few cases the single detectable site) was as follows: naphazoline > or = BDF 7579 (4-chloro-2-isoindolinyl guanidine) > or = clonidine > or = cirazoline > or = BDF 6143 (4-chloro-2-(2-imidazoline-2-ylamino)-isoindoline hydrochloride) > BDF 7572 (4,7-chloro-2-(2-imidazolin-2-ylamino)-isoindoline) > moxonidine = rilmenidine > BDF 6100 (2-(2-imidazoline-2-ylamino)-isoindoline) = idazoxan > phentolamine > aganodine = guanabenz > amiloride > histamine. This rank order is compatible with the pharmacological properties of the I1-IBS. The non-hydrolysable GTP-analogue Gpp(NH)p (5'guanylylimidodiphosphate; 100 mumol/l) inhibited specific [3H]clonidine binding by about 50%. Equilibrium [3H]clonidine binding was also significantly reduced by K+ and Mg2+.(ABSTRACT TRUNCATED AT 250 WORDS)

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Diet has a high relevance in health. Hypertension is a major risk factor for cardiovascular diseases and has an important impact on public health, and consequently on countries economy. Scientific research gathered strong evidence about the role of several dietary factors either in etiology or in treatment/prevention of these diseases. Peptides from different food matrices have been studied, and indicated as compounds with particular interest in the context of hypertension. The classical approach involves the identification of peptides with an in vitro ACE inhibitory activity and the assumption that the observed in vivo effects are due to this enzyme blockade. However, in some cases the potency of ACE blockade does not correlate with the antihypertensive activity in vivo. This paper reviews the current literature that identifies mechanisms of action, other than ACE inhibition, that might explain antihypertensive effects of biologically active peptides from different food sources.

1 This investigation was undertaken to compare pre-and postjunctional receptors involved in the responses of the canine mesenteric and pulmonary arteries to angiotensin II. 2 In the mesenteric artery, angiotensin II caused an enhancement of tritium over¯ow evoked by electrical stimulation (EC 30% =5 nM), the maximal eect representing an increase by about 45%. Postjunctionally, angiotensin II caused concentration-dependent contractions (pD 2 =8.57). Saralasin antagonized both pre-and postjunctional eects of angiotensin II, but it was more potent at post-than at prejunctional level (pA 2 of 9.51 and 8.15, respectively), while losartan antagonized exclusively the postjunctional eects of angiotensin II (pA 2 =8.15). PD123319 had no antagonist eect either pre-or postjunctionally. 3 In the pulmonary artery, angiotensin II also caused an enhancement of the electrically-evoked tritium over¯ow (EC 30% =1.54 nM), its maximal eect increasing tritium over¯ow by about 80%. Postjunctionally, angiotensin II caused contractile responses (pD 2 =8.52). As in the mesenteric artery, saralasin antagonized angiotensin II eects at both pre-and postjunctional level and it was more potent postjunctionally (pA 2 of 9.58 and 8.10, respectively). Losartan antagonized only the postjunctional eects of angiotensin II (pA 2 =7.96) and PD123319 was ineective. 4 It is concluded that in both vessels: (1) pre-and postjunctional receptors belong to a dierent subtype, since they are dierently antagonized by the same antagonists; (2) postjunctional receptors belong to AT 1 subtype, since they are blocked by losartan but not by AT 2 antagonists; (3) prejunctional receptors apparently belong to neither AT 1 or AT 2 subtype since they are blocked by neither AT 1 nor AT 2 antagonists.

Ultraviolet radiation is the major environmental insult to the skin and stimulates the synthesis of melanin in melanocytes, which then distribute it to the neighboring keratinocytes where it confers photo-protection. Skin color results from the paracrine interaction between these two cell types. Recent studies suggest that endocannabinoids are potential mediators in the skin. Here, we investigated whether cannabinoid drugs play a role in melanogenesis and if ultraviolet radiation modifies the cutaneous endocannabinoid system. We used human melanotic melanoma cell line (SK-mel-1) in monoculture or co-culture with human keratinocytes (HaCat). Endocannabinoid levels, cannabinoid receptors expression, and melanin content were evaluated under basal conditions and after ultraviolet-B irradiation (311 nm). We provide evidence that human melanoma cells (SK-mel-1) express CB(1) receptors, and when in co-culture with keratinocytes (HaCat), the selective CB(1) receptor agonist arachidonyl-2-chloroethylamide (ACEA 1 and 10 μM) inhibited (by 33.4 and 37.3%, respectively) basal melanogenesis. In addition, ultraviolet-B-induced melanogenesis in co-cultures was abolished by ACEA 10 μM. Both ACEA inhibitory effects were reversed by AM251 (1 μM), a selective CB(1) antagonist. Furthermore, ultraviolet-B radiation increased endocannabinoids levels only in keratinocytes, whereas CB(1) cannabinoid receptor expression was up-regulated only in melanoma cells. Our results collectively suggest that ultraviolet radiation activates paracrine CB(1)-mediated endocannabinoid signaling to negatively regulate melanin synthesis. The endocannabinoid system in the skin may be a possible target for future therapies in pigmentary disorders.

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