Endogenous kinins are important vasoactive peptides whose effects are mediated by two G-Protein-coupled receptors (R), named B2R (constitutive) and B1R (inducible). They are involved in vascular homeostasis, ischemic pre- and post- conditioning, but also in cardiovascular diseases. They contribute to the therapeutic effects of angiotensin-1 converting enzyme inhibitors (ACEI) and angiotensin AT1 receptor blockers. Benefits derive primarily from vasodilatory, antiproliferative, antihypertrophic, antifibrotic, antithrombic and antioxidant properties, which are associated with the release of endothelial factors such as nitric oxide, prostacyclin and tissue plasminogen activator. Uncontrolled production of kinins or the inhibition of their metabolism may lead to unwanted pro-inflammatory side effects. Thus, B2R antagonism is salutary in angioedema, septic shock, stroke, and Chagas vasculopathy. B1R is virtually absent in healthy tissues, yet this receptor is induced by the cytokine pathway and the oxidative stress via the transcriptional nuclear factor NF-κB. The B1R may play a compensatory role for the lack of B2R, and its up-regulation during tissue damage may be a useful mechanism of host defense. Activation of both receptors may be beneficial, notably in neovascularisation, angiogenesis, heart ischemia and diabetic nephropathy. At the same time, B1R is a potent activator of inducible nitric oxide and NADPH oxidase, which are associated with vascular inflammation, increased permeability, insulin resistance, endothelial dysfunction and diabetic complications. The dual beneficial and deleterious effects of kinin receptors and, particularly B1R, raise an unsettled issue on the therapeutic value of B1R/B2R agonists versus antagonists in cardiovascular diseases. Hence, the Janus-face of kinin receptors needs to be seriously addressed in the upcoming clinical trials for each pathological setting.

The effect of epinephrine was tested on the proliferation of rat arterial smooth muscle cells (SMC) in secondary cultures. Epinephrine added daily to the culture medium caused a striking stimulation of growth. The effect increased with time and was dose-dependent. Maximal stimulation was observed at a concentration of 10(-5) M and after 72 hours. At higher concentrations (10(-3) M) epinephrine exhibited toxic effects on SMC. When SMC were maintained quiescent by deprivation of serum, the subsequent addition of epinephrine required serum to significantly enhance growth. This growth stimulation increased with serum concentration (from 0.1% to 10%). All the adrenergic agonists tested were found to stimulate SMC growth, with an activity classified by decreasing order as follows: norepinephrine greater than epinephrine greater than isoproterenol. Finally, this mitogenic response of SMC to catecholamines was specific since it could be blocked by adrenergic blocking agents, phentolamine being more efficient than propranolol in that connection. The results suggest that epinephrine and other catecholamines may act as growth factors for aortic SMC, at least in rat, mostly through adrenoreceptors.

Abstract-Angiotensin II regulates vascular structure through growth and apoptosis, with implications in pathophysiology.Subtypes of vascular smooth muscle cells with specific morphology, growth, or apoptotic features have been isolated. Here, we investigated the effects of angiotensin II on apoptosis of 2 morphologically different rat aortic smooth muscle cell phenotypes. Key Words: angiotensin II Ⅲ apoptosis Ⅲ calcium Ⅲ muscle, smooth, vascular Ⅲ cells V ascular smooth muscle cells (VSMCs) maintain vascular tone mainly through coordinated contraction/relaxation, and they play a role in arterial wall remodeling through proliferation, hypertrophy, and apoptosis. 1 The arterial tree exhibits heterogeneity in response to vasoactive stimuli and in alterations induced by hypertension or atherosclerosis. The concept that distinct VSMC subtypes may play specific roles, at different locations or pathophysiological situations, is well documented in animals, 2-6 and VSMC heterogeneity also exists in human arteries. 7 In the rat arterial model, 2 major VSMC subtypes have been discerned on the basis of stable distinct morphologies in culture: spindle versus epithelioid. 2,8,9 They also differ in growth properties or protein synthesis 2,8 -11 ; however, their responses to vasoactive stimuli are barely known. 12 Angiotensin (Ang) II, the main effector peptide of the renin-angiotensin system, plays an important role in normal vascular physiology and cardiovascular diseases, 13 mostly through the Ang II type 1 (AT 1 ) receptor and partly through the Ang II type 2 (AT 2 ) receptor. AT 1 receptor-mediated intracellular calcium concentration ([Ca 2ϩ ] i ) signaling is a major determinant of VSMC contraction. 14 Ang II is a modulator of VSMC growth with proliferative/hypertrophic effects mediated by the AT 1 receptor through complex, partly calcium-dependent, signaling. 14 Heterogeneity exists in Ang II calcium signaling 14 -16 and long-term responses 17-19 between individual VSMCs, arteries, or arterial layers. In vivo, Ang II can induce a delayed apoptosis through AT 1 receptor activation. 20,21 Inversely, in vitro, Ang II induces apoptosis through AT 2 receptor activation in AT 2 -transfected VSMCs, 22 whereas AT 1 receptors might also protect native VSMCs against acute NO-induced apoptosis. 23 The question of whether the diversity in Ang II biological effects could originate from variations in the different VSMC subtypes has not been addressed. Therefore, the aim of the present study was to investigate whether VSMC subtypes responded differently to Ang II in [Ca 2ϩ ] i signaling and long-term survival. We used 2 stable cell lines, Sp-SMC and Ep-SMC, as respective models of spindle and epithelioid rat arterial VSMC subtypes. The results show dramatically different Ang II responses in the 2 VSMC lines. A delayed AT 1 receptor-mediated calcium-dependent apoptosis was

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