No abstract

The endothelium releases the powerful vasodilator and antiaggregatory substance, EDRF, both under basal conditions and upon stimulation by a wide variety of agents. Endothelial injury or dysfunction may play an important role in the spasmogenicity of the coronary artery, although other possible alterations related to atherosclerosis should also be considered. Among the possible stimuli, aggregating platelets are important as a source of vasoconstrictor substances. The endothelium may also produce the vasoactive substances EDHF and EDCF(s). Their pathophysiologic significance remains to be determined.

Experiments were designed to determine the effects of cooling on alpha 1- and alpha 2-adrenergic responses in isolated canine cutaneous veins. Rings of saphenous veins were suspended for isometric tension recording in physiological salt solution. Cooling (from 37 to 24 degrees C) augmented contractions to norepinephrine under control conditions and after alpha 1-adrenergic blockade (prazosin) but not following alpha 2-adrenergic blockade (rauwolscine). Cooling augmented contractions evoked by the alpha 2-adrenergic agonists B-HT 920 and UK 14304 but did not affect responses to the full alpha 1-adrenergic agonist phenylephrine. These experiments suggest that cooling augments alpha 2-adrenergic responsiveness without affecting alpha 1-adrenergic responsiveness. However, the contractions evoked by the partial alpha 1-adrenergic agonist St 587 were virtually abolished by cooling. Moreover, following partial irreversible blockade of the alpha 1-adrenoceptors with phenoxybenzamine, cooling also reduced the contractions evoked by phenylephrine. Therefore, cooling reduces alpha 1-adrenergic responsiveness in canine cutaneous veins, but in the case of full alpha 1-adrenergic agonists such as norepinephrine and phenylephrine the inhibitory effect of cooling is buffered by an alpha 1-adrenoceptor reserve. With norepinephrine, this permits the potentiating effect of cooling on the alpha 2-adrenergic component of the response to predominate.

Stimulation of thymidine incorporation by basic fibroblast growth factor or epidermal growth factor treatment of cultured quiescent smooth muscle cells (rat and human) was attenuated by the concomitant treatment with interleukin-1 beta in the presence of indomethacin. Platelet-derived growth factor-AB and -BB-induced thymidine incorporation was not inhibited by the presence of the cytokine under similar experimental conditions. Elevation of nitrite levels in the conditioned medium of cultures exposed to interleukin-1 beta correlated with the inhibition of thymidine incorporation. Platelet-derived growth factor-AB and -BB inhibited the production of nitric oxide (measured as nitrite levels in conditioned medium) by cells treated simultaneously with interleukin-1 beta and growth factor. However, platelet-derived growth factor-AA neither affected nitrite production nor thymidine incorporation by smooth muscle cells. Levels of cytokine-stimulated nitrite production by smooth muscle cells were increased synergistically by the presence of fibroblast growth factors or epidermal growth factor. The inhibition of thymidine incorporation and concomitant elevation of nitrite production was abolished in the presence of nitro-L-arginine. Cultures maintained in the presence of low levels of the cytokine for 9 days were growth-inhibited, and this was reversed when culture medium was supplemented with nitro-L-arginine. The treatment of smooth muscle cells, which were grown in coculture inserts with the cytokine to induce nitric oxide production, before their combination with other quiescent layers of cells resulted in the inhibition of thymidine incorporation by this second layer of cells regardless of the growth factor used for stimulation. Nitric oxide may act as an endogenous inhibitor of smooth muscle cell proliferation in the vessel wall, and impairment of its production may be one action of potent vascular mitogens such as platelet-derived growth factor.