R C Miller

Enhanced responsiveness of rat isolated aorta to clonidine after removal of the endothelial cells

With the endothelium present, the maximum response of rat isolated aorta to clonidine was much lower than that to noradrenaline. Removal of endothelium enhanced the response to both adrenoceptor agonists and the clonidine‐induced maximum contraction became almost equal to that produced by noradrenaline, although it was much more sensitive to inhibition by flunarizine and nifedipine. These results indicate that clonidine and noradrenaline activate receptors present in the endothelial cells and that these receptors are highly sensitive to clonidine.

Selective alpha 1- and alpha 2-adrenoceptor agonist-induced contractions and 45Ca fluxes in the rat isolated aorta.

1 Contractile responses produced by the α1‐adrenoceptor selective agonist, phenylephrine, and the α2‐adrenoceptor selective agonists, oxymetazoline and clonidine, have been compared to those produced by noradrenaline (non selective) in the rat aorta. 2 The relative order of potency of the agonists was noradrenaline > phenylephrine > clonidine > oxymetazoline. Noradrenaline and phenylephrine produced similar maximal responses. The maximal responses produced by oxymetazoline and clonidine were about 59% and 24% respectively of those produced by noradrenaline. 3 Concentrations of agonists producing maximal contractions exhibited different response‐time relationships. Responses to noradrenaline and phenylephrine were biphasic while responses induced by oxymetazoline and clonidine were monophasic. 4 In calcium‐free solution, contractions stimulated by oxymetazoline and clonidine were almost abolished while those stimulated by noradrenaline and phenylephrine were reduced by about 60–70%. The calcium entry blocker, cinnarizine, almost completely inhibited responses to oxymetazoline and clonidine and reduced noradrenaline‐ and phenylephrine‐stimulated responses by about 60%. 5 All the agonists stimulated the uptake of 45Ca into the La3+‐resistant Ca2+ fraction of the artery but only noradrenaline and phenylephrine stimulated the efflux of 45Ca into calcium‐free solution. The 45Ca uptake stimulated by oxymetazoline and clonidine was abolished by cinnarizine and that stimulated by noradrenaline and phenylephrine was reduced by about 85%. 6 It is concluded that clonidine and oxymetazoline stimulate contractions that are totally dependent on extracellular calcium. Noradrenaline and phenylephrine stimulate contractions that are partly dependent on extracellular calcium and partly dependent on intracellular calcium stores.

Actions of Prostaglandin-f2-alpha and Noradrenaline On Calcium Exchange and Contraction in Rat Mesenteric-arteries and Their Sensitivity To Calcium Entry Blockers

1 The actions of prostaglandin F2α (PGF2α) and noradrenaline on contraction and 45Ca exchange have been studied in rat mesenteric arteries. 2 PGF2α and noradrenaline contracted rat isolated mesenteric artery preparations to about the same extent. The PGF2α‐stimulated contractions, unlike those produced by noradrenaline, were completely inhibited in calcium‐free physiological solution. 3 The calcium entry blocking drugs, cinnarizine and flunarizine, had little effect on the resting exchange of calcium in the arterial smooth muscle, but inhibited PGF2α‐stimulated contractions and 45Ca uptake to a similar extent. 4 Flunarizine was about 7 fold more potent as an inhibitor of noradrenaline‐ than of PGF2α‐mediated contraction and 45Ca uptake and this ratio was about 50 for cinnarizine. 5 EGTA (1.25 mm) produced a relaxation of noradrenaline and PGF2α‐induced maximal contractions. Measured over the first 2 min of EGTA contact, the rate of relaxation was much faster in noradrenaline than in PGF2α‐stimulated preparations. 6 Turnover of cellular calcium (influx plus efflux) during the first 2 min of noradrenaline contact was much greater than that produced by PGF2α, largely due to a greater effect of noradrenaline on calcium efflux. 7 The results suggest that PGF2α‐ but not noradrenaline‐induced contractions are entirely dependent on the influx of extracellular calcium and that the agonists may stimulate calcium gating mechanisms differently.

Effects of histamine and the histamine antagonists mepyramine and cimetidine on human coronary arteries in vitro.

1 The effects of histamine have been studied on human isolated coronary artery preparations taken from hearts ranging in age from 9 to 73 years. 2 Histamine in large concentrations (100 μM) contracted arteries which were without tone or spontaneous activity and sometimes induced rhythmic contractile activity. If spontaneous rhythmic activity was present it was enhanced by histamine. The contractile effects of histamine were inhibited by mepyramine but not by cimetidine. 3 Arteries which were contracted by depolarization responded with relaxation to histamine concentrations lower than those required to evoke a contraction; arteries from younger hearts were more sensitive than those from older hearts. 4 Mepyramine potentiated the maximal relaxant effect of histamine in arteries from hearts of all ages but cimetidine had very little effect. 5 In the presence of mepyramine, cimetidine antagonized the relaxant effect of histamine, shifting the concentration‐effect curve to the right. 6 It is concluded that human coronary arteries contain both H1‐ and H2‐type receptors, the H1‐receptors mediating contraction. The relaxant effects of histamine can only be inhibited by a combination of both H1‐ and H2‐receptor antagonists.

Effects of yohimbine, rauwolscine and corynanthine on contractions and calcium fluxes induced by depolarization and prostaglandin F2 alpha in rat aorta.

1 The effects of the selective α2‐adrenoceptor antagonists yohimbine and its stereo‐isomer rauwolscine and the selective α1 ‐adrenoceptor antagonist corynanthine (a third yohimbine stereoisomer) on contractions induced in rat aorta by depolarization and prostaglandin F2α (PGF2α) have been compared. 2 In calcium‐free solution, depolarization with 100 mM K+ failed to produce a contraction of rat aorta but PGF2α (3 μM) stimulated a contraction equal to about 23% of maximal elicited in normal physiological solution. 3 Yohimbine had no significant effect on depolarization‐induced contractions except at concentrations greater than 30 μM. Rauwolscine and corynanthine (1 to 100 μM) depressed depolarization‐induced contractions in a concentration‐dependent manner, but the characteristics of inhibition were not identical. 4 Contractions induced by PGF2α (3 μM) were depressed in a concentration‐dependent manner by rauwolscine (3 to 100 μM) but were unaffected by yohimbine or corynanthine. 5 Depolarization‐stimulated 45Ca influx was depressed by rauwolscine and corynanthine to about the same extent as were the contractions; while rauwolscine (100 μM) completely inhibited PGF2α‐stimulated 45Ca influx, it also depressed part of the PGF2α‐stimulated contraction dependent on intracellular calcium. 6 Rauwolscine (100 μM) partly inhibited PGF2α‐stimulated release of 45Ca from aortic smooth muscle in calcium‐free solution. 7 It is concluded that the yohimbine structure possesses a calcium entry blocking action as well as a depressant action on contractions not dependent on calcium entry. The predominant effect depends on the structural configuration and the nature of the stimulating agent.