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The effect of the enantiomers of a novel 5-HT2 receptor antagonist, (+/-)-(1R,3S)-1-[2-[4-[3-(p-fluorophenyl)-1-indanyl]-piperazinyl] ethyl]-2-imidazolidinone, was studied on serotonin (5-HT), noradrenaline (NA), potassium (K+), and calcium (Ca2+)-induced contractions in isolated rat thoracic aorta. The enantiomers shifted the 5-HT, NA, K+, and Ca2+ concentration-response curves to the right in a concentration-dependent manner and depressed the maximal contractile responses. The (+)-enantiomer was a far more potent inhibitor of 5-HT-induced contractions than the (-)-enantiomer. The (+)-enantiomer and phentolamine, both at 10(-6) M, had equal inhibitory effects on NA-evoked contractions. The (+)-enantiomer was again more potent inhibiting NA-induced contractions than the (-)-enantiomer. Both enantiomers had an equieffective inhibitory effect on K+ and Ca2(+)-induced contractions. The results show that the 5-HT and alpha-adrenoceptor antagonism of the two enantiomers is stereoselective, the (+)-enantiomer being more potent than the (-)-enantiomer. In contrast the enantiomers had equal, nonstereoselective inhibitory effects on K+ and Ca2(+)-evoked contractions.

Isolated preparations of the thoracic aorta from spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NWR) were contracted by noradrenaline (NA) 1.8 X 10(-5)M, and potassium (K+) 127 mM, after 30 min. pretreatment in a Ca++-free medium. In both SHR and NWR aortae, the contractions were markedly reduced; no significant differences were found between the two types of vessels in Ca++-free medium. On addition of Ca++, the contractions were restored to a significantly greater extent in the NWR than in the SHR aortae. In the presence of nifedipine 7.2 X 10(-9)M, the response to Ca++ was significantly more reduced in the SHR than in the NWR preparations. Relaxation of NA and K+ contracted preparations was induced by wash-out of the contractile agents, by addition of nifedipine 2.9 X 10(-8)M, and by introduction of a Ca++-free medium. After wash-out of NA, relaxation was slower in SHR than in NWR vessels. Relaxation induced by nifedipine and Ca++-free medium was more complete in SHR than in NWR preparations. After wash-out of K+, relaxation was more rapid in NWR than in SHR aortae. Nifedipine and Ca++-free medium induced relaxation was more complete in SHR than in NWR preparations. The results suggest that in the SHR aortae contraction induced by NA and K+ is more dependent on extracellular Ca++ than is the response in the NWR preparations; the SHR vessels are also more sensitive to the relaxing effects of nifedipine.

1. Crural, mesenteric and pulmonary vessels obtained during surgery were studied. Isometric tension was recorded and contractions were induced by potassium 127 mM (K), noradrenaline 18 microM (NA), prostaglandin F2 alpha 2.9 microM (F2 alpha), ergotamine 3.8 microM (Erg) or digoxin 1.0 microM (Dig). 2. Spontaneous myogenic activity was only observed in pulmonary veins. F2 alpha induced spontaneous activity in mesenteric arteries. 3. In all types of vessels, except in mesenteric arteries, the response to K+ had a greater amplitude than contractions developed by NA. Erg induced a slowly developing contraction in mesenteric veins but no contraction in mesenteric arteries. Dig induced a long-lasting monophasic response in arteries and a biphasic response in the veins. 4. After immersion for 30 min in a Ca-free medium the amplitudes to both NA and K+ were significantly reduced. The veins were more susceptible to the effects of Ca-deprivation than the arteries.

The effects of prostaglandin F2alpha (PGF2alpha 2.8 X 10(-7) --2.8 X 10(-5) M) on isolated segments of human peripheral arteries and veins were investigated. In both types of vessel, PGF2alpha had a concentration-dependent contracting effect. The contraction developed more slowly and had a longer relaxation time after washing than responses induced by noradrenaline or potassium. In the veins, the maximum response to the prostaglandin was 128 +/- 3.6% of that to potassium (P less than 0.01); in the arteries, the maximum amplitudes of PGF2alpha and potassium induced contractions were of similar magnitude. The arterial preparations were less responsive to PGF2alpha than to noradrenaline. On a molar basis, noradrenaline was approximately 10 times more potent than PGF2alpha. Veins, maximally contracted by noradrenaline or potassium, increased their tension further on addition of PGF2alpha. Similarly, preparations maximally contracted by PGF2alpha also showed a further increase in tension after addition of noradrenaline or potassium. The PGF2alpha induced contractions were not affected by alpha-adrenoceptor blockade (phentolamine, prazosin). The calcium antagonists verapamil and nifedipine relaxed preparations contracted by PGF2alpha, and reduced the responses in a concentration-dependent way when added 15 min. before the prostaglandin. Immersion for 30 min. in a calcium-free medium, reduced the PGF2alpha induced response in both arteries and veins. In the veins, but not in the arteries, the responses to potassium and noradrenaline were more reduced than that to PGF2alpha (P less than 0.01). Contractions induced by all agents were further depressed by verapamil and nifedipine after exposing the preparations to the calcium-free medium. It is suggested that PGF2alpha induces contraction both by enhancing the transmembrane flow of calcium, and by facilitating release of calcium from intracellular stores.

The effect of histamine (0.01-200 microM) was studied in isolated human pulmonary vessels. Histamine induced concentration dependent contractions in both arteries and veins. In veins the maximal response to histamine was lower than in arteries. Histamine and 2-methyl-histamine had a dual action in both arteries and veins clearly demonstrated in vessels precontracted with potassium. In these vessels histamine and 2-methyl-histamine induced relaxation at low concentrations and contractions at high concentrations. Veins were more sensitive to the relaxant effect of histamine than arteries. Mepyramine eliminated the dual action of 2-methyl-histamine and histamine and unveiled a mepyramine resistant relaxation at the highest histamine concentrations used which was resistant to the effect of cimetidine and metiamide. The H2 receptor agonist dimaprit (10-400 microM) induced a slight relaxation in both arteries and veins that could be eliminated by metiamide (100 microM). The results show that histamine has a dual action in human pulmonary vessels which includes a contractile effect mediated via H1 receptors and a relaxant response partly mediated through H1 receptors and partly via unspecific mechanisms. However, an H2 mediated relaxant effect cannot be excluded.

The effect of a new 1,4-dihydropyridine derivative, methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate, BAY K 8644, was studied on isolated thoracic aortae obtained from male Wistar-Kyoto rats. In rat aorta BAY K 8644 had dual actions as the compound induced contractions in the concentration range 10(-8)-10(-5)M and relaxation at higher concentrations. In low concentrations (10(-8)M) BAY K 8644 increased the contractile response to both noradrenaline and potassium and shifted the concentration response curves to the left while in high concentrations BAY K 8644 (10(-4)M) had a relaxant effect on preparations precontracted by potassium. The contractile response to BAY K 8644 was resistant to wash out in drug free medium but was totally abolished in Ca-free medium. Re-addition of Ca restored the contractile response in a concentration dependent manner. BAY K 8644, 10(-6)M, shifted the Ca-concentration response curve in high potassium solution to the left and increased the maximal response. Phentolamine or propranolol had no effect neither on the contractile nor on the relaxant effect of BAY K 8644. The findings suggest that BAY K 8644 acts mainly by increasing the transmembrane influx of Ca in the vascular smooth muscle cells, and that this effect could be opposite to that of nifedipine. However, in high concentrations BAY K 8644 also seems to have a Ca-entry blocking effect.

The inhibitory and relaxing effects of prazosin, nifedipine, and dihydralazine on contractions induced by noradrenaline (NA), or potassium (K+), were investigated in isolated human crural and mesenteric arteries and veins. Vascular ring preparations were suspended in organ baths and isometric tension was recorded. Prazosin was the most potent of the drugs in counteracting NA-induced contractions in all types of vessels except crural veins, in which the effect of nifedipine was the more pronounced. On K+-induced contractions prazosin was completely devoid of relaxing or inhibitory effects, whereas nifedipine was by far the most effective of the investigated drugs. Nifedipine had a more marked effect in venous than in arterial preparations from the peripheral circulation, but no such difference was seen in mesenteric vessels. Dihydralazine was found to have a very low potency in all types of vessels, and no difference between the effects on arterial and venous preparations was found. The results suggest that the in vitro effects of prazosin, nifedpine, and dihydralazine are different from those observed in vivo. Thus, the balance between the effects on arteries and veins in vitro was quite different from those reported in clinical studies on the three vasodilatators. The results give no support to the hypothesis of an unspecific vasodilatating effect of prazosin. The clinical usefulness of dihydralazine cannot be explained from the poor in vitro effects of the unmetabolized drug.

In isolated human mesenteric and crural veins, ergotamine induced long-lasting contractions. These contractions were resistant to repeated wash-out and were not affected by alpha-adrenoceptor blockade, but could be abolished by removal of extracellular calcium or by the presence of the calcium-blocker nifedipine. In contrast to its effect on human mesenteric and crural veins, ergotamine had no contractile effect, but a marked relaxant effect on mesenteric arteries mediated via blockade of alpha-receptors. The ergotamine-induced contraction was not affected by indomethacin (0.28--2.8 microM) nor was it influenced by serotonin (5-HT). In both mesenteric and crural veins, the ergotamine-induced contraction was diminished by the 5-HT blocking agent, methysergide. In veins, development of tachyphylaxis to 5-HT was demonstrated. It is concluded that ergotamine has a direct contractile effect on isolated human mesenteric and crural veins. These effects are dependent on unhindered influx of extracellular calcium and are at least partly mediated via 5-HT receptors. In mesenteric arteries, ergotamine acted as an alpha-adrenoceptor blocker, and had no contractant effect.

Isolated ring preparations of human vein were contracted by potassium (127 mM) and noradrenaline (1.8 X 10(-5) M). The potassium-induced contracture developed more rapidly and had a higher maximum amplitude than that produced by noradrenaline. Addition of phentolamine (10(-5) M) reduced the amplitude of the potassium contracture by 22% and abolished the noradrenaline response. Verapamil and nitroglycerin relaxed preparations contracted by potassium and noradrenaline, and, when added prior to stimulation, reduced the contractile responses to these agents. Both verapamil and nitroglycerin inhibited the contractile effect of noradrenaline more strongly than that of potassium. After immersion of the preparations for 30 min. in a calcium-free medium, the responses to potassium and noradrenaline were reduced to 21.3 +/- 2.5% and 7.1 +/- 0.8%, respectively, of the control. Addition of verapamil caused a further reduction of the response to potassium, but not of that to noradrenaline. Nitroglycerin caused a further reduction of the contractions induced by both agents. When the calcium concentration in the extracellular medium was increased from 0 to 4 mM, the contractile responses to potassium and noradrenaline returned to the control level. Both verapmil and nitroglycerin inhibited the contractile responses to calcium; the inhibiting effects of verapamil were significantly more marked than those of nitroglycerin. Tachyphylaxis to nitroglycerin was demonstrated on contractions induced by potassium, but not on noradrenaline-produced responses.

Ring preparations of human mesenteric arteries and veins were contracted by noradrenaline (1.8 x 10(-5)M) or potassium (127mM). Isometric tension was recorded. In the arterial preparations, the maximum response to noradrenaline was 97 +/- 8% (mean +/- S.E.M.) of that to potassium. In the veins, the corresponding figure was 38 +/- 4%. The calcium antagonists verapamil (2.2 x 10(-7)-2.2 x 10(-5)M) and nifedipine (2.9 x 10(-8)-2.9 x 10(-6)M) relaxed both arteries and veins contracted by noradrenaline or potassium, and reduced the responses to these agents when added 15 min. before stimulation. The time course of relaxation of potassium contracted preparations, induced by verapamil and nifedipine, was more rapid and complete than that produced by a calcium-free, high potassium solution. In contrast to verapamil, nifedipine caused a more pronounced inhibition of the potassium than of the noradrenaline evoked contractions in both arteries and veins. After exposure to a calcium-free medium for 30 min., the arterial response to noradrenaline was significantly (P less than 0.05) greater than that to potassium. However, the reverse was found in the veins. In both types of vessel, verapamil (2.2 x 10(-6)M) and nifedipine (2.9--10(-7)M) were equi-effective in reducing the noradrenaline reactivity, not only between mesenteric arteries and veins, but also between, e.g. peripheral and mesenteric vessels. The calcium antagonists nifedipine and verapamil do not have an identical mode of action. However, both agents seem to inhibit influx of extracellular calcium, and might also have an inhibitory effect on the release of intracellular calcium.

In isolated portal veins from rats, Bay K 8644 (methyl-1, 4-dihydro-2, 6-dimethyl-3-nitro-4 (2-trifluoromethyl-phenyl) pyridine-5-carboxylate) increased the spontaneous mechanical activity in low but not in high concentrations. The Bay K 8644-induced increase in spontaneous mechanical activity was abolished in Ca-free medium and restored by readdition of Ca. Nifedipine abolished the augmenting effect of Bay K 8644 on the spontaneous mechanical activity; this effect of nifedipine could be eliminated by further increasing the concentration of Bay K 8644. The results are consistent with the conclusion that in rat portal vein, Bay K 8644 increases the entry of extracellular Ca by a mechanism antagonistic to that of nifedipine and in high concentration has a Ca-entry blocking effect.

The effect of thapsigargin (Tg) was studied in rat thoracic aorta. Tg (10(-8)-10(-5) M) had a dual effect on rat aorta. Thus, Tg induced a concentration dependent increase in basal tone in normal physiological salt solution (PSS), while Tg in potassium (K+) precontracted aortic rings caused a concentration related relaxation and shifted the K+-concentration response curve to the right and depressed the maximal response to K+. Removal of vascular endothelium abolished the relaxant response to Tg and increased the sensitivity of the preparations to the contractile effect of Tg. The contractile response to Tg was resistent to wash-out in drug-free PSS and was not affected by phentolamine, indomethacin or mepyramine but partly reduced by the calcium-antagonist nitrendipine and eliminated by wash-out in calcium-free PSS. Atropine eliminated the endothelium dependent relaxant effect of carbachol, but had no effect on the Tg or on the calcium ionophore A 23187 evoked relaxation. Ultraviolet radiation decreased the relaxant effect of Tg and A 23187 without affecting the carbachol induced relaxations. The results showed that vascular endothelium depressed the contractile effect of Tg and that Tg like A 23187 had an endothelium dependent relaxant effect on rat aorta different from that of carbachol. The results indicate that Tg in vascular smooth muscle acts by stimulating the transmembranal influx of extracellular calcium.