Rat brain cortex slices preincubated with 3H-5-hydroxytryptamine were superfused with physiological salt solution and stimulated electrically, or they were superfused with Ca2+-free solution containing 25 mM K+ and stimulated by introduction of 1.3 mM CaCl2 for 2 min. After blockade of neuronal 5-hydroxy-tryptamine (5-HT) uptake with clomipramine or paroxetine, the 3H overflow evoked by both methods of stimulation was decreased by unlabelled 5-HT and increased by methiothepin. The inhibition caused by 5-HT was antagonized by simultaneous administration of methiothepin. The inhibition by 5-HT of Ca2+-induced overflow was also observed in the presence of tetrodotoxin. These results suggest that 5-HT regulates its own release from central serotoninergic neurones by activating presynaptic 5-HT autoreceptors, thus decreasing the availability of Ca2+ for stimulus-release coupling.

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Contractions produced by endothelin-1 (0.3-30 nM) have been investigated in aorta, renal arteries and mesenteric arteries from 2- and 24-month-old Sprague-Dawley rats. In senescent rats the EC50 values of endothelin-1 for aorta and renal artery were significantly increased (aorta: from 6.2 to 12 nM; renal artery: from 5.2 to 7.8 nM). For mesenteric artery the EC50 value (4.3 nM) was unchanged by aging, whereas the maximal contractile response to endothelin-1 was enhanced (from 8.3 to 11.7 mN). In contrast, there was no significant age-related difference in the maximal endothelin-1 response of aorta and renal artery. The present data demonstrate a reduced sensitivity for aorta and renal artery and an enhanced maximal response to endothelin-1 in the mesenteric artery in senescent rats.

By using the calmodulin antagonists, calmidazolium and N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7), the hypothesis was investigated as to whether calmodulin is involved in the sequence of events leading to the endothelium-dependent vascular smooth muscle relaxation. Endothelium-dependent relaxations were studied on two different preparations, the rabbit aorta and the pulmonary artery of the guinea pig. Relaxations were produced in the precontracted rings (noradrenaline 3 X 10(-6) mol/l) in response to acetylcholine, 10(-8) to 10(-6) mol/l (aorta), histamine, 3 X 10(-8) to 1 X 10(-6) mol/l (pulmonary artery) or the calcium ionophore A 23187, 1 X 10(-8) to 3 X 10(-7) mol/l (aorta and pulmonary artery). In the presence of calmidazolium and W-7 the endothelium-dependent relaxation was inhibited in a dose dependent manner. This inhibition was seen in a concentration range that coincides with calmodulin inhibition. The half maximal concentrations of calmidazolium for the inhibition of the relaxation of the aorta induced by acetylcholine and A 23187 were 3 X 10(-6) mol/l and 1.4 X 10(-6) mol/l and that of W-7 were 3.1 X 10(-5) and 3.6 X 10(-5) mol/l, respectively. Complete inhibition was obtained both for acetylcholine-and for A 23187-induced relaxations by preincubation with 1 X 10(-5) mol/l calmidazolium or 1 X 10(-4) mol/l W-7. The half maximal concentrations of calmidazolium for the inhibition of the relaxation of the pulmonary artery in response to histamine and A 23187 were 2.7 X 10(-6) mol/l and 3 X 10(-6) mol/l and complete inhibition was achieved at 1 X 10(-5) mol/l.(ABSTRACT TRUNCATED AT 250 WORDS)