Abstract-We studied the effect of oral cholecalciferol treatment on the endothelium-dependent vascular relaxation and hyperpolarization induced by acetylcholine (ACh), which is impaired in spontaneously hypertensive rats (SHR). Adult female SHR and normotensive Wistar-Kyoto rat (WKY) controls received 125 g of cholecalciferol per kilogram body weight per day for 6 weeks. The responses to ACh of the isolated mesenteric vascular bed and mesenteric artery rings were measured, as well as the smooth muscle cell membrane potential. After cholecalciferol treatment, the systolic blood pressure and basal perfusion pressure of the mesenteric vascular bed of the SHR fell to control levels. The relaxant and hyperpolarizing effects of ACh, which are reduced in SHR, were also brought to control levels after cholecalciferol treatment. These effects of ACh were inhibited by N -nitro-L-arginine in SHR and by apamin in WKY. After cholecalciferol treatment, SHR hyperpolarizing responses showed the same inhibition pattern as those of WKY. This indicates that, after cholecalciferol treatment, SHR vascular mesenteric preparation responses to ACh are mediated by endothelium-derived hyperpolarizing factor, which induces activation of Ca 2ϩ -dependent K ϩ channels, as in WKY. In untreated SHR, the ACh-mediated response is entirely due to ACh acting via the release of nitric oxide.

1 The mechanism responsible for blood pressure reduction in spontaneously hypertensive rats (SHR) after prolonged cholecalciferol treatment was studied. Two-week treatment of SHR with 0.125 mg cholecalciferol kg 71 body weight per day orally caused signi®cant reductions of systolic blood pressure and of the resting perfusion pressure of the mesenteric vascular bed at constant¯ow. 2 In addition, the treated animals presented a normalization of the maximum vasoconstriction response to noradrenaline and a reduction of the maximum eect of the adrenaline concentrationresponse curves. This latter eect probably was due to recovery of the impaired Ca 2+ -dependent K + channels coupled to a 2 -adrenoceptors since it was prevented by apamin. 3 The treatment with cholecalciferol also normalized the smooth muscle cell membrane potential of de-endothelialized mesenteric arteries of SHR and their hyperpolarizing responses to a 2 -adrenergic agonists, which were depressed in untreated SHR. 4 In mesenteric rings with endothelium, a 2 -adrenergic agonists caused similar hyperpolarizing responses in the SHR and in normotensive Wistar (NWR) and Wistar Kyoto (WKY). In non cholecalciferol-treated SHR the hyperpolarizing mediator involved in this eect was NO, while in NWR it was the endothelium-derived hyperpolarizing factor (EDHF). After cholecalciferol treatment, the hyperpolarization induced by a 2 -adrenergic agonists in SHR smooth muscle cells was mediated by EDHF, as in NWR. 5 Our results indicate that the hypotensive eect of cholecalciferol in the SHR is probably due to the normalization of vascular reactivity, by restoring the functioning of apamin-and ATP-sensitive K + channels located in the vascular smooth muscle cell membrane, which are impaired in the SHR.

1 The a 2 -adrenoceptor function in mesenteric arteries of spontaneously hypertensive rats (SHR) was investigated by comparing membrane potential changes in response to adrenergic agonists in preparations from female SHR, Wistar-Kyoto (WKY) and normotensive Wistar rats (NWR). 2 Resting membrane potential was found to be less negative in mesenteric arteries from SHR than in those from NWR and WKY. Apamin induced a decrease in the membrane potential of mesenteric artery rings without endothelium from NWR and WKY, but had no e ects in those from SHR. Both UK 14,304 and adrenaline, in the presence of prazosin, induced a hyperpolarization that was signi®cantly lower in de-endothelialized mesenteric rings from SHR than in those from NWR and WKY. In mesenteric rings with endothelium, however, similar hyperpolarization was observed in the three strains. 3 In NWR mesenteric rings with endothelium the hyperpolarization induced by activation of a 2 -adrenoceptors was abolished by apamin, whereas in intact SHR mesenteric rings this hyperpolarization was slightly reduced by apamin and more e ciently reduced by N o -nitro-L-arginine. 4 It is concluded that the activity of potassium channels coupled to a 2 -adrenoceptors is altered in the smooth muscle cells of SHR mesenteric arteries, contributing to their less negative membrane potential. On the other hand, the endothelial a 2 -receptors are functioning in mesenteric vessels from SHR and their stimulation induces a hyperpolarization mainly through the release of nitric oxide.

1 The role of a 2 -adrenoceptors in the response of aorta smooth muscle rings to the a 2 -adrenoceptors agonists UK 14,304 and clonidine was studied. 2 Stimulation by 1 ± 10 nM UK 14,304 caused dose-dependent relaxant responses in BaCl 2 -contracted endothelium-denuded aorta rings, and hyperpolarization in rings with or without endothelium, which were inhibited by yohimbine and glibenclamide, but not aected by prazosin, propranolol, apamin or iberiotoxin. At higher concentrations (10 nM ± 10 mM) UK 14,304 also induced a depolarizing eect which was potentiated by yohimbine and inhibited by prazosin. These results indicate that UK 14,304 acts on a 2 -adrenoceptors at lower concentrations and on both a 1 -and a 2 -adrenoceptors above 10 nM. 3 In rings, with or without endothelium, noradrenaline had a depolarizing eect which was inhibited by prazosin. Adrenaline did not aect the membrane potential but in the presence of prazosin caused hyperpolarization, which was inhibited by yohimbine and glibenclamide. These results indicate that noradrenaline is more selective for a 1 -, whereas adrenaline has similar anities for a 1 -and a 2 -adrenoceptors. 4 In aortae with endothelium, L-NNA caused a small depolarization but did not aect the hyperpolarization induced by UK 14,304, indicating that NO is not involved in that response. 5 Glibenclamide induced a small depolarization in aortae, with or without endothelium, indicating that ATP-sensitive K + channels may play a role in maintaining the smooth muscle's membrane potential. 6 Our results indicate that, in rat aorta, a 2 -adrenoceptors are also present in the smooth muscle, and that these receptors act through small-conductance ATP-sensitive K + channels.

1 The dual action of bradykinin (relaxation and contraction) on the rat duodenum was investigated by studying its effect on adenosine 3':5'-cyclic monophosphate (cyclic AMP)