Selectivity of phenytoin and dihydropyridine calcium channel blockers for relaxation of the basilar artery

We addressed the questions of whether or not phenytoin is a direct vasodilator and if it is selective for brain blood vessels, by studying the relaxant effects of phenytoin on isolated segments of canine basilar, femoral, and brachial arteries. Two dihydropyridine calcium channel blockers, nifedipine and PY 108-068, were also studied for comparison with phenytoin and to test for cerebral selectivity. Blood vessels were contracted with K+, prostaglandin F2 alpha, or serotonin. Phenytoin relaxed the basilar artery with low potency (pD2, 4.71 +/- 0.14) and moderate selectivity. Phenytoin also antagonized Bay K 8644 contractions of basilar artery in a noncompetitive manner. Basilar arteries contracted with 60 mM K+ were the most sensitive to nifedipine (pD2, 8.72 +/- 0.18), followed by the mesenteric (pD2, 8.24 +/- 0.07), femoral (pD2, 8.04 +/- 0.18), and brachial (pD2, 7.66 +/- 0.23) arteries. A similar pattern was observed in potassium-depolarized arteries relaxed by PY 108-068. The calcium dependence of contraction was studied using intact muscles depolarized in 60 mM K+ as well as chemically skinned basilar artery. Mean pD2 values for Ca2+-induced contractions of intact, depolarized arteries were not different (basilar, 4.15 +/- 0.13; mesenteric, 4.04 +/- 0.07; femoral, 4.24 +/- 0.11). The mean Ca2+ EC50 of chemically skinned basilar arteries was 8.7 X 10(-7) M, which is similar to the Ca2+ sensitivity of other skinned smooth muscles. The beneficial effect of phenytoin in treating cerebral ischemia may be due in part to relaxation of vascular smooth muscle. The dihydropyridines were potent smooth muscle relaxants with selectivity for the basilar artery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential Vasorelaxant Effects of K+-Channel Openers and Ca2+-Channel Blockers on Canine Isolated Arteries

Abstract— The vasorelaxant effects of the K⁺-channel openers, pinacidil and cromakalim, were compared with those of the Ca²⁺-channel blockers, verapamil and KB-2796 (1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride), in canine isolated coronary, renal, basilar and mesenteric arteries precontracted with U46619, a thromboxane A₂ mimetic. The relaxation induced by pinacidil and cromakalim was greater in coronary than in other arteries, the magnitude of relaxation being in the order of coronary > renal > basilar > mesenteric arteries. The relaxant responses to both drugs were inhibited by glibenclamide, a blocker of ATP-sensitive K⁺ channels. The relaxation induced by verapamil and KB-2796, in contrast, was greater in basilar than in other arteries, the magnitude of relaxation being in the order of basilar > coronary > renal and mesenteric arteries. In fura-2-loaded, U46619-stimulated arteries, pinacidil and cromakalim produced a greater reduction in intracellular Ca²⁺ concentration and muscle tension in coronary than in mesenteric arteries, while verapamil and KB-2796 reduced these values more potently in basilar than in mesenteric arteries. These results suggest that K⁺-channel openers exhibit a vasorelaxant selectivity for coronary arteries, whereas Ca²⁺-channel blockers exhibit such selectivity for cerebral arteries. The selective vasorelaxant action induced by these drugs appears to correspond, in part, to their effects on the concentration of intracellular Ca²⁺.     

Comparison of vasorelaxants in human basilar arteries and umbilical arteries

The vasodilatation produced by adenosine, sodium nitrite, and papaverine was compared on isolated human basilar arteries and umbilical arteries precontracted with 30 mM KCl or submaximal concentrations of serotonin and prostaglandin F2 alpha. The basilar artery was far more sensitive to the vasodilators than the umbilical vessel. Papaverine, for instance, was 133 times more effective (EC50 = 3.9 x 10(-6) M) in basilar arteries precontracted with KCl than it was in the umbilical artery (EC50 = 5.2 x 10(-4) M) and all dilators inhibited by at least 95% basilar arteries precontracted with serotonin or prostaglandin F2 alpha. In contrast, umbilical arteries precontracted with KCl or prostaglandin F2 alpha failed to relax significantly to adenosine and sodium nitrite at concentrations that exceeded 10(-3) M, and contractions elicited by serotonin were inhibited by less than 40%. The results support the concept that physiological mechanisms responsible for dilation in most vessels are deficient in the umbilical artery and that the deficiency may be related to the role this atypical vessel plays in closure of the extracorporeal circulation at birth.     

Characterization of K(ATP)-channels in rat basilar and middle cerebral arteries: studies of vasomotor responses and mRNA expression

Changes in the activity of K+ channels represent a major mechanism that regulates vascular tone. Cerebrovascular adenosine 5'-triphosphate-sensitive K+(K(ATP)) channels were characterized in studies of the molecular expression and vasomotor reactivity to different K(ATP) channel openers in rat basilar and middle cerebral arteries. Both arteries showed strong mRNA expression of the subunits of the pore-forming inward-rectifying K+ channel type 6.1 (Kir6.1), Kir6.2 and the connected sulfonylurea receptor (SUR) subunits, SUR1 and SUR2B, while only weak bands for SUR2A were seen. The K(ATP) channel openers induced relaxation of prostaglalndin F2alpha-precontracted isolated basilar and middle cerebral arteries with the order of potency N-Cyano-N-(1,1-dimethylpropyl)-N'-3pyridylguanidine (P-1075)>levcromakalim>N-(4-Phenylsulfonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (ZM226600)>pinacidil>diazoxide. The responses induced by levcromakalim, ZM226600 and diazoxide were significantly more potent in basilar arteries than in middle cerebral arteries, while pinacidil and P-1075 were equipotent. Endothelium removal decreased (P<0.05) the sensitivity (pIC50) of basilar arteries, but not of middle cerebral arteries, to pinacidil, levcromakalim, P-1075 and ZM226600. The maximum relaxant response to P-1075 was stronger (P<0.005) in basilar arteries with endothelium than without endothelium. Correlation of the relaxant potency of K(ATP) channel openers in rat basilar and middle cerebral arteries with historical measurements of affinity obtained in COS-7 cell lines expressing either SUR1, SUR2A or SUR2B showed that vasodilatation by K(ATP) channel openers correlated with binding to either the SUR2A or the SUR2B subunit. Glibenclamide was a blocker of relaxation induced by pinacidil, levcromakalim, P-1075 and ZM226600 in basilar arteries. Only a weak antagonistic effect of glibenclamide on pinacidil-, levcromakalim- and ZM226600-induced relaxations was found in middle cerebral arteries. The subunit profile and the observed pharmacological properties suggest that the K(ATP) channels expressed in rat basilar and middle cerebral artery are likely to be composed of SUR2B co-associated with Kir6.1 or Kir6.2. In basilar arteries, but not in middle cerebral arteries, endothelial K(ATP) channels may be involved.     

Comparison of vasoconstrictor actions of endothelin-1 in cerebral, coronary, and mesenteric arteries of the dog.

Vasoconstrictor actions of endothelin-1 (ET) were compared between endothelium-removed strips of cerebral (basilar, posterior cerebral, and middle cerebral) and peripheral (coronary and mesenteric) arteries of the dog. ET produced a concentration-dependent contraction in these arteries. A threshold concentration and EC50 value for ET were significantly lower in the basilar, posterior cerebral, middle cerebral, and coronary arteries than in the mesenteric artery. In the basilar artery, nifedipine caused a rightward displacement of the concentration-response curve for ET with a significant reduction in the maximum response to ET. On the other hand, nifedipine showed a typical noncompetitive antagonism against ET in the mesenteric artery. Contractile responses of the mesenteric artery to ET determined under an elevation of extracellular K+ concentration were comparable to the responses of the basilar artery to this peptide determined under normal K+ concentrations. The cerebral and coronary arteries, but not the mesenteric artery, relaxed significantly from the resting level when placed in a Ca(2+)-free solution containing 0.1 mM EGTA (0-Ca solution). The readdition of Ca2+ to the cerebral and coronary arteries soaked in the 0-Ca solution caused a biphasic contraction that was susceptible to inhibition by nifedipine. When ET in concentrations below 10(-9) M was introduced before the Ca(2+)-induced contraction, this peptide produced no detectable contraction, but potentiated the Ca(2+)-induced contraction. The extent of potentiation induced by ET was much greater in the cerebral and coronary arteries than in the mesenteric artery. Even in the 0-Ca solution, higher concentrations of ET (1 x 10(-8) and 3 x 10(-8) M) produced a contraction that was weaker in the basilar artery than in the mesenteric artery. These results indicate that the cerebral and coronary arteries exhibited more potent contractions in response to lower concentrations (below 10(-9) M) of ET than the mesenteric artery. A likely possibility for these enhanced responses to ET in the cerebral and coronary arteries appears to be that the voltage-dependent Ca2+ channels in these arteries are more activated in the resting state than those in the mesenteric artery.     

Purinergic and non-purinergic innervation in the cerebral arteries of the dog.

1 Possible involvement of sympathetic purinergic transmission in the neurogenic response of dog cerebral and basilar arteries was examined with the use of alpha, beta-methylene ATP and adrenoceptor, cholinoceptor blocking agents. 2 In the isolated basilar arteries, electrical transmural stimulation produced a transient contraction which was frequently followed by a relaxation. This transient contraction was abolished after desensitization of P2-purinoceptors with alpha, beta-methylene ATP or by treatment with guanethidine. The relaxant response induced by electrical stimulation was also attenuated but was not abolished by such treatments. Prazosin, propranolol and atropine had no significant effect on the responses to electrical stimulation. Yohimbine augmented both the contractile and relaxant responses. 3 In most preparations of the dog middle cerebral arteries, electrical transmural stimulation produced only a relaxation. This relaxation was little affected after treatment with alpha, beta-methylene ATP or guanethidine, and was not inhibited by the other adrenoceptor and cholinoceptor blocking agents. 4 Tetrodotoxin abolished the responses induced by electrical transmural stimulation in both the basilar and middle cerebral arteries. 5 Exogenous ATP (10(-6) and 10(-5)M) produced a transient contraction followed by a relaxation of the basilar arteries and a relaxation of the middle cerebral arteries. Desensitization of P2-purinoceptors abolished the contractile response to ATP without affecting the amplitude of relaxation. 6 In the basilar and middle cerebral arteries preincubated with [3H]-noradrenaline, electrical transmural stimulation evoked an increase in 3H-efflux and this response was markedly inhibited by guanethidine or tetrodotoxin but was not affected by alpha, beta-methylene ATP. Yohimbine increased the evoked 3H-efflux.(ABSTRACT TRUNCATED AT 250 WORDS)     

Actions of some prostaglandins and leukotrienes on rat cerebral and mesenteric arteries

The effects of some prostaglandins (PG's) and leukotrienes (LT's) on rat middle cerebral, basilar and mesenteric arteries were evaluated in vitro. The order of potency of some prostanoids with respect to their contractile effects in basilar arteries was: U44069 greater than PGF2 alpha greater than PGI2 approximately equal to PGE2 greater than 6-keto-PGE1 greater than 6-keto-PGF1 alpha, whereas 6,15-diketo-PGF1 alpha was inactive. Middle cerebral and basilar arteries were 3-5 times more sensitive than mesenteric arteries to PGF2 alpha. LTD4 and LTC4 were inactive in all three vessel types. PGI2 produced a concentration-related relaxation of similar potency in all three arteries contracted by PGF2 alpha. Arteries preactivated by other agents (K+, noradrenaline, 5-hydroxytryptamine) either failed to relax or inconsistently relaxed after PGI2 application. Among the PGI2 metabolites (6-keto-PGF1 alpha, 6,15-diketo-PGF1 alpha, 6-keto-PGE1), only 6-keto-PGE1 elicited relaxation in the PGF2 alpha-contracted basilar artery. However, the drug potency was significantly smaller than that of PGI2. Nifedipine inhibited the PGF2 alpha-induced contraction by 68% in middle cerebral arteries and by 80% in mesenteric arteries. Exposure to Ca2+-free medium for a time period which almost completely abolished the contractile response to K+ (less than 5% left), reduced the PGF2 alpha-induced contraction by 54, 61 and 85% in middle cerebral, basilar and mesenteric arteries, respectively. The PGF2 alpha-induced contraction of cerebral arteries in Ca2+-free medium was usually composed of a rapidly developing first phase, which levelled off after 1-2 min, and a second slowly developing tonic phase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of gamma-aminobutyric acid (GABA) on vasodilation in resistance-sized arteries isolated from the monkey, rabbit, and rat

The effect of gamma-aminobutyric acid (GABA) and papaverine on cerebral arteries of rat, rabbit, and monkey and the small mesenteric arteries of the rat were studied in vitro with a microvessel apparatus. GABA (1 x 10(-7) to 1 x 10(-3) M) did not affect the basal tension of arteries of rats at rest. In PGF2 alpha-contracted monkey basilar artery and middle cerebral artery and rat basilar artery, cumulative addition of GABA (1 x 10(-7) to 1 x 10(-3) M) did not produce any relaxation. Also in K+-contracted rat basilar artery and small mesenteric artery, cumulative additions of GABA, muscimol, or bicuculline did not result in relaxation. In K+-contracted rabbit basilar artery, GABA did not produce relaxation. However, the addition of papaverine (1 x 10(-7) to 1 x 10(-4) M) in either PGF2 alpha- or K+-contracted arteries, produced a concentration-dependent relaxation in all arteries tested. These results suggest that the failure of GABA or muscimol to induce relaxation is not due to a defect of the arterial smooth muscle relaxant mechanism, but rather is due to the inability of GABA or muscimol to directly relax the artery in this in vitro preparation. Therefore, the hypotensive effect of GABA seen in the rat is probably not due to direct vasodilation of mesenteric or cerebral arteries. These findings lend further support to the idea that GABA mediates its hypotensive effect through its action as an inhibitory neurotransmitter, as previously suggested by others.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relaxant effect of sildenafil in the rabbit basilar artery

We hypothesized that sildenafil, inhibitor of phosphodiesterase-5 (PDE-5), interacts with the nitric oxide (NO)-cGMP pathway in the cerebral arteries and shows vasoactive effects. To prove it in the isolated rabbit basilar artery, we compared the effects of sildenafil with other PDE-5 inhibitors, assessed the endothelial dependence of the vasoactive responses, and used modulators of the cGMP and cAMP signaling processes. Sildenafil (10 nM-0.1 mM) induced concentration-dependent relaxations of endothelin-1 (10 nM)-precontracted basilar artery, which were partially inhibited both in endothelium-denuded arteries and in arteries precontracted by depolarization with KCl (50 mM). Endothelin-1 (1 pM-30 nM) induced concentration-dependent contractions that were inhibited by sildenafil (0.1-100 microM). Zaprinast (10 nM-0.1 mM) and MBCQ (1 nM-0.1 mM), PDE-5 inhibitors, induced concentration-dependent relaxations with lower and higher potency than sildenafil, respectively. Sildenafil-induced relaxation was inhibited in arteries preincubated with the NO synthase inhibitor L-NAME (0.1 mM) or the soluble guanylyl cyclase inhibitor ODQ (10 microM). Preincubation with sildenafil (0.1 microM) enhanced the relaxations induced by acetylcholine (0.1 nM-0.1 mM) and the NO donor sodium nitroprusside (0.1 nM-0.1 mM), but not those induced by the cell-permeable cGMP analogue 8-Br-cGMP (1 nM-0.1 mM) and the adenylyl cyclase activator forskolin (0.1 nM-10 microM). These results show that sildenafil has vasoactive effects in isolated cerebral arteries. By enhancing the NO-cGMP signaling pathway in the cerebrovascular wall, sildenafil induces vasodilation, prevents vasoconstriction, and potentiates the effect of other NO-dependent vasodilators.     

Role of CA(2+)-activated K+ channels in the regulation of basilar arterial tone in spontaneously hypertensive rats

1. Ionic channels appear to play an important role in contractile responses of the cerebral arteries and, thereby, contribute to the regulation of cerebral circulation. In the present study, we investigated the role of large-conductance Ca(2+)-activated K+ (BK(Ca)) channels in the regulation of cerebral arterial tone during chronic hypertension. 2. Ring segments of the basilar artery from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were placed in bath chambers and the isometric tension of each ring was measured. 3. Application of inhibitors of BK(Ca) channels, namely tetraethylammonium (TEA; > or = 0.1 mmol/L) and charybdotoxin (CTX; > or = 0.1 nmol/L), produced spontaneous contraction with rhythmic oscillation in the basilar artery from SHR. 4. The oscillatory contraction was not induced by 5-hydroxytryptamine (0.01-10 micromol/L) or depolarization by external high K+ (20-60 mmol/L). 5. The rhythmic contraction was completely abolished by either the removal of external Ca(2+) or the application of nicardipine (10 nmol/L). 6. The oscillation was not affected by the substitution of external Cl(-) by various equimolar anions (i.e. acetate, benezenesulphonate, bromide and isethianate). 7. The amplitude of the oscillation was dose-dependently increased by the vasodilators forskolin and sodium nitroprusside, as well as by stimulation of the endothelium with histamine and acetylcholine, whereas the frequency was decreased. 8. In contrast, the oscillation was eliminated by depletion of Ca(2+) stores by caffeine. Neither TEA (10 mmol/L) nor CTX (10 nmol/L) produced any significant contraction of the basilar artery in WKY rats. 9. These results suggest that BK(Ca) channels may play an important role in regulating the resting tone of the cerebral artery in SHR.     

Effect of hypoxia on vasodilator responses to S-nitroso-N-acetylpenicillamine and levcromakalim in guinea pig basilar artery

Ischaemic stroke is characterised by reduction of blood flow, tissue hypoxia, energy depletion and neuronal death. Drugs causing vasodilatation of cerebral arteries may potentially enhance blood supply to the ischaemic area and improve clinical outcome. However, vasodilators could also reduce cerebral blood flow in the ischaemic region by acting on blood vessels in non-ischaemic tissue, a phenomenon known as blood flow steal. To explore whether these drugs could act selectively on cerebral blood vessels in a hypoxic environment, we examined the effect of hypoxia on vasodilator responses to the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) and the ATP-dependent potassium channel (K(ATP)) opener levcromakalim in guinea-pig basilar arteries contracted by endothelin-1. Hypoxia considerably enhanced the vasodilator responses to SNAP, while those to levcromakalim were unaffected. In the presence of the NO synthase inhibitor N(G)-nitro-L-arginine, hypoxia no longer enhanced the vasodilator response to SNAP and suppressed responses to levcromakalim. The results show that the NO donor SNAP, but not the K(ATP) opener levcromakalim, is a more effective vasodilator of cerebral arteries contracted by endothelin-1 during hypoxia than under control conditions. Hypoxia-induced inhibition of basal NO synthesis could explain this enhancement of the vasodilator response to SNAP. Thus, NO donors may have a selective effect on blood vessels in ischaemic brain areas and therefore warrant further evaluation as therapeutic agents in cerebral ischaemia.     

脑动脉上神经纤维存在强啡肽A(英文)

免疫组织化学方法显示豚鼠脑动脉上有含强啡肽A_(1-17)免疫样物质的神经纤维存在,大脑前和中动脉上分布最高。乙醛酸诱发荧光法显示有丰富的单胺能神经纤维分布在大的和小的脑血管上,大鼠预先给予6-羟多巴胺或利血平,血管壁上强啡肽含量明显下降。以上结果提示:血管壁上有强啡肽A纤维存在,并且它可能与单胺类神经递质共存。     

Responses of human and baboon arteries to prostaglandin endoperoxides and biologically generated and synthetic prostacyclin: their relevance to cerebral arterial spasm in man.

1 Isolated strips of human or baboon basilar, middle cerebral, vertebral or common carotid arteries were set up in an isolated organ bath or in a superfusion cascade system. 2 These arteries relaxed to prostacyclin but contracted to prostaglandin endoperoxide (PGH2). 3 Human and baboon isolated arteries also generated prostacyclin from exogenous endoperoxide (PGH2). 4 Human arteries generated prostacyclin 36 h post-mortem but not 40 h post-mortem. The biologically generated prostacyclin relaxed the basilar artery and overcame the contractile effects of PGH2. 5 Thromboxane A2-like activity generated during human platelet aggregation by arachidonic acid caused contractions of the human basilar artery. 6 Prostacyclin reversed contractions of human basilar arteries caused by an unidentified vasoconstrictor factor in cerebrospinal fluid obtained from patients with cerebral arterial vasospasm after subarachnoid haemorrhage following rupture of cerebral arterial aneurysms. 7. The above vasospasm may be due at least in part to disordered physiological control of the calibre of cerebral arteries caused by diminished synthesis of prostacyclin.     

Impaired vasodilator response to organic nitrates in isolated basilar arteries

1. The differential responsiveness of various sections and regions in the vascular system to the vasodilator activity of organic nitrates is important for the beneficial antiischaemic effects of these drugs. In this study we examined the vasodilator activity of organic nitrates in cerebral arteries, where vasodilation causes substantial nitrate induced headache. 2. Isolated porcine basilar and coronary arteries were subjected to increasing concentrations of glyceryl trinitrate (GTN), isosorbide-5-nitrate (ISMN) and pentaerythritol tetranitrate (PETN). S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and endothelium-dependent vasodilation was investigated for comparison purpose. 3. The vasodilator potency (halfmaximal effective concentration in -logM) of GTN (4.33+/-0.1, n=8), ISMN (1.61+/-0.07, n=7) and PETN (>10 microM, n=7) in basilar arteries was more than 100 fold lower than that of GTN (6.52+/-0.06, n=12), ISMN (3.66+/-0.08, n=10) and PETN (6.3+/-0.13, n=8) observed in coronary arteries. 4. In striking contrast, the vasodilator potency of SNAP (halfmaximal effective concentration in -logM) was almost similar in basilar (7.76+/-0.05, n=7) and coronary arteries (7.59+/-0.05, n=9). Likewise, no difference in endothelium dependent relaxation was observed. 5. Denudation of the endothelium resulted in a small increase of the vasodilator potency (halfmaximal effective concentration in -logM) of GTN (4.84+/-0.09, n=7, P<0.03) in basilar arteries and similar results were obtained in the presence of the NO-synthase inhibitor N(omega)-nitro-L-arginine (4.59+/-0.05, n=9, P<0.03). 6. These results suggest that cerebral conductance blood vessels such as porcine basilar arteries seems to have a reduced expression and/or activity of certain cellular enzymatic electron transport systems such as cytochrome P450 enzymes, which are necessary to bioconvert organic nitrates to NO.     

Pharmacological characterization of postjunctional alpha-adrenoceptors in cerebral arteries from the sheep.

1. The responsiveness to noradrenaline was characterized in cerebral arteries from the sheep, since this species was large enough to permit a comparison of arteries from different parts of the cerebral vasculature. 2. Noradrenaline caused contraction of the basilar artery, middle cerebral artery and small pial arteries by stimulation of alpha 1-adrenoceptors. 3. The maximum contraction to noradrenaline was small in the basilar artery (28% of the 5-hydroxytryptamine (5-HT) maximum) but larger in the middle cerebral artery (78% of the 5-HT maximum) and pial artery (92% of the 5-HT maximum) of the sheep. 4. Cocaine (10 microM) potentiated noradrenaline-induced contractions in the sheep middle cerebral artery but not in the sheep basilar artery. 5. The noradrenaline contraction, relative to the 5-HT contraction, was not affected by removal of the endothelium in either the sheep basilar or middle cerebral artery. 6. The results showed a variation within the sheep cerebral vasculature in the response to noradrenaline which cannot be explained by regional differences in alpha-adrenoceptor subtypes, noradrenaline uptake mechanisms or endothelial function.     

Vascular responses of isolated mesenteric resistance and basilar arteries from short- and long-term diabetic rats

Vascular dysfunctions, e.g. alterations in the reactivity of blood vessels to neurotransmitters and hormones, are a well-established complication of diabetes mellitus. Whether these impairments are a consequence of direct postsynaptic deficits and/or indirect presynaptic deficits remains to be determined. To this end, we investigated the influence of the duration of diabetes on relaxation and contraction responses of isolated mesenteric resistance and equally-sized basilar arteries to postsynaptic activation by various vasoactive agents, using streptozotocin-induced diabetic rats and age-matched controls. Relaxation responses to vasodilator agents were studied in KCl-precontracted arteries. The duration of diabetes (4 or 40 weeks) did not affect the vasodilator responses to sodium nitroprusside or salbutamol in either artery. In mesenteric resistance vessels from short-term (4 weeks) and long-term (40 weeks) diabetic rats the vasoconstrictor responses to KCl, serotonin and vasopressin were the same as those in non-diabetic rats; however, the sensitivity (EC₅₀) to noradrenaline was slightly but significantly enhanced after the long-term diabetic state. In contrast to the mesenteric arteries, noradrenaline did not cause contraction in basilar arteries taken from diabetic and control rats. Thus, there appear to be important differences in the reactivity to noradrenaline of the peripheral and cerebral vasculature. The basilar artery from short-term and long-term diabetic rats did not show different responsiveness to vasopressin whereas to serotonin a significant enhanced and decreased sensitivity (EC₁₀ and EC₅₀) was demonstrated in short-term and long-term diabetes, respectively. Our findings indicate that postsynaptic impairments do not play a major role in the alterations of vasoreactivity to vasodilators, noradrenaline or vasopressin seen in experimental diabetes. However, the duration of the diabetic state may have serious consequences for vasoreactivity of basilar arteries to serotonin and, therefore, warrants further investigations. Received: 17 June 1998 / Accepted: 3 August 1998     

The resistance of some rat cerebral arteries to the vasorelaxant effect of cromakalim and other K+ channel openers.

1. Cromakalim (0.01-30 microM) and sodium nitroprusside (SNP, 0.01-100 microM) were tested for their ability to relax a number of pre-contracted small arteries (approximate diameter 200-700 microM at 100 mmHg) from the rat, rabbit and guinea-pig. 2. In the rat, SNP (0.01-100 microM) caused near maximal relaxation in all vessels studied including the middle cerebral, anterior cerebellar, basilar, mesenteric and renal arteries. Cromakalim (0.01-30 microM) relaxed pre-contracted mesenteric and renal arteries but was only a weak relaxant of all the rat cerebral arteries with the exception of the basilar artery. Similar experiments using mesenteric and cerebral vessels from the rabbit and guinea-pig showed cromakalim could relax pre-contracted vessels in a concentration-dependent manner. 3. Two other K+ channel openers, nicorandil and pinacidil, were also tested for their ability to relax rat cerebral arteries. Nicorandil (0.01-100 microM) was ineffective in the rat anterior cerebellar artery at concentrations up to 100 microM. Pinacidil (0.01-100 microM) caused significant vasorelaxation, although high concentrations were required (greater than 10 microM) and the response was insensitive to the effects of glibenclamide (3 microM). 4. Electrophysiological experiments with the rat anterior cerebellar artery showed that cromakalim (up to 30 microM) failed to influence the resting membrane potential of impaled single smooth muscle cells. 5. The results showed that some rat small cerebral arteries were resistant to the effects of K+ channel openers including cromakalim, pinacidil and nicorandil. This is peculiar to this vascular tree since the same vessels from other species do not exhibit the same behaviour.(ABSTRACT TRUNCATED AT 250 WORDS)