Vasodilator actions of TRK-100, a new prostaglandin I2 analogue.

TRK-100, a stable analogue of prostaglandin I2 (PGI2), relaxed isolated arteries of the dog precontracted with PGF2 alpha or K+; the relaxation was in the order of mesenteric and renal greater than coronary and femoral greater than basilar and middle cerebral arteries. The relaxation by TRK-100 was not affected by treatment with atropine, propranolol, cimetidine, aminophylline, and indomethacin, but was suppressed by diphloretin phosphate, a prostaglandin antagonist. Treatment with TRK-100 attenuated the contraction induced by PGF2 alpha and Ca2+ in mesenteric and basilar arteries previously exposed to Ca2+-free medium, but did not significantly alter the contractile response to Ca2+ in the arteries exposed to Ca2+-free medium and depolarized by excess K+. TRK-100 and nitroglycerin relaxed isolated mesenteric arteries to a similar extent; however, when continuously infused into mesenteric arteries in anaesthetized dogs, TRK-100 produced greater vasodilatation than nitroglycerin. It is concluded that TRK-100 relaxes dog mesenteric and renal arteries more than cerebral arteries; the relaxation appears to derive from interference with the release of Ca2+ from intracellular stores and with the transmembrane Ca2+ influx through a receptor-operated channel. TRK-100 may vasodilate large and small mesenteric arteries and resistance vessels to a similar extent, whereas nitroglycerin preferentially dilates the large artery.     

Vasodilator actions of felodipine, a new Ca2+ entry blocker

Felodipine [ethylmethyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate], a new Ca2+ entry blocker, relaxed isolated canine arteries and veins precontracted with prostaglandin (PG) F2 alpha, in a concentration-dependent manner. Felodipine dilated cerebral arteries predominantly over the other arteries. Relaxations by felodipine, in low concentrations, were greater in mesenteric vein strips than in mesenteric artery strips isolated from the same dogs. The inhibitory effect of felodipine in high concentrations (10(-7)M or higher) were not reversed by repeated washing. In coronary arteries exposed to Ca2+-free media under anoxia, PGF2 alpha and Ca2+ produced persistent contractions. Reoxygenation from anoxia elicited an additional contraction. Felodipine did not affect PGF2 alpha-induced contraction in Ca2+-free media, but significantly reduced the contractions caused by Ca2+ and reoxygenation. These findings suggest that felodipine is a potent, long-acting Ca2+ entry blocker with characteristics such as a greater action on cerebral arteries and mesenteric veins than coronary and mesenteric arteries.     

Potentiation by ouabain of the response to vasoconstrictor agents of isolated dog cerebral and mesenteric arteries soaked in Ca2+-free media

In helical strips of dog cerebral arteries soaked in Ca2+-free media and treated with prostaglandin (PG) F2 alpha or K+, the addition of Ca2+ produced a transient contraction, transient relaxation, and slowly developing, persistent contraction. Treatment with 2 X 10(-7) M ouabain did not alter the contractile response to PGF2 alpha in Ca2+-free media, but potentiated the response to Ca2+. Relaxations following the transient contractions were abolished by ouabain. On the other hand, ouabain potentiated the contractile response to serotonin in Ca2+-free media, and also the response to Ca2+. In mesenteric arterial strips soaked in Ca2+-free media, ouabain at 2 X 10(-7) M insufficient to produce contractions increased the contractile response to Ca2+, and the increase in the concentration to 2 X 10(-5) M potentiated the response to PGF2 alpha and serotonin. It may be concluded that ouabain increases the influx of Ca2+ across cell membrane caused by vasoconstrictors and enhances the drug-induced release of Ca2+ from intracellular storage sites.     

Vasodilatation induced by pinacidil in dogs. Comparison with hydralazine and nifedipine

In helical strips of dog arteries precontracted with prostaglandin (PG) F2 alpha, pinacidil and nifedipine produced a dose-related relaxation. The potencies of pinacidil were in the order of coronary and renal greater than mesenteric greater than basilar and middle cerebral arteries, whereas those of nifedipine were in the order of basilar and renal greater than mesenteric and coronary arteries. Pinacidil caused a greater relaxation in mesenteric veins than in the arteries. Hydralazine consistently relaxed the arteries only at 10(-3) M. In mesenteric artery strips exposed to Ca2+-free, high K+ media, contractions induced by Ca2+ were reduced by 10(-8) M nifedipine, but they were not influenced by 10(-5) M pinacidil or by 10(-4) M hydralazine. In the arteries exposed to Ca2+-free media and stimulated by PGF2 alpha or norepinephrine, tonic contractions induced by Ca2+ were reduced moderately by 10(-5) M pinacidil but only slightly by 10(-8) M nifedipine. In Ca2+-free media, PGF2 alpha-induced contractions were inhibited only by pinacidil. In isolated mesenteric vasculature, perfusion pressure was lowered by pinacidil and hydralazine. It may be concluded that pinacidil produces vasodilatation due to interference with the transmembrane influx of Ca2+ into smooth muscle evoked by receptor stimulation but not that due to inhibition in the Ca2+ influx associated with K+-induced membrane depolarization. Decreased release of Ca2+ from intracellularly stored sites or increased sequestration to the sites may also be involved. Pinacidil appears to dilate arteries and veins as well as resistance vessels, whereas hydralazine appears to act exclusively on resistance vessels.     

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)     

Inhibition by Cd2+ verapamil and papaverine of Ca2+-induced contractions in isolated cerebral and peripheral arteries of the dog.

1 In helically cut strips of canine cerebral arteries exposed to Ca2+-free media and depolarized by K+, the addition of Ca2+ caused biphasic (transient and sustained) contractions, while in coronary and mesenteric arteries, the additon of Ca2+ produced a sustained contraction sometimes preceded by a slight transient contraction. 2. These Ca2+-induced contractions were attenuated by Cd2+ (50 to 100 micron) in a dose-dependent manner, the attenuation being greater in cerebral than in coronary and mesenteric arteries. The inhibitory effect of Cd2+ was prevented and partially reversed by 1 mM cysteine. 3. Verapamil and papaverine were also effective in attenuating the Ca2+-induced contrations in cerebral and peripheral arteries: susceptibility to verapamil was in the order, cerebral greater than coronary greater than mesenteric, while that to papaverine was in the order, cerebral=coronary greater than mesenteric. 4. It may be concluded that the agents that interfere with trans-membrane influxes of Ca2+ cause a greater relaxation in cerebral than in peripheral arteries, as is seen with papaverine, a non-specific vasodilator.     

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 F2 alpha (PGF2 alpha) and noradrenaline on contraction and 45Ca exchange have been studied in rat mesenteric arteries. 2 PGF2 alpha and noradrenaline contracted rat isolated mesenteric artery preparations to about the same extent. The PGF2 alpha-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 PGF2 alpha-stimulated contractions and 45Ca uptake to a similar extent. 4 Flunarizine was about 7 fold more potent as an inhibitor of noradrenaline- than of PGF2 alpha-mediated contraction and 45Ca uptake and this ratio was about 50 for cinnarizine. 5 EGTA (1.25 mM) produced a relaxation of noradrenaline and PGF2 alpha-induced maximal contractions. Measured over the first 2 min of EGTA contact, the rate of relaxation was much faster in noradrenaline than in PGF2 alpha-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 PGF2 alpha, largely due to a greater effect of noradrenaline on calcium efflux. 7 The results suggest that PGF2 alpha-but not noradrenaline-induced contractions are entirely dependent on the influx of extracellular calcium and that the agonists may stimulate calcium gating mechanisms differently.     

Action of atrial natriuretic peptide (ANP) on dog cerebral arteries: evidence that neurogenic relaxation is not mediated by release of ANP.

1. Atrial natriuretic peptide (ANP) (10(-9) to 10(-8) M) produced a concentration-related relaxation in helical strips of dog cerebral arteries partially contracted with prostaglandin F2 alpha. The relaxation was not affected by treatment with ouabain, quinidine, oxyhaemoglobin, methylene blue, or removal of endothelium. 2. Relaxations induced by nicotine or transmural electrical stimulation were not reduced in arteries in which tachyphylaxis to ANP had developed. 3. In arteries exposed to Ca2+-free media under severe hypoxia, contractions due to prostaglandin F2 alpha and Ca2+ were attenuated by treatment with ANP, whereas the reoxygenation-induced contraction was unaffected. 4. The results suggest that ANP does not mediate neurogenic relaxation of dog cerebral arteries. The ANP-induced relaxation is not associated with activation of the sodium pump but is due to an inhibitory action on the release and influx of Ca2+, probably as a result of stimulation of guanylate cyclase.     

Inhibition by KB-2796, a new Ca2+ entry blocker, of the contractile response of isolated cerebral and peripheral arteries in the dog

In helical strips of dog cerebral and peripheral arteries, KB-2796 (1-[bis(4-fluorophenyl)-methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride), a new Ca2+ entry blocker, inhibited the contractile responses induced by K+, prostaglandin (PG) F2 alpha and serotonin in a non-competitive manner. KB-2796 inhibited the contraction induced by K+ more effectively than those induced by PGF2 alpha or serotonin. In cerebral arteries, the inhibition produced by KB-2796 was more prominent than in peripheral arteries. In renal arteries, serotonin produced contractions in concentrations 200-1,200 times higher than those sufficient to contract the other arteries. KB-2796 inhibited renal arterial contractions induced by serotonin and K+ to a similar extent. In renal arteries depolarized by replacement of the entire amount of NaCl in the bathing medium with KCl, PGF2 alpha produced additional contraction of the artery, whereas serotonin did not contract the artery. These results suggest that KB-2796 inhibits the contractility of cerebroarterial smooth muscle more preferentially than that of other arteries. The contractile response to serotonin of the renal artery appears to be associated with the voltage-dependent influx of Ca2+ as suggested in the cerebral arteries.     

A cytochemical bioassay method for the determination of luteinizing hormone in biological fluids and tissues

1 In helically-cut strips of dog coronary, superior mesenteric, right gastro-epiploic and renal arteries contracted with prostaglandin F2 alpha (PGF 2 alpha), histamine produced a dose-related relaxation, while, in contrast, the amine caused only a contraction of cerebral arterial strips. 2 The contractile response of cerebral arteries to histamine was attenuated by chlorpheniramine (10(-6)M) but was unaffected by cimetidine (10(-5)M). Relaxant responses to histamine of coronary and renal arteries were significantly attenuated by treatment with cimetidine and to a similar extent by combined treatment with cimetidine and chlorpheniramine. Chlorpheniramine alone was ineffective. 3 In mesenteric and gastro-epiploic arteries, relaxant responses to histamine were attenuated only slightly by cimetidine. Chlorpheniramine slowed the development of histamine-induced relaxations but did not alter the magnitude of the relaxations. Combined treatment with these H1- and H2- antagonists attenuated the histamine-induced relaxations to an appreciably greater extent than treatment with cimetidine alone. 4 It may be concluded that the cerebroarterial contraction induced by histamine is mediated through H1-receptors and the relaxations of coronary and renal arteries induced by histamine are mediated through H2-receptors. It appears that H1- and H2-receptors interact with each other to produce potentiation of histamine-induced relaxations of mesenteric and gastro-epiploic arteries.     

Influence of extracellular calcium and calcium antagonists on contractions induced by potassium and prostaglandin F2 alpha in isolated cerebral and mesenteric arteries of the cat.

1 The effects of a number of calcium antagonists (diltiazem, nifedipine, nimodipine and verapamil) have been studied on feline isolated pial arteries contracted by potassium (127 mM) or prostaglandin F2 alpha (PGF2 alpha, 2.5 microM) and mesenteric arteries contracted by potassium (127 mM). 2 Withdrawal of Ca2+ from the extracellular medium for 30 min reduced the contractile response to potassium in cerebral vessels by 92% and in mesenteric vessels by 96%. Subsequent addition of Ca2+ caused reproducible contractions which were inhibited by both nifedipine and nimodipine. 3 The four calcium antagonists relaxed the isolated middle cerebral artery contracted either by potassium or PGF2 alpha, and mesenteric arteries contracted by potassium, in the following order of potency: nimodipine greater than nifedipine greater than verapamil greater than diltiazem. 4 Nimodipine was more potent than nifedipine in cerebral arteries, and more potent in cerebral than in mesenteric arteries. Otherwise, the potassium-contracted cerebral and mesenteric vessels showed no major differences in sensitivity to calcium antagonists.     

Modification by severe hypoxia and diltiazem of dog coronary artery contractions in vitro

The contractions induced by prostaglandin (PG) F2 alpha and by Ca2+ in helical strips of canine coronary arteries exposed to Ca2+-free medium under severe hypoxia and stimulated by PGF2 alpha or K+ were augmented by the return to normoxia. Inhibition under hypoxia was ranked as follows: Ca2+-induced contractions in the strips stimulated by PGF2 alpha greater than Ca2+-induced contractions in the K+-depolarized strips greater than PGF2 alpha-induced contractions in the Ca2+-free medium. The inhibition of arterial contractions during severe hypoxia was not influenced by removal of the endothelium. Treatment with indomethacin attenuated the inhibitory effect of hypoxia on Ca2+-induced contractions in arteries stimulated by PGF2 alpha or serotonin but affected neither the Ca2+-induced contractions in the strips depolarized by excess K+ or the PGF2 alpha-induced contractions in Ca2+-free medium. Diltiazem attenuated the Ca2+-induced contractions in arteries stimulated by PGF2 alpha or K+ but did not attenuate the PGF2 alpha-induced contractions in the Ca2+-free medium during hypoxia or normoxia. Diltiazem also inhibited the contractions caused by re-oxygenation. In conclusion, severe hypoxia inhibited the contractions induced by Ca2+ in the presence of PGF2 alpha receptor activation more than those associated with membrane depolarization. The PGF2 alpha-induced contractions in the Ca2+-free medium (possibly due to the release of intracellularly stored Ca2+) may be relatively resistant to severe hypoxia. The hypoxia-induced inhibition of contractions due to Ca2+ in PGF2 alpha-stimulated arteries could be associated partly with the release of PGI2 but not with endothelium-derived relaxing factor(s).     

Role of endothelium in the response to prostaglandin H2 in isolated dog arteries

Prostaglandin (PG) H2 produced a transient contraction followed by a relaxation in helical strips of dog coronary, mesenteric and renal arteries contracted with PGF2 alpha. The contraction was in the order of mesenteric greater than renal greater than coronary artery. Removal of endothelium abolished the contraction in these arteries and significantly potentiated the relaxation only in mesenteric arteries. The relaxation was greater in mesenteric arteries than in renal and coronary arteries, denuded of endothelium. PGI2-induced relaxations were not influenced by endothelium denudation. In the arteries contracted with K+, PGH2-induced relaxations were attenuated, compared to those contracted with PGF2 alpha. Treatment with ONO3708, an antagonist of vasoconstrictor PGs, abolished the PGH2-induced contraction and potentiated the relaxation in the K+-contracted arteries. The relaxant response was suppressed by diphloretin phosphate, a PG receptor antagonist, as was the response to PGI2. PGH2-induced contractions in dog coronary, mesenteric and renal arteries would be due to vasoconstrictor PGs produced preferentially in the endothelium. However, production of PGI2 from PGH2 in endothelial and subendothelial tissues do not appear to differ.     

Mechanism of noradrenaline potentiation by prostaglandin E2 in rat mesenteric artery.

1 Effects of prostaglandins E2 and F2 alpha (PGE2 and PGF2 alpha) on vasoconstrictor responses to noradrenaline (NA) and methoxamine in isolated mesenteric arteries of the rat were investigated. 2 PGE2 and to a lesser extent PGF2 alpha potentiated vasoconstrictor responses to NA and methoxamine. 3 Prior treatment with reserpine increased, and bretylium reduced, the extent of potentiation significantly. 4 NA vasoconstriction persisted for 1 h after Ca2+ was removed from the perfusing Krebs solution. Prostaglandin-induced potentiation was absent in Ca2+-free Krebs, but increased proportionately with increase in external Ca2+ concentration. 5 Vasoconstriction induced by high potassium, was not potentiated by PGE2. 6 It is concluded the PGE2 potentiates NA vasoconstriction by facilitating Ca2+ influx.     

Endothelium and Ca2+ in the prostaglandin F2 alpha potentiation of vasoconstrictor responses

Prostaglandin F2 alpha (PGF2 alpha), at a concentration that did not induce vascular contraction (10(-9) and 10(-10) M), potentiated the dose-response curves to norepinephrine (NE) in rat mesenteric ring segments only when the endothelium was present. Moreover, PGF2 alpha, in both unrubbed mesenteric artery and mesenteric vascular bed, was able to increase the contraction to NE as well as the ratio of the amplitude of two NE-induced contractions under previously standardized conditions, in the absence of extracellular calcium. In addition, without extracellular Ca2+, PGF2 alpha increased in both tissues the refilling of Ca2+ induced by 80 mM KCl plus 1.5 mM Ca2+. The mechanism of this potentiation is unknown, but it may be related to cellular events including the intracellular Ca2+ mobilization. This study suggests that the endothelium plays a necessary role in PGF2 alpha potentiation of vasoconstrictor response, possibly through the release of an endothelial vasoconstrictor factor which probably increases the Ca2+ bioavailability for the contraction.     

Different utilization of Ca2+ in the contractile action of endothelin-1 on cerebral, coronary and mesenteric arteries of the dog.

Vasoconstrictor responses to endothelin-1 (ET) were compared between endothelium-denuded strips of cerebral, coronary and mesenteric arteries of the dog. Contractile responses to lower concentrations (below 3 x 10(-10) M) of ET were significantly greater in the cerebral and coronary arteries than in the mesenteric artery. The cerebral and coronary arteries, but not the mesenteric artery, relaxed significantly from the resting level when placed in a 0-Ca solution. Readdition of Ca2+ to the cerebral and coronary arteries placed in the 0-Ca solution caused a biphasic contraction which was susceptible to inhibition by nifedipine. When ET below 10(-10) M was introduced before the Ca2+ contraction, this peptide produced no detectable contraction, but augmented the Ca2+ contraction. The augmented Ca2+ contractions were abolished by 10(-7) M nifedipine. These effects of ET were not observed in the mesenteric artery. The contractile responses of the mesenteric artery to ET determined in the presence of elevated extracellular K+ concentrations were comparable to the responses of the cerebral artery to this peptide determined in the presence of normal K+ concentrations. These results indicate that the enhanced responses to ET in the cerebral and coronary arteries were dependent on the Ca2+ influx through voltage-dependent Ca2+ channels and suggest that these channels are in an activated state when these arteries are in a resting state.     

Vasoconstrictor response of large cerebral arteries of cats to endothelin, an endothelium-derived vasoactive peptide

Endothelin, a 21-amino acid peptide produced by vascular endothelial cells, caused a sustained constriction of isolated large cerebral arteries of cats in a dose-dependent manner. The increased tone of the tissue did not return to the resting level after repeated washings. No vasodilator response was evoked by endothelin in the presence of an active tone. The contractile response of cerebral arteries was not inhibited by rubbing of the endothelium, cold storage denervation or indomethacin. In contrast, nicardipine or diltiazem antagonized the endothelin-induced contraction non-competitively. No contraction was evoked by endothelin in a Ca2+-free solution while the addition of Ca2+ ions in the presence of endothelin in a Ca2+-free solution caused a sustained contraction. Ca2+-induced contraction in the Ca2+-free solution containing endothelin was also inhibited by nicardipine. Therefore, endothelin causes a direct contraction of the smooth muscles of cat cerebral arteries, probably by activating the influx of Ca2+ ions through L-type Ca2+ channels of smooth muscles.     

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.     

Phentolamine-induced rhythmic contractions in bladder detrusor muscle of guinea-pig.

Phentolamine caused a rhythmic contraction concentration-dependently without affecting resting tone in the detrusor muscle. Prazosin, yohimbine, propranolol, noradrenaline, clonidine or isoprenaline failed to cause the rhythmic contraction. These agents did not modify the response to phentolamine suggesting no involvement of alpha- or beta-adrenoceptors in the response to phentolamine. Chlorpheniramine, cimetidine, methysergide, SK&F 83566, atropine, bretylium, hemicholinium or tetrodotoxin failed to inhibit the response to phentolamine. These results suggest that the effect of phentolamine is not mediated through histaminergic, 5-hydroxytryptaminergic, dopaminergic or cholinergic systems, or through transmitter release from nerve endings. Prostaglandin F2 alpha (PGF2 alpha), arachidonic acid but not ATP caused rhythmic contractions which resembled the response to phentolamine. Potassium also caused a contraction with increasing resting tone. Following treatment with nifedipine, or incubation in a Ca2+-free medium, the responses to phentolamine, PGF2 alpha, arachidonic acid and potassium were markedly inhibited or abolished. Cyclo-oxygenase inhibitors such as indomethacin, aspirin and corticosterone inhibited or abolished the responses to phentolamine and arachidonic acid but did not inhibit the response to PGF2 alpha. The results suggest that the phentolamine-induced rhythmic contraction may, at least in part, result from the cyclo-oxygenase metabolite of arachidonic acid in guinea-pig detrusor muscles and a consequent increase in the transmembrane Ca2+-influx.     

Analysis of ouabain-induced contractions in isolated coronary arteries

Contractile responses to ouabain in helical strips of dog and monkey coronary arteries were investigated. Ouabain (5 X 10(-8) to 5 X 10(-6) M) caused a dose-related contraction in dog and monkey arteries; the response of monkey coronary arteries was significantly greater. In dog coronary arteries, contractile responses to high concentrations of ouabain were potentiated by treatment with propranolol. In the arteries contracted with ouabain, the addition of phentolamine caused a relaxation. Contractile responses of dog coronary arteries to ouabain were markedly suppressed by exposure to Ca2+-free media or by treatment with verapamil. Reduction of external concentration of K+ or lowering the temperature of bathing media did not selectively influence the ouabain-induced contraction. These results suggest that ouabain-induced contractions of dog coronary arteries are associated mainly with an increase in the Ca2+-influx, which does not result from an inhibition of the Na+, K+-activated ATPase nor from an activation of alpha adrenoceptors by noradrenaline released from adrenergic nerves. Ouabain in high concentrations seems to liberate noradrenaline from adrenergic nerves, which preferentially activates beta adrenoceptors in dog coronary artery.