Relaxing effects of dilazep and lidoflazine in dog cerebral and renal arteries independent of adenosine

The adenosine potentiating drugs dilazep and lidoflazine were studied for their relaxing ability in isolated dog cerebral and renal arteries contracted under conditions which induce the opening of potential-dependent calcium channels (using K+ at 30, 50 and 100 mmol/l) and under conditions which induce the opening of receptor-operated calcium channels (prostaglandin F2 alpha, PGF2 alpha; 5-hydroxytryptamine, 5-HT) and compared with those of adenosine and a standard calcium entry blocker, diltiazem. Dilazep, lidoflazine and diltiazem exerted concentration-dependent relaxation in cerebral and renal artery ring strips contracted with 30, 50 and 100 mmol/l K+. However, dilazep was slightly more potent at 100 mmol/l K+. In contrast, whereas the high concentration of adenosine (1 X 10(-5)-3.7 X 10(-4) mol/l) relaxes these arteries only at 30 mmol/l K+, it produced a more pronounced concentration-dependent relaxation when PGF2 alpha or 5-HT was used as a contracting agent. The order of relaxing responses of both cerebral and renal arterial ring strips contracted by PGF2 alpha were: diltiazem greater than adenosine greater than lidoflazine greater than dilazep. On the other hand, the relaxing responses on cerebral and renal arteries contracted with 5-HT were: diltiazem greater than lidoflazine greater than adenosine greater than dilazep and diltiazem greater than adenosine greater than lidoflazine greater than dilazep, respectively. Adenosine deaminase reversed the relaxation produced by adenosine, but was unable to reverse the relaxing responses to diltiazem, lidoflazine and dilazep. These findings suggest that dilazep and lidoflazine have a direct relaxing effect independent of adenosine in cerebral and renal artery ring strips possibly through their calcium entry blocking activity. The data suggest that adenosine is more effective on the receptor-operated contractions, whereas dilazep and lidoflazine are more effective on the potential-dependent contractions.     

Effects of adenosine analogs and ouabain on rhythmicity in human coronary artery

The effects of adenosine receptor agonists and ouabain on rhythmicity were studied in coronary arteries obtained from 12 human donors. Ring segments of left anterior descending coronary arteries were suspended in organ baths for measurement of isometric tension. Prostaglandin F2 alpha (PGF2 alpha:10 microM) produced tonic contractions followed by phasic relaxations. The phasic relaxations were completely abolished by either 100 nM ouabain or 50 mM KCl and changed to tonic contraction. The rhythmicity was also inhibited in K+-free medium. The adenosine analogs, 5'-N-ethylcarbo-xamidoadenosine (NECA) and 2-chloroadenosine (CAD) caused a concentration-dependent relaxation of the maximum force, minimum force, and decreased the frequency of rhythmicity. In rings that did not show phasic activity in response to PGF2 alpha, NECA and CAD produced concentration-dependent relaxation of the tonic contraction. Prior treatment with ouabain (100 nM) prevented the relaxing response of these compounds and the development of rhythmicity. Our data show that PGF2 alpha-induced rhythmicity in human coronary arteries could be inhibited by ouabain, alterations in K+ concentrations and by adenosine analogs. The relaxations produced by adenosine analogs could also be inhibited by ouabain.     

Inhibitory effects of cadralazine and its metabolite, ISF-2405, on contractions and the level of cytosolic Ca2+ in vascular smooth muscle

The inhibitory effects of a hypotensive agent, cadralazine and its metabolite, ISF-2405, on the level of cytosolic Ca2+ ([Ca2+]cyt) and on contractions were examined in isolated vascular smooth muscle. Cadralazine slightly inhibited the transient norepinephrine-induced contraction in rabbit aorta and canine femoral, renal and mesenteric arteries and saphenous vein, and prostaglandin F2 alpha-induced contractions in canine basilar and coronary arteries. In contrast, ISF-2405 inhibited the contractions induced by prostaglandin F2 alpha in canine basilar and coronary arteries and those induced by norepinephrine in canine renal and femoral arteries and rabbit aorta. In aorta, ISF-2405 inhibited the increase in [Ca2+]cyt and muscle tension caused by norepinephrine. A Ca2+ channel blocker, verapamil, inhibited the norepinephrine-stimulated increase in [Ca2+]cyt more potently than it inhibited the increase in muscle tension, and ISF-2405 inhibited the verapamil-resistant part of the contraction. In Ca2(+)-free solution, norepinephrine induced transient increases in [Ca2+]cyt and muscle tension. ISF-2405 inhibited these changes. However, ISF-2405 did not inhibit the transient contraction induced by caffeine in the aorta. These results suggest that cadralazine is metabolized to ISF-2405 and inhibits vascular smooth muscle contraction by inhibiting receptor-mediated Ca2+ influx, Ca2+ release and Ca2+ sensitization of contractile elements.     

Endothelium-removal decreases relaxations of canine coronary arteries caused by beta-adrenergic agonists and adenosine

Experiments were designed to investigate the importance of the endothelium in relaxation of isolated coronary arteries caused by beta-adrenoceptor agonists or adenosine. Rings of canine left circumflex coronary arteries were suspended for isometric tension recording in organ chambers filled with physiological salt solution. Norepinephrine, isoproterenol, adenosine, acetylcholine, and sodium nitroprusside caused relaxations of control rings contracted with prostaglandin F2 alpha or KCl. The relaxations to all substances tested were relatively smaller during contractions evoked by KCl than those caused by prostaglandin F2 alpha. Mechanical removal of the endothelium abolished the relaxations caused by acetylcholine, reduced those caused by the catecholamines and adenosine, and did not affect the relaxations to sodium nitroprusside during contractions to prostaglandin F2 alpha. Endothelium-removal did not affect relaxations to beta-adrenergic agonists or adenosine during contractions to KCl or after pretreatment of the arteries with indomethacin. Indomethacin did not affect responses to acetylcholine or sodium nitroprusside, but augmented those in response to beta-adrenoceptor stimulation and adenosine. These results suggest that the endothelial cells of the canine coronary artery produce a signal in response to beta-adrenergic agonists and adenosine, which facilitates the direct inhibitory action of these substances on vascular smooth muscle.     

Differential vasorelaxant effects of milrinone and amrinone on contractile responses of canine coronary, cerebral, and renal arteries

The vasorelaxant effects of milrinone and amrinone in canine coronary, cerebral, and renal arterial rings or strips contracted by either K+-depolarization, U46619 (a thromboxane mimetic), or prostaglandin F2 alpha (PGF 2 alpha) were quantitated. Milrinone was more potent as a vasorelaxant in coronary arteries relative to cerebral or renal arteries regardless of the mode of contraction; amrinone was coronary selective with K+ contraction only. When comparing potency in arteries contracted by different agonists, milrinone was significantly more potent as a vasorelaxant in all three arteries contracted by either U46619 or PGF2 alpha than in arteries contracted by K+ depolarization, whereas amrinone was only selective for U46619-induced contractions in cerebral arteries. This profile of activity for milrinone was similar to that of sodium nitrite and isoproterenol and dissimilar from the calcium entry blocking agents nimodipine and nifedipine. In conclusion, this study shows that coronary vascular selectivity exists for milrinone and amrinone. Moreover, the relaxant profiles of milrinone and amrinone, with different sources of vascular smooth muscle, are unlike those of calcium entry blocking agents and more similar to the profiles of agents that modulate cyclic nucleotide levels.     

Mechanisms controlling caffeine-induced relaxation of coronary artery of the pig.

1. We studied the effects of caffeine on coronary artery smooth muscle of the pig by measuring changes in isometric tension, cytosolic free Ca(2+) concentration ( [Ca2+]i) and transmembrane potential. 2. In the absence of tone, caffeine induced a concentration-dependent transient contraction of coronary artery strips, followed by sustained relaxation. Simultaneously with the relaxation, caffeine, 25 mM, hyperpolarized the smooth muscle cells by 7.7 +/- 0.9 mV. 3. Caffeine caused a concentration-dependent relaxation of strips precontracted with 10(-5)M acetylcholine (ACH). A supramaximal relaxing concentration of 25 mM caffeine produced an additional transient increase in [Ca2+]i on the Ca2+ plateau of ACh tonic contraction, which was followed by a decrease in [Ca2+]i to a level slightly below the basal concentration. This relaxation was accompanied by a hyperpolarization of 7.3 +/- 0.9 mV. 4. KCI 120 mM (high K+) contracted the strips with a concomitant depolarization of 38.6 +/- 1.6 mV and sustained increase in [Ca2+]i. Caffeine caused a concentration-dependent relaxation of high K+-induced contraction. Caffeine, 25 mM, decreased the Ca2+ plateau to a level that remained above the basal concentration of Ca2+ but did not change the membrane potential. 5. When strips were placed in a Ca(2+)-free medium with EGTA 2mM, and, in addition, ACh was applied successively three times, both intracellular and extracellular mobilizable Ca2+ pools were depleted. In these conditions, phorbol 12,13 dibutyrate (PDBu) 10(-7) M and prostaglandin F 2 alpha (PGF 2 alpha) 10(-5) M contracted the strips. Caffeine (25 mM) inhibited these contractions with no change in [Ca2+]i.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ryanodine reveals multiple contractile and relaxant mechanisms in vascular smooth muscle: simultaneous measurements of mechanical activity and of cytoplasmic free Ca2+ level with fura-2.

1. The effects of ryanodine on changes in cytoplasmic Ca2+ level ([Ca2+]i) and muscle tension induced by maximum concentrations of phenylephrine (Phe; 1 microM), prostaglandin F2 alpha (PGF2 alpha, 10 microM), caffeine (Caf, 30 mM) and isoprenaline (Iso, 1 microM) were examined in rat aortic strips using fura-2. 2. In normal media, Phe and PGF2 alpha produced a phasic contraction, followed by a tonic one. Caf elicited only a transient contraction. When the preparation was treated with 10 microM ryanodine, an increase in [Ca2+]i was induced accompanied by a nicardipine (1 microM)-resistant contraction which was [Ca2+]o-dependent. 3. In Ca2(+)-free solution, the three stimulants elicited transient increases in [Ca2+]i. Transient contractions to Phe and Caf were accompanied by changes in [Ca2+]i. The transient increase in [Ca2+]i induced by PGF2 alpha was not accompanied by a corresponding contraction. 4. Sustained contractions were induced by Phe and PGF2 alpha in the absence of external Ca2+, while the increase in [Ca2+]i was reduced. A larger maximum contraction was induced by PGF alpha than by Phe. 5. Ryanodine abolished both the Caf- and Phe-induced [Ca2+]i transient increases and the corresponding contractions, but had no substantial effect on the PGF2 alpha-induced [Ca2+]i transient increase. Ryanodine had no influence on the sustained contractions induced by Phe and PGF2 alpha. 6. Iso relaxed both sustained contractions almost completely, without any detectable change in [Ca2+]i. Treatment of the preparation with ryanodine had no effect on the concentration-response curves for Iso in relaxing the 0.1 microM Phe- or 40 mM K(+)-induced precontraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Regional differences in the response of isolated human vessels to vasoactive substances

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 influence of magnesium on the release of calcium from intracellular depots in vascular smooth muscle cells

Vasoconstrictor responses to prostaglandin F2 alpha and noradrenaline were investigated in ring segments of feline femoral, coronary and cerebral arteries incubated in calcium-free solutions containing different concentrations of magnesium (1.2, 4.4 and 13.2 mM). Contractions produced by prostaglandin F2 alpha and noradrenaline were depressed when calcium was omitted from the incubation solution. The presence of raised concentrations of magnesium (4.4 or 13.2 mM) in the tissue bath further depressed the prostaglandin F2 alpha and noradrenaline contractions in calcium-free medium. In a separate set of experiments the vessel wall contents of cAMP and cGMP were measured before and after the additions of 4.4 or 13.2 mM magnesium; stable relaxations by magnesium were noted but there was no parallel change in the vessel content of cAMP or cGMP. The results indicate that magnesium may interfere with the release of calcium from intracellular depots, and that neither adenylate cyclase, nor guanylate cyclase are involved in the dilator activity of magnesium in isolated arteries.     

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).     

Inhibitory effects of nitrendipine on myometrial and vascular smooth muscle in human pregnant uterus and placenta

Human myometrial visceral and vascular preparations and placental chorionic and stem villous vessels were dissected from myometrial and placental specimens obtained at term Caesarean section and after vaginal delivery. Vascular ring preparations and myometrial strips were mounted in organ bath and isometric tension recorded. Only myometrial preparations developed spontaneous contractile activity, which was effectively blocked by the calcium channel blocker nitrendipine (NTD) 10(-7) M. Pretreatment with calcium-depleted medium for 30 min. almost abolished myometrial responses to high K+ (124 mmol), oxytocin (OX) and prostaglandin F2 alpha (PGF2 alpha). Vascular responses to high K+ (124 mmol) were also nearly abolished by such treatment. However, noradrenaline (NA), vasopressin (VP) and PGF2 alpha in myometrial arteries and PGF2 alpha in chorionic vessels and stem villous arteries induced significant, but reduced contractions after calcium depletion. In all vascular preparations, exposed to calcium-depleted medium, NTD (10(-8) M) almost abolished contractions induced by calcium (0.1-4.0 mM) in the presence of K+ (124 mmol) and depressed responses to calcium in the presence of the other agonists tested. NTD (10(-10)-10(-7) M) depressed myometrial contractions induced by K+, OX and PGF2 alpha more effective than vascular responses to K+, NA, VP and PGF2 alpha in the myometrial arteries and K+ and PGF2 alpha in the placental arteries. It is concluded that activation of contraction in vessels from the human utero-placental unit implies multiple cellular sources of calcium, while in myometrial smooth muscle, influx of superficially bound calcium may be an important initial step in contractile activation. Treatment with calcium channel blockers during late human pregnancy might involve relaxation of the myometrium together with vasodilatation of the myometrial and foetal placental vascular beds.     

Progesterone induces endothelium-independent relaxation of rabbit coronary artery in vitro.

The effect of progesterone on isolated rabbit coronary arteries and its possible mechanism was investigated by measuring changes of isometric tension. Progesterone (1, 3, 10 and 30 microM) induced significant coronary relaxation in K+ (30 mM)-, prostaglandin F2 alpha (3 microM)- or Bay K 8644 (1 microM plus 15 mM K+)- precontracted arteries. There was no difference between endothelium-intact and -denuded coronary arteries from both male and female rabbits, precontracted with these three agents. Haemoglobin, indomethacin, methylene blue, glibenclamide or barium chloride did not affect the relaxation. In endothelium-denuded rabbit coronary arteries, progesterone shifted calcium concentration-dependent constrictor-response curves to the right, the maximal contraction was also reduced. The -log ED50s were 3.6 in control, and 3.3 and 2.9 after incubation with progesterone (3 and 30 microM), respectively. Similar results were obtained in rat aorta. We conclude that progesterone induces significant endothelium-independent relaxation in rabbit coronary arteries in vitro, possibly by affecting calcium influx.     

Roles of calcium and the endothelium in the relaxations produced by 5'-N-ethylcarboxamidoadenosine (NECA)

The aim of the present investigation was to evaluate the endothelium dependency in the relaxations by the adenosine analog, 5'-N-ethylcarboxamidoadenosine (NECA), and the requirement for extracellular calcium in endothelium-dependent and independent relaxations. In prostaglandin F2 alpha (PGF2 alpha)-contracted bovine coronary arteries with intact endothelium, bradykinin produced relaxations in calcium medium but not in calcium-free medium. Removal of the endothelium abolished the relaxing response to bradykinin. In calcium medium, NECA produced similar relaxations in coronary arteries with intact and mechanically disrupted endothelium. The relaxation-response curves for NECA were shifted to the right in parallel in calcium free medium. Sodium nitroprusside produced concentration-dependent relaxations which were endothelium-independent. Removal of calcium from the bathing medium caused partial but significant attenuation of these relaxations. The results indicated that in bovine coronary artery, relaxations induced by NECA were endothelium-independent. Also bradykinin-induced relaxations are totally dependent on calcium whereas the endothelium-independent relaxing agents such as NECA and sodium nitroprusside require calcium only partially for their relaxations.     

Evidence for an A2 adenosine receptor in human coronary arteries

The present study was an attempt to characterize the type of adenosine receptor in human coronary arteries obtained from organ donors with the use of adenosine analogs. Prostaglandin F2 alpha (10(-6) M) produced tonic contractions followed by phasic contractions and diltiazem (10(-6) M) pretreatment changed the phasic contractions to tonic contractions. Adenosine and its analogs (5'-N-ethyl-carboxamide adenosine, NECA and N6-L-phenyl-isopropyl adenosine, L-PIA), produced concentration-dependent relaxations of the tonic contractions and the order of potency was found to be: NECA greater than L-PIA greater than adenosine. 8-Phenyltheophylline (5 X 10(-6) M) antagonized the relaxations produced by adenosine and its analogs. The data suggest the existence of A2 adenosine receptor in human coronary arteries.     

Acetylcholine-induced positive inotropy mediated by prostaglandin released from endocardial endothelium in mouse left atrium

The possible involvement of the endocardial endothelium in the positive inotropic response of the mouse left atrium to acetylcholine was examined pharmacologically. In mouse left atria, acetylcholine produced a biphasic inotropic response: a transient decrease in contractile force followed by a late increase. The positive response was not affected by the presence of phentolamine and propranolol, but was almost abolished by pretreatment of the preparation with 1% Triton X-100, which denudes the endocardium of its endothelium. Nordihydroguaiaretic acid, NG-nitro-L-arginine, BQ-123 and BQ-788 had no effect on the inotropic responses to acetylcholine, but indomethacin completely abolished the positive response. Prostaglandins and their analogues had a positive inotropic effect with a potency order PGF2alpha>PGD2>PGE2>U46619, whereas beraprost had no effect. Neither Triton X-100 pretreatment nor the presence of indomethacin affected the positive inotropic effect of PGF2alpha. Acetylcholine and PGF2alpha prolonged the action potential duration similarly. These results suggest that the acetylcholine-induced positive inotropic response in mouse left atria is mediated by prostaglandin released from the endocardial endothelium.     

Actions of a novel thromboxane A2-receptor antagonist, S-145, on isolated monkey and cat arteries

The effects of a novel thromboxane (Tx) A2-receptor antagonist, S-145, were investigated mainly in helical strips of monkey and cat arteries. S-145 (3 x 10(-10) to 3 x 10(-9) M) attenuated the contraction induced by U46619 (2 x 10(-10) to 10(-7) M), which produced concentration-dependent contraction in monkey cerebral, coronary, and mesenteric arteries, and cat cerebral arteries. The attenuation in the different monkey arteries did not differ much, and it tended to be greater in cat cerebral arteries than in monkey at concentrations of less than 10(-9) M S-145. S-145 also suppressed contractions in cat cerebral arteries induced by prostaglandin (PG) F2 alpha, PGE2, and PGD2. However, S-145 did not affect the contractile responses to PGF2 alpha in cat iris sphincter muscle and to PGE2 in guinea pig ileum. In cat mesenteric arteries, S-145 did not affect contractions induced by norepinephrine or K+, or relaxations induced by PGI2 or adenosine. The addition of S-145 (10(-9)-10(-8) M) produced a transient contraction in cat cerebral arteries, and when S-145 (3 x 10(-11) to 3 x 10(-7) M) was cumulatively added, the contraction was not produced. The measurement of antagonistic potency of S-145 was not complicated by its agonistic effect, since the former potency was always determined after confirming absence of the latter effect. These results suggest that S-145 is a potent TxA2-receptor antagonist with partial agonistic activity in vascular smooth muscle. PGF2 alpha, PGE2, and PGD2, however, at least in part, seemed to interact with the TxA2 receptor in vascular smooth muscle.     

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.     

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.     

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.