Modulation of beta adrenergic responsiveness by arachidonic acid metabolites in isolated bovine coronary arteries

The present study was designed to determine whether interference with endogenous arachidonic acid metabolism or exogenously administered cyclooxygenase and lipoxygenase products affects the relaxation of bovine coronary artery in response to isoproterenol. Rings of bovine coronary artery were suspended for isometric tension recordings in organ chambers filled with Krebs-Ringer bicarbonate solution (37 degrees C) gassed with 95% O2-5% CO2 (pH 7.4). In depolarized coronary artery rings (35 mM KCI) isoproterenol induced a dose-dependent relaxation, which was significantly augmented by the cyclooxygenase inhibitor indomethacin and depressed by arachidonic acid. The mixed lipoxygenase/cyclooxygenase inhibitor phenidone or the lipoxygenase products leukotriene D4 and C4 did not affect beta adrenergic responsiveness. Phenidone antagonized the facilitatory action of indomethacin. Exogenous arachidonic acid in the presence of indomethacin and phenidone depressed the relaxation induced by isoproterenol. Prostacyclin and prostaglandin E2 reduced beta adrenergic responsiveness, which was not affected by indomethacin. The data suggest that arachidonic acid depresses beta adrenergic responsiveness in the bovine coronary artery via cyclooxygenase and some noncyclooxygenase, nonlipoxygenase metabolites. Lipoxygenase products, other than leukotrienes D and C, may have a facilitatory action.     

Vasorelaxing effects of prostaglandin I2 on the canine basilar and coronary arteries

The effects of prostaglandin (PG) I2 on canine basilar and coronary arteries were studied. PGI2 caused a relaxation from the basal level more effectively in the endothelium-intact preparations of the coronary artery than in those of the basilar artery. The PGI2-induced relaxation in the basilar artery was enhanced by removal of the endothelium, and by treatment with indomethacin (10(-6) M), aspirin (5 X 10(-5) M), both cyclooxygenase inhibitors, OKY-046 (3 X 10(-5) M) and RS-5186 (10(-6) M), both thromboxane (TX) A2 synthetase inhibitors and ONO-3708 (10(-8) M), a TXA2 antagonist. The enhancing effects of removal of the endothelium and treatment with indomethacin and aspirin on the PGI2-induced relaxation were greater than those of treatment with OKY-046, RS-5186 and ONO-3708. The PGI2-induced relaxation in the coronary artery was not affected by removal of the endothelium, treatment with indomethacin (10(-6) M) or methylene blue (10(-6) M). In the endothelium-removed preparations precontracted with a TXA2 agonist, PGI2-induced relaxation was less in the basilar artery than in the coronary artery. The present experiments suggest that endothelium-derived factors (TXA2 and other cyclooxygenase products) counteract the vasorelaxing effect of PGI2 in the canine basilar artery, but not in the coronary artery.     

Arachidonic acid metabolites and airway epithelium-dependent relaxant factor

Exogenous arachidonic acid (10(-8) to 10(-4) M) contracted epithelium-free guinea pig tracheal strips. Intact tracheal strips were contracted slightly by low concentrations of arachidonic acid (10(-8) to 10(-5) M), but higher concentrations relaxed them. In contrast, when tracheal strips were precontracted with histamine or carbachol, exogenous arachidonic acid had no effect on epithelium-free preparations but induced concentration-dependent (10(-8) to 10(-4) M) relaxation of intact tracheal strips. The effects of arachidonic acid both in epithelium-free and epithelium-containing trachea were blocked by either indomethacin (10(-6) M) or aspirin (10(-4) M). Studies on the effects of exogenous arachidonic acid, performed with a "sandwich protocol," demonstrated that the postulated airway epithelium-dependent relaxant factor released by an intact tracheal strip relaxes an adjacent epithelium-free strip in the same organ bath. This relaxation is antagonized by indomethacin suggesting the involvement of a cyclooxygenase product in this phenomenon. Comparison of concentration-response curves for contractile agonists in epithelium-free preparations and in one containing epithelium suggests the mobilization of airway epithelium-dependent relaxant factor by histamine but not by carbachol. The effects of cyclooxygenase and lipoxygenase inhibitors indicated that both relaxant and contractile arachidonic acid metabolites are generated by epithelial and nonepithelial cells alike in response to contractile agonists.     

Adrenergic transmission failure via the blockade of presynaptic beta receptors in guinea-pig pulmonary arteries

Mechanisms related to the inhibitory actions of low concentrations of l- and d-propranolol on adrenergic transmission were investigated in isolated preparations of guinea-pig pulmonary arteries. In sympathetic nerve-radial muscle preparations, l-propranolol (3.3 X 10(-8) and 10(-7) M) dose-dependently inhibited by 15 to 20% contractile responses to nerve stimulation (1 Hz, 2-msec pulse width, 100-sec period and 30-min intervals) 30 and 60 min after the addition, whereas 3.3 X 10(-7) M produced a maximal inhibition. Contractile responses to cumulatively applied norepinephrine were not modified by pretreatment with l-propranolol (10(-7) - 10(-6) M). d-Propranolol (10(-7) M) produced no inhibition of adrenergic transmission. In superfused spiral preparations preloaded with [3H]norepinephrine, l-isoproterenol (3 X 10(-8) - 10(-6) M) dose-dependently facilitated total 3H efflux by transmural field stimulation by 10 to 35% under the same conditions; this facilitation was antagonized by l-propranolol (10(-7) M) but not by d-propranolol (10(-7) M). Phentolamine (3 X 10(-6) M) increased 3H efflux by approximately 3-fold. In the presence of phentolamine, l-propranolol (10(-7) M) significantly inhibited 3H efflux, whereas d-propranolol (10(-7) M) produced no effect. Presynaptic beta adrenoceptors are present on sympathetic nerve endings which innervate guinea-pig pulmonary arteries and low concentrations of propranolol inhibit adrenergic transmission via blockade of these receptors.     

Endothelial potentiation of relaxation response to phentolamine in rat thoracic aorta

In this study the role of the endothelium was evaluated in the relaxation of rat aortic rings induced by a number of alpha adrenergic antagonists. Phentolamine, a nonselective alpha adrenergic antagonist, relaxed rat aortic rings that were previously contracted with an EC80 dose of phenylephrine, in a concentration-dependent manner. Removal of the endothelium significantly reduced the sensitivity but not the amplitude of the response. The presence of endothelium also enhanced the vascular relaxation induced by yohimbine, a specific alpha-2 adrenergic antagonist (10(-8)-10(-6) M), and by prazosin, a specific alpha-1 adrenergic antagonist (10(-11)-10(-9) M). Both methylene blue (10(-5) M), an inhibitor of soluble guanylate cyclase, and eicosatetraynoic acid (3.2 X 10(-5) M) blocked the endothelial augmentation of vascular relaxation to phentolamine. Vessels precontracted with potassium chloride were slightly relaxed by phentolamine (10(-8)-10(-6) M) only with the endothelium was intact. Both methylene blue and eicosatetraynoic acid also inhibited the response to phentolamine in the intact vessels precontracted with potassium chloride. Prazosin (10(-9)-10(-7) M) and yohimbine (10(-8)-10(-6) M), unlike phentolamine, failed to induce relaxation in potassium chloride-precontracted vessels. When the vessels were precontracted with the thromboxane analog U46619 none of the three alpha antagonists induced vascular relaxation. These results indicate that the endothelium has a significant role in promoting relaxation induced by the three alpha adrenergic antagonists tested.     

Endothelium-dependent effects of carteolol

Experiments were designed to study the effect of the beta adrenergic antagonist, carteolol, on the endothelium-dependent responsiveness of isolated arteries. Rings of canine coronary arteries were suspended in organ chambers for isometric tension recording; carteolol inhibited the relaxation to isoproterenol and abolished the difference in responsiveness to the beta adrenergic agonist between rings with and without endothelium. Carteolol did not cause endothelium-dependent relaxations of femoral or coronary arteries. In bioassay experiments, carteolol augmented the basal release of relaxing factors from the endothelium of the femoral artery; this effect was prevented by indomethacin. In rings of femoral arteries, carteolol increased the endothelium-dependent relaxations induced by the alpha-2 adrenergic agonist UK 14,304; this was not affected by indomethacin but prevented by propranolol. Carteolol did not modify the endothelium-dependent relaxations to acetylcholine, adenosine diphosphate, bradykinin, thrombin and the Ca+-ionophore A23187. Carteolol inhibited the endothelium-dependent hypoxic contraction of the canine coronary artery. It did not affect endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. These experiments suggest that carteolol facilitates the abluminal release of endothelium-dependent relaxing factor caused by alpha-2 adrenergic activation, and causes the intraluminal release of vasodilator prostaglandins. The compound prevents the endothelium-dependent contractions which are not mediated by products of cyclooxygenase. These actions may contribute to the vasodilatator properties of carteolol in the intact organism.     

Isoproterenol-induced inhibition of immunoglobulin E-mediated release of histamine and arachidonic acid metabolites from the human lung mast cell

The inhibitory effect of isoproterenol was examined on the release of histamine, leukotriene C4 (LTC4), and prostaglandin D2 (PGD2) from human lung mast cells. Isoproterenol was more potent in inhibiting anti-immunoglobulin (Ig) E-induced LTC4 and PGD2 release than histamine release from the dispersed lung cell preparations (2-5% mast cells). The negative log molar EC50 values of isoproterenol for inhibiting histamine, LTC4 and PGD2 release were 8.2 +/- 0.2, 8.9 +/- 0.2 and 8.7 +/- 0.3, respectively (mean +/- S.E.M., n = 8). Isoproterenol seldom inhibited histamine release by more than 60%, but usually abolished the release of LTC4 and PGD2. The potency of propranolol (KB = 6 X 10(-10) M) was the same for competitively antagonizing isoproterenol mediated inhibition of histamine, LTC4 or PGD2 release. Using the irreversible beta adrenergic receptor antagonist, bromoacetylalprenololmenthane, the estimated dissociation constant of isoproterenol was 2 X 10(-7) M irrespective of whether inhibition of anti-IgE-induced histamine or LTC4 release was examined. When the divalent cation ionophore A23187 was used to induce histamine release, isoproterenol had either no effect or potentiated the release. In contrast, isoproterenol was capable of virtually abolishing A23187-induced LTC4 release. Qualitatively similar effects of isoproterenol were observed on purified mast cell preparations (greater than 80% mast cells); however, the potency of isoproterenol in inhibiting mediator release from these preparations was reduced. The results demonstrate that there is a substantial receptor reserve for isoproterenol-mediated inhibition of histamine, LTC4 and PGD2 release from the human lung mast cell. The intrinsic efficacy of isoproterenol in inhibiting anti-IgE-induced release of arachidonic acid metabolites is approximately 3 times greater than that for inhibiting histamine release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytochrome P-450-dependent monooxygenase activity and endothelial-dependent relaxations induced by arachidonic acid

The authors have recently identified a cytochrome P-450-dependent monooxygenase in vascular tissue, localized primarily to the endothelium. As this enzyme system can metabolize arachidonic acid (AA) to novel products, some of which produce vasodilation, the pathways involved in the vascular actions of AA (10(-8) to 5 X 10(-6) M) were examined on rings of rabbit pulmonary artery. In pulmonary rings with a low basal tension (1.5 g), AA produces a weak contraction which is prevented by removal of the endothelium or the addition of indomethacin (10(-6) M) but not SKF 525A (10(-5) M), suggesting the formation of an endothelial-dependent vasoconstrictor cyclooxygenase product. In contrast, rings precontracted to 3.5 to 4 g tension with phenylephrine (7 X 10(-7) M) exhibit a dose-related relaxation to AA, which is significantly greater (P less than .001, n = 32) in preparations with an intact endothelium. The endothelium-independent relaxation is suppressed by indomethacin whereas indomethacin fails to attenuate the endothelium-dependent response. In contrast, SKF 525A, an inhibitor of cytochrome P-450-dependent monooxygenase, markedly inhibits (P less than .001) AA-induced relaxations in intact rings in a dose-dependent manner while not affecting the response in rings denuded of endothelium. Intact vessels treated with SKF 525A (10(-6) M) appear to show diversion of the AA to vasodilator cyclooxygenase products, since the subsequent addition of indomethacin produces a further reduction of the AA-induced relaxations, whereas by itself indomethacin has no effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abolition of spontaneous rhythmic contractions of isolated monkey coronary arteries by diltiazem, nifedipine, verapamil and nicorandil but not by nitroglycerin

Three of 12 coronary artery rings obtained from one of 9 rhesus monkeys (Macaca mulatta) (113 rings in all) and 4 of 12 coronary artery rings obtained from one of 2 patas monkeys (Erythrocebus patas patas) (28 rings in all) developed spontaneous rhythmic contractions. In 5 of these 7 coronary artery rings, rhythmic contractions occurred long enough to be subjected to examinations of drug effects. In these preparations the effects of the calcium entry blockers, diltiazem, nifedipine and verapamil, and nicorandil, a nitrate vasodilator thought to produce vasodilatation by an increase in membrane potassium permeability, and nitroglycerin were investigated on rhythmic contractions. Diltiazem (10(-7) and 10(-6) M), nifedipine (10(-8) and 10(-7) M), verapamil (10(-7) and 10(-6) M) and nicorandil (10(-5) and 10(-4) M) suppressed rhythmic contractions in a concentration-dependent manner, but nitroglycerin (10(-7)-10(-5) M) was entirely ineffective. The results were discussed in relation to the mechanisms underlying spontaneous rhythmic contractions of coronary arteries and their role in vasospastic angina pectoris.     

EFFECTS OF CICLETANINE ON HISTAMINE-INDUCED CONTRACTIONS OF ISOLATED RABBIT MESENTERIC ARTERIES

The antagonism by cicletanine of contractile responses to histamine has been examined in vitro on ring preparations of rabbit mesenteric arteries. Cicletanine (10(-8)-10(-6) M) caused a parallel rightward shift of histamine concentration response curve, with a pA2 value of 7.48 (slope = 0.89 +/- 0.19, not significantly different from unity). Histamine-induced contractions were nifedipine-sensitive and associated with cicletanine-sensitive increased 45Ca uptake. Endothelium removal resulted in enhanced contractile responses to histamine, but did not significantly modify cicletanine-induced antagonism: KB (dissociation constant) values for cicletanine antagonism in the presence or absence of endothelium were: 3.7 (+/- 0.1) X 10(-8) M and 3.6 (+/- 0.3) X 10(-8) M, respectively. Cicletanine (greater than 10(-4) M) also significantly attenuated 10 mM caffeine-induced contractions in rings exposed to Ca-free 100 mM K+ depolarizing medium. The results suggest that cicletanine-induced antagonisms of histamine H1 receptor-mediated contractions of rabbit mesenteric arteries is associated with interference with calcium entry as well as at high concentrations, release from intracellular stores.     

Interaction of neutrophils with vascular smooth muscle: identification of a neutrophil-derived relaxing factor

Experiments were designed to study the interaction of rat peritoneal neutrophils with the vascular smooth muscle of the rat aorta. Rings of aorta, suspended in 10-ml organ chambers containing a physiologic salt solution, were precontracted with phenylephrine. Neutrophils (1 X 10(5) -4 X 10(7) cells/organ chamber) caused a cell number-dependent relaxation of the rat aorta that was augmented by superoxide dismutase (100 U/ml) or changing the oxygen content from 95 to 21%. The neutrophil-induced smooth muscle relaxation occurred in rings with and without endothelium and in rings precontracted with increasing concentrations of phenylephrine, prostaglandin F2 alpha or KCI. Catalase (1000 U/ml) and mannitol (1 X 10(-3) M) did not block the neutrophil-induced relaxation, whereas phenazine methosulfate (1 X 10(-5) M), hydroquinone (3 X 10(-5) M) and methylene blue (1 X 10(-5) M) reversed the neutrophil-induced relaxation. Pre-exposure of endothelium-rubbed rings to neutrophils (2 X 10(7) cells/organ chamber; 15 min) depressed the subsequent concentration-response curve to phenylephrine but augmented the relaxation induced by the phosphodiesterase inhibitor zaprinast (1 X 10(-5) M). The effluent from a column restraining the neutrophils induced a relaxation of endothelium-rubbed aortic rings that was prevented by methylene blue (1 X 10(-5) M). These results demonstrate that rat neutrophils release a factor that has a pharmacologic profile similar to that previously reported for the relaxing factor released from the vascular endothelium.     

Ouabain inhibits endothelium-dependent relaxations to arachidonic acid in canine coronary arteries

Experiments were designed to analyze the effects of ouabain on the actions of exogenous arachidonic acid on endothelial and vascular smooth muscle cells. Rings or strips were prepared from left circumflex canine coronary arteries and suspended for isometric tension recording in organ chambers filled with oxygenated modified Krebs-Ringer-bicarbonate solution. During contractions evoked by prostaglandin F2 alpha, arachidonic acid caused relaxations both in the presence and the absence of endothelium. However, removal of the endothelium reduced its inhibitory action. Indomethacin prevented the relaxations in rings without endothelium, but did not affect the response to high doses (10(-6) to 10(-5) M) of arachidonic acid in preparations with endothelium. The inhibitor of lipoxygenase, nordihydroguaiaretic acid, had no effect on the inhibitory responses to arachidonic acid in rings with or without endothelium. Ouabain abolished both the endothelium-dependent and the direct relaxations to arachidonic acid. Endothelium-dependent relaxations in response to oleic acid, elaidic acid, adenosine diphosphate and thrombin were not affected by ouabain. In the presence of indomethacin, coronary artery strips without endothelium were relaxed by arachidonic acid only when layered (intimal surface against intimal surface) with a longitudinal strip with endothelium. In layered preparations, treatment of the intact longitudinal strip with ouabain before layering prevented the relaxation, whereas pretreatment of the strip without endothelium had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prostaglandin E1-induced vasorelaxation in porcine coronary arteries.

The mechanism of prostaglandin E1 (PGE1)-induced vasorelaxation was studied in the porcine left anterior descending artery (diameter = 2.0-3.0 mm) and its branches (diameter = 0.6-1.0 mm). In the large coronary arteries, PGE1 increased the basal tone at concentrations from 10(-8) to 3 x 10(-7) M and decreased the tone at concentrations above 3 x 10(-7) M. However, in the small coronary arteries, PGE1 did not affect the basal tone at concentrations below 3 x 10(-6) M and evoked only relaxation at above 10(-5) M. PGE1 caused dose-dependent relaxation of vessels previously contracted by prostaglandin F2 alpha or endothelin-1 at concentrations above 10(-7) M in large coronary arteries and above 10(-8) M in small coronary arteries. Removal of the endothelium did not influence the relaxant response to PGE1 of either type of artery. In addition, 10(-4) M aspirin did not influence the PGE1-induced vasorelaxation of large and small coronary arteries. However, treatment with 5 x 10(-6) M ouabain or partial replacement of Na+ with Li+ (Na+ concentration, 25 mEq/l) significantly attenuated the relaxant response to PGE1 in large and small coronary arteries. These results indicate that the responsiveness of large and small coronary arteries to PGE1 differs in the pig and that the electrogenic Na+ pump has a primary role in the relaxant effect of PGE1 on both small and large arteries.     

Hypoxic contraction of isolated rat pulmonary artery

This study was undertaken to test if isolated rat pulmonary artery (PA) rings contract in response to hypoxia, if the response behaves similarly to previously described physiologic and pharmacologic features of hypoxic pulmonary vasoconstriction (HPV) in the isolated perfused rat lung and if the endothelium is necessary for the response. Rings (2-3 mm wide) cut from the main extrapulmonary PA branches were studied. Hypoxic contractions of up to 80 mg (mean +/- S.E. 34 +/- 5 mg, n = 20) were seen in resting rings. The contraction was more reproducible and was potentiated in rings prestimulated with either phenylephrine, norepinephrine, KCl, angiotensin II or the thromboxane mimetic U46619. The magnitude of the hypoxic contraction was proportional to the level of prestimulation and the severity of the hypoxia, with maximum hypoxic contraction seen during exposure to 0% oxygen. The hypoxic dose response showed a threshold bath pO2 of between 30 and 60 Torr, was potentiated by BAY K8644 (10(-7) M), was inhibited by both nifedipine (10(-7) M) and cooling to 29 degrees C and was not inhibited by meclofenamate (1.6 x 10(-6) M). All these characteristics are comparable to previously described features of HPV in the isolated perfused rat lung. Removal of the endothelium resulted in a 48-80% reduction in maximum PA hypoxic contraction. Similar hypoxic contraction was seen in precontracted aortic rings. We conclude that the hypoxic contraction of isolated rat PA may be a useful in vitro model of HPV, that both the endothelium and smooth muscle may be involved in the sensing of PO2 and that the direct hypoxic response is not unique to pulmonary arteries.     

Propranolol promotes cocaine-induced spasm of porcine coronary artery

Case reports suggest that cocaine use is associated with acute myocardial infarction which may be due to coronary spasm. The present study reports the effect of cocaine on the isolated coronary artery. Ring segments were prepared from the porcine left anterior descending coronary artery and suspended in tissue baths under isometric conditions. Cocaine was ineffective by itself in promoting contraction, but a cumulative concentration-response curve was obtained in the presence of DL-propranolol (1.3 x 10(-6) M); D-propranolol failed to promote cocaine-induced vasoconstriction. The maximum contractile response to cocaine was one-third of the response to histamine and was in the same range as the response to U46619, prostaglandin F2 alpha and norepinephrine. Phenylephrine had a weak effect. In the presence of DL-propranolol, the vasoconstrictive effect of cocaine was subject to rapid tachyphylaxis. Prazosin (5 x 10(-9) M), also in the presence of DL-propranolol, significantly displaced the cocaine concentration-response curve to the right and diminished contractile force by one-half. We conclude that cocaine-induced coronary vasoconstriction elicited in the presence of DL-propranolol can be mediated through local adrenergic mechanisms involving beta receptor antagonism and activation of both alpha-1 and alpha-2 adrenoceptors.     

Endothelial potentiation of relaxation response to beta adrenoceptor blocking agents

A number of beta adrenergic blocking drugs were evaluated on ring preparations of endothelium intact and denuded segments of the rat aorta. The preparations were preconstricted under isometric conditions with an EC80 dose of phenylephrine. Labetalol (10(-7)-10(-5) M), MK-761 10(-7)-10(-5) M), timolol (10(-7)-10(-4) M) and propranolol (10(-6)-10(-4) M) relaxed both endothelium intact and denuded vessels in a dose-dependent manner. Spirendalol (2.8 X 10(-8)-8.1 X 10(-6) M), a specific beta-2 receptor antagonist and L643717 (1.8 X 10(-7)-3.6 X 10(-6) M), a specific beta-1 receptor antagonist did not elicit relaxation. Labetalol, MK-761, timolol and propranolol promoted relaxation only when vascular segments were preconstricted with phenylephrine or norepinephrine and failed to do so when prostaglandin F2 alpha or U46619 were used. This indicates a possible displacement of alpha adrenergic agonists with the beta antagonists. The degree of relaxation induced by labetalol, MK-761, timolol and propranolol was significantly less (P less than .05) when the endothelium was removed. Eicosatetraynoic acid (3.2 X 10(-5) M) significantly attenuated the relaxation response to labetalol, MK-761 and timolol in the intact but not in denuded vascular preparations. These studies suggest that some of the vascular effects of beta blockers may relate to the endothelium.     

Vasodilatory property of N-alpha benzoyl-L-arginine ethyl ester in the rat isolated pulmonary artery and perfused lung

L-arginine has been proposed to be the precursor of the endothelium-derived relaxing factor. In this study, we evaluated the pulmonary vascular effects of L-arginine-HCl and its benzoyl derivative N-alpha-benzoyl-L-arginine ethyl ester (BAEE) in the rat, in comparison with other vasodilators such as acetylcholine and sodium nitroprusside. In isolated pulmonary artery rings incubated with indomethacin (10 microM) and precontracted with phenylephrine (2 microM), BAEE (10(-6)-10(-5) M) significantly (P less than .05) relaxed the rings more than L-arginine. This effect was potentiated by the endothelium (P less than .05). The relaxing effect of BAEE (ED50 = 2.1 X 10(-6) M) and acetylcholine (ED50 = 2.4 X 10(-7) M) was significantly less potent than that of sodium nitroprusside (ED50 = 1.1 X 10(-8) M). Moreover, pretreatment with the soluble guanylate cyclase inhibitors methylene blue (10(-5) M) and hemoglobin (10(-5) M) antagonized BAEE-induced relaxation in intact pulmonary rings but had no effect on the relaxation elicited with atrial natriuretic peptide. In the isolated lung preparations perfused with the endoperoxide analog U46619 (5-10 nmol/min), sodium nitroprusside (10(-10)-10(-8) M) elicited potent vasodilation (ED50 = 2.8 X 10(-9) mol) whereas no vasodilation was observed with acetylcholine (10(-8)-10(-5) mol). BAEE (10(-6)-10(-5) M) decreased in a dose-dependent manner pulmonary perfusion pressure, and similar doses of L-arginine showed only a mild vasodilating effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanical response in the wall of ovarian follicles mediated by adrenergic receptors.

The identity of the adrenergic receptors involved in the contractility of the follicular wall was studied in bovine ovaries. Strips were prepared mainly from the protruding part of large Graafian follicles and mounted in an organ bath for recording of mechanical activity. Some intact ovaries and strips from the bottom of follicles were also studied. The latter two preparations showed spontaneous rhythmic contractions, and the tension was increased by norepinephrine and reduced by terbutaline. Norepinephrine, epinephrine, phenylephrine, isoproterenol and terbutaline alone or in combination with various concentrations of the inhibitors, phenoxybenzamine, piperoxan and propranolol, were used to analyze adrenoceptors in strips from the protruding portion of the follicle. Such strips showed no appreciable spontaneous contractions. A contractile response was found to be mediated by alpha receptors. The KA value for norepinephrine (determined in combination with phenoxybenzamine) was found to be 2.26 X 10- minus 6 M and KB for piperoxan (determined in combination with norepinephrine) was 1.02 X 10-minus 8 M (pA2 = 8.19). Adrenergic beta receptors mediated relaxation of the strips, and the KB value for propranolol (determined in combination with terbutaline) was 7.28 X 10-minus 9 M (pA2 = 8.17).     

Vascular actions of TA 3090, a novel analog of diltiazem: interaction with endothelium-dependent relaxation in canine femoral and coronary arteries

The effects of a new 1,5-benzothiazepine calcium antagonist, TA 3090 (an analog of diltiazem), were analyzed in isolated canine femoral and coronary arteries suspended in organ chambers or studied in a bioassay system. TA 3090 (10(-9) to 10(-4) M) caused comparable relaxations in arterial rings with and without endothelium contracted by prostaglandin F2 alpha. Coronary arteries were more sensitive to the Ca++ antagonist. In both preparations, TA 3090 was more potent than diltiazem. In femoral (but not coronary) artery rings with endothelium, acetylcholine (10(-8) M) inhibited relaxations to TA 3090. Previous treatment of femoral or coronary arteries with TA 3090 (10(-6) M) had no effect on endothelium-dependent relaxations to acetylcholine. In a bioassay system, TA 3090 (2 x 10(-7) M) caused partial reversal of acetylcholine-induced relaxation in perfused femoral arteries and superfused coronary arterial rings. The dihydropyridine enantiomer (-)-202,791 did not affect acetylcholine-induced relaxations and did not prevent the reversal by TA 3090. These data indicate that, in addition to a direct action on vascular smooth muscle, this novel benzothiazepine Ca(++)-antagonist interferes with the synthesis/release of endothelium-derived relaxing factor stimulated by acetylcholine in canine femoral arteries. These findings, which are similar to those obtained with d-cis-diltiazem, support the hypothesis that a specific benzothiazepine-dependent mechanism(s) can suppress the production of endothelium-derived relaxing factor in endothelial cells.     

Effects of milrinone on contractile responses of guinea pig trachea, lung parenchyma and pulmonary artery

The effects of milrinone, a bipyridine with known vasodilator activity, on guinea pig tracheal-spirals, lung parenchymal strips and pulmonary artery rings in vitro were compared with the effects of isoproterenol and aminophylline on these tissues. The concentration of milrinone that produced 50% relaxation (IC50) of tracheal spirals constricted by carbachol was 3.6 X 10(-5) M. Isoproterenol (IC50, 9.5 X 10(-8) M) was significantly (P less than .001) more potent and aminophylline (IC50, 1.2 X 10(-4) M) was significantly (P less than .001) less potent than milrinone in this effect. The IC50 for milrinone for lung parenchymal strips contracted by histamine was 3.2 X 10(-5) M, whereas the IC50 for isoproterenol was significantly (P less than .001) less, 1.4 X 10(-7) M; aminophylline produced only limited relaxation of lung parenchymal strips. Milrinone relaxed pulmonary artery rings constricted by norepinephrine with an IC50 of 3.8 X 10(-6) M, whereas neither isoproterenol nor aminophylline produced a 50% relaxation. Pretreatment of tracheal spirals, lung parenchymal strips and pulmonary artery rings with 1.6 X 10(-4) M milrinone inhibited subsequent contraction by carbachol, histamine and norepinephrine, respectively. The relaxant effects of milrinone were not influenced by treatment with atropine, cimetidine, mepyramine, phentolamine or propranolol. However, indomethacin blocked milrinone's relaxant effects on tracheal spirals effectively, but not on pulmonary artery rings or lung parenchymal strips, suggesting distinct modes of action on various tissue types.