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PubMed1983

Endralazine, a new peripheral vasodilator. Evaluation of safety and efficacy over a 3 year period.

Nineteen out-patients with moderate to severe essential hypertension were treated daily for 3 years, with an average dose of 13 mg endralazine, a new peripheral vasodilator, in free combination with pindolol 3 x 5 mg. The blood pressure showed a statistically significant reduction from 172/110 mmHg to 154/92 mmHg after treatment for 3 years. Tachyphylaxis was not observed during the 3 years period. Oedema was the most frequent side-effect, but it disappeared spontaneously. No difference in efficacy and tolerance between slow and fast acetylators was found. Only 2 patients developed a weak positive antinuclear antibody titre, which disappeared spontaneously from one during continued treatment. No clinical evidence of a systemic lupus erythematosus-like syndrome was noted. It is concluded that the differences between endralazine and hydralazine in dosage and metabolism may explain the lower immunogenic activity of endralazine.

Acetylation↗
PubMed1985

The effect of nicotine and cytisine on 3H-acetylcholine release from cortical slices of guinea-pig brain.

Nicotine 1.8 X 10(-5)-1.8 X 10(-4) mol/l enhanced the spontaneous 3H-efflux from guinea-pig cortical slices preloaded with 3H-choline and perfused in the presence of hemicholinium (HC-3). The facilitation of tritium outflow was prevented by tetrodotoxin 5 X 10(-7) mol/l and by D-tubocurarine 4.5 X 10(-6) mol/l. Nicotine 1.8 X 10(-6)-1.8 X 10(-4) mol/l, and the agonist cytisine 5 X 10(-7)-5 X 10(-5) mol/l increased, in a concentration-dependent way, 3H-efflux from electrically-stimulated slices (0.2 Hz). The concentration-response curves of both drugs were parallelly shifted to the right by D-tubocurarine 4.5 X 10(-6) mol/l. The EC50 values (i.e. the concentrations required to cause a 50% increase in the S2/S1 ratio) changed for nicotine from 5.58 X 10(-5) to 4.34 X 10(-4) and for cytisine from 6.3 X 10(-6) to 2.75 X 10(-4) mol/l in the absence and in the presence of the antagonist, respectively. In the range of 0.2-2 Hz the magnitude of the effect of nicotine was inversely related to the rate of stimulation. The response to nicotine was subject to rapidly developing tachyphylaxis; it was resistant to atropine. It is concluded that nicotine and cytisine facilitate 3H-efflux from the cholinergic nerve endings of guinea-pig cerebral cortex. This effect involves sodium-dependent mechanisms and is due to an interaction of the drugs with receptors showing affinity for D-tubocurarine.

Acetylcholine↗
PubMed1989

Humoral factors released during trauma of Aplysia body wall. I. Body wall contraction, cardiac modulation, and central reflex suppression.

1. Mechanical or electrical stimulation of isolated sections of body wall produced contractions that were graded with the intensity of the stimulus. Injury of body wall with shallow incisions produced extremely persistent contractions. 2. Long-lasting contraction of isolated body wall was also produced by brief application of "stimulated body wall wash" (SBW), sea water which was first washed through another section of body wall subjected to intense mechanical or electrical stimulation. Contractions were produced by SBW diluted to concentrations as low as 1% of the initial concentration. Contractions produced by prolonged application of SBW showed little fatigue, tachyphylaxis, or desensitization. 3. SBW caused contraction of isolated sections of body wall from all regions of the body, including tail, parapodia, siphon, purple gland, rhinophores, and anterior tentacles. SBW also caused contraction of isolated lateral columellar muscle and of the gill. 4. 30 mM CoCl2 blocked the release of contractile factors into electrically stimulated body wall and reduced but did not abolish contractile responses of unstimulated body wall to perfused SBW. SBW contractions were unchanged by disconnection of the perfused tissue to the CNS. 5. Hemolymph collected from the neck of an intact donor following strong electrical stimulation of the tail or excision of a parapodium ('stimulated hemolymphh, SHL) caused long-lasting contractions which were larger than those produced by control hemolymph (CHL) collected prior to stimulation of the donor. 6. Similarities between body wall contractions produced by SHL and by SBW, including their occurrence in 30 mM CoCl2, suggest that some of the contractile activity in SHL may be directly released from traumatized body wall. 7. SHL caused significantly greater cardioacceleration of the isolated heart than did CHL. Similarities between the cardioacceleration produced by SHL and by SBW suggest that a source of cardiac activity in SHL may be traumatized body wall. 8. SBW suppressed the gill-withdrawal reflex when applied selectively to the sheathed or desheathed abdominal ganglion. SBW-induced suppression was associated with significant reduction of evoked spike activity in identified gill motor neurons. SHL collected 1-2 h after noxious stimulation caused weak but significant suppression of the gill-withdrawal reflex when applied to the fully sheathed abdominal ganglion.

Animals↗
PubMed1990

Mediation of prolonged increases in nasal mucosal blood flow by calcitonin gene-related peptide (CGRP).

Calcitonin gene-related peptide (CGRP) is a vasoactive and smooth muscle contractile neuropeptide, which is released during human nasal allergic reactions. Mean values for nasal blood flow (NBF), quantified in each nostril by a laser Doppler technique, varied no more than +/- 25% of a mean initial reading in normal human subjects over 4 hr in a controlled environment. Intranasal administration of multiple doses of CGRP to 17 normal subjects stimulated significant mean increases in NBF at 30-1000 ng of CGRP, with maximal mean rises of 86-130% after 100 and 300 ng of CGRP. Delivery of incremental doses of CGRP every 30 min for 2 hr evoked repetitive responses without tachyphylaxis. A single vasoactive dose of CGRP, which achieved nasal fluid concentrations similar to those elicited by antigen challenge, elicited the sensation of nasal obstruction in most subjects at 1 hr and for up to 4 hr after CGRP, without elevating nasal fluid concentrations of histamine. CGRP thus is a potent histamine-independent mediator of allergic reactions.

Administration, Intranasal↗
PubMed1995

Stable expression of a functional rat angiotensin II (AT1A) receptor in CHO-K1 cells: rapid desensitization by angiotensin II.

The octapeptide angiotensin II mediates the physiological actions of the renin-angiotensin system through activation of several angiotensin II receptor subtypes; in particular the AT1. In many tissues, the presence of multiple angiotensin II receptor subtypes, together with a low number of receptors, makes it difficult to study biological responses to physiological concentrations (10(-11)-10(-9) M) of angiotensin II. Also, cultured cells show diminished angiotensin II receptor binding with respect to time in culture and passage number. To address these problems, we expressed the recombinant AT1A receptor in CHO-K1 cells. The stably transfected receptor was characterized using radioligand binding studies and functional coupling to cytosolic free calcium. Radioligand binding of [125I] angiotensin II to the angiotensin II receptor was specific, saturable, reversible and modulated by guanine nucleotides. Like the endogenous AT1A receptor, reported in a variety of tissues, the specific, noncompetitive, nonpeptide AII receptor antagonist, EXP3174, blocked binding of [125I] angiotensin II to the transfected receptor. Scatchard analysis demonstrated that the transfected receptor had a dissociation constant of 1.9 nM with a density of 3.4 pmol/mg protein. An important feature of many of the responses to angiotensin II is the rapid desensitization that occurs following agonist occupancy and the development of tachyphylaxis. In AT1A receptor transfected CHO-K1 cells, angiotensin II (10(-9) M) stimulated a rapid increase in cytosolic free calcium that was completely desensitized within 50 sec following receptor occupancy. Agonist induced desensitization was unaffected when receptor internalization was blocked by pretreatment with concanavalin A or incubation at 4 degrees C, and no changes in AT1A receptor affinity or number were observed. Receptor desensitization was also unaffected by inhibition or activation of protein kinase C. Thus, we have established a permanent, high-level transfectant of the AT1A receptor in CHO-K1 cells and have shown that these receptors rapidly desensitize following exposure to physiological concentrations of agonist. The mechanism of rapid desensitization is not related to receptor sequestration, internalization or controlled by PKC phosphorylation. This provides an excellent model for studying AII actions mediated through a specific receptor subtype, at subnanomolar concentrations.

Angiotensin II↗
PubMed1981

Effects of truncal vagotomy and antrectomy on bombesin-stimulated pancreatic secretion, release of gastrin, and pancreatic polypeptide in the anesthetized dog.

The short-term effects of truncal vagotomy and antrectomy on bombesin-stimulated pancreatic secretion and release of gastrin and pancreatic polypeptide (PP) were studied in 18 anesthetized dogs. Together with an intravenous infusion of secretin (250 ng/kg/hr) bombesin (500 ng/kg/hr) was given before and after truncal vagotomy, antrectomy, and sham operation (N = 6 dogs per group). Peak incremental pancreatic protein output in response to bombesin was about 2-3 times higher before than after the different surgical procedures (tachyphylaxis). Neither truncal vagotomy nor antrectomy significantly altered the pancreatic protein response to bombesin when compared with sham operation. Bombesin produced a mean 1-hr increase over basal of 196 pM for gastrin, which was abolished by antrectomy but not appreciably affected by truncal vagotomy and sham operation. The mean 1-hr increment (207 pM) for PP in response to bombesin was not changed by truncal vagotomy, antrectomy, and sham operation. This study shows in the anesthetized dog that exogenous bombesin stimulates release of PP as well as gastrin; that the release of gastrin by bombesin is not vagally dependent; that neither truncal vagotomy nor antrectomy alter the release of PP by bombesin; and that the action of bombesin on pancreatic protein secretion does not depend on release of gastrin or on intact vagal nerves.

Animals↗
PubMed1992

Recurrent episodes of gram-negative bacteremia or endotoxemia change reactivity of pre- and post-capillary pulmonary segments to angiotensin or free radicals.

OBJECTIVE: Recurrent episodes of Gram-negative bacteremia (from intraperitoneal abscesses) or endotoxemia cause lung microvascular injury in the rat. Change in vascular reactivity was assessed in response to challenge. DESIGN: In the isolated lung preparation, resistance was partitioned between pre-(PVRa) and post-capillary (PRVv) segments: vasoreactivity was assessed by challenge with Angiotensin II (AII) or reactive oxygen metabolites. Animals received 4 weekly intra-abdominal implants of live E. coli and B. fragilis in a carrier of sterile cecal content and barium sulfate (SEPSIS) or carrier alone (SHAM SEPSIS): or 4 weekly intravenous infusion of E. coli endotoxin (ENDO) or of saline (SHAM ENDO). A fifth group were untreated controls (CONTROL). MEASUREMENTS AND RESULTS: In the SEPSIS and ENDO lungs, PVRa and PVRv before challenge were normal. In the SEPSIS lung, AII increased PVRa more than in the control lung, PVRv to a similar degree in both. In the ENDO lung it increased PVRa compared with its effect on the SHAM ENDO lung: In both it also increased PVRv, to a similar degree and well above the baseline. Always tachyphylaxis developed with increases in dosage (to 25 microns and 50 microns, respectively). Oxygen free radical challenge in the SEPSIS and ENDO lung caused significant vasoconstriction, particularly PVRv, whereas no response was observed in the CONTROL or SHAM-treated lung from either group. CONCLUSION: Abnormal lung vascular reactivity after SEPSIS or ENDOTOXIN is evident on challenge, the two agents used here detecting site specific changes.

Angiotensin II↗
PubMed1982

[Captopril in congestive heart failure (author's transl)].

Captopril (Lopirin, Squibb, von Heyden) is an inhibitor of the angiotensin-I converting enzyme. In congestive heart failure angiotensin mediated vasoconstriction and aldosterone secretion is reversed by captopril. Both effects of captopril induce reduction of cardiac preload and afterload. The clinical state of patients with congestive heart failure therefore improves since cardiac output increased and pulmonary pressures decrease. Captopril acts orally and the dosage used for the treatment of congestive heart failure ranges from 50 to 150 mg daily. After oral ingestion of a single dose the maximum haemodynamic effect is observed after 45-90 min. No tolerance induction or tachyphylaxis has been observed during maintenance therapy over a period of 18 months. There are some reversible adverse reactions like pruritus, skin rash and partial or complete taste loss which are dose related. Serious side effects include leucopenia, agranulocytosis, renal failure and membranous glomerulonephritis. Therefore regular urinary and blood analysis is necessary during captopril therapy.

Acute Kidney Injury↗
PubMed1984

Influence of digitalis and diuretics on ouabain binding sites on human erythrocytes.

It has been reported that during chronic treatment with digitalis, the number of digitalis binding sites is increased in human erythrocytes [22]. From this finding a tachyphylaxis for cardiac glycosides has been postulated. We reinvestigated this problem in several groups of patients. The number of 3H-ouabain binding sites per erythrocyte in control persons (group I) was 214 +/- 60, n = 43 (means +/- SD). The dissociation constant (KD) was 1.8 +/- 0.5 nM. Thirteen patients (group II) taking cardiac glycosides only, for at least 6 months, had 281 +/- 99 (p less than 0.05) ouabain binding sites per single red cell, KD = 1.8 +/- 0.7 nM. Group III (34 patients) took digitalis for more than 6 months and diuretics for at least 3 months (352 +/- 126 (p less than 0.001), KD = 1.6 +/- 0.6). Twenty-three of these (group IV) were taking a combination with "K+-saving" diuretics (336 +/- 194 (p less than 0.01), KD = 1.6 +/- 0.5) and (group V, 11 patients) a combination with "K+-losing" diuretics (462 +/- 133 (p less than 0.001), KD = 1.4 +/- 0.4). Nine patients (group VI) had a chronic hypokalemia, mainly due to taking furosemide (437 +/- 98 (p less than 0.001), KD = 1.5 +/- 0.4). Four control persons took 50 mg hydrochlorothiazide daily for more than 4 months without measurable K+-losses and without changes in ouabain binding sites. It is concluded from these findings that diuretic treatment with chronic hypokalemia in addition to digitalis is accompanied by a significant increase in ouabain binding sites in human red cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

A multicenter comparison of isradipine and prazosin for treatment of essential hypertension.

Isradipine is a dihydropyridine calcium-entry blocking agent with pronounced vasodilator activity and no significant cardiac effects at clinical doses, a desirable profile for an antihypertensive drug. Prazosin, a post-junctional alpha-adrenoceptor blocking agent, may produce a similar hemodynamic pattern. Therefore, we compared the effects of isradipine (2.5-10 mg bid) with those of prazosin (2-8 mg bid) in 83 patients with established essential hypertension, using a randomized, double-blind, parallel-group design. Patients received a placebo for 3-5 weeks, then either isradipine or prazosin over a 6-week titration period, followed by a 4-week plateau phase. During the plateau period, isradipine therapy lowered sitting blood pressure more effectively than did the administration of prazosin: Mean systolic BP fell 16.7 versus 8.1 mmHg (p less than 0.001) and mean diastolic BP was reduced 15.6 versus 12.6 mmHg (p less than 0.01). In the dosing range used (while also noting that prazosin is occasionally titrated up to doses of 30 mg qd), 83% of isradipine-treated patients had at least a 10 mmHg reduction in diastolic BP, compared with 64% of prazosin-treated patients (p = 0.05, FET). Tachyphylaxis did not occur with either drug. The rate of occurrence of side effects was similar in both treatment groups; the most common adverse event seen with isradipine was headache (20%) and with prazosin, dizziness (19%).

Adult↗
PubMed1991

Influence of short- and long-term inhalation of salbutamol on lung function and beta 2-adrenoceptors of mononuclear blood cells in asthmatic children.

Clinical observations have shown that some asthma patients develop tachyphylaxis to beta-sympathomimetic drugs. As down-regulation of the number of beta-adrenoceptors in different human tissues after exposure to catecholamines and beta-adrenergic drugs is well known, we investigated whether a interrelation exists between beta-adrenoceptor down-regulation and clinically detectable beta-adrenergic subsensitivity during beta-sympathomimetic treatment. The following results were obtained: 1. beta 2-Sympathomimetic inhalation treatment with salbutamol in therapeutic doses led to a significant down-regulation of beta 2-adrenoceptors and consecutive cyclic adenosine monophosphate response to isoprenaline. This effect was already detectable after short-term treatment of 3-7 days in 9 asthmatic children. 2. In the long-term study over 6 months, salbutamol inhalation in 12 asthmatic children led to a significant down-regulation of beta-adrenoceptor binding sites on mononuclear blood cells (MNC) from 1539 +/- 91 to 1115 +/- 99 after 14 days, remaining in this range thereafter. 3. The mean airway resistance (Raw) of these 12 patients decreased significantly within 14 days from 8.1 +/- 0.8 to 5.7 +/- 0.5 cm H2O/l/s to remain stable throughout the 6 months of salbutamol treatment. The differences in Raw before and immediately after inhalation of 0.2 mg salbutamol (2 puffs) were unchanged during the study period. It is concluded, that long-term inhalative treatment with salbutamol over a period of 6 months does not result in refractoriness to beta-adrenergic drugs in the airways of asthmatic children, even though a significant down-regulation of beta 2-receptors on peripheral MNC occurs.

Administration, Inhalation↗
PubMed1986

Indomethacin inhibits the increased airway responsiveness to histamine following inhalation of C5a des Arg in rabbits.

It has been shown that inhalation of C5a des Arg increases rabbit airway responsiveness to histamine and that this is associated with an influx of neutrophils into the airway walls. This study was undertaken to see if the augmented response to histamine can be blocked by the cyclo-oxygenase inhibitor indomethacin. Spontaneously breathing, anesthetised rabbits were studied in a volume displacement plethysmograph and pulmonary resistance (R1) was measured using the electrical subtraction technique. Histamine does response curves (HDR) were generated by measuring R1 after serial nubulisation of saline and histamine (1, 3, 10, 30 and 100 mg/ml). Aerosols of either saline or C5a des Arg (1.5 ug/ml) were then inhaled by the animals over a time period of 2 min. An HDR was then repeated 4 hours later. In 9 rabbits the inhalation of C5a des Arg resulted in an upward shift of the repeat HDR: the area under the HDR was significantly greater than under the first HDR (p less than 0.05). In 6 rabbits the repeat HDR 4 hours after saline was shifted downwards (N.S.) indicating some degree of tachyphylaxis. When rabbits were pretreated with indomethacin (5 mg/kg i.v.) the repeat HDR following either C5a des Arg (n = 7) or saline (n = 6) were also shifted downwards i.e., the increased airway responsiveness noted after C5a des Arg was abolished. There was no significant difference in baseline saline R1 during the first or second HDR in any group. These results suggest that the increased airway responsiveness following nebulisation of C5a des Arg may be due to release from neutrophils of products of the cyclo-oxygenase pathway.

Administration, Inhalation↗
PubMed1986

The characterization of lodoxamide, a very active inhibitor of mediator release, in animal and human models of asthma.

A most active biologue of disodium cromoglycate (DSCG) available, lodoxamide tromethamine (LT), has been studied and characterized pharmacologically, in animal and human models of asthma. It has self-tachyphylaxis, but has oral activity (lodoxamide ethyl) in rats, primates, and man. In rats (LT) was 2,500 X more active than DSCG (ID50 = 0.001 mg/kg), in primates the drug was also active by several routes (inhalation 1 microgram/kg, IV 0.001 mg/kg, and oral 10 mg/kg). In isolated rat peritoneal mast cells, the compound displayed a biphasic dose response inhibition to histamine release initiated by (48/80, anti-IgE, and the calcium ionophore A23,187) with IC50 values of 0.1-50 microM. The consistent finding relating to its mode of action was its ability to inhibit 45calcium flux into the mast cell in response to antigen or A23,187. Clinical evaluations of lodoxamide tromethamine showed that at aerosol doses of 1.0 mg or less, it demonstrated significant inhibitory activity against antigen or exercise induced bronchospasm. However, in pilot evaluation studies in clinical asthma settings, the compound could not be shown to spare bronchodilator usage, relative to placebo, or be shown to be more effective than placebo treated patients based on other clinical endpoints. The reason for rat and primate models not being predictive for human long-term clinical asthma in the characterization of anti-release compounds is not known.

Amino Acids↗
PubMed1985

Characterization of FPL-52694 [5-(2-hydroxypropoxyl)-8-propyl-4-oxo-4H-benzopyran-2-carboxylic acid Na] on histamine release from rat peritoneal mast cells induced by antigen, compound 48/80 and A 23187.

We studied the in vitro effects of FPL-52694 [5-(2-hydroxypropoxyl)-8-propyl-4-oxo-4H-benzopyran-2-carboxylic acid Na] on histamine release from rat peritoneal mast cells. These cells exposed to ascaris antigen, compound 48/80 or the ionophore A 23187 concentration-dependently released histamine. About a 30-40% histamine release was obtained by 1 X 10(-4) g/ml of antigen, 1 X 10(-7) g/ml of compound 48/80 and A 23187. FPL-52694 (10(-9)-10(-4) g/ml) concentration-dependently inhibited the histamine release from mast cells in response to antigen (1 X 10(-4) g/ml) and compound 48/80 (1 X 10(-7) g/ml), but only slightly inhibited the histamine release induced by A 23187 (1 X 10(-7) g/ml). Similar results were obtained with disodium cromoglycate (DSCG), in the same dose ranges. However, the inhibitory activity of FPL-52694 on histamine release by antigen and compound 48/80 was approximately 10 times more potent than that of DSCG at certain concentrations. Tachyphylaxis was observed when these two agents were preincubated with mast cells for 10 min. These results show FPL-52694 to be a novel mast cell stabilizer.

Animals↗
PubMed1986

N-Methyldimaprit (SK&F92054). A chemical control for the histamine H2-receptor agonist dimaprit.

Dimaprit analogues having alkyl substituents on the isothiourea group have no detectable H2-agonist activity on the guinea-pig atrium. N-Methyldimaprit [S-[3-(N,N-dimethylamino)propyl]-N'-methylisothiourea] (SK&F92054) is identified as a compound which may serve as a suitable chemical control when studying the actions of dimaprit at putative H2-histamine receptors. Concentrations of N-methyl-dimaprit (up to 3 X 10(-3) M) had no agonist activity in vitro on the guinea-pig atrium (less than 0.005% of the activity of histamine), rat uterus (up to 2 X 10(-3) M,) or as a stimulant of guinea-pig ventricular adenylate cyclase (up to 10(-3) M). N-Methyldimaprit at 10(-3) M also did not significantly stimulate acid secretion in the rat isolated stomach preparation; it was a very weak stimulant of gastric acid secretion (less than 0.2% of the activity of histamine) in vivo in the lumen-perfused stomach of the anaesthetised rat but exhibited marked tachyphylaxis on repeated administration. N-Methyldimaprit has two basic centres, macroscopic pKa values 8.31 and 9.58 at 40 degrees C.

Adenylyl Cyclases↗
PubMed1992

Actions and cross-reactivity of antiallergic agents and a calcium channel antagonist on rat peritoneal mast cells. Difference in the action mechanisms and cross-reactivity among the agents.

The actions of the antiallergic agents, disodium chromoglycate (DSCG), tranilast and ketotifen, and of a calcium channel antagonist, nicardipine, and cross-reactivity among the agents were examined by observing the inhibition of 45Ca uptake and histamine release in rat mast cells stimulated by antigen and compound 48/80 (comp. 48/80). 1) All agents inhibited 45Ca uptake and histamine release in mast cells stimulated by antigen. The inhibition of 45Ca uptake by the antiallergic agents paralleled the inhibition of histamine release, while nicardipine inhibition of 45Ca uptake was stronger than its inhibition of histamine release. 2) The action of DSCG on 45Ca uptake and histamine release was significantly decreased in cells stimulated with antigen and phosphatidylserine (PS), while tranilast inhibition of histamine release was not affected by the addition of PS despite a significant decrease in the inhibition of 45Ca uptake. 3) The inhibitory effect of DSCG and tranilast was significantly lower in mast cells stimulated by comp. 48/80 than in the cells stimulated by antigen. 4) Tachyphylaxis was observed in cells re-exposed to DSCG and tranilast following previous exposure to the agents. 5) Cross-reactivity was found between DSCG and tranilast.

Animals↗
PubMed1991

Anomalous responses to histamine stimulation of guinea-pig oesophageal muscularis mucosae.

The incomplete tachyphylaxis of the contractile response to the H1-stimulants observed on guinea-pig oesophageal muscularis mucosae seems to be H2- and H3-antagonist as well as atropine- and tetrodotoxin-resistant. Lidocaine and eserine partially prevented this process probably by a mechanism independent of their main activity. The dualistic antagonism exerted by mepyramine and methysergide on reproducible histamine responses could be explained by a kinetic condition of "hemi-equilibrium state" together with changes of drug-receptor interaction and by non-specific properties of methysergide. On the whole, the present data indicate that the role of histamine in this tissue has still to be defined.

Animals↗
PubMed1990

Adenosine constricts the isolated and perfused monkey coronary artery.

Adenosine constricted 37 of 58 isolated and perfused monkey coronary arteries, whereas it dilated dog coronary arteries in all cases. The vasoconstriction induced by 0.1-10 micrograms (0.37-37.4 nmol) of adenosine was examined, since adenosine in large doses produced tachyphylaxis. The adenosine-induced vasoconstriction was significantly attenuated by diltiazem (100 micrograms [0.24 mumol]), although it was not affected by aminophylline (100 micrograms [0.23 mumol]), phentolamine (100 micrograms [0.36 mumol]), or methysergide (10 micrograms [28 nmol]. Forty-minute treatment with indomethacin (5 x 10(-6) mol/l) completely prevented the adenosine-induced vasoconstriction, but it did not significantly inhibit vasoconstriction induced by KCl (3 mg [40 mumol])- or norepinephrine (NE, 0.1 micrograms [0.59 nmol]). These results suggest that: (1) adenosine constricts monkey coronary arteries by increasing Ca2+ influx across the smooth muscle cell membrane; (2) cyclooxygenase products may be involved in the adenosine-induced vasoconstriction; (3) adenosine receptors may not be involved in the vasoconstriction.

Adenosine↗