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Nitric oxide (NO) formed via endothelial NO synthase (eNOS) plays crucial roles in the regulation of coronary blood flow through vasodilatation and decreased vascular resistance and in the inhibition of platelet aggregation and adhesion, leading to the prevention of coronary circulatory failure, thrombosis, and atherosclerosis. NO restrains myocardial oxygen consumption, when coronary perfusion is restricted. Endothelial function is impaired by pathogenic factors including smoking, excess salt intake, obesity, aging, hypercholesterolemia, hyperglycemia, and hypertension. The mechanisms involved in endothelial dysfunction are reduced NOS expression and activity, decreased NO bioavailability, and increased production of oxygen radicals and endogenous NOS inhibitors. NADPH oxidase, xanthine oxidase, and NOS uncoupling are involved in increased superoxide generation. Plasma levels of asymmetric dimethylarginine, the endogenous NOS inhibitor, are increased by an impairment of enzymatic degradation by dimethylarginine dimethylaminohydrolase and alanine-glyoxylate aminotransferase 2. Impairment of coronary arteriolar dilatation induced by perivascular nitrergic nerve activation is involved in decreased coronary blood flow. NO derived from nNOS singly or in combination with eNOS protects against serious myocardial injury through ischemic insults. Ischemia-induced iNOS upregulation contributes to myocardial contractile dysfunction. Preventive and therapeutic measures, such as improvement of life-style and treatment with therapeutic agents, to eliminate pathogenic factors for endothelial dysfunction or nNOS-derived NO deprivation would be quite important for the prophylaxis and minimizing the development of coronary artery disease., (Copyright © 2011 Elsevier B.V. All rights reserved.)

We compared the mechanisms of vasorelaxation of acetylcholine and of substance P with reference to K(+) channels, and analyzed pharmacologically the nature of endothelium-derived substance(s) other than NO and prostanoids in monkey and dog coronary arteries. Coronary arteries were isolated from monkeys and dogs, and the isometric tension of the artery strips was measured. In canine coronary artery strips treated with indomethacin plus N(G)-nitro- L-arginine ( L-NA) and partially contracted with prostaglandin F(2alpha), acetylcholine induced concentration-related relaxation, which was abolished by removal of the endothelium. The relaxation was markedly suppressed but not abolished in the strips exposed to high K(+) media. Charybdotoxin plus apamin potently inhibited the relaxation to the similar extent to that by high K(+) media, whereas glibenclamide or iberiotoxin had no effect. The relaxation was markedly inhibited by quinacrine, a phospholipase A(2) inhibitor, and ketoconazole, a selective cytochrome P450 (CYP) 3A inhibitor, but not by sulfaphenazole, a selective CYP 2C inhibitor. In contrast to acetylcholine, endothelium-dependent and indomethacin-plus- L-NA-resistant relaxation induced by substance P was not inhibited by high K(+) media, charybdotoxin plus apamin, or ketoconazole. Quinacrine and AA861, a 5-lipoxygenase inhibitor, inhibited the relaxation induced by substance P. In monkey coronary artery, acetylcholine-induced relaxation resistant to indomethacin plus L-NA was abolished by endothelial denudation and by treatment with high K(+) media, charybdotoxin plus apamin, progesterone and ketoconazole, but was not affected by iberiotoxin or sulfaphenazole. Substance P did not relax monkey coronary arteries. It is concluded that endothelium-dependent, nitric oxide- and prostanoid-independent relaxation induced by acetylcholine in monkey and dog coronary arteries are mediated by charybdotoxin plus apamin-sensitive but iberiotoxin-insensitive Ca(2+)-activated K(+) channel opening substance(s), which may be CYP3A-derived arachidonic acid metabolite(s). Contrasting to the response to acetylcholine, endothelium-dependent, indomethacin-plus- L-NA-resistant relaxation induced by substance P in dog coronary artery is not associated with K(+) channel opening, and may be mediated by 5-lipoxygenase product(s).

Mechanisms underlying celiprolol-induced vasodilatation were analyzed in isolated porcine coronary arteries. Celiprolol induced dose-related relaxation of the artery rings with endothelium, an effect which was suppressed by N(G)-nitro-L-arginine methylester (L-NAME), nitric oxide (NO) scavenger, guanylate cyclase inhibitor, endothelium denudation, and removal of Ca(2+). L-NAME contracted, and superoxide dismutase relaxed, the arteries only when the endothelium was preserved. Neither superoxide dismutase nor beta-adrenoceptor antagonists changed celiprolol-induced relaxations. Celiprolol increased the cyclic GMP content in the tissue. The release of NO from endothelium, estimated by the extracellular production of cyclic GMP in arteries incubated in medium containing guanylate cyclase and GTP, was augmented by celiprolol, and L-NAME abolished this action of celiprolol. It is concluded that celiprolol elicits relaxation by acting on sites other than beta-adrenoceptors in the endothelium and by releasing NO, which activates soluble guanylate cyclase in smooth muscle and produces cyclic GMP. Scavenging of superoxide anions from the endothelium does not seem to account for the induced relaxation.

Objective: The present study was undertaken to examine whether arginine vasopressin (AVP) relaxes primate coronary artery and to analyse the mechanisms of its action in reference to endothelial nitric oxide and AVP receptor subtype., Methods: Isometrical tension responses to AVP and desmopressin were recorded in isolated monkey coronary arteries., Results: AVP (10(-9) to 10(-7) mol/l) induced a concentration-related relaxation; endothelium-denudation abolished the response. Treatment with N(G)-nitro-L-arginine, but not the D-enantiomer, abolished the endothelium-dependent relaxation, which was restored by L-arginine. Treatment with SR49059 and [Pmp1,Tyr(Me)2]-Arg8-vasopressin, selective inhibitors of V1 receptor subtype, attenuated the relaxant response to AVP, whereas the relaxation induced by sodium nitroprusside was not affected by SR49059. Desmopressin, a V2 receptor agonist, up to 10(-8) mol/l did not elicit relaxation., Conclusions: It is concluded that AVP-induced monkey coronary arterial relaxation is mediated via nitric oxide synthesized from L-arginine in association with stimulation of V1 receptor subtypes in the endothelium.

Background: Pancuronium has sympathomimetic actions but does not change or lowers systemic blood pressure in some studies of anesthetized humans and dogs. The present study was done to determine the actions and mechanisms of action of pancuronium on coronary and renal arteries other than those as a sympathomimetic agent., Methods: Helical strips of coronary and renal arteries from mongrel dogs were suspended in oxygenated, warmed Ringer-Locke solution, and changes in the isometric tension were recorded. In some strips, transmural electrical stimulation (5 Hz for 40 s) was applied to activate perivascular adrenergic nerves., Results: Pancuronium (10[-7] to 10[-5] M) caused dose-dependent relaxation in coronary and renal arteries contracted with prostaglandin (PG) F2alpha, whereas no significant response was induced with vecuronium. The relaxation was endothelium independent and abolished by indomethacin or tranylcypromine, a PGI2 synthase inhibitor. Transmural electrical stimulation caused coronary arterial relaxation, which was augmented by pancuronium and vecuronium. Desipramine also increased the response, and additional potentiation of the response was not elicited by pancuronium and vecuronium. In renal arteries, electrical stimulation caused contraction, which was also augmented by pancuronium and vecuronium. With desipramine treatment, these muscle relaxants did not potentiate the response. Endothelium-dependent coronary arterial relaxation caused by bradykinin was not affected by pancuronium., Conclusions: Pancuronium-induced relaxations in canine coronary and renal arteries appear to be mediated by PGI2 released from subendothelial tissues. Potentiations by pancuronium and vecuronium of the response to adrenergic nerve stimulation are expected to be due to an inhibition of the norepinephrine uptake but not to facilitated release of the amine.

Isolated dog internal thoracic arteries (ITA) responded to norepinephrine and phenylephrine with concentration-related contractions, which were suppressed by prazosin, but not by yohimbine. Clonidine did not contract ITA. In coronary arterial strips, norepinephrine produced a relaxation. Isoproterenol relaxed coronary arterial strips contracted with serotonin but did not alter the tone of ITA. Forskolin and beraprost, an analog of prostaglandin I2, relaxed coronary and ITA strips to a similar extent. The beta-adrenoceptor density, assayed by [3H]dihydroalprenolol binding, was markedly less in ITA than in coronary arteries. Nicotine and transmural electrical stimulation did not alter the tension of ITA. Immunohistochemical study indicated that nerve fibers containing tyrosine hydroxylase immunoreactivity were markedly less in ITA than in coronary and mesenteric arteries. These results indicate that beta-adrenoceptor function and adrenergic innervation are considerably reduced in dog ITA. Norepinephrine-induced vasocontraction appears to be mediated by alpha 1-adrenoceptors in the arteries.

Dopamine is widely used for the treatment of cardiogenic and hypovolemic shock. This study was undertaken to compare the response to dopamine in epicardial conduit coronary arteries of humans, Japanese monkeys, and dogs, and to determine the mechanism of vasoconstriction and vasodilation. In helical strips of coronary arteries from humans and monkeys partially contracted with prostaglandin F2 alpha, dopamine produced a concentration-related contraction; the human artery contraction was greater. The contractions were reversed to a relaxation by treatment with phentolamine. Relaxation of monkey arteries treated with the alpha adrenoceptor antagonist was not influenced by metoprolol, a beta 1 antagonist, or endothelium denudation, but was reversed to contraction by SCH23390, a dopamine1 receptor antagonist. On the other hand, dog coronary arteries responded to dopamine with a relaxation that was abolished by metoprolol, but not influenced by SCH23390 or butoxamine, a beta 2 antagonist. We conclude that dopamine in clinical doses elicits significant contractions, mediated possibly by alpha adrenoceptors, in human and monkey coronary arteries; thus, care has to be taken when the amine is used in patients with variant angina pectoris. Relaxation of monkey coronary arteries appears to be associated with activation of dopamine1 receptors, whereas those of the dog arteries are mediated mainly by beta 1 receptors.

The endothelium-dependency of vasodilator responses was compared in helical strips of canine internal thoracic (ITA) and coronary arteries partially contracted with serotonin. The addition of acetylcholine produced a concentration-related relaxation in ITA and coronary arterial strips with an intact endothelium. The relaxations were not influenced by indomethacin, but were markedly inhibited or abolished by methylene blue, NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthase inhibitor, and endothelial denudation. The responses to low concentrations of acetylcholine were significantly greater in ITA than in coronary arteries, whereas relaxations induced by substance P, Ca2+ ionophore (A23187) or NO in ITA were significantly less. The substance P-induced relaxation in ITA and coronary arteries was endothelium-dependent, and it was almost abolished by L-NA. Relaxations induced by ATP in ITA were abolished by endothelium denudation and treatment with L-NA. In the coronary arteries, relaxing responses were inhibited only partially by removal of endothelium and L-NA. Acetylcholine, ATP and substance P relax canine ITA possibly by a mediation of endothelium-derived NO, but not prostaglandin I2. Coronary arterial relaxations induced by ATP appear to be mediated by an indirect action via NO released from the endothelium, in addition to a direct action on the smooth muscle.

In isolated porcine coronary arteries, acetylcholine elicited contractions that were potentiated by endothelium denudation. In endothelium-intact strips, the contraction deteriorated by repeated trials and was reversed to a relaxation. NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthesis inhibitor, abolished the relaxation or reversed it to a contraction. Endothelium-dependent relaxations caused by serotonin were also reversed to a contraction by treatment with L-NA. Relaxations caused by substance P were dependent on the endothelium and were abolished by oxyhemoglobin; however, L-NA did not completely abolish the relaxation. It may be concluded that porcine coronary arteries respond to acetylcholine with contractions by a direct action on smooth muscle that are minimized by stimulated release of NO from the endothelium. It appears that the relaxation caused by serotonin is due to NO released from the endothelium, whereas the substance P-induced relaxation is associated mainly with endothelium-derived NO produced by NO synthase sensitive to L-NA and also with NO produced via a L-NA-resistant process or via a pathway distinct from that through NO synthase.

1. Endothelin-3 (ET-3) elicited relaxations at low concentrations (up to 10(-8) M) and contractions at higher concentrations in dog isolated coronary arteries precontracted with prostaglandin F2 alpha (PGF2 alpha). The relaxation by ET-3 was not affected by endothelium denudation nor treatment with NG-nitro-L-arginine, but was abolished or reversed to a contraction by treatment with indomethacin and markedly suppressed by tranylcypromine, a PGI2 synthetase inhibitor, or diphloretin phosphate, a prostaglandin receptor antagonist. ET-1 produced only concentration-dependent contractions. 2. BQ-123, a new selective ETA receptor antagonist, caused relaxation of the strips contracted with ET-3 in a dose-dependent manner and prevented the ET-3-induced contraction but did not affect the contraction produced by PGF2 alpha. The relaxation caused by ET-3 was enhanced by treatment with BQ-123. 3. It is concluded that the relaxations elicited by ET-3 in dog coronary arteries are mediated via liberation of PGI2 by activation of non-ETA receptors, located in subendothelial tissues, possibly smooth muscle cells, whereas the peptide-induced contractions are mediated via ETA receptors.

In monkey coronary artery strips contracted with prostaglandin (PG) F2 alpha or K+, exchange of entire N2 for O2 in the gas aerating the bathing media produced a contraction. Endothelium denudation did not alter the response. Aspirin, indomethacin, and ONO 3708, a PG receptor antagonist, markedly inhibited the hypoxia-induced contraction, whereas superoxide dismutase and OKY 046, a thromboxane (Tx) A2 synthesis inhibitor, were ineffective. Diltiazem depressed the contraction. Hypoxia increased the release of PGE2 but not 6-keto-PGF1 alpha and TxB2. Contractions induced by hypoxia of human coronary artery strips were also independent of the endothelium but were suppressed by indomethacin and diltiazem. On the other hand, dog coronary artery contractions induced by hypoxia were attenuated by endothelium denudation but were not influenced by indomethacin. It may be concluded that the hypoxia-induced contraction of monkey and human epicardial coronary arteries is associated with vasoconstrictor PGs released from subendothelial tissues; however, TxA2 and superoxide anion are not involved. The dog coronary artery contraction appears to be elicited by substance(s), other than cyclooxygenase products, released from the endothelium.

Isolated human, Japanese monkey and dog epicardial coronary arteries and dog renal and mesenteric arteries treated with phentolamine responded to isoproterenol with a concentration-related relaxation. The KB values of metoprolol, a beta-1 antagonist, in the coronary arteries from different mammals did not differ, but were appreciably smaller than those in the dog renal and mesenteric arteries. Treatment with butoxamine, a beta-2 antagonist, inhibited the relaxation of dog mesenteric arteries to a greater extent than that of monkey and dog coronary arteries. Terbutaline, a beta-2 agonist, produced a greater relaxation in monkey mesenteric and dog renal and mesenteric arteries than in human, monkey and dog coronary arteries. Norepinephrine relaxed the monkey and dog coronary arteries dose-dependently via mainly beta-1 adrenoceptors, but elicited a contraction or a minute relaxation in dog mesenteric arteries even when treated with high concentrations of phentolamine. Contractile responses to electrical stimulation of adrenergic nerves in monkey coronary arteries were potentiated by treatment with metoprolol and propranolol, whereas the contractions in dog mesenteric arteries were unaffected. It is concluded that the amine-induced relaxation of human and monkey epicardial coronary arteries is mediated mainly by beta-1 adrenoceptor subtype, as is the response of dog coronary arteries. Involvement of beta-1 subtype in coronary artery relaxations would be a mechanism underlying potentiation by beta antagonists of the contraction caused by norepinephrine released from adrenergic nerves in primates.

Diltiazem induced a concentration-dependent relaxation of monkey coronary arterial strips which were partially contracted with clonidine, phenylephrine, norepinephrine, prostaglandin F2 alpha. This relaxation occurred to a similar extent, but was significantly less than that observed in arteries contracted with K+. Contractions mediated via alpha 2-adrenoceptors do not appear to be more susceptible to diltiazem than those caused by activation of alpha 1-adrenoceptors and prostaglandin F2 alpha receptors.

In helically-cut strips of dog cerebral, coronary and mesenteric arteries, contracted with prostaglandin (PG) F2 alpha or K+, the addition of verapamil caused a dose-related relaxation. Verapamil-induced relaxations were greater in cerebral than in the other arteries when contracted with PGF2 alpha, but did not significantly differ in the arteries contracted with K+. Similar results were obtained with diltiazem and nifedipine. The contractile response to PGF2 alpha was attenuated by pretreatment with verapamil, the ateenuation being greater in cerebral than in mesenteric arteries. Nitroglycerin and sodium nitroprusside relaxed cerebral, coronary and mesenteric arteries contracted with PGF2 alpha to a similar extent. It may be concluded that dog cerebral arteries contracted with PGF2 alpha, one of endogenous vasospastic substances, are more susceptible to agents which interfere with the influx of Ca++ across cell membranes than coronary and mesenteric arteries; these agents may thus be of value in the treatment and prophylaxis of cerebral vasopasm.

In epicardial conduit coronary artery strips obtained during autopsy within 2.5 h after death, relaxations induced by low concentrations of histamine were reversed to contractions by removal of endothelium, whereas those caused by bradykinin, substance P, and Ca2+ ionophore A23187 were almost abolished. In the artery strips with intact endothelium, which responded to histamine, bradykinin, and substance P with moderate or marked relaxations, acetylcholine elicited contractions. Endothelium denudation failed to potentiate the contractile response to acetylcholine and serotonin. Relaxant responses to histamine, bradykinin, and substance P did not significantly differ in coronary arteries from adults (35-48 yr old) and seniors (63-82 yr old). Two strips from a 2-mo-old male responded to acetylcholine only with contractions, and their responses to the vasodilators were not greater than those seen in the adult and senior arteries. Histamine increased guanosine 3',5'-cyclic monophosphate (cGMP); the increments did not differ in the arteries from adults and seniors. It may be concluded that endothelium is a major site for relaxant actions of histamine, bradykinin, and substance P, whereas muscarinic receptors, if any, in endothelium do not play an important role in the generation of relaxing factor from human coronary arteries. The endothelium-dependent relaxations do not appear to be altered with increasing age or in the arteries with slight atherosclerotic changes.

With advancing age from 2 to 12 years, relaxations induced by norepinephrine and epinephrine were suppressed or reversed to contractions in large and medium-size coronary arteries isolated from beagles. Norepinephrine-induced contractions in the senescent beagle arteries treated with propranolol were greater than those in the young beagle arteries and were inhibited by prazosin but not by yohimbine. Relaxant responses to isoproterenol were less in the arteries from old beagles than in the young beagle arteries. The magnitude of relaxations induced by norepinephrine and epinephrine was greatest in small arteries from old beagles, followed by medium and large arteries, in that order. Transmural electrical stimulation tended to produce a contraction in the old beagle arteries and a relaxation in the strips from young beagles. It appears that alpha 1 adrenoceptor function increases with advancing age in beagle coronary arteries of large and medium sizes, and beta receptor function declines. Vasoconstriction mediated by alpha 1 receptors is postulated to be related inversely to the distance from the coronary orifice in senescent beagles, and vice versa with vasodilatation mediated by beta receptors.

In helical strips of pig coronary arteries, histamine, serotonin, acetylcholine and a stable analogue of thromboxane A2 (9, 11-epithio-11, 12-methano TXA2: s-TXA2) produced a dose-dependent contraction. The histamine-induced contraction was suppressed by treatment with chlorpheniramine, suggesting an involvement of H1 receptors. Contractile responses to serotonin were attenuated by not only ketanserin, an S2 antagonist, but also by cinanserin and methysergide. Relaxation induced by serotonin in preparations treated with high concentrations of ketanserin were inhibited by cinanserin and methysergide. Norepinephrine contracted coronary arteries treated with propranolol. Contractile responses to norepinephrine were reversed to relaxations by prazosin, which were abolished by treatment with yohimbine. Contractile responses to histamine were potentiated by treatment with low concentrations of serotonin or s-TXA2. Contractile responses to serotonin were also potentiated by low concentrations of histamine or s-TXA2. Removal of the endothelium from pig coronary arterial strips potentiated contractions induced by serotonin, histamine and norepinephrine. These results suggest that, in addition to damaged endothelium, integrating action of endogenous vasoconstrictors, including histamine, serotonin, TXA2 and norepinephrine, may play an important role in producing coronary vasospasm.

PGD2, PGF2 alpha, and CTA2 are compounds that increase vascular contractility indirectly by potentiating responses to nerve stimulation or vasoconstrictor agents and directly by acting on vascular smooth-muscle receptors. The direct vasoconstrictor potency is in the order of CTA2 greater than PGF2 alpha greater than PGD2 (5,6,9). The ratio of concentrations for directly- and indirectly-induced contractions is approximately 1,000 with PDG2, 100 with PGF2 alpha, and 10 with CTA2. PGD2, PGF2 alpha, and TXA2 may contribute to provoking coronary vasospasm because of potentiating actions on responses to adrenergic and other vasoconstrictor stimuli and to their vasoconstrictor actions. The former effect is induced by appreciably lower concentrations. On the other hand, PGI2 appears to counteract responses to the vasoconstrictor interventions. PGD2 and PGF2 alpha act on presynaptic receptors and increase the release of norepinephrine; these actions are resistant to diphloretin, a PG antagonist. In contrast, CTA2 and PGI2 act on postsynaptic receptors and alter smooth-muscle reactivity to vasoconstrictors; these actions are sensitive to the PG antagonist.

Concentration-response curve for prostaglandin (PG) F2 alpha in helical strips of dog cerebral, coronary and mesenteric arteries were compared in control media and in those in which all the NaCl was replaced with isomolar KCl. Contractile responses to PGF2 alpha in concentrations up to 2 x 10(-6) M in cerebral arteries, to 10(-5) M in coronary arteries and to 5 x 10(-7) M in mesenteric arteries were not attenuated by excess K+. Contractions caused by PGF2 alpha, at least at these concentrations or lower, may not be associated with membrane depolarization.

Contractile responses to 30 mmol . litre-1 K+ of helical strips of coronary arteries from human cadavers did not change within 5 h after death; however, they were suppressed 8 h after death. In coronary arteries from monkey cadavers, the K+-induced contractions did not significantly differ within the first 5 h, but were suppressed 12 h after death. On the other hand, K+-induced contractions were retained without deterioration in cerebral artery strips from human cadavers 20 to 24 h after death and those from monkey cadavers 8 to 16 h. Acetylcholine caused contractions of human coronary arteries, but caused only a relaxation of monkey coronaries which was abolished by rubbing off the endothelium. These responses were attenuated by no more than K+-induced contractions up to 12 h after death. Maximum contractions induced by noradrenaline, histamine and serotonin remained the same in human coronary arteries for 3 to 5 h after death. Similar magnitudes of contraction were elicited by noradrenaline in human cerebral arteries up to 20 h after death. It appears that the reactivity of human coronary arteries to K+ and other vasoconstrictor agents used is normally retained for at least 6 h after death and that of human cerebral arteries up to 24 h.

In helically cut strips of dog cerebral, coronary, mesenteric and femoral arteries, the contractile response to prostaglandin (PG) F2alpha, and E2, relative to contractions induced by 30 mM K+, did not appreciably differ, whereas relaxations induced by PGE1 relative to those induced by 10(-4) M papaverine were significantly different; the least in cerebral arteries and the greatest in mesenteric arteries. The relaxation of human cerebral arteries in response to PGE1 was similar to that of dog cerebral arteries. Treatment for 60 min with polyphloretin phosphate (3 X 10(-5) and 10(-4) g/ml) suppressed the contractile response to PGF2alpha and E2 but did not alter the response to 25 mM K+. The relaxing effect of PGE1 was not influenced. Aspirin (5 X 10(-5) and 2 X 10(-4) M) significantly potentiated the contractile response to PGF2alpha and E2 but did not alter the relaxation induced by PGE1. In contrast, contractions induced by serotonin were attenuated. It is concluded that dog cerebral, coronary, mesenteric and femoral arteries relaxed differently in response to PGE1. It appears that arterial responses to vasoconstricting PGs, but not to the vasodilating PG, are significantly attenuated by polyphloretin phosphate and potentiated by aspirin.

In helically cut stripes of monkey coronary arteries of different sizes, contracted with prostaglandin F2 alpha or K+, responses to norepinephrine, epinephrine, isoproterenol, and transmural electrical stimulation were compared. In response to norepinephrine, only contractions were induced in large arteries, contractions at low concentrations and relaxations at high concentrations in medium-size arteries, and only relaxations in small arteries. Epinephrine produced a greater contraction than norepinephrine in the arteries. Relaxant effects of isoproterenol were greater in small and medium-size arteries than in large arteries. Transmural electrical stimulation applied at frequencies of 2,5, and 20 Hz to strips of medium-size arteries produced a frequency-dependent contraction that was reversed to a relaxation following treatment with phentolamine. Propranolol abolished the relaxation. In strips of dog coronary arteries of medium size, transmural stimulation elicited only a relaxation which was suppressed or reversed to a contraction by propranolol. Dog arteries of this size responded to norepinephrine and epinephrine with only a relaxation. It may be concluded that the quantity or the susceptibility of alpha-adrenoceptors is in the order of large greater than or equal to medium greater than small-size arteries from monkeys, whereas that of beta-adrenoceptors is in the order of medium = small greater than large arteries. Monkey coronary arteries appear to respond to endogenous and exogenous norepinephrine with a contraction more consistently than dog coronary arteries.

In helical strips of proximal and distal coronary arteries from beagles of different ages (30 days, 3 months and 1 and 3 years old) precontracted partially with prostaglandin F2 alpha, responses to catecholamines, transmural electrical stimulation, tyramine and acetylcholine were compared. Proximal coronary arteries from infant beagles responded to norepinephrine and epinephrine with contractions, whereas those from adult (1 and 3 years old) beagles responded with dose-related relaxations. Isoproterenol-induced relaxations were in the order of infant less than young less than adult beagle arteries. Norepinephrine produced contractions in the proximal arteries from infant beagles but relaxations in the distal arteries. Relaxations induced by norepinephrine and isoproterenol were in the order of small greater than medium greater than large-size arteries from adult beagles. Transmural stimulation and tyramine produced contractions in the infant and young beagle arteries of proximal portion but only relaxations in the adult beagle arteries. The contractions induced by transmural stimulation and norepinephrine were suppressed by prazosin but not by yohimbine. Acetylcholine produced similar magnitude of relaxations in the arteries from beagles of different ages. It may be concluded that contractions of coronary arteries mediated by alpha-1 adrenoceptors decrease with age, whereas beta receptor-mediated relaxations increase with age. Alpha-1 adrenoceptor functions appear to be in the order of large greater than medium greater than small-size coronary arteries from beagles of different ages, and beta receptor functions to be in the reverse order.

In isolated dog coronary arteries contracted with prostaglandin F2 alpha, tyramine in concentrations of 10(-6) and 5 x 10(-6) M caused relaxations, but it produced contractions at 2 x 10(-5) M or higher. The relaxant response to tyramine was attenuated, but the contractile response was enhanced at the second trial as compared with the responses at the first. Relaxations induced by low concentrations of tyramine were reversed to contractions by treatment with propranolol (10(-6) M) or sotalol (10(-5) M), and were abolished by cocaine (3 x 10(-6) M) or bretylium (2 x 10(-5) M). In coronary arteries isolated from reserpine (0.5 mg/kg)-pretreated dogs, tyramine produced only a contraction. Under resting conditions, contractions induced by tyramine (5 x 10(-6) to 2 x 10(-3) M) were potentiated by cocaine and propranolol, and were inhibited by phentolamine. Norepinephrine produced a dose-dependent relaxation in the arteries contracted with prostaglandin F2 alpha. In the presence of propranolol, the arteries under resting conditions were contracted by norepinephrine, the contraction being suppressed by treatment with phentolamine. It may be concluded that relaxations of dog coronary arteries induced by tyramine are mediated by liberation of norepinephrine from adrenergic nerves which stimulates beta-adrenoceptors in the smooth muscle. It seems likely that the tyramine (2 x 10(-5) M or higher)-induced contraction is not mediated by norepinephrine released, but it is partly due to a direct action on alpha-adrenoceptors.

Helical strips of human coronary arteries contracted in response to histamine concentration dependently, they relaxed with low concentrations and contracted with high concentrations. Treatment with cimetidine potentiated contraction in the strips with intact and damaged endothelium to a similar extent and attenuated relaxation. Removal of endothelium abolished relaxation and potentiated contraction in the cimetidine-treated strips. Methylene blue increased the contractile response to histamine in the strips with endothelium but did not alter the response in the damaged-endothelium strips. Histamine-induced relaxations in the intact strips were suppressed or abolished by treatment with ETYA, AA861, a lipoxygenase inhibitor, and by chlorpheniramine but were unaffected by indomethacin. Chlorpheniramine also abolished amine-induced contraction. It may be concluded that histamine-induced contraction in human coronary arteries is mediated by H1 receptors in smooth muscle, and relaxation is mediated by H2 receptors in smooth muscle and H1 receptors in endothelium. Also, stimulation of the endothelial H1 receptor liberates vasodilator substance and possibly activates smooth muscle guanylate cyclase to accumulate cellular cyclic guanosine monophosphate.

Responses to vasoactive agents were compared in helical strips of coronary arteries isolated from beagles of 30 days, 3 months, 2 years and 12 years old. Serotonin contracted the arterial strips dose-dependently, the contraction being greater in the arteries of proximal portion than in the distal arteries. The contraction increases with age from 3 months to 12 years, although EC50 values did not differ. Angiotensin II contracted distal coronary arteries to a greater extent than the proximal ones. Age did not alter the peptide-induced contraction. In prostaglandin F2 alpha-contracted coronary arteries, acetylcholine-induced relaxations, dependent on endothelium, were less in the arteries from senescent beagles than in those from adult beagles (2 years old). Histamine relaxed the infant beagle arteries to a lesser extent than the adult and senescent beagle arteries. Histamine-induced relaxations were attenuated selectively by cimetidine. Relaxations caused by adenosine and prostaglandin I2 did not differ in coronary arteries from beagles of different ages. It may be concluded that greater responsiveness to serotonin of senescent beagle coronary arteries is due preferentially to increased function of serotonergic receptors rather than impaired function of the arterial endothelium responsible for the release of relaxing factor(s), although some impairment of the function is supposed, on the basis of interferences with acetylcholine-induced relaxation in the aged beagle arteries. Histaminergic H2 receptor function appears to develop in beagle coronary arteries until 3 months of age.

Relaxant responses to vasodilators, including nitroglycerin, sodium nitroprusside, prostaglandin I2 sodium salt (PGI2), prostaglandin E1 (PGE1), diltiazem hydrochloride and adenosine, were compared in helical strips of dog coronary arteries of different sizes and in coronary and mesenteric arterial strips. The relaxant responses to nitroglycerin, sodium nitroprusside, diltiazem and adenosine were significantly greater in coronary arteries than in mesenteric arteries, whereas the responses to PGI2 and PGE1 in these arteries did not significantly differ. In coronary arteries of different sizes, the relaxation induced by nitroglycerin was in the order of large greater than medium greater than small-size, while in contrast, the relaxations by adenosine, PGI2 and PGE1 were greatest in the small-size arteries and least in the large-size arteries. The relaxant responses to sodium nitroprusside and diltiazem did not differ in the coronary arteries of different sizes. Nitroglycerin, sodium nitroprusside and diltiazem appear to dilate coronary arteries more predominantly than mesenteric arteries. The preferential dilator action of PGI2 and PGE1 on distal coronary arteries, like that of adenosine, may lead more blood to re-distribute to the non-ischemic region of the heart in anginal patients.

Contractile responses to vasoconstrictor agents were compared in helical strips of dog and monkey epicardial coronary arteries of different sizes. Contractions of large, medium and small arteries induced by KCl ( 30mM ) were virtually identical. Contractions induced by 5-hydroxytryptamine (5-HT) (10(-9) - 2 X 10(-6) M) were in the order of large greater than medium greater than small arteries in dogs, and large = medium greater than small arteries in monkeys. Cinanserin suppressed these responses. In contrast, contractions produced by angiotensin II (AII) (10(-7) M) were in the order of small greater than medium greater than large arteries in dogs, and small greater than medium = large arteries in monkeys. Sar1-Ala8-angiotensin II markedly attenuated the peptide-induced contractions. Contractions induced by prostaglandin F2 alpha (PGF2 alpha) were significantly greater in large and medium sized arteries than in small arteries in dogs, while those of the arteries of different sizes isolated from monkeys did not differ. Contractions induced by carbocyclic thromboxane A2 (c-TXA2), in arteries of different sizes in dogs and monkeys, did not differ. These results suggest that the sensitivity and/or the population of 5-HT receptors are greater in proximal coronary arteries than in distal arteries, while, in contrast, the sensitivity and/or population of AII receptors are greater in distal coronary arteries. Receptors for PGF2 alpha and c-TXA2 appear to react to a similar degree in monkey arteries of different sizes, although receptors for PGF2 alpha appear to be fewer in distal coronary arteries in dogs.

Dopamine contracted isolated canine coronary arteries at initial concentrations of 5 times 10(-6) mol/l. In the presence of phentolamine or phenoxybenzamine and after contraction of the arteries with K+ or prostaglandin F2alpha, dopamine caused dose-related relaxation at initial concentrations of 5 times 10(-6) mol/l and 10(-6) mol/l. Propranolol, 10(-6) mol/l, and haloperidol, 10(-5) mol/l, did not antagonize the relaxation.

Isolated canine coronary arteries were contracted with prostaglandin F2a and the relaxing effects of dopamine, adenosine, isoproterenol and acetylcholine were compared. Relaxation induced by dopamine in phenoxybenzamine-treated arteries was not significantly influenced by propranolol and atropine in concentrations sufficient to shift dose-respone curves of isoproterenol and acetylcholine, respectively, to the right. Dose-response curves of isoproterenol were shifted significantly to the left by 2 x 10(-5) M aminophylline. In contrast, the relaxing effect of adenosine was significantly attenuated by aminophylline (5 x 10(-6)-10(-4) M) in a dose-dependent manner. Kinetic analysis showed that aminophylline competitively antagonized the effect of adenosine, and the pA2 was 5.57. At these concentrations, aminophylline did not alter the relaxing action of dopamine and acetylcholine. It may be concluded that dopamine produces relaxation at a different site and with a different mechanism of action from those of isoproterenol, the effect of the latter being presumably mediated by cellular cyclic AMP, and that dopamine also does not share the site of action with adenosine and acetylcholine. It appears that receptive sites specific for adenosine are present in canine coronary arteries.

In helical strips of dog coronary arteries contracted with prostaglandin F2 alpha, transmural electrical stimulation and nicotine elicited a transient relaxation. The response to electrical stimulation was abolished by tetrodotoxin, bretylium or pretreatment of the dogs with reserpine, and was potentiated by cocaine. Atropine was ineffective. The relaxations were abolished or converted to contractions by sotalol; the contraction was suppressed by phentolamine. The nicotine-induced relaxation was suppressed by hexamethonium, cocaine, bretylium and sotalol. Atropine and tetrodotoxin did not affect the response. Following pretreatment with reserpine, relaxant responses to nicotine were partly reduced; the remaining relaxations were suppressed by atropine, slightly inhibited by sotalol and potentiated by physostigmine. It may be concluded that electrical stimulation liberates norepinephrine from adrenergic nerves, which preferentially activates beta-adrenoceptors. The reuptake mechanism appears to function to inactivate liberated norepinephrine. Nicotine-induced relaxations are mediated mainly by liberated norepinephrine; however, as shown by the pretreatment with reserpine, the release of an acetylcholine-like substance may also be involved.

Relaxations induced by histamine in helical strips of monkey coronary arteries were attenuated either by chlorpheniramine or cimetidine; the H1 antagonist suppressed the fast component of relaxation, whereas the H2 antagonist reduced the slow component. Combined treatment with these antagonists abolished the amine-induced relaxation. The relaxation was not influenced by indomethacin; however, the fast component of relaxation was inhibited by 5, 8, 11, 14-eicosatetraynoic acid, AA861, a lipoxygenase inhibitor, and methylene blue. In the arteries treated with methylene blue, relaxations were abolished by cimetidine. Removal of the endothelium reduced the relaxation markedly or reversed the relaxation to a contraction; chlorpheniramine reversed the contraction to a relaxation. In dog coronary arterial strips, histamine-induced relaxations were not attenuated by removal of the endothelium. Cimetidine shifted the dose-response curve for histamine to the right, but chlorpheniramine did not alter the response. Indomethacin, AA861 and methylene blue failed to inhibit the relaxation. The response of monkey coronary arteries to histamine appears to be a sum of the slight, persistent contraction, the transient relaxation and the slowly developing relaxation. The transient relaxation may be mediated by H1 receptors in the endothelium, the activation of which yields relaxing factor, resulting in an increase of cellular cyclic GMP in smooth muscle. The contraction and the slow relaxation appear to be associated with H1 and H2 receptors, respectively, in smooth muscle cells. Dog coronary arterial relaxations induced by histamine may be mediated exclusively by H2 receptors in muscle cell membrane.

In helical strips of human epicardial coronary arteries, norepinephrine produced a concentration-related contraction; the contractions relative to those induced by 30 mM K+ were greater in the proximal portion of the arteries than in the distal portion. The amine-induced contraction was suppressed by treatment with phentolamine. Acetylcholine contracted human coronary arteries but, in contrast, relaxed the monkey coronary arteries (both freshly excised and cadaver) previously contracted with prostaglandin F2 alpha. Both the contraction and relaxation induced by acetylcholine were suppressed by atropine. Removal of the endothelium abolished the relaxation of monkey arteries but did not significantly alter the contraction of human arteries. Human coronary arteries responded to histamine with contractions, which were reversed to relaxations following treatment with chlorpheniramine. It is concluded that, as far as the portions of human coronary arteries used in the present study are concerned, the arterial contraction mediated via alpha-adrenoceptors is inversely related to the distance from the coronary artery orifice. Acetylcholine produces contractions of human coronary arteries, possibly due to activation of muscarinic receptors on smooth muscle cells. Histamine-induced contractions appear to be mediated via H1-receptors.

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.