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Mechanisms underlying vasodilatation to nerve stimulation by electrical pulses and nicotine were analyzed in isolated canine small labial arteries. Transmural electrical stimulation (5 and 20 Hz) produced a contraction followed by a relaxation in labial arterial strips denuded of the endothelium, partially contracted with prostaglandin F2alpha. The contraction was abolished by prazosin or combined treatment with alpha, beta-methylene ATP. In the treated strips, neurogenic relaxation was abolished by NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthase inhibitor, and restored by L-arginine. The D-enantiomers were without effect. Nicotine (10(-4) M) also relaxed the arteries, in which the contractile response was abolished by prazosin and alpha, beta-methylene ATP. The relaxant response was attenuated but not abolished by L-NA; the inhibition was reversed by L-arginine. The remaining relaxation by nicotine was abolished by calcitonin gene-related peptide (CGRP)-[8 to 37], a CGRP1 receptor antagonist. Relaxations elicited by a lower concentration of nicotine (2 x 10(-5) M) sufficient to produce similar magnitudes of response to those induced by 5-Hz electrical nerve stimulation were also inhibited partially by L-NA. Histochemical study with the NADPH-diaphorase method demonstrated positively stained nerve fibers and bundles in the arterial wall, suggesting the presence of neuronal NO synthase. It is concluded that the relaxation induced by electrical nerve stimulation of small labial arteries is mediated exclusively by NO synthesized from L-arginine in nerve terminals, whereas nicotine in the concentrations used evokes relaxations by a mediation of nerve-derived NO and also CGRP, possibly from sensory nerves. The reason why nicotine but not electrical pulses stimulates sensory nerves and elicits vasorelaxation remains unsolved.

Isolated monkey cerebral arteries denuded of the endothelium responded to transmural electrical stimulation (5 Hz for 40 sec) with relaxations that are mediated by nitric oxide (NO) synthesized from L-arginine. The relaxant response was slightly inhibited by duroquinone, a superoxide anion-generating agent. The agent markedly inhibited the response after treatment with diethylthiocarbamic acid, an inhibitor of copper/zinc superoxide dismutase. The inhibition was partially reversed by superoxide dismutase. The neurogenic relaxation was reduced by acetylcholine acting on prejunctional muscarinic receptors. Neuropeptide Y, morphine, ATP, clonidine and pituitary adenylate cyclase-activating polypeptide did not change the response to nerve stimulation. Sodium nitroprusside in a dose sufficient to produce relaxation attenuated the neurogenic response. It is concluded that the neurotransmitter liberated from vasodilator nerves in monkey cerebral arteries is free NO rather than a stable analog of NO, like S-nitrosocysteine. Substances other than acetylcholine released as neuromodulators do not seem to regulate the NO-mediated nerve function.

Canine retinal central arterial strips responded to acetylcholine with a relaxation that was endothelium-independent. Indomethacin and atropine abolished the relaxation at low doses (10(-7) to 10(-6) M) and moderately attenuated the response to high concentrations (10(-5) and 10(-4) M). The residual relaxation at 10(-5) and 10(-4) M in indomethacin-treated strips were abolished by NG-nitro-L-arginine, hexamethonium, oxyhemoglobin and methylene blue, and the NG-nitro-L-arginine-induced inhibition was reversed by L-arginine. Cerebral arterial strips with endothelium responded to acetylcholine with a transient relaxation followed by a contraction, whereas only a relaxation was induced when endothelium was denuded. The relaxations at low and high doses were modified by atropine, indomethacin, hexamethonium and NG-nitro-L-arginine quite similarly to those seen in retinal arteries. Histochemical study demonstrated the presence of perivascular nerves containing NADPH diaphorase in whole mount preparations of the retinal artery. It is concluded that acetylcholine-induced retinal arterial relaxations, independent of endothelium, are mediated possibly by prostaglandin I2 in activation of muscarinic receptors and by nitric oxide derived from perivascular nerves in response to nicotinic receptor stimulation. On the other hand, vasoconstrictor prostanoids appear to be liberated from the endothelium by muscarinic receptor stimulation in cerebral arteries, and mechanisms underlying the relaxation are similar to those seen in retinal arteries.

In cat middle cerebral arterial strips denuded of the endothelium, nicotine produced a relaxation that was abolished by treatment with hexamethonium. The relaxation was partially inhibited by treatment with NG-nitro-L-arginine (L-NNA), a nitric oxide (NO) synthase inhibitor, and oxyhemoglobin, an NO scavenger. The remaining relaxation in the media containing L-NNA was abolished in the strips made unresponsive to calcitonin gene-related peptide (CGRP) by its repeated application. However, this was not the case when the strips were made tachyphylaxic to vasoactive intestinal polypeptide. The nicotine-induced relaxation was also partially attenuated by pretreatment with capsaicin; the remaining relaxation was abolished by L-NNA but not by its D-enantiomer. The inhibitory effect of L-NNA was reversed by L- but not D-arginine. Histochemical study revealed that injections of ethanol into the vicinity of pterygopalatine ganglion abolished the positive staining for nicotinamide adenine dinucleotide phosphate diaphorase activity and the CGRP immunoreactivity in perivascular nerves innervating the middle cerebral artery of the ipsilateral side. The nicotine-induced relaxation in the middle cerebral artery from the ethanol-injected side was markedly inhibited compared with that from the nontreated side, whereas the relaxations induced by exogenously applied NO and CGRP were unaffected. We conclude that nicotine stimulates nicotinic receptors in nerve terminals and liberates NO or NO-like substance(s) and CGRP as neurotransmitters in cat middle cerebral arteries.

Nicotine produced a transient contraction followed by biphasic (rapid and slow) relaxations in dog superficial temporal arterial strips denuded of the endothelium. The responses to nicotine were abolished by treatment with hexamethonium. The nicotine-induced contraction was abolished by phentolamine and potentiated by NG-nitro-L-arginine (L-NA), a nitric oxide synthase inhibitor. The slowly developing relaxation was markedly suppressed by indomethacin and tranylcypromine, a prostaglandin I2 synthetase inhibitor, whereas the rapid relaxation was abolished by L-NA. The inhibitory effect of L-NA was reversed by L-, but not D-, arginine. NG-nitro-D-arginine had no effect. Transmural electrical stimulation elicited a transient relaxation in phentolamine-treated arteries. The relaxation was not influenced by indomethacin but was abolished by L-NA and tetrodotoxin. Nicotine increased intracellular cyclic AMP and cyclic GMP in the endothelium-denuded arteries. The increment of cyclic AMP was inhibited by indomethacin but not by L-NA, whereas that of cyclic GMP was not influenced by indomethacin but was abolished by L-NA. It may be concluded that nicotine stimulates the adrenergic and nitroxidergic nerves innervating the temporal arterial wall, resulting in a contraction and a rapidly developing relaxation, respectively; the latter is mediated by cyclic GMP. Potentiation by the nitric oxide synthase inhibitor of the contractile response to nicotine is expected to be a suppression of the relaxation mediated by the nerve-derived nitric oxide. Slow relaxations caused by nicotine appear to be associated with the elevation of cyclic AMP produced possibly by prostaglandin I2, which is released from subendothelial, non-neuronal tissues.

Effects of selective (nicardipine) and nonselective (Cd++) Ca++ channel antagonists on the responses of isolated dog cerebral arteries to vasodilator nerve stimulation, substance P, serotonin and prostaglandin F2 alpha were investigated; the relaxation caused by the nerve stimulation and the peptide is mediated by NO, possibly from the nerve and endothelium, respectively. Relaxant responses to nerve stimulation by electrical pulses and nicotine in the endothelium-denuded arteries were attenuated by Cd++, but not influenced by nicardipine; the concentrations of these antagonists were sufficient to suppress contractions caused by prostaglandin F2 alpha and serotonin to a similar extent. Increase in cyclic GMP by nicotine was also suppressed solely by Cd++. In the endothelium-intact arteries treated with indomethacin, relaxations induced by substance P were not affected by nicardipine, but were significantly attenuated by Cd++. The peptide-induced increase in cyclic GMP was suppressed by Cd++, but not by nicardipine. It is concluded that functional properties of the Ca++ channel responsible for increasing cytosolic Ca++ in the nerve and endothelium for the synthesis and release of nitric oxide or endothelium-derived relaxing factor differ from those of the channel in smooth muscle. Because Ca++ is a prerequisite for the synthesis of NO, smooth muscle does not appear to be the site of production of NO that transmits vasodilator information from the nerve or endothelium to cerebroarterial smooth muscle.

Dog duodenal longitudinal muscle strips precontracted with bradykinin responded to K+ (10 mM) with a transient relaxation, which was abolished by tetrodotoxin and oxyhemoglobin, but not influenced by atropine, ouabain and apamin. The induced relaxation was suppressed by treatment with 10(-5) M NG-nitro-L-arginine (L-NNA) a nitric oxide synthesis inhibitor, but not by the D-enantiomer. The inhibitory effect was antagonized by L- but not D-arginine. High concentrations (20 mM or higher) of K+ produced a relaxation followed by a sustained contraction; nicardipine abolished the contraction, but did not alter the relaxation. Nicotine produced a contraction, which was converted to a relaxation by atropine. The relaxant response was abolished by tetrodotoxin, hexamethonium and oxyhemoglobin, but was unaffected by timolol and phentolamine. L-NNA suppressed the relaxation, and L-arginine reversed the inhibition. The addition of K+ (20 mM) increased the content of cyclic GMP in the strips, the effect being prevented by tetrodotoxin and L-NNA. These findings suggest that K+ selectively stimulates the nonadrenergic inhibitory nerve, whereas nicotine stimulates both the excitatory cholinergic and inhibitory nerves. Nitric oxide released from the inhibitory nerve appears to transmit information to duodenal smooth muscle by increasing the production of cyclic GMP.

Transmural electrical stimulation and nicotine produced a relaxation of dog cerebral artery strips denuded of endothelium, which was abolished by tetrodotoxin and hexamethonium, respectively, and also suppressed by treatment with NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthesis inhibitor. The inhibition was reversed by L-arginine but not by the D-enantiomer. L-NA also suppressed the endothelium-dependent relaxation by substance P but not the response to NO and nitroglycerin. Treatment with high concentrations of nitroglycerin or sodium nitroprusside markedly inhibited the relaxant response to nicotine, substance P and NO but not the response to papaverine. Slight, slowly developing relaxations caused by L-arginine in the endothelium-denuded arteries were not potentiated by repeated applications of the amino acid or by exposure of the strips for 24 hr to the bathing medium. Ca++ ionophore-induced contractions in the denuded strips were not potentiated by L-NA. Nicotine significantly increased the level of cyclic GMP in the arteries without endothelium; the increment was abolished by treatment with L-NA and hexamethonium. NO does not seem to be synthesized in smooth muscle in an amount sufficient to produce significant relaxation. It may be concluded that NO liberated from vasodilator nerves activates guanylate cyclase in smooth muscle and produces cyclic GMP, resulting in cerebroarterial relaxation.

Isolated human gastroepiploic vein tributaries responded to dopamine only with contractions, whereas the gastroepiploic artery branches in the same region of the omentum responded with relaxations. Treatment with phentolamine converted the vein contraction to a relaxation, which was not influenced by propranolol but was abolished by droperidol. The relaxation was converted to a contraction by SCH23390 but unaffected by domperidone. Endothelium denudation abolished the relaxation caused by substance P but did not significantly alter the dopamine-induced relaxation. Dopamine increased the cyclic AMP content in the human veins. Monkey mesenteric, renal and portal veins and vena cava contracted in response to dopamine. Treatment with phentolamine converted the contraction to a slight relaxation in the mesenteric and renal veins; however, even in the presence of high concentrations of the alpha adrenoceptor antagonist, no relaxation was induced in the portal vein and vena cava partially contracted with prostaglandin F2 alpha. It is concluded that gastroepiploic veins and arteries in the human omentum respond quite differently to dopamine; the alpha adrenoceptor-mediated contraction predominates over the relaxation mediated via dopamine D1 receptor subtype in the veins, and vice versa in the arteries. Dopamine relaxes the human vein, possibly as a result of increased production of intracellular cyclic AMP by stimulation of D1 receptors. The predominant action of dopamine on alpha adrenoceptors may contribute to increasing venous return and cardiac output.

In dog renal artery strips with intact and damaged endothelium, relaxations induced by angiotensin II possibly mediated via the release of prostaglandin (PG) I2 were abolished or reversed to contractions by treatment with methylene blue and indomethacin. Relaxations elicited by arachidonic acid were also inhibited markedly. PGH2-induced contractions in the arteries with endothelium were potentiated, and relaxations caused by PGH2 in the endothelium-denuded arteries were suppressed by methylene blue, whereas these responses were not influenced by indomethacin. Relaxant responses to PGI2 and beraprost, a stable analog of PGI2, were not reduced by methylene blue. The amount of 6-keto PGF1 alpha in the bathing media released from the renal artery was decreased by treatment with methylene blue and indomethacin, whereas amounts of PGE2 and thromboxane B2 were not influenced by methylene blue but were reduced by indomethacin. It may be concluded that methylene blue interferes with the synthesis and release of PGI2 in the dog renal arteries; therefore, the relaxation mediated by endogenous PGI2 is suppressed. However, methylene blue does not appear to inhibit the synthesis of other cyclooxygenase products.

In isolated dog coronary arteries, serotonin (5-HT) produced a contraction, whereas 5-carboxamidotryptamine (5-CT), a serotonergic 5-HT1-like receptor agonist, mainly relaxed the arteries, and the contraction, if any, was slight. Human and Japanese monkey coronary artery strips responded to these amines only with contractions, the magnitude being markedly greater than that of serotonin-induced contractions in the dog arteries. Removal of endothelium slightly potentiated the serotonin-induced contraction and abolished the relaxation by 5-CT or reversed it to a contraction in the dog arteries; however, contractions elicited by serotonin and 5-CT in the human and monkey arteries were not influenced. Treatment with 10(-7) M 5-CT suppressed the contraction by serotonin in the dog arteries but did not alter the response of the monkey arteries. Relaxation of the dog arteries with endothelium caused by 5-CT and contraction of the arteries denuded of endothelium were not inhibited by ketanserin but they were by methysergide. 5-CT-induced contractions of human and monkey coronary arteries were attenuated by ketanserin and methysergide, although the inhibition was less with the 5-HT2 antagonist. Ketanserin inhibited the contraction by serotonin to a greater extent than the 5-CT-induced contraction in the monkey arteries. It may be concluded that 5-CT stimulates 5-HT1-like and 5-HT2 receptor subtypes in smooth muscle of human and monkey epicardial coronary arteries but acts exclusively on 5-HT1-like receptors in endothelium and smooth muscle of dog coronary arteries. Serotonin contracts the primate arteries, possibly by predominant activation of 5-HT2 over 5-HT1-like receptors.

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.

In monkey and dog cerebral artery strips, angiotensin (ANG) II (10(-7) M) produced a transient contraction, which was abolished or suppressed by treatment with indomethacin, aspirin, ONO3708, diphloretin phosphate, antagonists of prostaglandins (PGs) and OKY046, a thromboxane A2 synthesis inhibitor, and by endothelium denudation. On the other hand, PGF2 alpha-induced contractions were not influenced by indomethacin and aspirin, but were suppressed by treatment with ONO3708 and OKY046. Treatment with indomethacin or aspirin potentiated the contractile response of monkey mesenteric arteries, whereas treatment with ONO3708 and removal of endothelium did not alter the response significantly. Saralasin abolished the response to ANG II in these arteries. These findings may indicate that ANG II contracts monkey and dog cerebral arteries by activation of ANG II receptors mainly in endothelium, releasing arachidonic acid and synthesizing vasoconstrictor PGs, such as PGF2 alpha, E2, A2 and D2. Involvement of thromboxane A2 is if any minimal. Vasoconstrictor and dilator PGs released by ANG II appear to modify differently the contraction caused by direct actions of the octapeptide on smooth muscle in monkey cerebral and mesenteric arteries.

In helical strips of human and monkey cerebral arteries, norepinephrine produced a greater contraction than that in dog cerebral arteries. In monkey cerebral arteries, phenylephrine and norepinephrine produced a similar magnitude of maximum contractions, although the ED50 value of phenylephrine was approximately 5.6 times greater than that of norepinephrine. Clonidine (up to 10(-5) M) did not produce contractions. Dog cerebral arteries responded to phenylephrine in high concentrations with a greater contraction than that induced by norepinephrine and to clonidine with significant contractions. Contractions induced by norepinephrine of human and monkey cerebral arteries were attenuated by low concentrations of prazosin but were not influenced by yohimbine in concentrations up to 10(-8) M. In contrast, norepinephrine-induced contractions of dog cerebral arteries were attenuated by yohimbine but were unaffected by prazosin. It appears that norepinephrine-induced contractions are mediated by alpha-2 adrenoceptors in dog cerebral arteries and by alpha-1 receptors in human and monkey cerebral arteries as well as monkey and dog mesenteric arteries. The relative unresponsiveness of monkey and dog cerebral arteries to adrenergic nerve stimulation may not be explained by a paucity of alpha adrenoceptors in neuroeffector junction.

In helical strips of mesenteric arteries from 30-day (28-35 day), 3-month (80-110 day), 2-year (10-40 month) and 12-year (135-161 month)-old beagles, contractile responses to vasoconstrictors were compared. The responses to transmural stimulation and norepinephrine, relative to those caused by 30 mM K+, were greater in the infant beagle arteries than in those from the older beagles. Equipotent concentrations of the amine for producing the same magnitude of contraction as that evoked by 5 or 20 Hz stimulation in beagles of different ages did not differ. Treatment with 10(-9) M prazosin or 10(-8) M yohimbine attenuated the response to norepinephrine in 30-day and 12-year-old beagles to a similar extent. Contractions induced by transmural stimulation in the infant beagle arteries were potentiated slightly by 10(-9) M yohimbine and, in contrast, attenuated at 10(-8) M. On the other hand, the stimulation-evoked contraction in the senile beagle arteries was potentiated by these concentrations of yohimbine in a dose-dependent manner. Angiotensin II potentiated responses to electrical stimulation in 30-day and 12-year-old beagles to a similar extent. Contractions by angiotensin II and serotonin did not alter with age. It may be concluded that alpha adrenoceptor function reduces during an early postnatal period, but does not decline further through senescence. It appears that prejunctional, but not postjunctional, alpha-2 receptor function develops after birth, whereas pre- and postjunctional angiotensin receptors already mature in beagles until the age of 30 days.

Nicotine in concentrations ranging from 5 times 10- minus 6 to 10- minus 4 M caused a transient relaxation in strips of isolated canine basilar, middle cerebral and posterior cerebral arteries contracted with prostaglandin F2a (PGF). Transmural neural stimulation did not produce changes in the tension of these arteries. Tyramine contracted the arterial strips. Relaxation induced by nicotine was markedly attenuated by hexamethonium (10- minus 5 M), cocaine (10- minus 5M), bretylium (2 times 10- minus 5 M), sotalol (5 times 10- minus 5 M), propranolol (10- minus 6 M) and removal of Ca-++ from the bathing media. Relaxation was not significantly influenced by atropine, physostigmine, ouabain, tetrodotoxin, aminophylline and sotalol (10- minus 5 M). In cerebral arterial strips, the addition of K-+ also elicited a transient relaxation which was abolished by treatment with ouabain but not with other blocking agents. In mesenteric arterial strips, nicotine caused a transient contraction as did transmural stimulation. The nicotine-induced contraction was markedly attenuated or completely abolished by hexamethonium, cocaine, bretylium and phentolamine and also high concentration of sotalol (5 times 10- minus 5 M), and propranolol. Tetrodotoxin did not affect the contractile response to nicotine but did abolish the response to transmural stimulation. It is strongly suggested that relaxation induced by nicotine in cerebral arterial strips is the result of a specific action on nicotinic receptors as is the contraction observed in mesenteric arteries. It appears that beta adrenergic and cholinergic mechanisms do not play major roles in the genesis of nicotine-induced relaxation nor does it appear that an electrogenic Na-+ pump mechanism is involved.

Acetylcholine and substance P applied to the donor tissue, dog femoral artery segments with endothelium, produced moderate relaxations of the assay tissue, endothelium-denuded dog coronary artery strips. The relaxation was attenuated markedly by treatment of the assay tissue with hydroquinone and abolished by oxyhemoglobin or methylene blue. In this bioassay system, the effect of AA861 and TMK777, new 5-lipoxygenase inhibitors, was evaluated. When the donor tissue was treated with AA861 or TMK777, the responses to acetylcholine and substance P were attenuated moderately, whereas the relaxation by nitroglycerin was not influenced by AA861. However, the inhibitors when infused just below the donor tissue did not attenuate relaxant responses to acetylcholine and substance P. Application of superoxide dismutase (SOD) to the donor tissue caused a relaxation of the assay tissue, and potentiated the relaxation by acetylcholine and substance P. AA861 and TMK777 suppressed the relaxant responses to acetylcholine and substance P, respectively, in the presence and absence of SOD to a similar extent and abolished the SOD-induced relaxation. Pyrogallol abolished the relaxation by acetylcholine, but did not inhibit the response when the donor tissue was pretreated with SOD. Therefore, it appears that AA861 and TMK777 do not degrade endothelium-derived relaxing factor (EDRF) in the perfusate via generation of superoxide anion or block the action of EDRF on vascular smooth muscle, but interfere with the synthesis and/or release of EDRF. The findings obtained so far support the idea that lipoxygenase products participate in the generation of EDRF.

The addition of prostaglandin (PG) H2 produced a transient contraction followed by a relaxation in helical strips of dog cerebral arteries partially contracted with PGF2 alpha or K+. The contraction was abolished by removal of endothelium, and the relaxation was potentiated. Relaxation induced by PGI2 was not influenced by endothelium denudation. The PGH2-induced contraction in strips with intact endothelium was not influenced by OKY-046, a thromboxane A2 synthesis inhibitor, but was abolished by treatment with ONO3708, an antagonist of vasoconstrictor PGs, whereas the relaxation was inhibited by tranylcypromine or diphloretin phosphate, a nonselective PG antagonist. Contraction induced by arachidonic acid (AA) was reversed to relaxation by removal of endothelium or treatment with ONO3708. Treatment with indomethacin attenuated the AA-induced contraction in the intact strips and also the relaxation in the strips treated with ONO3708 or denuded of endothelium. It may be concluded that vasoconstrictor PGs are synthesized from PGH2 or AA mainly in endothelium, and the production of PGI2 from PGH2 is not dependent on endothelium. Thromboxane A2 in concentrations sufficient to elicit significant contractions does not appear to be liberated from the cerebroarterial wall stimulated by PGH2.

In helical strips of dog mesenteric and gastroepiploic arteries contracted with prostaglandin (PG) F2 alpha, the addition of histamine (10(-6) M) caused a relaxation, which was markedly attenuated by treatment with aspirin, indomethacin or tranylcypromine. Treatment with chlorpheniramine prevented the inhibitory effect of aspirin or tranylcypromine. Combined treatment with chlorpheniramine plus aspirin or tranylcypromine slowed the development of histamine-induced relaxations as did the treatment with chlorpheniramine alone. Relaxations of mesenteric and gastroepiploic arteries induced by histamine were markedly attenuated or abolished by combined treatment with chlorpheniramine and cimetidine. Histamine-induced relaxations of coronary and renal arterial strips were suppressed by cimetidine alone but were unaffected by aspirin. Contractile responses of cerebral arterial strips to histamine were attenuated by chlorpheniramine and potentiated by aspirin. The collagen-induced platelet aggregation was inhibited by treatment with bathing media in which mesenteric arteries were stimulated by histamine; the inhibition was prevented by treatment of the arteries with aspirin. It may be concluded that relaxation of mesenteric and gastroepiploic arteries induced by histamine is mainly associated with the release of prostaglandin I2 from the arterial wall, which results from an activation of histaminergic H1 receptors. Histamine-induced cerebroarterial contractions mediated via H1 receptors appear to be partly counteracted by prostaglandin I2 released.

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 helically cut strips of dog and human cerebral arteries, the addition of 5-hydroxykynurenamine (5-HK) caused dose-related contractions, and this contractile response was attenuated by methysergide and lysergic acid diethylamide (LSD). Treatment of the strips with 5-HK in concentrations higher than 2 X 10- minus 6 M shifted the dose-response curve of serotonin to the right and downward. The inhibitory effect of 5-HK was reversed only partially by repeated washings, whereas the inhibition caused by methysergide and LSD was completely reversed. The contractile response to K-+ (30 mM) was reduced only slightly even at the highest concentration of 5-HK used (5 X 10-minus 5 M). In strips of rabbit aortas, the contractile effect of serotonin was markedly attenuated by 5-HK, whereas that of norepinephrine was reduced only slightly. In isolated rabbit right atria, 5-HK produced a transient increase in the rate as did serotonin, 5-HK being approximately 1/20 as potent as serotonin. The positive effect was not influenced by methysergide but was markedly attenuated or abolished by 10-minus 6 M propranolol and 3 X 10-minus 6 M cocaine. Treatment with 5-HK (5 X 10-minus 5 M) did not modify the chronotropic response to isoproterenol. It appears that 5-HK produces vascular contractions via serotonergic receptors, inhibits specifically the contractile response of arteries and aortas to serotonin and causes a tachycardia in rabbit atria by liberating catecholamines from adrenergic nerves.

In tracheal muscle strips isolated from rabbits of different ages (3-360 days), median effective concentrations of acetylcholine and K+ increased with age. Nicotine (10(-4) M)-induced contractions decreased with increasing age. Concentrations of acetylcholine sufficient to elicit the same contraction as that induced by nicotine also decreased with age. The contractile response to histamine was reduced with age. Tracheas from mature rabbits, contracted with acetylcholine, relaxed in response to histamine in a dose-dependent manner. The histamine-induced contractions were suppressed by cholorpheniramine, while the relaxations were attenuated by cimetidine. The relaxing response to isoproterenol of tracheal strips contracted with acetylcholine was related inversely to age, whereas the response to prostaglandin E1 was increased at day 360. It may be concluded that the amount of acetylcholine released from cholinergic nerves by nicotine decreases with age and that excitatory processes related to H1-receptor stimulation in the tracheal smooth muscle decrease with age, whereas inhibitory processes related to H2-receptor stimulation are enhanced. The beta adrenoceptor mechanism apparently deteriorates with age.

Transmural electrical stimulation (2-20 Hz) produced a frequency-dependent contraction in dog mesenteric, monkey mesenteric and human gastroepiploic arterial strips, which was abolished by tetrodotoxin and suppressed by phentolamine. Treatment with yohimbine (10(-9) and 10(-8) M) potentiated the response to nerve stimulation dose-dependently in the dog arteries, but rather attenuated the response of the primate arteries. Yohimbine (10(-8) M) attenuated the contraction caused by exogenous norepinephrine in the dog and monkey arteries. Angiotensin (ANG) II (2 X 10(-10) M) and ANG I (10(-9) M) potentiated the response to transmural stimulation in the dog and monkey arteries, whereas the response to norepinephrine was unaffected. The ANG I-induced potentiation was suppressed by treatment with ANG converting enzyme inhibitors. 3H-Overflow evoked by transmural stimulation in tissues prelabeled with [3H] norepinephrine was increased by yohimbine in the superfused dog arteries but was not increased significantly in the monkey arteries. The overflow was increased significantly by ANG II in the dog and monkey arteries. It may be concluded that prejunctional alpha-2 adrenoceptors mediating the inhibition of transmitter release do not function significantly in human gastroepiploic and monkey mesenteric arteries, and postjunctional alpha-2 receptors are involved partly in contractions of the monkey arteries due to adrenergic nerve stimulation. ANG II appears to be synthesized from ANG I via ANG converting enzyme in the primate arteries; the octapeptide potentiates the contraction caused by adrenergic nerve stimulation, possibly due to prejunctional ANG receptor activation and increased norepinephrine release.

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.

Responses to vasoactive agents were compared in helical strips of basilar arteries isolated from rabbits, 15 to 360 days of age, which were stretched under optimal resting forces. Contractions induced by serotonin, histamine, norepinephrine, angiotensin II and K+ increased with increasing age. However, the maximum forces developed by these drugs relative to those by 50 mM K+ as well as ED50 values of these drugs were not significantly different in the arteries from mature and immature rabbits; only the response to serotinin at day 360 was significantly less. Basilar arteries contracted with histamine relaxed in response to isoproterenol; the relaxing effect was suppressed by treatment with 10-6 M propranolol and was inversely related to age. On the other hand, relaxations induced by adenosine and prostaglandin E1 did not significantly differ in the arteries from rabbits of different ages. Relaxations induced by small amounts of K+ (0.5-10 mM) increased with age; the relaxations were suppressed by ouabain. It may be concluded that the cerebroarterial relaxation related specifically to the beta adrenergic mechanism is reduced with increasing age. The electrogenic Na+ pump mechanism appears to mature in rabbit basilar arteries during an early postnatal period.