Acetylcholine applied extraluminally to isolated, perfused dog mesenteric artery segments produced an endothelium-dependent depressor response when the perfusion pressure was raised by continuous infusion of noradrenaline; the potency was 1/30 to 1/60 that of intraluminal acetylcholine. Contractions induced by transmural electrical stimulation were attenuated by treatment with intra- and extraluminal acetylcholine; the inhibitory effect of intraluminal acetylcholine was greater than that of extraluminal acetylcholine. Removal of endothelium did not significantly alter the inhibitory effect. In mesenteric artery strips with endothelium, treatment with oxyhaemoglobin suppressed the relaxant response to acetylcholine but did not influence the inhibitory effect of acetylcholine on stimulation-evoked contractions. Acetylcholine reduced the 3H-overflow and contraction of superfused mesenteric artery strips, preloaded with 3H-noradrenaline, response to transmural stimulation. By the use of bioassay (dog femoral artery segment with endothelium/coronary artery strip without endothelium), the release of EDRF was first determined in the perfusate, which was introduced to dog mesenteric artery strips loaded with 3H-noradrenaline. The 3H-overflow and contraction caused by the stimulation were not attenuated by EDRF and were also observed following treatment with superoxide dismutase. Inability of the perfusate to reduce the stimulation-evoked 3H-overflow was also observed when the donor and assay tissues were treated with superoxide dismutase. It may be concluded that the inhibition by acetylcholine of the release of neuronal noradrenaline is not dependent on endothelium. Extraluminally applied acetylcholine would reach the endothelium and release EDRF, and intraluminal acetylcholine is presumed to act directly on prejunctional muscarinic receptors; however, acetylcholine appears to cross the medial layer more efficiently from intima to adventitia than in the reverse direction.

Acetylcholine↗

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Cerebral vasoconstrictor mediators.

Endogenous cerebral vasoconstrictor mediators regulate vascular resistance and blood flow in the brain as a whole and in various regions and participate in the pathogenesis of cerebral circulatory disturbances. Vasoconstrictors are effective in the treatment of diseases associated with cerebral vasodilatation. There are variations in the response of cerebral arteries from primate and subprimate mammals; therefore, information as to similarities and differences in their response is quite important in evaluating the physiological role, involvement in pathogenesis and therapeutic usefulness of the mediators in healthy men and patients. In this review we described characteristics of the action of vasoconstrictors (amines, peptides, prostanoids, and others) on isolated cerebral arteries from mammals, including humans and monkeys.

Animals↗

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Regulation of blood pressure by nitroxidergic nerve.

We discovered vasodilator innervation first in canine cerebral arteries, in which nitric oxide (NO) acts as a neurotransmitter; thus, the nerve is called nitroxidergic. Then, reciprocal innervation of noradrenergic and nitroxidergic nerves in canine peripheral arteries was determined; adrenergic nerve-mediated vasoconstriction is predominant over vasodilatation mediated by NO derived from the nerve. In anesthetized dogs, hypertension induced by NO synthase inhibitors is suppressed by hexamethonium. It is hypothesized that impairment of nitroxidergic nerve function by NO synthase inhibition is mainly involved in the genesis of hypertension.

Adrenergic alpha-Antagonists↗

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Influence of disopyramide, compared with procainamide and quinidine, on isolated dog arteries in response to transmural stimulation and norepinephrine.

In helically cut strips of dog cerebral, coronary, and mesenteric arteries contracted with prostaglandin (PG) F2 alpha, disopyramide phosphate produced moderate contractions that were unaffected by phentolamine, chlorpheniramine, cinanserin, or aspirin. Procainamide and quinidine elicited only a slight contraction. Mesenteric arterial strips contracted with norepinephrine slightly contracted in response to disopyramide but significantly relaxed with procainamide and quinidine. The contractile response of mesenteric arterial strips to transmural electrical stimulation was attenuated by high concentrations (5 x 10(-5) M) of disopyramide or procainamide and by low concentrations of quinidine. Disopyramide-induced attenuation was greater in the response to high-frequency stimulation. Disopyramide at high concentrations potentiated the contractile response of mesenteric arteries to norepinephrine and tyramine, while, in contrast, procainamide and quinidine shifted the dose-response curve for norepinephrine to the right. Treatment with procainamide and quinidine, but not with disopyramide, protected alpha-adrenoceptors from persistent blockade by phenoxybenzamine; quinidine was far more effective than procainamide. It may be concluded that disopyramide possesses a nonspecific vasoconstricting action but not an alpha-adrenoceptor blocking property, whereas quinidine and procainamide show a reversible, competitive alpha-adrenoceptor antagonism. Different hemodynamic actions of these antiarrhythmics in situ appear to be related to such contrasting effects on arterial smooth muscle.

Animals↗

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Effects of dobutamine on isolated canine cerebral, coronary, mesenteric, and renal arteries.

The effects of dobutamine on helical strips of isolated canine cerebral, coronary, mesenteric, and renal arteries was investigated. Dobutamine contracted only renal arterial strips under resting condition. When renal and mesenteric arterial strips were partially contracted with prostaglandin F2 alpha (PGF2 alpha), dobutamine caused further concentration-related contraction, while coronary arterial strips were relaxed. Cerebral arterial strips, on the other hand, did not significantly respond to dobutamine. After treatment with 10(-5) M dl-phenoxybenzamine hydrochloride (POB) for 1 h, dobutamine-induced contractions of partially precontracted mesenteric and renal arterial strips were converted to relaxations. Relaxations of coronary arteries were not potentiated by the alpha-antagonist, but were attenuated by treatment with 10(-6) M propranolol and 10(-6) M metoprolol to a similar extent. On the other hand, relaxations of mesenteric and renal arterial strips were not inhibited by metoprolol but by propranolol. Droperidol (3 X 10(-5) M) failed to significantly alter the concentration-response curve for dobutamine. These results suggest that dobutamine causes vasoconstriction mediated by apha-adrenergic receptor and vasodilatation mediated by beta 1- and beta 2-adrenoceptors. Dobutamine does not appear to act on dopamine receptors.

Animals↗

PubMedDate not supplied

Potentiation by ouabain of the response to vasoconstrictor agents of isolated dog cerebral and mesenteric arteries soaked in Ca2+-free media.

In helical strips of dog cerebral arteries soaked in Ca2+-free media and treated with prostaglandin (PG) F2 alpha or K+, the addition of Ca2+ produced a transient contraction, transient relaxation, and slowly developing, persistent contraction. Treatment with 2 X 10(-7) M ouabain did not alter the contractile response to PGF2 alpha in Ca2+-free media, but potentiated the response to Ca2+. Relaxations following the transient contractions were abolished by ouabain. On the other hand, ouabain potentiated the contractile response to serotonin in Ca2+-free media, and also the response to Ca2+. In mesenteric arterial strips soaked in Ca2+-free media, ouabain at 2 X 10(-7) M insufficient to produce contractions increased the contractile response to Ca2+, and the increase in the concentration to 2 X 10(-5) M potentiated the response to PGF2 alpha and serotonin. It may be concluded that ouabain increases the influx of Ca2+ across cell membrane caused by vasoconstrictors and enhances the drug-induced release of Ca2+ from intracellular storage sites.

Animals↗

PubMedDate not supplied

Vasodilatation induced by pinacidil in dogs. Comparison with hydralazine and nifedipine.

In helical strips of dog arteries precontracted with prostaglandin (PG) F2 alpha, pinacidil and nifedipine produced a dose-related relaxation. The potencies of pinacidil were in the order of coronary and renal greater than mesenteric greater than basilar and middle cerebral arteries, whereas those of nifedipine were in the order of basilar and renal greater than mesenteric and coronary arteries. Pinacidil caused a greater relaxation in mesenteric veins than in the arteries. Hydralazine consistently relaxed the arteries only at 10(-3) M. In mesenteric artery strips exposed to Ca2+-free, high K+ media, contractions induced by Ca2+ were reduced by 10(-8) M nifedipine, but they were not influenced by 10(-5) M pinacidil or by 10(-4) M hydralazine. In the arteries exposed to Ca2+-free media and stimulated by PGF2 alpha or norepinephrine, tonic contractions induced by Ca2+ were reduced moderately by 10(-5) M pinacidil but only slightly by 10(-8) M nifedipine. In Ca2+-free media, PGF2 alpha-induced contractions were inhibited only by pinacidil. In isolated mesenteric vasculature, perfusion pressure was lowered by pinacidil and hydralazine. It may be concluded that pinacidil produces vasodilatation due to interference with the transmembrane influx of Ca2+ into smooth muscle evoked by receptor stimulation but not that due to inhibition in the Ca2+ influx associated with K+-induced membrane depolarization. Decreased release of Ca2+ from intracellularly stored sites or increased sequestration to the sites may also be involved. Pinacidil appears to dilate arteries and veins as well as resistance vessels, whereas hydralazine appears to act exclusively on resistance vessels.

Animals↗