Biomedical subjects
Publications and source records attributed to N Toda.
Effects of indapamide, trichlormethiazide and hydralazine on isolated, perfused dog mesenteric vasculature and helical strips of the dog mesenteric artery were compared. It appears that indapamide-induced hypotension is associated with a direct relaxant action on arterial and arteriolar smooth muscle, whereas hydralazine acts exclusively on resistance vessels.
It is becoming obvious that the reactivity of vascular smooth muscle to vasoactive agents is not homogeneous in different arteries (cerebral vs. other arteries) from the same animal species or in cerebral arteries from different species. In this communication, the reactivity of human cerebral arteries to norepinephrine (NE), dopamine (DA), small amounts of K+ and ouabain and their mechanisms of action are compared with those in monkey and dog cerebral arteries. NE produces moderate contractions in the primate arteries, mediated by alpha 1 adrenoceptors, and slight contractions in the dog arteries, possibly mediated by alpha 2 receptors. DA relaxes human and monkey cerebral arteries but contracts the dog arteries. The primate artery relaxation mediated by dopaminergic receptors is large enough to predominate over the alpha 1 receptor-mediated contraction. Minute amounts of K+ preferentially relax cerebral arteries from humans, monkeys, and dogs, possibly activating the electrogenic Na+ pump. Ouabain, a Na+ pump inhibitor, contracts these cerebral arteries with low concentrations. Human and monkey cerebral arteries respond similarly to vasoactive agents presented so far, and appear to share the same mechanisms of action; however, the responsiveness of dog cerebral arteries differs.
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.
In control dogs and those made hypertensive for 1 and 8 months by partially occluding a renal artery, contractile responses of mesenteric artery strips to adrenergic nerve stimulation and to norepinephrine, plasma renin activity and vascular angiotensin converting enzyme (ACE) activity were compared. Contractile responses to norepinephrine were potentiated in the artery strips from 8-month-hypertensive dogs; however, the response to electrical stimulation of adrenergic nerves was not influenced. Contractions induced by the nerve stimulation were potentiated by a low concentration (2 X 10(-10) mol/l) of angiotensin (ANG) II; the potentiating effect was enhanced in 8-month-hypertensive dog arteries. 3H-overflow evoked by adrenergic nerve stimulation was increased by ANG II to a greater extent in superfused mesenteric artery strips obtained from hypertensive (8-month) dogs, previously soaked in 3H-norepinephrine. Angiotensin converting enzyme activity was markedly greater in 8-month-hypertensive dog mesenteric arteries than in normotensive dog arteries. It may be concluded that the hypertension is maintained by increased sensitivity of post-synaptic alpha 1-adrenoceptors and pre-synaptic ANG receptors and increased vascular ACE activity, possibly promoting the production of ANG II in the vascular wall.
Angiotensin (ANG) II produced a slight, transient contraction followed by a moderate relaxation in dog renal artery strips precontracted with prostaglandin (PG) F2 alpha. Treatment with acetylsalicylic acid indomethacin, ibuprofen and sodium meclofenamate reduced the relaxant response to ANG II or reversed the relaxation to a contraction, but did not significantly alter the relaxant response to PGI2. The inhibitory potencies were in the order of meclofenamate greater than indomethacin greater than ibuprofen greater than acetylsalicylic acid. Sodium salicylate and gentisic acid, metabolites of acetylsalicylic acid, in concentrations up to 5 X 10(-4)M did not influence the ANG II-induced relaxation. Treatment with salicylate (5 X 10(-4)M) prevented the inhibitory effect of acetylsalicylic acid, indomethacin or meclofenamate, whereas combined treatment with salicylate and ibuprofen elicited an inhibition of ANG II-induced relaxations to a similar extent to that seen in preparations treated with ibuprofen alone. It appears that acetylsalicylic acid, indomethacin and meclofenamate share the same mechanism for inhibiting the cyclooxygenase activity, but the mechanism of inhibitory action of ibuprofen differs.
Responses to vasoconstrictor agents were compared in helical strips of proximal and distal middle cerebral arteries isolated from the same dogs. Contractions induced by 30 mM K+ per cross-sectional areas in the large and small artery strips did not differ significantly so that contractions induced by the agents could be compared relative to those induced by K+. The contractions induced by serotonin were greater in the proximal than in the distal arteries. Histamine produced a greater contraction in the proximal arteries under resting conditions. Distal arteries partially precontracted with prostaglandin F2 alpha responded to histamine with relaxations. The histamine-induced contraction was attenuated by chlorpheniramine, whereas the relaxation was suppressed by cimetidine. Prostaglandin F2 alpha or carbocyclic thromboxane A2 produced similar magnitudes of contractions in the proximal and distal arteries. Thrombin contracted the distal arteries to a greater extent. Contractions induced by norepinephrine or bradykinin did not differ in the proximal and distal arteries. It may be concluded that the ratio of histaminergic H1 and H2 receptor functions decreases peripherally along middle cerebral arteries, whereas the contractile response to bradykinin was not influenced in these arteries of a relatively short distance. The functions of receptor sites for serotonin and thrombin appear to be quite different in large and small cerebral arteries of such a short distance, but alpha-adrenoceptor functions seem to be identical.
Some functions of pre- and postsynaptic alpha-receptors were compared in isolated dog arteries. In mesenteric and renal arteries, contractile responses to transmural electrical stimulation were potentiated by yohimbine, a selective alpha 2-antagonist; the potentiation was greater in mesenteric arteries. Concentration-response curves for norepinephrine were shifted to the right by high concentrations of yohimbine. Prazosin, a selective alpha 1-antagonist, in low concentrations preferentially attenuated the contractile response to transmural stimulation, when compared with the response to equiactive concentrations of norepinephrine. Relaxant responses of coronary arteries to transmural stimulation were also potentiated by yohimbine. Relaxations induced by norepinephrine were not influenced by yohimbine but were potentiated by prazosin. Contractile responses of coronary arteries treated with propranolol to transmural stimulation were abolished by prazosin. It is concluded that the involvement of presynaptic alpha 2-receptors in the negative feedback mechanism in transmitter release differs in a variety of dog arteries and that the adrenoceptors subserving contraction are of both subtypes (alpha 1 and alpha 2) in the mesenteric and renal arteries, but only of the alpha 1 subtype in coronary artery.
Treatment with prostaglandin (PG) D2 in concentrations (10(-8) to 10(-7) M) insufficient to alter the basal tone potentiated the contractile response of helical strips of dog mesenteric arteries to transmural electrical stimulation but did not influence the response to norepinephrine. The potentiating effect of PGD2 was not prevented by treatment with diphloretin phosphate, a PG antagonist, whereas contractions of dog cerebral arteries induced by PGD2 were suppressed. The 3H-overflow evoked by transmural stimulation in superfused mesenteric arterial strips previously soaked in 3H-norepinephrine containing media was significantly increased in PGD2. It is concluded that PGD2 increases the stimulation-evoked release of norepinephrine from adrenergic nerves innervating the arterial wall. PGD2 appears to act differently on receptive sites responsible for increasing the release of norepinephrine and for producing arterial contraction.
Angiotensin-converting enzyme (ACE) activity in blood vessels of different species was determined. ACE was solubilized by Nonidet P-40, and assayed by reversible phase high performance liquid chromatography. Approximately 98% ACE was recovered in the liquid phase by the use of the detergent. The ACE activity varied with chloride ion (Cl-) concentrations; the maximum activities in dog, human, monkey and rabbit tissues were obtained at the concentrations of 800, 600, 600 and 300 mmol/l respectively. The optimal Cl- concentration was quite similar in different tissues and plasma obtained from the same species. The ACE activity in the cerebral, mesenteric, pulmonary and renal arteries was in a range between 1.01 and 1.60 m-units/mg of protein in dogs and between 0.43 and 0.94 m-unit/mg of protein in monkeys. The activity in dog aortae was 0.20 +/- 0.02 m-unit/mg of protein, and the activity in aortic endothelial cells was 2.61 +/- 0.65 m-units/mg of protein. ACE activities in the dog lung, kidney cortex and cerebral cortex were 28.6 +/- 2.6, 15.7 +/- 3.0 and 3.5 +/- 0.6 m-units/mg of protein respectively. SA-446, a captopril-like ACE inhibitor, reduced the ACE activity in arteries in a dose-dependent manner. Vascular ACE appears to be concentrated in the endothelium and may contribute to regulate vascular muscle tone and local blood flow by a conversion of angiotensin I into II.
Helically-cut strips of dog cerebral, coronary, mesenteric, renal and femoral arteries contracted with prostaglandin (PG) F2 alpha or K+ responded to amrinone (10(-5) to 10(-4) mol X litre-1) with relaxation, which was not influenced by treatment with propranolol, atropine, cimetidine, aminophylline or aspirin. The contractile response of mesenteric arteries to transmural electrical stimulation (2, 5 and 20 Hz) and noradrenaline was attenuated by amrinone (3 X 10(-5) and 10(-4) mol X litre-1); the attenuation of the response to nerve stimulation and noradrenaline did not significantly differ. Ca2+-induced contractions in mesenteric arteries exposed to Ca2+-free media and depolarised by excess K+ were inhibited by amrinone, and the inhibition could not be reversed by the addition of excess Ca2+. Treatment with amrinone potentiated the relaxant responses of mesenteric arteries to adenosine but did not alter the response to isoprenaline. Amrinone in concentrations sufficient to produce moderate and marked relaxation did not significantly alter the content of cyclic AMP in mesenteric arteries. Attenuation by amrinone of the contractile response to transmural stimulation, noradrenaline and Ca2+ and the relaxation of a variety of arteries induced by amrinone may not be due to interference with the transmembrane influx of Ca2+ and intracellular accumulation of cyclic AMP but to a nonspecific action on arterial smooth muscle. Amrinone appears to increase the metabolic vasodilatation by potentiating the vasodilator action of adenosine.
In helical strips of dog renal and mesenteric arteries pre-contracted with prostaglandin F2 alpha (PGF2 alpha), endothelium-dependent relaxations were investigated. Removal of the endothelium was shown histologically by staining with silver nitrate and functionally by testing the inability of acetylcholine to induce arterial relaxations. When the endothelium was removed, relaxation of renal arteries to angiotensin (Ang) II was markedly suppressed, whereas relaxations induced by PGI2 or isoprenaline were attenuated only slightly. Removal of the endothelium attenuated the relaxant response of mesenteric arteries to histamine but did not significantly alter the response to PGI2. Treatment with indomethacin caused an additional attenuation of the relaxant response to histamine or a reversal of the Ang II-induced relaxation to a contraction in the arterial strips, from which the endothelium had been removed. Relaxation of renal arteries induced by Ang II and of mesenteric arteries induced by histamine is postulated to result from PGI2 released from the arterial wall. Therefore, it appears that the endothelium is a major site but not the only site responsible for drug-induced release of PGI2.
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.
Carbocyclic thromboxane A2 (cTxA2), a stable analogue of TxA2, and prostaglandin (PG) F2 alpha contracted helical strips of human, monkey and dog coronary arteries in a concentration-dependent manner. Apparent ED50 values for cTxA2 were markedly less (1/58 in humans, 1/373 in monkeys and 1/397 in dogs) than those for PGF2 alpha; maximum contractions induced by cTxA2 and PGF2 alpha relative to those induced by 30 mM K+ were approximately identical in the human and monkey arteries. PGI2 caused a concentration-related relaxation in human and dog coronary arteries maximally precontracted with cTxA2 and in human, monkey and dog coronary arteries partially precontracted with PGF2 alpha. The relaxation response was greatest in the dog arteries and least in the monkey arteries. Contractions induced by cTxA2 or PGF2 alpha and relaxations induced by PGI2 were selectively antagonized by treatment with diphloretin phosphate. Human coronary artery strips contracted with cTxA2 responded to nitroglycerine with a rapid, transient relaxation and to verapamil with a slowly-developing, persistent relaxation, as did monkey and dog coronary artery strips. Thromboxane (Tx) A2 appears to be one of the most potent endogenous vasoconstrictors in human coronary arteries, if cTxA2 acts on TxA2 receptors. It is suggested that PGI2, nitroglycerine and verapamil are effective vasodilators in human conduit coronary arteries maximally contracted with cTxA2, although the extent and the duration of vasodilatation induced by these agents were quite different.
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An inhibitor of angiotensin I (ANG I) converting enzyme, SA446, reduced the response to ANG I of blood vessels isolated from dogs and monkeys, but did not abolish the response even at high concentrations. The residual action of ANG I in the presence of high concentrations of SA446 could be abolished by (Sar1, Ala8)-ANG II. Vascular strips and crude extracts of vessels and lungs possessed the enzymic activity generating ANG II from ANG I, or hippuric acid from hippuryl-histidyl-leucine (HHL). The HHL-hydrolysing activity of the crude extracts was completely inhibited by SA446 (10(-7) mol/l) and/or Na2-EDTA (10(-3) mol/l). However, the octapeptide generation was not abolished despite the combined treatment with SA446 (5 X 10(-4) mol/l) and Na2-EDTA (5 x 10(-3) mol/l). The residual activity forming ANG II was inhibited by chymostatin and soybean trypsin inhibitor, which however did not affect the HHL-hydrolysis. Combined treatment with SA446 (10(-5) mol/l) and chymostatin (2.5 X 10(-5) mol/l) abolished the vascular action of ANG I but did not alter the action of ANG II. These results strongly suggest that besides the ANG I converting enzyme, another enzyme which generates ANG II is present in vascular tissues and lungs, and may play an important role in the local generation of ANG II, which possibly regulates the regional vascular tone.
In helically cut strips of dog cerebral, mesenteric, and femoral arteries contracted with prostaglandin(PG)F2 alpha, trimethaphan (10(-5)-10(-3)M) caused a dose-related relaxation that was not influenced by atropine, propranolol, diphenhydramine, cimetidine, aminophylline, or indomethacin. Trimethaphan-induced relaxation was greater in extracerebral than in cerebral arteries. The relaxation was greater in phenylephrine-contracted arteries than in PGF2 alpha-contracted arteries. On the other hand, hexamethonium did not relax the arteries. Trimethaphan (10(-4)-10(-3)M) shifted the dose-response curve for norepinephrine in mesenteric arteries to the right, but failed to influence the contractile response to 25 mM KCl. Treatment with trimethaphan (10(-4)-10(-3)M) protected alpha-adrenergic receptors from persistent blockade by phenoxybenzamine. Trimethaphan (10(-7)-3 X 10(-6)M) and hexamethonium (3 X 10(-8)-10(-6)M) significantly attenuated the contractile response of mesenteric arteries to nicotine in a dose-dependent manner, but did not alter the response to transmural electrical stimulation. The antinicotinic potency of trimethaphan was approximately one-fourth that of hexamethonium. It is concluded that, unlike hexamethonium, trimethaphan acts directly on vascular smooth muscle to induce vasodilation, more prominently in extracerebral arteries than in cerebral arteries. In high concentrations, trimethaphan appears to possess an alpha-adrenergic blocking action.
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Referring to the experimental study on acute spinal cord injury, it is known that gray matter falls into an ischemia after injury, but opinions have not been unanimous whether or not the white matter falls into ischemia or hyperemia. The blood flow through the white matter varies according to the severity of the injury and degree of resultant paraplegia. Using rabbits, the authors carried out a series of experimental acute spinal cord impaction injury giving impactions at different strength stepwise, i.e., 400, 300, 200 and 100 gcf (g X cm X force) respectively at the 9th thoracic level of the spinal cord. Thus, upon observation of the paralysed levels and measurement of variable spinal cord blood flows according to the hydrogen clearance method, it was concluded as follows: In the 400 and 300 gcf impaction groups a complete paraplegia was observed with a decrease of spinal cord blood flow both in the gray and white matters. In the 200 gcf group mainly incomplete paraplegia was occurred, and while gray matter showed ischemia, white matter showed indefinite response consisting of both ischemia and hyperemia. In the 100 gcf impaction group the gray matter fell into ischemia, but white matter showed a biphasic increase of blood flow. From the above results it was noted that upon impaction causing complete paraplegia spinal white matter shows ischemia and upon impaction giving transient paraplegia blood flow increases. Ischemia thus does not appear to be a common behavior of spinal cord blood flow spinal cord injury.