Mechanisms of action of eperisone on isolated dog saphenous arteries and veins.

Effects of eperisone, an antispasmodic in skeletal muscle, were investigated in helical strips of dog saphenous artery and vein. Eperisone relaxed saphenous arteries and veins previously contracted with norepinephrine, serotonin, acetylcholine, K+, or Ba2+; but in contrast, it produced contractions in the blood vessels contracted with prostaglandin (PG) F2 alpha. Treatment with eperisone attenuated the contractions induced by norepinephrine and serotonin in the arteries and those by clonidine and phenylephrine in the veins.

The contractile responses of isolated dog cerebral and extracerebral arteries to oxybarbiturates and thiobarbiturates.

In helical strips of dog cerebral, coronary, mesenteric, renal, and femoral arteries, the addition of thiamylal and thiopental, 10(-5) to 10(-3) M, caused a dose-related contraction; the contraction was significantly more intense in cerebral than in extracerebral arteries. Secobarbital caused a slight contraction only in the cerebral artery. In contrast, pentobarbital did not produce a contraction in any artery studied.

Mechanisms underlying response to hypercapnia and bicarbonate of isolated dog cerebral arteries.

In helical strips of dog cerebral arteries contracted with K+ or prostaglandin F2 alpha, the increase in CO2 from 5 to 15% in the gas aerating the bathing media produced a persistent relaxation in association with a rise of PCO2 and a fall of pH and PO2. Elevation of the NaHCO3 concentration from 25 to 75 mM in the bathing media under hypercapnia almost reversed the arterial tone when the osmolarity was balanced; the pH was completely reversed, whereas PCO2 was maintained at the high level. When 50 mM NaHCO3 were applied to the hypercapnic media without having the osmolarity balanced, the arteries relaxed further.

Extraluminally applied acetylcholine and substance P on the release of EDRF.

Acetylcholine, substance P and nitroglycerin applied intra- and extraluminally to the perfused dog femoral artery segment with endothelium caused depressor responses. Endothelium denudation abolished the responses to acetylcholine and substance P. EC50 ratios of extra- versus intraluminal acetylcholine and substance P were 43 and 79, respectively, whereas those of nitroglycerin did not differ.

Prolonged exposure to oxyhemoglobin modifies the response of isolated dog middle cerebral arteries to vasoactive substances.

We exposed helical strips of dog middle cerebral arteries to oxyhemoglobin for 5 hours, rinsed them with bathing medium, and stored them overnight; we compared the responses of strips thus treated with the responses of strips without oxyhemoglobin treatment. Relaxation induced by nicotine was abolished by hexamethonium and was markedly inhibited after exposure to oxyhemoglobin. A low concentration of KCl (5 mM) elicited relaxation that was abolished by ouabain and significantly reduced by oxyhemoglobin.

Role of endothelium in the response to prostaglandin H2 in isolated dog arteries.

Prostaglandin (PG) H2 produced a transient contraction followed by a relaxation in helical strips of dog coronary, mesenteric and renal arteries contracted with PGF2 alpha. The contraction was in the order of mesenteric greater than renal greater than coronary artery. Removal of endothelium abolished the contraction in these arteries and significantly potentiated the relaxation only in mesenteric arteries.

An orally active renin inhibitor: cyclohexylnorstatine-containing dipeptide (KRI-1314).

In our continuing search for low molecular weight, human renin inhibitors, a dipeptide derivative, morpholino-naphthyl-acyl-histidyl-cyclohexyl-norstatine (KRI-1314), was newly synthesized and estimated for oral effectiveness. This compound inhibited plasma renin from humans and from Japanese monkeys in vitro, with 50% inhibitory concentrations (IC50) of 4.7 x 10(-9) and 2.

Endothelium-dependent and -independent mechanisms of action of acetylcholine in monkey and dog isolated arteries.

In helical strips of monkey coronary and mesenteric arteries and dog mesenteric arteries partially contracted with prostaglandin (PG)F2 alpha, the mechanism of action of acetylcholine (ACh) has been analyzed by the use of pharmacological antagonists and by the endothelium-derived relaxing factor (EDRF) bioassay and the 6-keto PGF1 alpha radioimmunoassay. In conclusion, ACh releases vasodilator substance(s) from endothelium (EDRF) and also PGs from subendothelial tissues. Vasoconstrictor PGs appear to counteract the dilator action of EDRF in monkey coronary arteries, whereas vasodilator PG, possibly PGI2, appears to facilitate the relaxation caused by EDRF in monkey and dog mesenteric arteries.

Vasodilator actions of flunarizine in isolated dog cerebral and extracerebral arteries.

Flunarizine relaxed isolated canine arteries precontracted with prostaglandin (PG) F2 alpha, epithio-methano-thromboxane A2 and K+; the relaxation was in the order of cerebral greater than renal greater than mesenteric = coronary arteries, when contracted with PGF2 alpha or the thromboxane A2 analogue. Flunarizine-induced relaxation was unaffected by treatment with atropine, propranolol, cimetidine, cimetidine, chlorpheniramine, aminophylline and indomethacin, and by removal of endothelium. Under normoxia, flunarizine attenuated contractions elicited by Ca2+ in the K+-stimulated cerebral and mesenteric arteries that had been previously exposed to Ca2+-free media to a greater extent than that in PGF 2 alpha-stimulated preparations.

Responses to dopamine of isolated human gastroepiploic arteries.

Responses to dopamine were compared in helical strips of human gastroepiploic arteries (proximal portion) and their epiploic branches (distal portion), partially contracted with prostaglandin F2 alpha. Dopamine produced a dose-related contraction in the proximal arteries, which was reversed to a relaxation by treatment with phentolamine. On the other hand, the distal arteries responded to low concentrations of dopamine with relaxations and to high concentrations with contractions.

Different involvement of endothelium-derived relaxing factor and prostacyclin in vasodilator response to bradykinin in isolated dog blood vessels.

The study presented so far demonstrates that there is a heterogeneity in the mechanisms of vasodilator action of BK in various dog blood vessels (coronary vs mesenteric artery, and mesenteric artery vs vein). The different mechanisms underlying the BK-induced vasodilatation are summarized in Fig. 3.

In vivo inhibition of tissue kallikreins by kininogen sequence analogue peptides.

Kininogen sequence analogs containing amino acid residues around the Arg-Ser cleavage site of bovine kininogens were prepared with bulky aliphatic residues in P3 position. KKI-7 (containing a cyclohexylacetyl group) and KKI-8 (containing an adamantaneacetyl group) both inhibited human urinary kallikrein (HUK) with Ki of 4 microM. These inhibitors were 40 times more potent than the corresponding peptide containing the naturally occurring Pro at P3 and were one-seventh as susceptible to hydrolysis by HUK.

Effects of sophoramine, an alkaloid from Sophora alopecuroides on isolated dog blood vessels.

In helical strips of dog mesenteric, coronary and cerebral arteries and mesenteric veins contracted with prostaglandin F2 alpha, sophoramine (10(-4) and 10(-3) M) produced a concentration-related relaxation, which was not influenced by treatment with indomethacin, atropine, aminophylline, propranolol, metoprolol, cimetidine, ouabain and methylene blue, and also not by removal of endothelium. Relaxations induced by sophoramine did not differ in strips of proximal and distal coronary arteries. Contractile responses to transmural stimulation in mesenteric arteries and veins were potentiated by treatment with sophoramine (10(-4) M).

Functional and histological changes in mesenteric arteries and aortas from monkeys fed a high cholesterol diet.

Treatment of Japanese monkeys for 8 months with a high fat, high cholesterol diet produced atherosclerotic lesions in the aorta and mesenteric arteries, such as fatty dots, streaks and plaques, intimal thickening with accumulation of spindle-shaped cells and macrophages and endothelial cell flattening. Contractile responses of mesenteric arteries from control and atherosclerotic monkeys to electrical stimulation of adrenergic nerves, norepinephrine and angiotensin II did not differ, whereas contractions caused by serotonin in the atherosclerotic monkey arteries were significantly greater. Ketanserin and cinanserin suppressed the serotonin-induced contraction.

Reoxygenation and calcium-induced cerebroarterial contractions as affected by vasodilator agents.

In helical strips of dog cerebral arteries exposed to Ca2+-free medium under hypoxic conditions (95% N2 and 5% CO2), prostaglandin (PG) F2 alpha produced a slight tonic contraction. The addition of Ca2+ evoked a phasic contraction followed by relaxation and a sustained contraction, and reoxygenation elicited an additional tonic contraction of moderate magnitude. When the PGF2 alpha-induced contraction was stabilized in Ca2+-free medium, reoxygenation contracted the arteries only slightly.

Role of vascular angiotensin converting enzyme in hypertension.

The possible role of vascular angiotensin converting enzyme (ACE) in the maintenance of one-kidney, one clip (1-K,1C) hypertensive rats was studied in comparison with age-matched, one-kidney (1-K) normotensive rats. Mean blood pressure was elevated after partial occlusion of the left renal artery with unilateral nephrectomy, and the high blood pressure persisted for at least 11 weeks, whereas no significant changes in mean blood pressure were observed in 1-K rats. Plasma and vascular renin activities and plasma ACE activity did not differ between the two groups of rats, both 5 and 11 weeks after operation.

Endothelium-dependent and -independent responses to vasodilators of isolated dog cerebral arteries.

We compared responses to calcium ionophore A23187, vasopressin, and substance P in helical strips of dog middle cerebral, basilar, and posterior communicating arteries to obtain a better understanding of humoral control of cerebrovascular tone in different brain regions and its potential impact on mechanisms of cerebral vasospasm. A23187 relaxed these different arterial strips partially precontracted with prostaglandin F2 alpha to a similar extent. Vasopressin produced concentration-dependent relaxation in basilar and posterior communicating arterial strips, whereas middle cerebral arterial strips either contracted or relaxed slightly.

Prostaglandins involved in contractions by angiotensin II and bradykinin of isolated dog sphincter pupillae.

1. The dog isolated sphincter pupillae contracted in response to acetylcholine, angiotensin II (AII), bradykinin, prostaglandins F2 alpha, D2, E2 and I2, and thionate thromboxane A2 (sTXA2) in a concentration-dependent manner. 2.

Different inhibition by vasodilators of coronary artery contraction.

Actions of a variety of vasodilators were compared in helical strips of the dog coronary artery, previously soaked in Ca2+-free medium under severe hypoxia. Ca2+ entry blockers, such as nifedipine and flunarizine, did not affect the PGF2 alpha-induced contraction in Ca2+-free medium, but strongly reduced the Ca2+-induced contraction under severe hypoxia in the strips stimulated by PGF2 alpha. The contraction obtained following reoxygenation was also reduced by the Ca2+ blockers.

Prejunctional alpha adrenoceptor and angiotensin receptor function in isolated human, monkey and dog arteries.

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.

Extraluminally applied acetylcholine and oxyhemoglobin on the release and action of EDRF.

Acetylcholine applied intra- and extraluminally to the donor tissue (dog femoral artery segment with endothelium) produced a relaxation of the bioassay tissue (coronary artery strip without endothelium). Extraluminal acetylcholine was 1/44 as potent as intraluminal acetylcholine (10(-7) M). Extraluminal treatment with oxyhemoglobin halved the relaxation caused by acetylcholine applied intraluminally.

Prostaglandin F2 alpha-induced contraction in isolated dog cerebral, coronary and mesenteric arteries soaked in excess potassium.

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.

Comparison of the response to angiotensin II of isolated dog coronary and mesenteric arteries of proximal and distal portions.

Helically cut strips of dog coronary and mesenteric arteries of proximal and distal portions contracted in response to angiotensin (ANG) II in a dose-dependent fashion. The contractions were greater in the distal portions than in the proximal portions. Mesenteric arteries responded to the peptide with a greater contraction than coronary arteries.

Modification by severe hypoxia and diltiazem of dog coronary artery contractions in vitro.

The contractions induced by prostaglandin (PG) F2 alpha and by Ca2+ in helical strips of canine coronary arteries exposed to Ca2+-free medium under severe hypoxia and stimulated by PGF2 alpha or K+ were augmented by the return to normoxia. Inhibition under hypoxia was ranked as follows: Ca2+-induced contractions in the strips stimulated by PGF2 alpha greater than Ca2+-induced contractions in the K+-depolarized strips greater than PGF2 alpha-induced contractions in the Ca2+-free medium. The inhibition of arterial contractions during severe hypoxia was not influenced by removal of the endothelium.

Responsiveness of isolated monkey coronary arteries contracted with alpha 1- and alpha 2-adrenoceptor agonists to diltiazem.

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.