Effect of propranolol on prolyl hydroxylase activity in blood vessels of rats.
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Biomedical subjects
Publications and source records attributed to K Iwatsuki.
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The secretory responses to seven dopamine amino acid conjugated derivatives were compared with those to dopamine, using blood-perfused canine pancreas preparations. Each of these dopamine derivatives produced a dose dependent increase in the secretion of pancreatic juice. The rank order of the secretory responses and relative potency (dopamine = 1) was: N-Ileu-dopamine (0.4) greater than N-Ala-Glu-dopamine (0.2) greater than N-gamma-Glu-dopamine (0.1) = N-Gly-Pro-dopamine (0.1) greater than N-Gly-=Gly-dopamine (0.01) greater than N-Gly-Gly-Leu-dopamine (0.005) = N-Gly-Gly-Pro-dopamine (0.005). The duration of action of doses of the derivatives which produced approximately equal secretory responses was about 1.2--2.7 times longer than that of dopamine. Dopamine and N-Ileu-dopamine which has the most potent secretagogue property among seven dopamine derivatives produced a secretin-like secretion of the pancreatic juice containing a high concentration of bicarbonate but had little effect on protein output with lower amylase activity.
The enzyme of prolyl hydroxylase was prepared from the rat aorta. The prolyl hydroxylase activity was measured by the tritium release assay in vitro. Propranolol at concentrations of 3 X 10(-6)M, 10(-5)M inhibited the prolyl hydroxylase activity by 20.6%, 69.8% and 93.7% of control activity, respectively, when the reaction mixtures were incubated for 30 min. It is suggested that propranolol may exert some influence on the collagen biosynthesis of the blood vessels.
The inotropic effects of five non-depolarizing muscle relaxants were examined using an isolated canine heart muscle preparation. Except for fazadinium, all drugs were studied in their commercially available forms. d-Tubocurarine chloride (dTc) and metocurine iodide (MTC) produced dose-dependent decreases in isometric force (F) and the maximum velocity of force development (dF/dt) at concentrations greater than 22.5 x 10(-3) g/L for dTc and greater than 15.0 x 10(-3) g/L for MTC, concentrations which are 3 and 6 times higher than estimated clinical serum concentrations, respectively. Myocardial depression was about 3 times less with MTC than with dTc at equipotent concentrations. The degree of depression in F and dF/dt produced by MTC was almost identical with that produced by phenol, a preservative of MTC, indicating that MTC-induced myocardial depression may be due to the effect of the preservative. Pancuronium bromide (PC) produced a dose-dependent increase in F and dF/dt and decrease in the time to peak force. PC-induced changes in F, dF/dt, and time to peak force were inhibited by administration of propranolol 10(-6) M. The results indicate that PC possesses a positive inotropic effect mediated by beta-adrenergic stimulation. Alcuronium chloride did not change F or dF/dt at concentrations from 5.0 x 10(-3) to 60.0 x 10(-3) g/L. Frazadinium bromide increased F and dF/ dt slightly at a low concentration (1.875 x 10(-2) g/L), but further increases in its concentration returned the values of F and dF/dt to control levels. F and dF/dt were not altered in vitro by concentrations of relaxants that would be anticipated in plasma in vivo in patients given clinically effective doses of 0.3 mg/kg of dTc, 0.1 mg/kg of MTC or PC, 0.2 mg/kg of alcuronium chloride, or 0.75 mg/kg of fazadinium bromide.
Purpura pigmentosa chronica comprises a group of vascular disorders of unknown etiology. In biopsied specimens obtained from 8 patients, we observed vascular changes such as fibrinoid degeneration and occlusive damage occasioned by a hyalinized substance as well as swollen endothelia in 3. However, in all biopsied specimens, direct immunofluorescence studies demonstrated depositions of C3 or C1q with or without immunoglobulins, and of fibrin in papillary vessels. These findings suggest the possibility that immunological processes are involved in producing the histopathologic features of this disorder.
The direct effect of protamine sulfate upon myocardial inotropism was studied using an isolated canine heart muscle preparation. Isometric force (F) was decreased to 87.6 +/- 1.2% of control values by a concentration of 50 x 10(-3) g/L protamine, which is approximately equal to the estimated serum concentration of protamine when administered clinically in doses of 4 mg/kg. The decrease in F was accompanied by a decrease in the maximum velocity of force development (dF/dt) but no alteration in time to peak force. Administration of the preservative of protamine sulfate did not alter F and dF/dt. This suggests that protamine produces a direct negative inotropic effect, mediated by a decrease in intensity but not by a decrease in duration of the active state.
The effect of papaverine on the secretion of pancreatic juice in the dog was investigated in preparations of isolated, blood-perfused pancreas. Small doses of papaverine (1-30 microgram) injected intra-arterially did not induce any secretory action. Relatively large doses of papaverine (0.1-1 mg) caused dose-dependent increases in the secretion of pancreatic juice after a delay of a few minutes. The secretory activity of 1 mg of papaverine was approximately equal to that of 0.06 units of secretin. The concentration of bicarbonate in the pancreatic juice induced by papaverine was increased. However, protein concentration was increased slightly. This effect is analogous to that of secretin. Papaverine-induced secretion was not modified by pretreatment with phentolamine, propranolol, atropine, guanethidine and haloperidol. On the other hand, papaverine significantly potentiated the secretion of pancreatic juice induced by secretin. From these results, it is concluded that large doses of papaverine may produce an increase in pancreatic secretion mediated through the increase of intracellular cyclic AMP concentration.
Effect of 5-dimethyldithiocarbamylpicolinic acid (YP-279), a dopamine beta-hydroxylase inhibitor, on the secretion of pancreatic juice induced by dopamine was investigated in preparations of the isolated blood-perfused canine pancreas. Either a single injection (300 micrograms) or an infusion (100 micrograms/min) of YP-279 intra-arterially (i.a.) caused no change in the outflow of the pancreatic juice, but the secretagogue effect of dopamine (1-10 micrograms, i.a.) was enhanced by the infusion of YP-279 (100 micrograms/min, i.a.) for 60 min. The previous conclusion obtained with fusaric acid was confirmed as follows; the dopamine beta-hydroxylase activity controls the dopaminergic mechanism of the pancreatic secretion.
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The neuromuscular blocking property of minocycline hydrochloride (MNC) was studied in 12 rabbits. In 2 of 6 animals, MNC, 60-160 mg/kg, alone caused a decrease in twitch tension. During partial neuromuscular blockade produced by a continuous infusion of pancuronium, the intravenous administration of MNC, 20--60 mg/kg, resulted in a dose-dependent decrease in twitch tension in 6 animals. MNC-induced or combined MNC-pancuronium-induced neuromuscular blockade was antagonized by calcium or by neostigmine.
The effect of guanethidine on collagen biosynthesis in the aorta and mesenteric artery was investigated in desoxycorticosterone acetate (DOCA)-salt hypertensive rats. Prolyl hydroxylase activity (EC 1.14.11.2; proline, 2-oxoglutarate dioxygenase) and 14C-proline incorporation into collagen, two markers of collagen biosynthesis, were significantly increased in blood vessels of hypertensive rats compared with those of controls. When guanethidine (5 mg/kg, i.p.) was given daily to the hypertensive rats for 4 weeks, the blood pressure was decreased to 150 +/- 7 mm Hg, whereas the blood pressure of the untreated hypertensive rats was 218 +/- 10 mm Hg. Prolyl hydroxylase activity in the aorta and mesenteric artery and 14C-proline incorporation into aortic collagen were significantly reduced concomitant with the decrease in blood pressure. These results suggest that the decrease in vascular collagen biosynthesis in hypertensive rats treated with guanethidine is related to the lowering of their blood pressure.
A thirty-year-old man who had sudden onsets of unconsciousness, right hemiparesis and conjugate deviation to the left side, was admitted to our clinic. The clinical symptoms were similar to an apoplexic attack. The neurologic examination showed right hyperactive knee and ankle reflexes, and left inferior temporal retinal arterial occlusion. The serial left carotid angiography, performed immediately after admission, showed the occlusion of left middle cerebral artery at the location of trifurcation. We diagnosed this case as a cerebral vascular disease, and then the large amount of Urokinase and Heparin were injected immediately after the diagnosis. The clinical symptoms were improved tremendously after the injection. Three days later, the second left carotid angiography showed the complete recanalization of the occlusion, and further did a tumor stain at the distal portion of the occlusion. The brain scintigram revealed an increased up-take of 99mTc in the left parieto-temporal region. We finally diagnosed brain tumor, and the tumor was subtotally removed by the left parieto-temporal craniotomy. The histological findings of the tumor showed angioblastic meningioma. The cerebral arterial occlusion secondary to the brain tumor should be caused by the compression of the vessels and the hemorrhage of the tumor. This case is rarely reported.
Clarification of the mechanisms of the myocardial depression produced by thiamylal was sought by studying the effect of thiamylal upon the sensitivity of contractile proteins to calcium (Ca2+), by using glycerinated muscle fibres from the canine right ventricle. The dose--response relationship between the concentration of Ca2+ and the force of contraction of the glycerinated cardiac muscle fibres was not shifted from the control curve by the administration of thiamylal 67 microgram ml-1. This result suggests that the changes in the sensitivity of contractile proteins to Ca2+ are not responsible for the depression of myocardial performance produced by thiamylal.
Collagen synthesis was increased in aortas, mesenteric arteries, cerebral microvessels, pial artery, basilar artery and decreased in the heart of rats made hypertensive with deoxycorticosterone acetate-salt or the spontaneously hypertensive animal. The markers of collagen biosynthesis that were elevated were prolyl hydroxylase, prolyl hydroxylase-related antigen, total collagen content and the incorporation of labelled proline into total protein and into collagen. The antihypertensive drugs reserpine and chlorthiazide could both prevent the increase or reduce the increase in collagen synthesis.
In two models of hypertension in rats, it was shown that collagen synthesis and deposition are increased in arteries where blood pressure is elevated. By contrast, there were no alterations in any of the markers of collagen synthesis in veins, where blood pressure was only slightly elevated. It would appear that the stimulus for vascular collagen synthesis is provided by a direct effect of the increased pressure on the arterial cells rather than by a humoral factor released into the general circulation.
beta-Aminopropionitrile, a specific inhibitor of lysyl oxidase prevented the rise in blood pressure induced by deoxycorticosterone-salt in rats. In addition, after the onset of hypertension, administration of beta-aminopropionitrile lowered the blood pressure. Concomitant with the lowering of blood pressure, there was a reduction in the more highly crosslinked form of vascular collagen. These findings would indicate that increases in vascular connective tissue are not only sequelae of hypertension, but may also contribute to the maintenance of elevated blood pressure.