Biomedical subjects
Publications and source records attributed to N C Nyborg.
The reactivity of bovine retinal resistance arteries (i.d. ca. 200 microns) to selective alpha 1-, beta- and combined alpha- and beta-adrenoceptor stimulation was studied in vitro using phenylephrine, isoproterenol and norepinephrine, respectively. The results indicate that only functional alpha 1-adrenoceptors, possibly in low numbers, are present in these vessels.
The relaxing effect of nitrendipine and D600 on isolated ring segments of calf retinal resistance arteries (i.d. ca. 200 microns) contracted with prostaglandin-F2 alpha (PGF2 alpha) or high potassium solution was studied. The vessel response to both PGF2 alpha and potassium stimulation was dependent on extracellular calcium. Removal of extracellular calcium reduced the vessel response to PGF2 alpha and potassium by 85% and 98%, respectively (P less than 0.01). Both calcium antagonists induced a concentration dependent relaxation of PGF2 alpha pre-contracted vessels with = -log[IC50(M)]-values of 8.01 and 7.13 for nitrendipine and D600 (P less than 0.05), respectively. The calcium antagonists were equieffective in relaxing the vessels amounting to 33% for nitrendipine at 10(-6) M and 37% for D600 at 10(-5) M. Further analysis of the data revealed that the nitrendipine induced relaxation of the PGF2 alpha response was linearly correlated with the internal lumen diameter of the vessels. No correlation was found for the D600 induced relaxation. At the highest concentrations of nitrendipine, 10(-6) M, and D600, 10(-5) M, the potassium induced response was reduced by 94 and 75%, respectively. The results show that calcium antagonists only partially relax retinal resistance arteries contracted with PGF2 alpha although the vessels are dependent on extracellular calcium for active force generation. Calcium must therefore be activated by PGF2 alpha through other pathways than those blocked by calcium antagonists.
The relaxant effect of irindalone [+)-(1R, 3.S)-1-[2-[4-[3-(p-fluorophenyl)-1-indanyl]-1-piperazinyl] ethyl]2-imidazolidinone) and ketanserin was studies on active tension in isolated rat thoracic aorta. Irindalone and ketanserin caused a concentration-related inhibition of serotonin-induced contractions and shifted the serotonin curve to the right. Irindalone was more potent in inhibiting the serotonin-induced contractions and ketanserin was. The slopes of the Schild plots for the two substances were slightly, but not significantly, different from each other. This indicates that irindalone had a more pronounced serotonin antagonistic effect than ketanserin.
The effect of aging on morphological and mechanical characteristics and the serotonin reactivity of ring preparations of coronary resistance arteries isolated from a specific part of the left coronary artery were studied in male Wistar rats at 6 weeks, 3 months, and 2 years of age. The media to lumen ratio of the coronary vessels was unaffected by aging, although the effective lumen diameter increased from 176 micron at 6 weeks to 212 micron at 2 years of age. The maximal active tension development, active pressure, and active media stress generation of the vessels were also unaffected by aging. At all ages the spontaneous calcium dependent intrinsic tone was similar, equal to 13% of maximal agonist induced tension development. Serotonin induced a concentration dependent contraction at all ages. Maximal vessel response to serotonin increased with age from 0.38 N.m-1 to 1.45 N.m-1 at 6 weeks and 2 years of age respectively. Serotonin sensitivity was higher in the older rats than in the younger rats. Tachyphylaxis to serotonin developed only in vessels from 6 week old rats. The results confirm that the morphology and mechanics of resistance arteries remain stable over a large age range but that the vascular reactivity to specific agents, such as serotonin, may change over that period. The results also indicate that the coronary blood flow may be seriously affected by serotonin induced vasoconstriction with increasing age in rats.
We have studied the influence of endothelium on BAY K 8644, CGP 28392, potassium, noradrenaline and calcium induced responses in isolated thoracic aorta from rats. In aortic preparations with intact endothelium BAY K 8466 and CGP 28392 (10(-9)-10(-5) M) had a concentration dependent contractile effect, but BAY K 8644 was more effective in contracting the vessels than CGP 28932. Removal of endothelium increased the contractile response to both substances without affecting the difference in contractile effect between the two calcium agonists. In high concentrations (10(-4) M) BAY K 8644 and CGP 28392 had an equal relaxing effect on potassium precontracted preparations, which was unaffected by removal of endothelium. Removal of endothelium caused a shift to the left of the potassium and noradrenaline concentration response curves without any change in maximal contractile response. The contractile response to calcium in BAY K 8644 and potassium activated vessels was unaffected by removal of endothelium. We conclude that endothelium derived factor(s) depress the contractile response to calcium agonists, potassium, and noradrenaline but has no influence on the relaxant effect of BAY K 8644 and CGP 28392 in rat aorta. The influence of endothelium on the contractile effect on BAY K 8644 and potassium seems not to be due to a direct effect on calcium influx but rather to an influence on the membrane potential of the smooth muscle cells.
alpha-Adrenergic receptor-related properties, specifically, norepinephrine affinity, occupancy and reserve during contraction, were determined in segments of rat resistance arteries. These were obtained from the superior mesenteric bed of spontaneously hypertensive rats and Wistar-Kyoto strain controls. Receptor affinity for norepinephrine in the spontaneously hypertensive rats was significantly greater than that for the Wistar-Kyoto controls. There were no differences in the estimates of receptor occupancy and reserve. This finding taken together with other studies is consistent with the conclusion that increased alpha-adrenergic receptor-mediated sensitivity of vascular smooth muscle of the spontaneously hypertensive rat reflects differences in the agonist site on the alpha-adrenergic receptor.
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We have investigated the active, passive and myogenic tension-internal circumference relations of rat intramural coronary and, as controls, mesenteric small arteries (internal diameter ca. 200 micron) using an isometric myograph. The active tensions of the vessels (when fully activated with 30 microM serotonin in K-saline) reached a maximum (2.54 N/m, coronary; 3.39 N/m, mesenteric) at an internal circumference, L0, where the passive tensions (measured in Ca-free solution) were 0.80 N/m (coronary) and 0.74 N/m (mesenteric). Below 0.8 L0 and above 1.2 L0 the active tensions fell linearly, the zero tension intercepts being 0.37 L0 and 1.74 L0 (coronary) and 0.40 L0 and 1.72 L0 (mesenteric). The passive wall tensions of the vessels rose exponentially as a function of internal circumference, the wall tension at 1.5 L0 being 10.0 N/m (coronary) and 8.5 N/m (mesenteric). In normal physiological salt solution, the coronary vessels had a Ca2+ dependent myogenic tone which was also dependent on the internal circumference. Maximum myogenic tone (0.54 N/m) was obtained at 1.18 L0. The mesenteric vessels had no such myogenic tone. Histological examination showed that the media/lumen ratios of both vessel types were the same, and that the smooth muscle content of the media was greater in the coronary (81%) than in the mesenteric (72%) vessels. The smaller active tension of the coronary vessels could not therefore be ascribed to a reduced smooth muscle content, but possibly in part to an observed heterogeneous arrangement of the smooth muscle cells in the coronary vessels.
The effect of nifedipine and nimodipine was studied on the spontaneous myogenic tone and on the serotonin-, potassium-, and calcium-induced contractile responses in coronary resistance arteries from 2-year-old male Wistar rats. Both drugs depressed completely and concentration-dependently the spontaneous myogenic tone. At the highest concentration, nifedipine and nimodipine reduced the serotonin and potassium responses to an average of 19% and 6% of control response. The drugs had an equipotent inhibitory effect on the serotonin response. Nimodipine, however, was more potent than nifedipine, inhibiting the potassium response. In vessels maximally activated by serotonin and potassium, both drugs concentration-dependently inhibited the calcium concentration-response curves. Nifedipine and nimodipine had an equieffective and equipotent inhibitory effect on the calcium responses in serotonin-activated vessels. Nimodipine was more potent than nifedipine, inhibiting the calcium response of potassium-activated vessels. In the highest concentration, nimodipine was also more effective than nifedipine (p less than 0.01) in inhibiting the calcium response. In conclusion, both nifedipine and nimodipine are potent and effective vasodilators, having similar actions on the spontaneous myogenic tone and serotonin-induced responses in the rat coronary resistance arteries, but nimodipine is more potent and more effective than nifedipine in inhibiting potassium-induced responses.
After dosage titration from the age of 1 month to the age of 3 months, spontaneously hypertensive rats (SHR) were treated with pinacidil 10 mg/kg daily until the age of 6 or 12 months. Morphometric data were obtained from the treated SHR as well as from untreated age-matched SHR and normotensive Wistar-Kyoto rats (WKY) at these two developmental stages. Heart:body weight ratios and media:lumen ratios for resistance vessels were determined. Vessels obtained from the mesenteric region were investigated on a myograph. Vessels from heart, kidney and lung were investigated by morphometric analysis of histological sections, only specimens from 12-month-old rats were used. In SHR no effects of either ageing or treatment were detectable, although their blood pressure had been effectively held at normotensive levels throughout the life of the treated animals from the age of 3 months. With the exception of the media index of the pulmonary vessels, which was not statistically different from treated or control SHR, the WKY morphological parameters were significantly lower. In conclusion, pinacidil normalized blood pressure without complications, but this did not affect SHR cardiovascular structure. It is suggested that development of this strain-specific enlargement can only be modified if blood pressure is kept at hypotensive levels, or if the effect of a hitherto unidentified causative factor is antagonized by more-specific pharmacological treatment.
6-Hydroxydopamine (6-OHDA) was injected on alternate days from birth to 3 weeks of age into spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) control rats. The effects of this neonatal treatment on cardiovascular structure and mesenteric resistance vessel calcium sensitivity was studied in young (6 week) and adult (5 month) rats. Mean arterial pressure of treated SHRs and WKYs was reduced by 10% compared with control rats, but the heart:body weight ratio was unaffected by treatment. Both pharmacological and histological studies suggested that at 6 weeks of age, mesenteric resistance vessels from treated WKYs were completely denervated, but that vessels from treated SHRs still had sparse innervation. At 5 months all vessels from the treated rats had some adrenergic innervation, but less than the control rats. In the WKYs, treatment was associated with reduced media:lumen ratio and reduced calcium sensitivity of the mesenteric resistance vessels, while no such changes were observed in the SHR vessels. The results indicate that the sympathetic nervous system in SHRs is more resistant to chemical denervation than the sympathetic nervous system of the WKYs. The results also suggest that sympathetic innervation of mesenteric resistance vessels may affect vessel structure and sensitivity.
Felodipine (4(2,3-dichlorophenyl)-1,4-dihydro-2, 6-dimethyl-3-ethoxycarbonyl-5-methoxycarbonyl pyridine)), a selective vasodilating anti-hypertensive drug, was used in the treatment of spontaneously hypertensive rats (SHRs) and age-matched Wistar-Kyoto rats (WKYs) from age 6 to 14 weeks, ie during the time of high blood pressure development in SHRs. The effect of treatment on heart weight and on mesenteric resistance vessels (i.d. ca 170 microns) characteristics was investigated. In a first study, two oral doses of felodipine were added to the diet of SHRs, in concentrations of either 0.5 or 1.5 mg X g-1 rat food. Both treatments lowered mean arterial pressure by about 19% (p less than 0.001). In a second study, the lower dose of felodipine (0.5 mg . g-1 rat food) was therefore used to treat both SHRs and WKYs. Treatment did not interfere with weight or food intake of either SHRs or WKYs but increased average weekly water intake significantly. In neither strain was the pulse rate or, surprisingly, heart/body weight ratio affected by treatment. Furthermore, mesenteric resistance vessel morphology and mechanics were not affected by the blood pressure reduction. The noradrenaline and calcium sensitivity of mesenteric resistance vessels from treated rats was greater (p less than 0.001) than those from control rats. These findings indicate that blood pressure reduction with felodipine does not affect cardiovascular structure in young SHRs.
We have investigated the effect of felodipine [4-(2,3,-dichlorophenyl)-1,4-dihydro-2, 6-dimethyl-3-ethoxycarbonyl-5-ethoxycarbonylpyridine] on the calcium concentration response relations of noradrenaline-activated mesenteric resistance vessels from 3-mo-old spontaneously hypertensive (SHR) and age-matched Wistar-Kyoto (WKY) rats. SHR vessels were more sensitive to calcium (ED50 approximately equal to 5.49 X 10(-5) M) than WKY vessels (ED50 approximately equal to 1.01 X 10(-4) M) in control condition. Also, maximal active tension development in SHR vessels was greater (3.14 N/m) than in WKY vessels (2.22 N/m). Felodipine (10(-12) M) decreased calcium sensitivity in vessels from both strains and also decreased maximal active tension development of SHR vessels. In a higher concentration (5 X 10(-10) M), the calcium sensitivity of both SHR and WKY vessels became similar. The active tension development was equally reduced in both rat strains. The results indicate that at least part of the antihypertensive effect of felodipine is due to a direct vasodilation, and also that vessels from SHRs may be more sensitive to felodipine than those from WKY rats.
We have investigated the effect of a synthetic 'atrial natriuretic factor' (ANF) on induced tone in rat isolated renal arcuate arteries (lumen diameter ca. 250 microns), and compared this with the effects of synthetic ANF on resistance vessels of similar size taken from the mesenteric, femoral, cerebral and coronary vasculature. Synthetic ANF was found to cause relaxation of the renal vessels when these were sub-maximally activated with K+, noradrenaline or 5-hydroxytryptamine, but had no effect on the responses of the other vessels to these agonists. Synthetic ANF had a near maximal effect (65% relaxation) at 100 nM, with an IC50 of 7.9 nM. The relaxant effect of synthetic ANF on the renal vessels was fully maintained for at least 15 min. Hydralazine (100 microM) caused relaxation of renal vessels (47%) and coronary vessels (42%), but had no effect on the other vessel types. By contrast, sodium nitroprusside (1 microM) relaxed all vessel types. The relaxant action of synthetic ANF on the renal vessels was seen in the presence of ouabain (1 mM), propranolol (1 microM), phentolamine (1 microM), atropine (1 microM) and felodipine (1 nM). In t renal vessels, synthetic ANF had no effect on membrane potential, measured with intracellular electrodes, despite the simultaneously measured relaxation. Synthetic ANF had no effect on the efflux of 22Na+ in either renal or mesenteric vessels. The results demonstrate that synthetic ANF has a specific and prolonged relaxant effect on renal small arteries, and are consistent with this effect being mediated through specific receptors.
The effect of CGP 28392 and BAY K 8644 was studied on isolated portal veins from male Wistar Kyoto rats. BAY K 8644 and CGP 28392 induced a concentration dependent increase in spontaneous mechanical activity in low but not in high concentrations. The portal vein was more sensitive to the effect of BAY K 8644 than to that of CGP 28392. In Ca free medium the increasing effect of BAY K 8644 and CGP 28392 on the mechanical activity was abolished and restored by readdition of calcium. Nifedipine abolished the augmenting effect of BAY K 8644 and CGP 28392 on mechanical activity. Ultraviolet radiation (UVR) depressed the effect of BAY K 8644 but had no effect on mechanical activity induced by CGP 28392. BAY K 8644 and CGP 28392 degradate slowly under influence of UVR; BAY K 8644 was far more resistant to the destroying effect of UVR than CGP 28392. The results indicate that both BAY K 8644 and CGP 28392 increase the spontaneous mechanical activity in rat portal vein by enhancing Ca influx. The effect of BAY K 8644 differs from that of CGP 28392 by being sensitive to UVR; this action seems not to be due to a direct UVR destroying effect of the substances, but rather to a BAY K 8644 induced sensibilisation of the tissue to UVR.
The effect of a new 1,4-dihydropyridine derivative, methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate, BAY K 8644, was studied on isolated thoracic aortae obtained from male Wistar-Kyoto rats. In rat aorta BAY K 8644 had dual actions as the compound induced contractions in the concentration range 10(-8)-10(-5)M and relaxation at higher concentrations. In low concentrations (10(-8)M) BAY K 8644 increased the contractile response to both noradrenaline and potassium and shifted the concentration response curves to the left while in high concentrations BAY K 8644 (10(-4)M) had a relaxant effect on preparations precontracted by potassium. The contractile response to BAY K 8644 was resistant to wash out in drug free medium but was totally abolished in Ca-free medium. Re-addition of Ca restored the contractile response in a concentration dependent manner. BAY K 8644, 10(-6)M, shifted the Ca-concentration response curve in high potassium solution to the left and increased the maximal response. Phentolamine or propranolol had no effect neither on the contractile nor on the relaxant effect of BAY K 8644. The findings suggest that BAY K 8644 acts mainly by increasing the transmembrane influx of Ca in the vascular smooth muscle cells, and that this effect could be opposite to that of nifedipine. However, in high concentrations BAY K 8644 also seems to have a Ca-entry blocking effect.
The effect of day light and ultraviolet radiation (360 nm) on mechanical responses to BAY K 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(-2-trifluoromethylphenyl)-py ridine- 5 -carboxylate), potassium (K+) and noradrenaline (NA) of rat aorta rings was investigated. The contractile response to BAY K 8644 (10(-6)M) obtained before and after exposure of the BAY K 8644 stock solution to ultraviolet radiation was unchanged and equal to that of K+, 125 mM. Ultraviolet radiation and day light did not affect responses evoked by K+ (125 mM) and NA (1.8 X 10(-5)M). In contrast to this both types of light relaxed vessels contracted by BAY K 8644 (10(-6)M). The light induced relaxations were reversible, unaffected by addition of propranolol (3 X 10(-6)M) and could not be eliminated by washing the preparations repeatedly with Krebs solution. In vessels contracted by K+ (125 mM) and NA (1.8 X 10(-5)M) ultraviolet radiation induced a reversible relaxation in the presence of BAY K 8644. BAY K 8644 (10(-4)M) and nifedipine (10(-8)M) relaxed preparations contracted by K+. Nifedipine (10(-6)M) totally relaxed preparations contracted by BAY K 8644 (10(-6)M). Ultraviolet radiation eliminated the relaxant effect of nifedipine and decreased the relaxant effect of BAY K 8644 (10(-4)M). The results indicate that BAY K 8644 is more light-stable than nifedipine and that BAY K 8644 sensitized the vascular smooth muscle to ultraviolet radiation as well as day light. Consequently this should be taken into account when BAY K 8644 is studied.
The action of a synthetic 'atrial natriuretic factor' (sANF) on induced tone in isolated rat renal resistance vessels (lumen diameter about 200 microns) was examined and compared with the effects of sANF on resistance vessels of similar size taken from the cerebral, mesenteric and femoral vasculature. Synthetic ANF caused a relaxation of the renal vessels when these were submaximally activated with noradrenaline or serotonin, but had no effect on the responses of the other vessels to these agonists. In contrast to previous reports concerning rabbit aortic vessels, methylene blue (which is thought to cause inhibition of guanyl cyclase) did not reduce the dilator response to sANF in the renal vessels. The results demonstrate that sANF has a specific relaxing effect on renal resistance vessels, and are consistent with its effect being mediated through specific receptors. The mechanism of this relaxant effect remains unknown.