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Biomedical subjects

A Hof

Publications and source records attributed to A Hof.

At least 37 records · Page 2Linked to original sources
PubMed1989

[Rheologic findings in patients with Eales disease].

In a retrospective analysis of findings in 12 patients with Eales' disease significant changes in blood fluidity were established. The six female and six male patients, aged between 15 and 59, were examined in the acute and subclinical stages and when a recurrence occurred. The rheologic parameters plasma viscosity, erythrocyte rigidity, and erythrocyte aggregation were significantly increased in the acute stage and when there was a recurrence, while in the subclinical stage the rheologic values improved to normal. No correlation could be found between the severity of the clinical picture in the various phases and the rheologic values. None of the other biochemical, microbiologic, and immunologic parameters were pathologic in any stage of the disease. In particular, virus serology, protein, immune, and hemoglobin electrophoresis were normal in all patients. While the etiology of Eales' disease remains unknown, deteroration in erythrocyte rigidity appears to play a part in the pathophysiology of the disease.

Adolescent↗
PubMed1989

Massive regional differences in the vascular effects of endothelin.

Endothelin was infused into seven anaesthetized open-chest rabbits during three 10-min periods, so that cumulative doses of 0.01, 0.1 and 1 nmol/kg were achieved. Endothelin increased blood pressure and caused systemic vasoconstriction only at the highest dose, but decreased the myocardial contractile force (measured with a strain-gauge) at all doses. In contrast to the modest systemic haemodynamic changes, vascular effects (measured with tracer microspheres) were found at each dose level and varied greatly from vasodilator (hepatic artery), through biphasic (spleen) to pure vasoconstrictor (adrenals, pancreas, stomach, colon) effects. Systemic circulatory parameters poorly reflect the regional vascular activity of endothelin.

Angiotensin II↗
PubMed1989

Effects of hCGRP I and II on gastric blood flow and acid secretion in anesthetized rabbits.

Effects of intravenously administered human calcitonin gene-related peptides (hCGRP) I and II on regional blood flow and gastric acid secretion were examined in barbiturate-anesthetized rabbits. Blood flow was measured by injection of radioactively labeled microspheres at 0, 10, 20, 30, and 60 min. hCGRP I and II and vehicle were infused intravenously in five rabbits in rising doses of 0.01 (0-10th min), 0.03 (11-20th min), and 0.1 microgram.kg-1.min-1 (21-30th min). hCGRP I and II increased gastric blood flow dose dependently. Moreover, hCGRP I raised regional conductance (inverse of vascular resistance) in the stomach, duodenum, heart, brain, and skeletal muscle. As a result of the increased total peripheral conductance the mean arterial pressure was reduced, but the cardiac output remained unchanged. hCGRP II increased blood flow and conductance selectively in the stomach and the pancreas. The total peripheral conductance and mean arterial pressure remained unchanged. Apparently, hCGRP II exerts a more localized effect on the stomach than hCGRP I. hCGRP I and II did not affect basal gastric acid secretion. Pentagastrin-stimulated acid secretion was increased by 28% with hCGRP I (0.025 micrograms.kg-1.min-1) and decreased by 27% with hCGRP II (0.025 micrograms.kg-1.min-1). The inverse effect of hCGRP I and II and the parallel stimulation of blood flow brought about with hCGRP I and II indicate a different mode of action of the peptides on gastric blood flow and gastric acid secretion.

Animals↗
PubMed1989

Differential effects of antihypertensive drugs on nutritive and nonnutritive blood flow in anaesthetized rabbits.

Arteriovenous (AV) shunt vessels connect arterioles directly to the venous side. These vessels play a role in thermoregulation and in the pathophysiology of migraine. Tracer microspheres are excellent tools to study drug effects on AV anastomoses. Microspheres with a diameter of 15 microns are unable to pass through capillary vessels, but they readily cross AV shunt vessels and are transported to the lungs and trapped there. We investigated the effects of antihypertensive agents on AV shunt flow in anaesthetized rabbits and we also measured nutritional blood flow in the ear, an organ known to have both nutritional and AV shunt vessels. Nitroprusside sodium tended to increase and prazosin strongly increased AV shunt flow. The calcium antagonist isradipine, by contrast, decreased AV shunt flow even though it is also a vasodilator. Spirapril, an angiotensin-converting enzyme inhibitor, elicited similar effects. The centrally acting antihypertensive agent guanfacine strongly decreased AV shunt flow. These effects did not correlate with the drug effects on nutritional blood flow, which were, however, so variable that none of them reached statistical significance. The following trends were seen: nitroprusside sodium, isradipine, and guanfacine increased nutritional blood flow, but prazosin, a dilator of AV shunts, did not. The amount of blood crossing through AV shunts from the arterial to the venous side is considerable (up to 15% of cardiac output before drugs). A drug-induced increase is not associated with an apparent benefit but causes a hyperdynamic circulation that might contribute to the hemodynamic load of the heart.

Anesthesia, Intravenous↗
PubMed1988

The renin-angiotensin system modulates the peripheral vascular effects of the calcium antagonist isradipine in anesthetized rabbits.

Dihydropyridine calcium antagonists such as isradipine (PN200-110) selectively increase blood flow to the heart, brain, and skeletal muscle. The role of the renin-angiotensin system in bringing about this pattern of selectivity was investigated in two groups of eight barbiturate-anesthetized rabbits. One group was and the other one was not pretreated with 1 mg/kg i.v. of the angiotensin converting enzyme inhibitor, spirapril. In the group with the intact renin-angiotensin system, isradipine (3 and 10 micrograms/kg i.v.) elicited the typical systemic and regional (measured with 15 micron tracer microspheres) hemodynamic effects of a noncardiodepressant dihydropyridine derivative. Inhibition of the angiotensin converting enzyme blunted the effects of isradipine on central venous pressure, cardiac output, and flow to the heart, brain, and skeletal muscle. The isradipine-induced decrease of hepatic arterial and pancreatic blood flow was prevented and a similar tendency was observed in the spleen, stomach, small intestine, cecum, and arteriovenous shunt flow, indicating that the renin-angiotensin system was totally (liver, pancreas) or partially responsible for the effects of isradipine on these vessels. The renin-angiotensin system thus counteracts the dilator effect of calcium antagonists in angiotensin II sensitive vascular beds and participates in bringing about the typical pattern of regional vasodilation of these agents.

Anesthesia↗
PubMed1988

Vasoconstrictor and vasodilator effects in normal and atherosclerotic conscious rabbits.

1. Rabbits were fed a cholesterol-rich diet for 5 two-week intervals. Polyvinyl catheters were then implanted into the femoral artery and vein. Dose-response curves to acetylcholine (ACh), noradrenaline (NA), phenylephrine (Phen) and angiotensin II (AII), were obtained in 6 cholesterol-fed and 6 control rabbits before and after isradipine (code name PN200-110) 100 micrograms kg-1. After these experiments the animals were killed and aortic rings were suspended in an organ bath. ACh but not nitroprusside-induced relaxation was impaired in atherosclerotic but not in control preparations. 2. ACh decreased blood pressure dose-dependently in both groups of rabbits even though ACh did not relax the aortae of the same rabbits in vitro. 3. Blood pressure effects reflect mostly changes in resistance vessels. The pressor effects of NA, Phen and AII were enhanced in atherosclerotic compared with normal rabbits. 4. After a dose of 100 micrograms kg-1 isradipine the dose-response curves of all agents were shifted to the right. The differences between atherosclerotic and control rabbits disappeared, except for the AII-induced pressor response, which remained enhanced in atherosclerotic animals. The calcium antagonist thus only partly corrected the atherosclerosis-associated hyperresponsiveness to vasoconstrictor agents.

Acetylcholine↗
PubMed1986

Mutual inhibition and synergistic effects of ergotamine and the calcium antagonist darodipine.

The interaction between ergotamine 3 and 30 micrograms/kg i.v. and darodipine (PY108-068) 30 micrograms/kg i.v. was studied in anaesthetized cats. Ergotamine decreased heart rate, cardiac output and total peripheral conductance dose-dependently. Ergotamine caused regional vasoconstriction (measured with tracer microspheres) in the heart, kidneys, adrenals, liver, spleen, skin and arterio-venous shunts but dilatation in the pancreas and skeletal muscle, possibly attributable to serotoninergic stimulation. Darodipine reversed most ergotamine effects except those on the spleen, skin and arterio-venous shunts. Since constriction of arterio-venous shunts was not inhibited, ergotamine is unlikely to lose its effectiveness in migraine patients under concomitant dihydropyridine treatment, while unwanted vasoconstrictor effects are likely to be diminished.

Animals↗
PubMed1985

Modification of the vasoconstrictor effects of noradrenaline and serotonin by the selective calcium antagonist PY 108-068 in the peripheral circulation of anesthetized cats.

The effects of a noradrenaline (NA, 1 microgram/kg min) or serotonin (5-HT, 10 micrograms/kg min) infusion on regional blood flow and conductance were assessed with tracer microspheres before and after administration of the calcium-antagonist PY 108-068 (PY; 30 micrograms/kg). Chloralose-urethane-anesthetized cats were pretreated with propranolol 1 mg/kg i.v. or chlorisondamine 1 mg/kg i.v. for the experiments with NA or 5-HT, respectively. PY attenuated the NA-induced increase of blood pressure and the decrease of total peripheral conductance. The NA-induced vasoconstriction, occurring mainly in the kidneys, adrenals, liver, spleen, and arteriovenous shunts, was significantly attenuated by PY. The vessels of heart, stomach, pancreas, and skeletal muscle were not constricted by NA. In contrast, 5-HT dilated or tended to dilate almost all vascular beds examined. Only arteriovenous shunts were constricted. PY did not antagonize this vasoconstrictor effect. Moreover, after but not before PY treatment, a coronary vasoconstrictor effect of 5-HT was seen. Antivasoconstrictor effects of PY were observed both in organs where dihydropyridines normally elicit vasodilatation and in organs where such compounds have no vasodilator effects in the absence of a vasoconstrictor infusion. The regional distribution of the antivasoconstrictor effects was different for each vasoconstrictor tested so far (angiotensin II, 5-HT, and NA). The sites of action of calcium antagonists in peripheral blood vessels appear to depend on the mechanism of activation operating at that site and at the time of the investigation.

Animals↗
PubMed1984

Studies on the mechanism of action of the vasoconstrictive dihydropyridine, CGP 28392.

The effects of the vasoconstrictive dihydropyridine, CGP 29392, upon tension development and 45Ca2+ uptake by vascular smooth muscle were studied using isolated rabbit aorta. CGP 28392 did not elicit contractile responses when administered alone but lowered the threshold for the contractile response to elevated extracellular K+. CGP 28392 also increased the magnitude of the contractions elicited by submaximal concentrations of K+. This effect was competitively antagonized by PY 108-068, a Ca antagonist of the dihydropyridine class. Similarly, the relaxing effects of PY 108-068 upon KCl-constricted rabbit aorta were competitively antagonized by CGP 28392. The calcium content of unstimulated tissues was only minimally increased by CGP 28392 but the 45Ca2+ uptake stimulated by depolarizing levels of K+ was markedly augmented by this agent. Further analysis of the data indicated that CGP 28392 did not alter the relationship between tension development and 45Ca2+ uptake. In contrast, CGP 28392 was much less effective in augmenting the contractile response and 45Ca2+ uptake elicited by noradrenaline. These results thus support the hypothesis that CGP 28392 predominantly facilitates Ca2+ entry through potential-operated Ca2+ channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1982

A simple cutter for fresh tissue to facilitate the investigation of intramyocardial blood flow with tracer microspheres in cats and rabbits.

Tracer microspheres (TM) allow the measurement of regional tissue blood flow. For this purpose the tissue must be cut into the regions selected for measurements. We describe a simple tissue cutter, that greatly facilitates accurate and reproducible cutting of fresh tissue. We have demonstrated its usefulness for obtaining measurements of myocardial blood flow in different layers of the left ventricular free wall of hearts of anesthetized cats and conscious rabbits. Since complete trapping of the TM is essential for blood flow measurements by this method, we investigated the minimal TM size needed by comparing results obtained with different size microspheres. 25 and 15 micrometer TM were trapped equally well by all layers of the left ventricle, but TM smaller than 15 micrometers were not trapped completely. From the size distribution of the 7-10 micrometer TM, we estimated that the functional diameter of the largest capillaries was somewhat smaller (about 7.6 micrometer) in the subepicardial (epi) than in the subendocardial (endo) layer (7.9 micrometer) in both species. When measured with 15 micrometer TM, intramyocardial distribution of blood flow was comparable to that reported for dogs and sheep. In open chest cats, the endo/epi ratio was 1.25 and 1.28, and in conscious rabbits it was 1.35. We conclude that TM with diameters between 10 and 15 micrometers are suitable for measuring intramyocardial blood flow in cats' and rabbits' hearts, and that unlike in dogs and sheep, 7-10 micrometer TM cannot be used.

Animals↗
PubMed1981

Acceleration of blood in the aorta: a parameter useful for evaluating cardiotonic and afterload reducing substances.

Peak acceleration of blood in the aorta was measured in chloralose-urethane anesthetized open-chest cats with an electromagnetic flow probe around the aortic root. The effects of substances used in the treatment of chronic congestive heart failure were evaluated in this model. Isoprenaline, noradrenaline, and ouabain increased peak acceleration dose-dependently, while blood pressure, cardiac output, and heart rate were influenced differently by each drug. Nitroglycerin and nitroprusside sodium, afterload reducing agents used for the treatment of congestive heart failure, also increased peak acceleration; an effect that in the case of nitroprusside sodium was shown to be mediated by beta-receptors and probably attributable to baroreceptor activation. This simple model was judged to be suitable for evaluating positive inotropic and afterload reducing substances as long as its low sensitivity to heart rate increasing interventions is correctly appreciated.

Animals↗
PubMedDate not supplied

PY 108-068, a dihydropyridine derivative, and verapamil interact differently with the ouabain effects on the heart and the peripheral circulation.

In previous experiments PY 108-068 (PY) has been found to have more potent calcium antagonistic effects on vascular smooth muscle than on myocardial tissue. We now investigated the effects of PY and verapamil (V) on the increases in myocardial contractile force (measured with a strain gauge) and regional vasoconstriction (measured with tracer microspheres) effected by an infusion of 40 micrograms/kg ouabain into anaesthetized cats. Ouabain significantly increased contractile force of the left ventricle and caused vasoconstriction in the heart, stomach, small intestine, pancreas, spleen and skin, but not in the kidneys, brain, adrenals and liver. PY (30 micrograms/kg i.v.) and V (0.3 mg/kg i.v.) antagonized the vasoconstrictor effects of the glycoside in all organs except the skin, i.e. also in organs, where the calcium antagonists normally do not cause vasodilatation. However, PY did not affect the increase in contractile force, whereas V attenuated both the cardiac and peripheral vascular effects of ouabain. The results demonstrate the preferential action of PY on peripheral blood vessels as opposed to left ventricular myocardial tissue. Heart rate was decreased by both PY and V but the PQ-interval was lengthened only by V suggesting that PY in contrast to V preferentially acts on the sinus node rather than A-V conduction. A combination of PY with a glycoside might be beneficial in the treatment of cardiac failure, since this calcium antagonist apparently does not antagonize the positive inotropic action of ouabain on the heart while reducing afterload and reversing the undesirable vasoconstriction induced by cardiac glycosides.

Animals↗
PubMedDate not supplied

Trapping and intramyocardial distribution of microspheres with different diameters in cat and rabbit hearts in vitro.

Microsphere trapping was determined in isolated perfused Langendorff hearts of cats and rabbits with 7.9-, 8.6-and 14.6-micrometers microspheres. Only the largest spheres were completely trapped whereas significant and relevant fractions of the smaller spheres were found in the perfusate leaving the heart. These fractions were 8.3 and 3.0% of the total activity for the cat and 6.7 and 2.1% for the rabbit hearts. The density of spheres trapped in the outer layer was similar with all three sizes of microspheres, whereas the density in the subendocardial layer increased with increasing microsphere size and paralleled overall trapping in both species. The complete trapping of 14.4-micrometer microspheres proves that there were no leaks and no arterio-venous shunts. The results obtained with the two smaller sphere sizes suggest regional differences in trapping and therefore regional differences in capillary size. Only selected batches of commercially available 7-10 micrometer spheres should be used. The mean diameter should be 10 micrometer with a standard deviation no larger than 1 micrometer. 15-micrometer spheres may not be ideal but, nevertheless, give reasonable values, for intramyocardial distribution of blood flow in cats and rabbits.

Animals↗
PubMedDate not supplied

Effect of PY 108-068, a new calcium antagonist, on general hemodynamics and regional blood flow in anesthetized cats: a comparison with nifedipine.

The hemodynamic effects of PY 108-068 (PY), a new benzoxadiazolyle dihydropyridine derivative with calcium antagonistic effects on vascular smooth muscle, were investigated in chloralose--urethane-anesthetized open-chest cats. Regional blood flow was measured with tracer microspheres. PY lowered blood pressure and increased cardiac output similarly to nifedipine (N). Unlike the latter drug, PY decreased heart rate without showing evidence of cardiodepression. Right atrial pressure increased slightly less than with N. All these effects were dose dependent in the dose range from 1 to 43 micrograms/kg i.v.. PY and N increased myocardial blood flow to the same extent initially, and redistributed it in favor of the outer layer of the left ventricle. The activity of sublingually administered PY was comparable to that of a similar intravenous dose. An approximately three times larger intraduodenal dose was needed for similar effects. Our results provide preliminary in vivo evidence that it is possible to separate the negative chronotropic from the negative inotropic effects of calcium antagonists.

Anesthesia↗
PubMedDate not supplied

Effects of the new calcium antagonist PN 200-110 on the myocardium and the regional peripheral circulation in anesthetized cats and dogs.

The effects of PN 200-110 (PN), isopropyl 4-(2,1,3- benzoxadiazol -4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dim ethyl-3- pyridinecarboxylate , on the cardiovascular system were investigated. In chloralose-urethane-anesthetized cats PN decreased blood pressure (BP) and heart rate (HR) and increased cardiac output (CO) and total peripheral resistance dose dependently after intravenous doses of 1-10 micrograms/kg. Regional blood flow changes effected by an intravenous dose of 10 micrograms/kg were measured with microspheres. Flow to the heart, brain, and skeletal muscle increased selectively, and intramyocardial flow was redistributed in favor of the left ventricular subepicardial layer. The duration of action differed for various effects. The bradycardia was short lasting, and the cerebral vasodilatation persisted longest. It was not possible to predict the duration of action of PN on different target tissues by observing only one variable such as BP. Chloralose-urethane-anesthetized open-chest dogs appeared to be more sensitive to PN than cats. A dose of 3 micrograms/kg i.v. markedly increased coronary flow, lowered BP, increased CO, and tended to lower HR and to increase myocardial contractility. Myocardial oxygen consumption was lowered. PN did not alter diastolic excitation threshold or any electrocardiographic intervals in closed-chest anesthetized dogs. Absence of myocardial depression, potent vasodilator activity, and long duration of action might render PN useful for the treatment of hypertension and angina pectoris.

Anesthesia↗
PubMedDate not supplied

Stereoselectivity at the calcium channel: opposite action of the enantiomers of a 1,4-dihydropyridine.

The stereoisomers of the new dihydropyridine derivative 202-791 [isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-3 -pyridinecarboxylate] were synthesized separately and tested on isolated rabbit aortic rings for effects on depolarization-induced contraction and depolarization-stimulated uptake of 45Ca2+. The racemic mixture enhanced contraction of rabbit aortic rings at low levels of depolarization but inhibited contraction and 45Ca2+ uptake at high levels of depolarization. The IC50 values were 2.0 X 10(-7) and 1.7 X 10(-7) M, respectively. The R enantiomer inhibited contraction and 45Ca2+ uptake with IC50 values of 3.2 X 10(-8) and 4.3 X 10(-8) M, respectively. This compound showed no stimulant activity. By contrast, the S enantiomer of 202-791 shifted the concentration-response curve for depolarization-induced contraction in an almost parallel fashion to the left, thus enhancing contraction. The EC50 value for this effect at a KCl concentration of 16 mM was 1.8 X 10(-7) M. This compound enhanced 45Ca2+ uptake concentration dependently at all levels of depolarization tested. Thus, the stereoisomers of a dihydropyridine derivative may behave as a calcium entry blocker or a calcium entry enhancer on vascular smooth muscle, depending only on the stereochemistry. If asymmetric compounds elicit effects suggesting a dualistic action at the calcium channel, then the stereoisomers should be prepared.

Animals↗
PubMedDate not supplied

Mechanism of the vasodilator effects of the cardiotonic agent DPI 201-106.

DPI 201-106 (DP) is a new cardiotonic agent. In experiment on cats anaesthetized with chloralose/urethane, it lowered blood pressure and caused peripheral vasodilatation at doses between 0.3 and 3 mg/kg, infused i.v. Furthermore, DPI lowered heart rate and increased coronary blood flow (measured with tracer microspheres). The mechanism of this vasodilator action was investigated in experiments in vitro using rabbit aorta. DPI inhibited depolarization-induced contraction. The effect was strongly dependent on the contact time. The pIC50 (-log IC50) values for 15 min, 1, and 2 h pretreatment were 4, 5.2, and 5.7, respectively. 45Ca2+ uptake into rabbit aorta was inhibited by DPI with pIC50 values of 4.3, 5.1, and 5.7, respectively, for the pretreatment periods indicated above. The excellent agreement between effects on tension development and calcium uptake suggests that the mechanism of vasodilatation observed in vivo is related to calcium antagonism.

Animals↗