Search PubMed⌕ Search

Biomedical subjects

C Aalkjaer

Publications and source records attributed to C Aalkjaer.

At least 55 records · Page 3Linked to original sources
PubMed1994

The effect of cocaine and desipramine on neuronal uptake of [3H]-noradrenaline and sensitivity to noradrenaline of rat mesenteric resistance arteries.

1. The effects of cocaine and desipramine (DMI) on neuronal uptake (uptake1) of [3H]-noradrenaline (NA) and isometric tension development to exogenous NA were assessed in mesenteric resistance arteries of Wistar rats. 2. Both drugs concentration-dependently inhibited [3H]-NA uptake1, DMI being more potent than cocaine. The maximum inhibition produced by each drug was the same as that produced by denervation with 6-hydroxydopamine. In denervated vessels there was no effect of cocaine on [3H]-NA uptake1. 3. Cocaine, in the same concentration range which caused inhibition of uptake1, increased the sensitivity to NA, while DMI, in a concentration range which inhibited uptake1, did not increase the sensitivity to NA and at high concentrations reduced the sensitivity and maximal response to NA. Since DMI affected responses to NA but not responses to vasopressin and potassium its effect is probably related to blockade of alpha 1-adrenoceptors. 4. We conclude that the effect of cocaine on the sensitivity to NA reflects inhibition of uptake1 in rat resistance arteries, while DMI cannot be used to assess the functional effect of uptake1 in this preparation.

Animals↗
PubMed1994

Normalization of resistance artery structure and left ventricular morphology with a perindopril-based regimen.

Twenty-five patients with newly diagnosed or poorly regulated essential hypertension were randomly selected from a larger group referred to hospital. Treatment was initiated with perindopril (4 to 8 mg od). If normotension was not achieved, isradipine (5 to 10 mg od) was added and, if necessary, hydralazine was added. Before treatment and at the end of a nine-month period of normotension (diastolic blood pressure less than 90 mmHg), 24 h blood pressure and echocardiographic measurements were performed and resistance artery structure was determined. Twenty age- and sex-matched normotensives were used as controls. During antihypertensive treatment, mean blood pressure was reduced from 128 +/- 11 to 103 +/- 6 mmHg. Left ventricular mass was reduced from 300 +/- 76 to 198 +/- 54 g. The media:lumen ratio of the resistance arteries decreased from 9.8 +/- 2.6% to 7.8 +/- 1.9%. Control subjects exhibited a media:lumen ratio of the same magnitude (7.9 +/- 2.0). Regression of left ventricular mass correlated significantly with regression of the media:lumen ratio with a coefficient of 0.59 (P < 0.05). Results indicate that a perindopril-based regimen is extremely efficient in normalizing resistance artery and cardiac ventricular structures within one year of treatment. The impact of these findings on the excess cardiovascular morbidity and mortality in arterial hypertension still remains to be demonstrated.

Antihypertensive Agents↗
PubMed1993

Free cytosolic Ca2+ measured with Ca(2+)-selective electrodes and fura 2 in rat mesenteric resistance arteries.

Free cytosolic Ca2+ was measured with sub-micrometer-tip, double-barrelled, Ca(2+)-selective electrodes and fura 2 in rat mesenteric resistance arteries. The purpose was to establish intracellular free Ca2+ concentration ([Ca2+]i) values in resting and stimulated vessels. Isolated vessels were mounted for isometric force measurements. Measured with electrodes, mean [Ca2+]i was 115 and 708 nM under resting and norepinephrine-activated conditions, respectively. Fura 2 was calibrated intracellularly including determination of the intracellular dissociation constant (Kd) of the fura 2:Ca2+ complex. The intracellular Kd was 342 nM. With this value of Kd, fura 2 measurements of mean [Ca2+]i were 129 and 537 nM under resting and norepinephrine-activated conditions, respectively. The values measured with the two techniques were thus in good accordance.

Animals↗
PubMed1993

Histology of subcutaneous small arteries from patients with essential hypertension.

The purpose of the present study was to determine the cellular basis for the increased ratio of media thickness to lumen diameter (media-lumen ratio) consistently found in the peripheral resistance arteries from patients with essential hypertension using an unbiased stereological principle (the "disector"). Segments of subcutaneous resistance arteries (approximately 200 microns internal diameter) were isolated from gluteal biopsies of skin and subcutaneous fat taken from 16 untreated patients with essential hypertension and 16 age- and sex-matched normotensive control subjects. Measured under standardized conditions (ie, relaxed and under controlled mechanical conditions) on an isometric myograph, vessels from hypertensive patients had a significant (P < .05) reduction in lumen diameter and an increase in media-lumen ratio (P < .05) compared with vessels from normotensive control subjects. These changes were not associated with alterations in the estimated media volume per segment length. After these measurements had been made, the arteries were fixed, serial sectioned, and stained. The volume fraction of smooth muscle cells within the media was estimated by point counting on photomicrographs of the vessels. Using the disector principle, we determined the numerical density (number per unit volume) of smooth muscle cells within the media of each vessel and calculated the average smooth muscle cell volume (1775 +/- 122 [mean +/- SEM] and 1532 +/- 112 microns 3, hypertensive and normotensive, respectively, P > .05) on the basis of these measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1993

Force, membrane potential, and [Ca2+]i during activation of rat mesenteric small arteries with norepinephrine, potassium, aluminum fluoride, and phorbol ester. Effects of changes in pHi.

In activated rat mesenteric small arteries, the effect of pHi on force, membrane potential, and free cytosolic calcium ([Ca2+]i) was assessed. Arteries were mounted in a myograph for isometric force development, and [Ca2+]i, pHi, or membrane potential was measured simultaneously with force. During activation with norepinephrine, potassium, aluminum fluoride (AlF-4), and phorbol 12-myristate 13-acetate (PMA, a phorbol ester), the vessels depolarized and [Ca2+]i increased, although the ratio of force to [Ca2+]i was less during potassium activation than with the other types of activation. Changes in pHi, with a constant pHo, were induced with NH4Cl or by changing PCO2. In resting vessels, the effects of the changes in pHi on tension, membrane potential, and [Ca2+]i were negligible. In vessels activated with norepinephrine or AlF-4, alkalinization caused an acute decrease of tone, which could be explained by a decrease in [Ca2+]i consequent to repolarization of the membrane. In vessels activated with potassium or PMA, the effects of alkalinization were smaller. This is consistent with acute alkalinization, affecting steps proximal in the excitation-contraction coupling distal to activation of G proteins. Acidification caused a transient increase in tone and [Ca2+]i, irrespective of the mode of stimulation, without affecting the membrane potential. Ryanodine did not abolish the transient increase in tone and [Ca2+]i. Thus, acute intracellular acidification may induce tone by release of an intracellular ryanodine-insensitive calcium pool or by affecting transmembranal calcium flux although in a membrane potential-independent way.

Aluminum↗
PubMed1993

Effects of ATP and related nucleotides on the tone of isolated rat mesenteric resistance arteries.

The relationship between ecto-ATPase activity and the vasoactive effect of ATP is unclear. Previously we have characterized the ectonucleoside triphosphatase activity of isolated rat mesenteric small arteries and now characterize the effect of nucleotides on the tone of these arteries. In resting arteries, ATP caused concentration-dependent contractions that were transient and could not be reproduced within 2 h. Transient contractions in response to ATP also were elicited in arteries precontracted with norepinephrine, but the potency of ATP was increased and responses to repeated stimulations could be obtained. Contractions were followed by relaxation. The response to ATP was unaffected by 100 microM theophylline, 1 microM propranolol or removal of the endothelium. Transient contractions followed by relaxation were caused also by ADP, 2-methyl-thio-ATP (2meSATP) and alpha, beta-methylene-ATP (alpha, beta-meATP). UTP caused sustained contractions, whereas GTP and ITP had little effect. The rank order of potency (alpha, beta-,mATP > ATP > ADP) suggested that P2x purinoceptors were responsible for the contractions, whereas the rank order of potency for the relaxation (alpha, beta-meATP > or = ATP > 2meSATP) was not consistent with the relaxation being mediated by P2Y purinoceptors as defined originally. Desensitization of the contractile response to ATP by alpha, beta-meATP was variable. In contrast, inhibition of the response to ATP was obtained consistently and dose-dependently with GTP.

Adenosine Triphosphate↗
PubMed1992

Tyrosine kinase inhibitors block calcium channel currents in vascular smooth muscle cells.

Selective inhibitors of tyrosine kinases, tyrphostin 23 and genistein, produced concentration-dependent inhibition of voltage-operated calcium channel currents in vascular smooth muscle cells isolated from rabbit ear artery. The potency of these two structurally dissimilar inhibitors was similar to that reported for their action as inhibitors of tyrosine kinases. Daidzein, an inactive analogue of genistein, had little inhibitory effect on calcium channel currents at concentrations below 300 microM consistent with an action of these agents at a tyrosine kinase. However, tyrphostin 1, a reportedly less active tyrphostin derivative, also inhibited calcium channel currents with a potency similar to tyrphostin 23. These findings suggest that voltage-operated calcium channels in vascular smooth muscle may be modulated by endogenous tyrosine kinase(s) which display different sensitivities to inhibitors compared with the epidermal growth factor (EGF) receptor. Alternatively the possibility of direct blocking actions of these inhibitors at voltage-operated calcium channels cannot be excluded.

Animals↗
PubMed1992

Endogenous and exogenous agonist-induced changes in the coupling between [Ca2+]i and force in rat resistance arteries.

The relationship between isometric tension and free cytoplasmic calcium, [Ca2+]i, was investigated in rat isolated resistance arteries using fura-2. Depolarisation with 125 mM K+ induced a tonic contraction, while [Ca2+]i increased transiently but stabilised above resting [Ca2+]i. Furthermore, the tension/[Ca2+]i ratio was lower during activation with 125 mM K+ if the effect of endogenous noradrenaline (NA) was inhibited. Concentration/response curves with NA and K+ indicated that NA increased the sensitivity to [Ca2+]i. Calcium concentration/response curves in the presence of 10 microM NA or 125 mM K+ showed that NA could induce force at or below resting [Ca2+]i, while for any given bath calcium concentration, [Ca2+]i was similar in the presence of NA or K+. Addition of NA or vasopressin (AVP) to vessels depolarised with 125 mM K+ caused force development but no increase in [Ca2+]i, suggesting that agonists increase the efficacy of [Ca2+]i. However, during activation with AVP the efficacy of [Ca2+]i decreased time-dependently. The results suggest that in resistance arteries [Ca2+]i plays a crucial role in excitation-contraction coupling, but the tension/[Ca2+]i relationship can be modified by exogenous and endogenous agonists.

Animals↗
PubMed1992

Age-dependent changes in alpha-adrenoceptor-mediated contractility of isolated human resistance arteries.

Human subcutaneous resistance arteries (122-298 microns), isolated from 139 patients undergoing surgery, were mounted in an isometric myograph. With the use of multiple regression analysis, five different modes of activation were examined for possible associations with age and mean arterial blood pressure of the patients: the contractile responses to 10 microM norepinephrine (mixed alpha 1-agonist/alpha 2-agonist), perivascular nerve stimulation, 10 microM phenylephrine (alpha 1-agonist), 100 microM B-HT 933 (alpha 2-agonist), and depolarization by potassium chloride. Blood pressure increased significantly with age. Blood pressure independently was not correlated to any mode of activation. With increasing patient age, however, responses to norepinephrine, phenylephrine, and perivascular nerve stimulation decreased, whereas the response to B-HT 933 increased; responses to potassium chloride were unaltered. Also corrected for changes in blood pressure, age independently was negatively correlated to the response to norepinephrine and phenylephrine, whereas a positive, though nonsignificant (P value = 0.12), correlation was observed between age independently and the response to B-HT 933. These data suggest that the ability of isolated human resistance arteries to evoke contractions medicated by postjunctional alpha 1-, but not alpha 2-adrenoceptors, decreases with age.

Adrenergic alpha-Agonists↗
PubMed1991

Characterisation of Ca2+ or Mg(2+)-dependent nucleoside triphosphatase from rat mesenteric small arteries.

When isolated rat mesenteric small arteries were submitted to 2 s of sonication, a nucleoside triphosphatase activity was released to the medium, mainly from the plasma membrane of the vascular smooth muscle cells. The activity was kinetically characterized: It hydrolysed ATP, UTP and GTP with the same substrate affinity and the same specific activity. CaATP, as well as MgATP were substrates for the enzyme with an apparent Km in the micromolar range. ATPase inhibitors: ouabain, vanadate, AlF4-, oligomycin and N-ethylmaleimide were without effect on the hydrolytic activity. Among other modifiers tested only N,N'-dicyclohexylcarbodiimide caused significant (greater than 30%) inhibition. In the presence of micromolecular concentrations of Ca2+ and Mg2+, small (less than 20 mM) concentrations of Na+, K+, Rb+, Cs+ and choline+, irrespective of the nature of the anion, activated the hydrolysis with an equilibrium ordered pattern, but concentrations of monovalent cation salts above 20 mM decreased the hydrolysis rate. No activation by monovalent cation salts was seen at millimolar concentrations of divalent cations and substrate. On the basis of the results a standard mixture is proposed, which allows a sensitive assay of the specific enzyme activity.

Adenosine Triphosphatases↗
PubMed1991

Nucleotide hydrolytic activity of isolated intact rat mesenteric small arteries.

Segments of isolated intact rat mesenteric small arteries were incubated in physiological bicarbonate buffer in the presence of nano- to millimolar concentrations of ATP. ATP was hydrolysed, and when the vessel was transferred from one incubation to another, the enzyme activity was transferred with the vessel, consistent with the presence of an ecto-ATPase. The substrate, ATP, was shown to induce a modification of the hydrolytic activity which occurred the more rapidly the higher the concentration of ATP. The modified system hydrolysed ATP with a decreased substrate affinity. As the substrate induced a modification of the hydrolytic activity, steady-state velocity measurements for determination of kinetic parameters could not be obtained. Nevertheless, it was possible to compare the modification caused by ATP and UTP, and to compare the hydrolysis rates measured with [32P]ATP, [32P]UTP and [32P]GTP. It was concluded that the hydrolytic activity of the vessels did not distinguish between the nucleoside triphosphates (NTPs). In a histidine buffer, the activity was shown to be activated by micromolar concentrations of either Ca2+ or Mg2+, and not to be influenced by inhibitors of P-type, F-type and V-type ATPases. Functional removal of the endothelium before assay did not reduce the measured NTP hydrolysis. At millimolar concentrations of trinucleotide the hydrolysis rate was 10-15 mumol per min per gram of tissue or 0.11-0.17 mumol per min per 10(6) vascular smooth muscle cells. This value is equivalent to the maximal velocity obtained for the Ca2+ or Mg(2+)-dependent NTPase released to the medium upon 2 s of sonication of the vessels (Plesner, L., Juul, B., Skriver, E. and Aalkjaer, C. (1991) Biochim. Biophys. Acta 1067, 191-200). Comparing the characteristics of the released NTPase to the characteristics of the activity of the intact vessel, they showed a strong resemblance, but the substrate-induced modification of the enzyme was seen only in the intact preparation.

Adenosine Triphosphatases↗
PubMed1991

Studies of the renin-angiotensin system in the wall of rat femoral resistance vessels.

The responses to angiotensinogen, angiotensinogen-(1-14) (tetradecapeptide, TDP), angiotensin I, and angiotensin II and the effect of the renin inhibitor, CH-66, the angiotensin-converting enzyme (ACE) inhibitor, perindopril, and the receptor antagonist, saralasin, were investigated in isolated femoral resistance arteries of the rat. The response to angiotensinogen in the presence of kallikrein was also investigated. Angiotensin I and TDP elicited a contraction which was not reduced by CH-66 but was inhibited by perindopril and saralasin. The response to angiotensinogen was small and not blocked by saralasin but the response to angiotensinogen that was mixed with renin for a few seconds was saralasin-sensitive and perindopril and CH-66 showed a tendency to block this response. The response to angiotensinogen was enhanced in the presence of kallikrein. These results suggest (1) the presence of a partial renin-angiotensin system (RAS) in this preparation, (2) that TDP is not converted via renin while both angiotensin I and TDP are converted through ACE in this preparation and (3) that the responses to angiotensinogen and TDP are different.

Angiotensin I↗
PubMed1991

Differential contractile effects of changes in carbon dioxide tension on rat mesenteric resistance arteries precontracted with noradrenaline.

The pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(and -6)-carboxyfluorescein (BCECF) was used to measure intracellular pH (pHi) in rat mesenteric resistance arteries (internal diameter 152-289 microns) mounted in an isometric myograph for simultaneous measurements of force. Extracellular pH was measured using a pH-sensitive electrode. Experiments were designed to test contractile electrode. Experiments were designed to test contractile effects of changes in carbon dioxide tension (PCO2) on vessels precontracted with noradrenaline. An acute increase in PCO2 caused acute intracellular acidification and potentiation of contractility. The longer-term effect, however, was recovery of intracellular pH and vaso-relaxation. Opposite changes in tension and intracellular pH were observed by decreasing PCO2. Qualitatively similar changes in contractility were observed in response to changes in pHi induced by NH4Cl. Thus, effects on vessels precontracted with noradrenaline were biphasic. In another set of experiments, the amplitude of the transient responses to 50 microM noradrenaline in calcium-free media was significantly augmented by an increase in the PCO2, whereas the response to 5 microM noradrenaline 1 min after readdition of calcium to the medium was depressed by the rise in PCO2. These data suggest that acute intracellular acidification causes acute tension development and are consistent with the possibility that the biphasic response to changes in noradrenaline-induced contractility caused by changes in PCO2 may be ascribed to differential effects on calcium mobilisation processes.

Ammonium Chloride↗
PubMed1991

Chloride and bicarbonate transport in rat resistance arteries.

1. The role of chloride and bicarbonate in the control of intracellular pH (pHi) was assessed in segments of rat mesenteric resistance arteries (internal diameter about 200 microns) by measurements of chloride efflux with 36Cl-, of pHi with the pH-sensitive dye 2',7'-bis-(2-carboxyethyl)-5 (and-6)-carboxyfluorescein (BCECF) and of membrane potential with intracellular electrodes. 2. The main questions addressed were whether the previously demonstrated sodium-coupled uptake of bicarbonate in these arteries was also coupled to chloride efflux, and whether sodium-independent Cl(-)-HCO3- exchange was present and played a role in regulation of pHi. 3. The 36Cl- efflux was unaffected by acidification induced by an NH4Cl pre-pulse in the presence as well as in the absence of bicarbonate. This was also true in sodium-free media and in vessels depolarized by high potassium. 4. The membrane potential was unaffected by the acidification associated with wash-out of NH4Cl, and the net acid extrusion during recovery of pHi from the acidification was not affected significantly by depolarization. 5. In the absence of bicarbonate, omission of extracellular chloride caused no change in pHi, but reduced 36Cl- efflux. By contrast, in the presence of bicarbonate, omission of chloride caused an increase in pHi but no change in 36Cl- efflux. Furthermore, the anion transport inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) inhibited the increase in pHi seen in the presence of bicarbonate and reduced the 36Cl- efflux in the presence of bicarbonate. 6. The presence of bicarbonate had no significant effect on the rate of recovery of pHi or the rate of increase of intracellular acid equivalents after an NH4Cl induced alkalinization; also the buffering power was not significantly different in the absence and presence of bicarbonate. Moreover these parameters were not significantly affected by DIDS, although DIDS as previously demonstrated reduced the rate of recovery of pHi from acidification. 7. The membrane potential was not significantly affected by the alkalinization associated with addition of NH4Cl and the rate of recovery of pHi from the alkalinization was not affected by depolarization. 8. The effects of NH4Cl and PCO2 on 36Cl- efflux were complex and could not easily be explained by the changes in pHi.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Steady-state effects of arginine vasopressin on force and pHi of isolated mesenteric resistance arteries from rats.

Control of intracellular pH (pHi) in rat intact resistance arteries has been assessed during activation with arginine vasopressin (AVP) or depolarization with a high potassium concentration. Isometric force of isolated arteries was measured simultaneously with pHi using 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. Under control conditions, pHi was unchanged during AVP-induced force development but fell during potassium activation. After inhibition of Na(+)-HCO3- cotransport, AVP-induced force development was associated with a fall in pHi. After inhibition of Na(+)-H+ exchange pHi was unchanged during activation with AVP. In the absence of bicarbonate, inhibition of Na(+)-H+ exchange caused an exaggerated fall in pHi during activation with AVP. When AVP was added to depolarized vessels, a further force development and an increase in pHi was seen. This increase in pHi was not affected by amiloride but disappeared after inhibition of Na(+)-HCO3- cotransport by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid or sodium-free conditions. These data suggest that AVP, but not depolarization, changes the characteristics of the Na(+)-HCO3- exchange and the Na(+)-H+ exchange so that these transport systems extrude the acid load associated with the force development more efficiently. We suggest that the importance of the effect of vasoconstrictor hormones on the characteristics of acid extrusion from vascular smooth muscle cells (VSMC) in situ lies in their ability to maintain pHi at resting levels during the metabolic load associated with contraction in the tonically active VSMC.

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