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J Ahlner

Publications and source records attributed to J Ahlner.

At least 73 records · Page 4Linked to original sources
PubMed1989

A novel neurogenic vasodilator mechanism in bovine mesenteric artery.

The presence of a neurogenic vasodilator mechanism was investigated in isolated bovine mesenteric arteries (BMAs) that were precontracted with phenylephrine. Electrical field stimulation induced tetrodotoxin-sensitive relaxations in guanethidine-pretreated BMAs. The relaxation occurred after a delay of about 5-8 seconds and amounted to 25-35% in different sets of experiments. The relaxation was not affected by classical receptor antagonists such as atropine (1 microM), cimetidine (3.9 microM), clemastine (2.8 microM), naloxone (1.2 microM), 8-phenyltheophylline (1 microM), propranolol (3.4 microM), ritanserin (5 microM), or droperidol (13 microM). The nicotinic acetylcholine-receptor stimulant 1,1-dimethyl-4-phenyl-piperazinium iodide (10 microM) was without effect on the relaxation, and removal of the endothelium of the arteries also had no effect. The bee venom component apamin (1 microM), which has been shown to block the nonadrenergic, noncholinergic relaxation in intestinal and vascular smooth muscle from other species, was also found to be without effect on the relaxation induced by electrical field stimulation in BMAs. Pretreatment of the arteries with capsaicin (1 microM) had no effect per se and did not affect the relaxation induced by a subsequent stimulation. Capsaicin has been suggested to release neurotransmitter and eventually deplete neurons containing substance P and calcitonin gene-related peptide. Furthermore, exogenously applied calcitonin gene-related peptide (1-100 nM), substance P (10 nM-1 microM), and vasoactive intestinal peptide (0.3-30 nM) gave relaxations amounting to less than 10%. It is postulated that electrical field stimulation induces a neurogenic relaxation of a nonadrenergic, noncholinergic nature in BMAs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Effect of pertussis toxin and the cGMP lowering agent LY83583 on the relaxation induced by nitrates in isolated bovine mesenteric artery. A comparison between glyceryl trinitrate, isosorbide dinitrate and isosorbide 5-mononitrate.

The effect of pertussis toxin (PTX) and the cyclic GMP-lowering agent LY83583 on the relaxatory response induced by glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN) and isosorbide-5-mononitrate (ISMN) in bovine mesenteric artery was investigated. Pretreatment with PTX (100 ng/ml; 2h) induced a 100-fold right shift of the concentration-effect curve for GTN, while no effect on the relaxatory response elicited by ISDN and ISMN was seen 10 microM LY83583 markedly reduced the relaxatory effect of all the organic nitroesters. Based on the different sensitivity towards PTX it is suggested that GTN induces vascular smooth muscle relaxation by a partly different mechanism than ISDN and ISMN. However, cGMP seems to play a crucial role in mediating the relaxatory response of all the tested organic nitroesters since LY83583 profoundly suppressed the relaxatory response.

Aminoquinolines↗
PubMed1989

Purification of soluble guanylate cyclase enzyme from human platelets.

Soluble guanylate cyclase enzyme was purified from human platelets. The soluble fraction of the lysed platelets was sequentially chromatographed over DEAE-sepharose, GTP-agarose and HPLC size-exclusion columns. About 0.1 mg of purified enzyme could be obtained from 2000 ml of platelet rich plasma. The purified enzyme had the specific activity of 205 nmoles cGMP/mg/min with Mn2+ as cofactor. The enzyme eluted at the 160,000 daltons position from the size-exclusion column. Electrophoresis in the presence of sodium dodecyl sulfate under reducing conditions revealed two subunits of 83,000 and 71,000 daltons respectively.

Blood Platelets↗
PubMed1988

Decreased plasma levels of cyclic GMP in patients with chest pain and angiographically normal coronary arteries.

Plasma levels of cyclic nucleotides were determined by radioimmunoassay in patients with (1) angina-like chest pain and normal coronary arteries (suspected spasm angina), (2) exercise-induced angina, and (3) heart diseases other than angina pectoris, as well as in (4) normal subjects. The concentration of cyclic GMP in plasma was significantly lower (by at least three-fold) in patients with suspected spasm angina, as compared with the other groups. No statistically significant difference in the plasma levels of cAMP was observed between the different patient groups. The low cGMP levels in plasma from patients with angina-like chest pain and normal coronary arteries might be an indication of a defect in the vasculature, making it more sensitive to contractile stimuli.

Adult↗
PubMed1988

Glyceryl trinitrate inhibits phosphatidylinositol hydrolysis and protein kinase C activity in bovine mesenteric artery.

The effect of glyceryl trinitrate (GTN) on relaxation, cGMP levels, phosphorylase a activity, phosphatidylinositol hydrolysis and protein kinase C activity was studied on isolated bovine mesenteric arteries (BMA). Two concentrations of GTN were tested, 0.1 nM representing a high affinity component and 1 microM representing a low affinity component of the GTN induced relaxation of BMA, giving a relaxation of 20% and 60% and a 2-fold and 5-fold increase in cGMP, respectively. Phosphatidylinositol hydrolysis and protein kinase C activity were significantly, and to the same extent, reduced at both concentrations tested, whereas the phosphorylase a activity was significantly reduced at the higher concentration only, which might indicate a reduction of the free intracellular Ca2+-concentration at high concentrations of GTN. It is concluded that a therapeutically relevant concentration (0.1 nM) of GTN induces relaxation and an increase in cGMP in bovine mesenteric arteries. The relaxation seems to be associated with an inhibition of phosphatidylinositol hydrolysis and a reduction of the protein kinase C activity.

Animals↗
PubMed1988

Once daily dosing of enalapril in congestive heart failure.

Enalapril 40 mg or tolerated dose was given once daily to 21 patients with congestive heart failure (CHF), NYHA class III, in addition to treatment with digoxin and/or diuretics. After an 8-week open period, 19 patients were randomized to continue enalapril or to receive a placebo in a double-blind manner. After the first enalapril dose of 10 mg, maximal reduction of blood pressure (BP) occurred after 4 hours (mean 34/17 mmHg; p less than 0.001). No further reduction was found after higher doses. After the open period significant improvement was shown as judged by NYHA class (p less than 0.01), stroke volume (p less than 0.05), maximal working capacity (p less than 0.05), heart volume (p less than 0.01) and maximum rate pressure product (RPPmax) (p less than 0.001). Urinary aldosterone markedly decreased (p less than 0.01), whereas serum potassium and serum creatinine slightly increased (p less than 0.05). At the end of the blind period enalapril was superior to placebo concerning NYHA class (p less than 0.01), heart volume (p less than 0.05) and RPPmax (p less than 0.05). Other parameters, including aldosterone in urine, did not differ between the groups. Carry-over effects may have diminished the differences between enalapril and placebo. Diarrhoea (n = 5) and hypotension (n = 5) were the most common side-effects. Overall, enalapril was well tolerated and seems to be useful in single daily doses in the treatment of CHF.

Adult↗
PubMed1988

Relaxation of bovine mesenteric artery induced by glyceryl trinitrate is attenuated by pertussis toxin.

Low concentrations (less than 1 nM) of glyceryl trinitrate (GTN) induced a considerable relaxation of bovine mesenteric arteries (BMA) brought to sustained contraction by the addition of phenylephrine. The concentration-response curve of GTN showed a biphasic pattern with a high and a low affinity component. Pretreatment with pertussis toxin (IAP) attenuated the high affinity relaxant component, but not the low affinity component or the relaxation induced by NaNO2. A polyclonal antibody to IAP counteracted the effect of the toxin on the GTN-response. Low concentrations of GTN increased the cGMP level in BMA via activation of the high affinity pathway. This effect was also inhibited in preparations pretreated with IAP. It is suggested from the present study that GTN induces relaxation of vascular smooth muscle via two separate pathways, the high affinity pathway might involve a receptor-complex interaction with a regulatory protein.

Animals↗
PubMed1988

Studies on vascular smooth muscle tolerance to different cGMP-mediated vasodilators and cross-tolerance to glyceryl trinitrate.

In the present study the possible existence of cross-tolerance between GTN, atrial natriuretic peptide and the endothelium-dependent vasodilators acetylcholine and calcium ionophore A23187 was investigated. Pretreatment of bovine mesenteric arteries (BMA) with GTN (0.44 mM) for 2 hrs caused a significant (P less than 0.001) right-shift of the concentration-effect curve for GTN as compared to controls (pD2 = 6.96 +/- 0.208 and 4.57 +/- 0.148 in controls and GTN treated vessels, respectively), thus indicating the development of tolerance. Cross-tolerance between GTN and the endothelium-dependent vasodilators acetylcholine and calcium ionophore A23187 was found as judged from cumulative concentration-effect curves. The cGMP response evoked by 1 microM GTN was markedly blunted in the GTN-pretreated vessels (P = 0.0056). Similarly the cGMP elevation induced by 10 microM acetylcholine and 0.1 microM calcium ionophore A 23187 was significantly reduced in GTN-pretreated muscle specimens (P = 0.0475 and P = 0.0103, respectively). No cross-tolerance between GTN and atrial natriuretic peptide (ANP) could be established from tension studies. Furthermore, the cGMP response induced by atrial natriuretic peptide was not significantly different in GTN-tolerant vessels as compared to in controls (P = 0.2097). BMA specimens were also incubated with acetylcholine and ANP (2 hrs and 6 hrs, respectively) and the vessels were thereafter tested for their responsiveness to acetylcholine, ANP and GTN. Preincubation with acetylcholine (10 microM) for 2 hrs did not affect the relaxant response to a subsequent challenge with acetylcholine or GTN. Preincubation of BMA with ANP (0.1 microM) for 6 hrs was also without effect on the responsiveness to ANP or GTN.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1987

Retention and subsequent liberation of glyceryl trinitrate in organ baths influences the relaxation of bovine mesenteric arteries contracted by various agents.

The present study compares the relaxant effect of glyceryl trinitrate (GTN) on isolated bovine mesenteric artery in commonly used organ baths made of glass and in disposable vials made of polyethylene, a material known to be inert to GTN. It is shown that the EC50-value for the GTN-induced relaxation is about 1000-fold lower when polyethylene vials are used. The study also shows that the reason for this is that the materials previously used in the experimental equipment retain and subsequently liberate GTN at re-use. In organ baths of glass with holders of acrylics, GTN concentrations of about 20 nM were found during equilibration, i.e. before start of the experiment. The vessel specimens become partly tolerant during equilibration in such organ baths and thus the vessels are less sensitive to GTN. The findings may explain the discrepancy between previous in vitro and in vivo studies. Low concentrations known to be effective in vivo have not been demonstrated to have a relaxant effect in earlier in vitro studies.

Animals↗
PubMed1987

Nitrates. Mode of action at a cellular level.

The nitrates used therapeutically in angina pectoris and congestive heart failure are, from a chemical point of view, organic nitroesters. Their principal pharmacological effect is vascular smooth muscle relaxation, leading to vasodilation, which explains their therapeutic effects. Several mechanisms have been proposed for their mode of action at the cellular level, in order to explain vascular smooth muscle relaxation. Today, there is strong evidence that organic nitroesters stimulate the enzyme guanylate cyclase in the smooth muscle cell. This enzyme produces a cyclic nucleotide, cyclic guanosine-3',5'-monophosphate (cGMP), which in turn eventually lowers the free calcium concentration in the cytosol to induce relaxation. The exact mechanism by which the organic nitroesters stimulate guanylate cyclase is still obscure. Preliminary results from our laboratory indicate that there may be more than one mechanism responsible for the activation of the enzyme. Knowledge of the mode of action at the cellular level is probably important in order to understand the mechanism(s) behind the development of tolerance towards the organic nitroesters.

Calcium↗
PubMed1987

Nitrate tolerance from a biochemical point of view.

Tolerance to nitrate vasodilators appears to be a general phenomenon that encompasses all known drugs belonging to this group, with the possible exception of molsidomine, for which tolerance has not yet been unambiguously proven. The mechanism behind tolerance development is still obscure, although decreased distribution of drug to the target tissue (i.e. the vascular wall) may be important. In addition, the production of cyclic guanosine-3',5'-monophosphate (cGMP) [the alleged mediator of nitrate-induced vascular smooth muscle relaxation] is reduced in tolerant tissue, while its degradation is increased. These changes could be due to a direct effect on the enzymes involved in the formation and degradation of cGMP in the cell, i.e. guanylate cyclase and phosphodiesterase, respectively. Furthermore, there is some evidence that the degradation of organic nitroesters in the vascular wall is reduced in tolerant tissue. This could result in a reduced production of unstable chemical intermediates (e.g. nitrosothiols), which have been suggested to act as mediators of guanylate cyclase.

Cyclic GMP↗
PubMed1987

Development of tolerance towards glyceryl trinitrate in vitro. Low concentration induced tolerance and changes in cyclic guanosine-3',5'-monophosphate metabolism.

Bovine mesenteric arteries were exposed to glyceryl trinitrate (GTN) in vitro for 2 and 8 h in a low concentration (0.1 nmol/l), that equals the plasma concentrations reached by using GTN-discs in patients with angina pectoris. After reexposure to GTN a significantly reduced relaxant response was observed. In the concentration range 1 pmol/l to 10 nmol/l a 10-fold right shift of the concentration-effect curve was noted as compared to control vessels not previously exposed to GTN. The reduced relaxant response was accompanied by a significantly impaired ability to form cyclic guanosine-3',5'-monophosphate (cGMP). The results are interpreted as a development of tolerance towards GTN at the level of the vascular smooth muscle cell. A concentration of GTN (0.1 mmol/l) previously used to induce tolerance in vitro, produced a much more pronounced shift to the right of the concentration-response curve, especially in the concentration range 10 nmol/l to 0.1 mmol/l. This might indicate that tolerance to GTN can be induced by 2 different mechanisms, which in turn might be interpreted as the existence of 2 mechanisms of action by GTN in inducing vascular smooth muscle relaxation.

Animals↗
PubMed1986

The relaxant effect of glyceryltrinitrate on isolated human peripheral vein and its relation to cyclic GMP metabolism.

The relaxant effect of glyceryltrinitrate (GTN) on human vena saphena magna was studied in vitro. Vessels contracted by serotonin (0.25 microM) and phenylephrine (0.1 mM) were relaxed to the same extent (EC50 = 10 microM) by GTN, whereas in 100 mM K+-depolarized vessels the relaxation was significantly lower. The relaxant effect produced by GTN was preceded by an elevation of cyclic guanosine-3',5'-monophosphate (cGMP). For 0.1 mM GTN there was a 3-fold increase in cGMP after 3 min. A correlation between relaxation and increase in cGMP was established. When GTN was combined with dipyridamole (5 microM) the relaxant effect of GTN was significantly greater (EC50 = 0.1 microM). Phosphodiesterase inhibition, as a possible mechanism behind the observed better relaxation for the combination (GTN+dipyridamole), is briefly discussed. In conclusion, the relaxant effect of GTN on isolated human vena saphena magna seems to be dependent on the contractile stimuli used, increased by the addition of DIP and to be mediated via cGMP.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Development of tolerance to glyceryl trinitrate in an isolated human peripheral vein and its relation to cyclic GMP metabolism.

Human peripheral vein (v. saphena magna) was exposed in vitro to glyceryl trinitrate (GTN) 0.1 mM for 1 h. The subsequent relaxant effect of GTN (10nM-0.1 mM) on vessels contracted by serotonin (0.25 microM) was significantly reduced on vessels preexposed to GTN as compared to control vessels, indicating a development of partial tolerance as far as the vascular smooth muscle relaxant effect is concerned. The impaired relaxant effect was paralleled by a reduced increment of intracellular cyclic GMP. This is, in turn, probably a consequence of both a diminished guanylate cyclase activity and an elevated phosphodiesterase activity in the GTN-tolerant vessels. The relaxant activity as well as the level of intracellular cyclic GMP were restored in GTN-tolerant vessels by dipyridamole (5 microM), an agent with phosphodiesterase inhibiting properties.

Cyclic GMP↗
PubMed1986

Biological effects of organic nitroesters and their mechanism of action.

Organic nitroesters e.g. glyceryltrinitrate (NTG) are of great clinical importance in the treatment of angina pectoris. The most important of their biological effects is vasodilation of peripheral arteries, peripheral veins and coronary arteries. Other biological effects, of unknown clinical relevance, are effects on myocardial metabolism and on platelet aggregation. In recent years evidences have accumulated that the vasodilating effects of organic nitroesters are mediated via the cGMP-system, although the exact mechanism of activation of the cGMP-producing enzyme guanylate cyclase is still obscure. Further research about this may elucidate the mechanism behind the development of tolerance. Another theory concerning the mechanism behind the vasodilating properties of NTG is that arachidonic acid metabolites are involved. However no clearcut evidences have been presented to support this theory. We show in this paper results indicating that arachidonic acid metabolites are of no importance for the vasodilating effects of NTG, at least not in vitro. NTG has also been shown to decrease the intracellular Ca2+ -concentration, an effect probably mediated via cGMP but the exact underlying mechanism is not yet fully understood.

Humans↗
PubMed1986

Tolerance to organic nitroesters in experimental animals. An assessment of in vitro and in vivo investigations.

This paper will present a short survey of the literature dealing with nitrate tolerance in experimental animals. Tolerance towards organic nitroesters has been experimentally established in animal models both in vivo and in vitro. However the dose of drug used to provoke tolerance has invariably been very high, which makes it difficult to apply experiences from animal experiments to the clinical setting. Several different hypothesis has been put forward in order to explain the mechanism of tolerance. Today, most evidence seem to point towards an altered metabolism of cGMP as a possible cause of tolerance. Cyclic GMP is the second messenger suggested to mediate the vasodilatory effect of organic nitroesters. The proposed role of critical tissue sulfhydryl groups in mediating the smooth muscle relaxant effect of nitroglycerin (NTG) have made experiments concerning reversal and prevention of tolerance to center on the use of various sulfhydryl reactive compounds. The results of these experiments are as yet ambiguous. Several studies show the existence of cross tolerance between NTG and various other vasodilatory organic nitroesters. In contrast no cross tolerance between NTG and chemically unrelated vasodilator drugs has been observed. The endogenous vasodilators acetylcholine and atrial natriuretic factor are known to induce cGMP increases. In view of this, their effect on NTG-tolerant bovine mesenteric arteries was investigated. However no cross-tolerance appears to exist under in vitro conditions.

Animals↗