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J Ahlner

Publications and source records attributed to J Ahlner.

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

Mechanisms of action of nitrates.

Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central nervous system and the myocardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.

Angina Pectoris↗
PubMed1993

Effect of low dose of dipyridamole on glyceryl trinitrate tolerance in healthy volunteers.

Tolerance to glyceryl trinitrate (GTN) was developed in healthy volunteers by treatment with GTN patches, 10 mg/24 h. The difference (supine position-erect position) in systolic blood pressure (SBP) observed after application of GTN patches at the first day disappeared after 24-h transdermal administration for 2-4 consecutive days, indicating that tolerance to GTN had developed in the group of 12 healthy volunteers treated with active drug. Increased HR during the first day also disappeared as a sign of tolerance development to GTN. The phosphodiesterase (PDE) inhibitor dipyridamole (Dip) showed no effect on SBP in either the GTN-tolerant group or in the placebo group, and the tolerance to GTN was not reversed. The present study shows that addition of Dip to GTN cannot reverse GTN tolerance. Plasma concentrations of GTN and its two dinitrate metabolites were measured after transdermal administration. Addition of Dip to GTN showed no influence on the pharmacokinetics of the nitrates in healthy volunteers.

Adult↗
PubMed1993

Involvement of nitric oxide and peptides in the inhibitory non-adrenergic, non-cholinergic (NANC) response in bovine mesenteric artery.

The cyclic GMP mediated non-adrenergic non-cholinergic (NANC) relaxation in field stimulated bovine mesenteric artery and its modulation by various factors was studied. Electrical field stimulation of precontracted (Phe 2.5 microM or histamine 5 microM) bovine mesenteric arteries resulted in relaxations varying between 10-70% in different preparations. Tetrodotoxin (3 microM) completely blocked the inhibitory NANC response. Preincubation with high concentrations (100 microM-1 mM) of NG-nitro-L-arginine for 15 min. significantly reduced the relaxation induced by electrical field stimulation. Blockade of cyclooxygenases and prostaglandin synthesis by indomethacin had no effect on the relaxatory response to electrical field stimulation. Neither the alpha 2-adrenoceptor selective antagonist yohimbine (1 microM) nor the alpha 2-adrenoceptor selective agonist UK 14,304 (1 microM) had any significant effect on the electrical field stimulation-induced relaxation. Pertussis toxin (100 ng/ml) was without effect on relaxations elicited by electrical field stimulation. GTP in the concentration range 10 microM-1 mM slightly potentiated the relaxant response. N-carboxymethyl-Phe-Leu (an inhibitor of enkephalinase) or aprotinin (an inhibitor of several proteases) had no significant effect on the electrical field stimulation response. Addition of trypsin (100 U/ml) in combination with chymotrypsin (20 U/ml) significantly reduced the electrical field stimulation-induced relaxation. In the present study we have found indications for the involvement of nitric oxide and possibly also peptides in mediating the inhibitory NANC response (relaxation) in bovine mesenteric arteries.

Adrenergic alpha-Agonists↗
PubMed1992

Dose-dependent effect of intravenous nitroglycerin on platelet aggregation, and correlation with plasma glyceryl dinitrate concentration in healthy men.

Nitroglycerin has been reported to reduce mortality in patients with acute myocardial infarction. This beneficial effect has been attributed to vasodilation, but it was speculated that part of this effect may be due to altered platelet function. The influence of intravenous nitroglycerin on platelet aggregation was assessed. Eight healthy subjects (aged 22 to 48 years) were studied using filtragometry at baseline, and 3 different nitroglycerin doses. Compared with baseline, aggregation time (which indexes platelet aggregation) increased dose-dependently by 91 +/- 68% (p less than 0.001) at the maximal dose of nitroglycerin (1.1 +/- 0.3 micrograms/kg/min). Plasma concentration-effect relations were observed between nitroglycerin as well as the glyceryl dinitrate metabolites and platelet aggregation (r = 0.6 [p less than 0.002] and r = 0.8 [p less than 0.0001], respectively). It is concluded that increasing doses of intravenous nitroglycerin profoundly and dose-dependently inhibit platelet aggregation. This inhibitory effect correlates with glyceryl dinitrate formation.

Adult↗
PubMed1992

Comparative in vitro study of a series of organic nitroesters: unique biphasic concentration-effect curves for glyceryl trinitrate in isolated bovine arterial smooth muscle and lack of stereoselectivity for some glyceryl trinitrate analogues.

Four different organic nitroesters, constituting a homologous series based on unbranched polyalcohols, were compared with regard to in vitro relaxation of isolated bovine mesenteric arteries contracted with 2.5 microM phenylephrine. The organic nitroesters included ethylene glycol dinitrate (EGDN), dinitratopropane (DPN), glyceryl trinitrate (GTN), and tetranitratobutane. Glyceryl trinitrate exhibited a biphasic concentration-effect relationship, with pD2 values of 11.5 +/- 0.5 and 7.2 +/- 0.2 for the high-pD2 and low-pD2 component of the relaxation curve, respectively. The high-pD2 and low-pD2 component contributed 28 and 72% of the maximal response, respectively. EGDN, DPN, and tetranitratobutane induced monophasic concentration-effect curves with pD2 values of 7.4 +/- 0.1, 7.8 +/- 0.2, and 6.9 +/- 0.6, respectively. Stereoisomeric forms of DPN and tetranitratobutane showed no difference with regard to relaxing potency in bovine mesenteric artery. GTN has a partly unique mechanism for vascular smooth muscle relaxation that distinguishes this compound from other related organic nitroesters.

Animals↗
PubMed1991

Heterogeneity in human soluble guanylate cyclase due to alternative splicing.

Two forms of the smaller subunit of the human soluble guanylate cyclase enzyme have been cloned by using PCR. One of the clones (HSGC-1) is identical to bovine and rat lung smaller subunit cyclase. However, the other (HSGC-2) is lacking 33 amino acids. Comparison of its sequence with published partial genomic sequences of bovine guanylate cyclase indicates that HSGC-2 is formed due to alternative splicing.

Animals↗
PubMed1991

Tissue levels of glyceryl trinitrate and cGMP after in vivo administration in rat, and the effect of tolerance development.

The present study compares the tissue distribution of glyceryl trinitrate (GTN) in plasma, heart, brain, aortic tissue, and adipose tissue from GTN tolerant and GTN nontolerant rats at various time points. Furthermore, the cGMP levels in brain, heart, and aortic tissue were studied at various time points as well as the concentration-effect relationship for GTN in aorta isolated at different time points after the last exposure to GTN. Concentrations of GTN were found to be higher in all tissues studied as compared with plasma, and the concentrations of GTN were higher in tissues from tolerant rats as compared with nontolerant rats, except for aortic tissue. Concentration-effect curves obtained in vitro showed that aortic smooth muscle was still tolerant 24 h after the last dose of GTN. The cGMP level in brain was significantly increased by 40% 2 h after a single dose of GTN (50 mg/kg) and in aortic tissue by 50% at 15 min and at 2 h after a single dose of GTN (50 mg/kg). There was no effect on cGMP in brain, while an increase was seen in aortic tissue 15 min after the last dose in tolerant animals. No change in cGMP level was seen in heart neither in nontolerant nor in tolerant animals at 15 min and at 2 h. No effect on cGMP levels in brain, heart, and aortic tissue was seen 8, 16, and 24 h after exposure to GTN in either tolerant or nontolerant rats. In conclusion, GTN does not involve the cGMP system in heart, and tolerance development caused a less pronounced GTN-induced cGMP increase in aortic tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Role of nitric oxide and cyclic GMP as mediators of endothelium-independent neurogenic relaxation in bovine mesenteric artery.

Electrical field stimulation (EFS) of phenylephrine-contracted bovine mesenteric arteries pretreated with guanethidine elicited a relaxation that amounted to roughly 40%. This relaxation was sensitive to tetrodotoxin pretreatment, suggesting a neurogenic origin. The EFS-induced relaxation was correlated to an increase in cGMP level, from 14.2 +/- 2.5 pmol/g wet wt in nonstimulated arteries to 31.6 +/- 3.4 pmol/g wet wt after 1 minute of EFS. cAMP values were not affected by EFS. Methylene blue (5 microM) and the compound LY 83583 (10 microM), inhibitors of soluble guanylate cyclase, inhibited the EFS-induced relaxation by 60% and 50%, respectively. Zaprinast (1 microM), a selective inhibitor of cGMP degradation, significantly (p = 0.005) potentiated the EFS-induced relaxation. The relaxation induced by EFS in bovine mesenteric arteries exhibits characteristics similar to the relaxations evoked by organic nitroesters and endothelium-dependent vasodilators, both of which are suggested to be mediated by cGMP and probably with nitric oxide as the common activator of the cGMP system. The possible involvement of nitric oxide as a mediator of EFS-induced relaxations was investigated with the use of known modulators of endogenous nitric oxide production. Preincubation of the arteries with 1 mM arginine or 1 mM N-alpha-benzoyl-L-arginine, both reported to potentiate endogenous nitric oxide production, or 5 mM L-canavanine, 0.25 mM NG-monomethyl-L-arginine, or 0.1 mM NG-nitro-L-arginine, alleged inhibitors of endogenous nitric oxide production, were without effect on the relaxation induced by EFS. However, pyrogallol, a generator of superoxide anions, was a potent inhibitor of relaxations induced by EFS in bovine mesenteric arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1990

Effects of pertussis toxin on vasodilation and cyclic GMP in bovine mesenteric arteries and demonstration of a 40 kD soluble protein ribosylation substrate for pertussis toxin.

The inhibitory nucleotide-regulatory protein (Gl) has been shown to lose its adenylate cyclase inhibitory effect upon treatment with pertussis toxin. To find out whether a pertussis sensitive mechanism is involved in the regulation of the cGMP-system, bovine mesenteric arteries were incubated in buffer containing pertussis toxin, and the relaxation and intracellular cGMP accumulation induced by different groups of vasodilating agents were studied. The present results show a pertussis toxin induced decrease in relaxation as well as a decrease in the cGMP-elevation induced by the endothelium dependent vasodilators acetylcholine and calcium ionophore A 23187. Arteries treated with atrial natriuretic peptide showed no alterations in relaxation or cGMP content after incubation with pertussis toxin. A 40 kD soluble ribosylation substrate for pertussis toxin was identified in bovine mesenteric artery. These results suggest that a pertussis toxin sensitive mechanism is involved in the vasodilating mechanism of acetylcholine and calcium ionophore A 23187, while no evidence for such a mechanism could be found regarding the vasodilatory action of atrial natriuretic peptide.

Acetylcholine↗
PubMed1990

Studies of the effect of glyceryl trinitrate and cyclic GMP on calcium turnover in bovine mesenteric artery.

It was recently observed that the relaxation induced by glyceryl trinitrate (GTN) showed a biphasic concentration-response curve; a high-sensitivity component represented by concentrations less than 1 nM and a low-sensitivity component represented by concentrations greater than 1 nM. The effect of two glyceryl trinitrate concentrations (0.1 nM and 1 microM) were tested on the uptake of 45Ca2+ to tissue pieces of bovine mesenteric arteries (BMA) as well as on the uptake of 45Ca2+ to a microsomal preparation of BMA. The effect of GTN and 8-Br-cGMP was also studied on the IP3-induced release of Ca2+ from the microsomal preparation preloaded with 45Ca2+. The influence of IP3 and GTN on the activity of Ca2(+)-ATPase in the microsomal preparation was tested as well. The phenylephrine-stimulated uptake of Ca2+ to tissue pieces of BMA was significantly reduced by the high GTN-concentration (1 microM) but not by the lower concentration. The uptake of Ca2+ to the microsomal preparation was significantly stimulated by the two GTN-concentrations tested, as well as by 8-Br-cGMP (0.1 mM). The calcium release induced by IP3 (1 microM) from the microsomal preparation was inhibited by both the low and the high GTN-concentration and by 8-Br-cGMP (0.1 mM). The Ca2(+)-ATPase activity was stimulated by both GTN-concentrations tested while it was inhibited by IP3. It is concluded that GTN is able to induce a reduction of the free intracellular Ca2+ by several mechanisms, which are of importance for the relaxation represented by the high-affinity component. The low-affinity component in addition reduces the inflow of Ca2+ over the plasma membrane.

Animals↗
PubMed1990

Relaxation of bovine mesenteric arteries by glyceryl trinitrate and other nitro-compounds: evidence for partly different mechanisms of action.

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), isosorbide-5-mononitrate (IS-5-MN) and sodium nitroprusside (SNP) in bovine mesenteric artery (BMA) was investigated. Pretreatment with PTX (100 ng/ml; 2 hr induced a 100-fold right shift of the concentration-effect curve for GTN, while no effect on the relaxatory response elicited by ISDN, IS-5-MN or SNP was seen. The relaxatory effect of all the substances tested was markedly reduced by LY83583 (10 microM). The basal cGMP level as well as the GTN induced increase in cGMP were markedly reduced when BMA was exposed to LY83583. The substance also reduced the activation of soluble guanylate cyclase by SNP. Based on the different sensitivity towards PTX it is suggested that GTN induces vascular smooth muscle relaxation by a partly different mechanism than ISDN, IS-5-MN and SNP. As far as the GTN induced relaxation is concerned the sensitivity towards PTX indicates the involvement of regulatory component, possibly a G-protein. However, cyclic GMP seems to play a crucial role in mediating the relaxatory response of all the substances tested since the cGMP-lowering agent LY83583 markedly inhibited the relaxant response induced by all the vascular relaxant agents investigated.

Aminoquinolines↗
PubMed1989

Influence of long-term prenalterol treatment on the heart rate and the beta-adrenoceptor binding-sites in rat myocardium.

The density of beta- adrenoceptors has been determined on membranes prepared from rat myocardium. Long-term administration of prenalterol resulted in an increase in the density of receptors, without any change in affinity. The average heart rate increase induced by intravenous prenalterol administration to denervated rats was, however, similar in the prenalterol pretreated and the control groups. We conclude that long-term treatment with a partial beta1-adrenoceptor agonist lead to an increased beta-adrenoceptor density in the myocardium.

Animals↗
PubMed1989

Tissue distribution of glyceryl trinitrate and the effect on cGMP levels in rat.

In order to study distribution in tissue, rats were treated subcutaneously with glyceryl trinitrate, GTN, (50 mg/kg). The concentrations of GTN were measured in plasma, brain, heart, adipose tissue and aortic tissue at different sampling times by a gas chromatographic method with electron-capture detection. The peak GTN-concentration was reached after 2 hours in all tissues examined. The highest concentration of GTN was found in adipose tissue, where the level was approximately forty times higher than in plasma. The concentration of GTN in brain, heart and aortic tissue was about 2-3 times as high as in plasma. The cGMP level was measured in heart and brain. An increase of the cGMP level was found in brain 2 hours after GTN administration. No cGMP increase was found in heart tissue. The results indicate a substantial distribution of GTN to tissue, and an increase of cGMP in brain. The distribution of the substance in the tissues as shown, might have both pharmacokinetic and pharmacodynamic implications.

Adipose Tissue↗