Relaxation of Bovine Mesenteric Arteries by Glyceryl Trinitrate and Other Nitro‐Compounds: Evidence for Partly Different Mechanisms of Action

Torfgård, Kristina; Ahlner, Johan; Axelsson, Krister L.

doi:10.1111/j.1600-0773.1990.tb00816.x

Cited by 24 publications

(12 citation statements)

References 29 publications

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“…In in vitro studies, pretreatment with pertussis toxin induced a 100-fold right shift of the concentration-effect curve for GTN, suggesting the involvement of a G protein. 31 Baseline GTNinduced relaxation was not significantly different between genotypes. After metabolic improvement, however, the response to GTN was enhanced in carriers of the 825T allele.…”

Section: Discussionmentioning

confidence: 83%

G Protein β3 Gene Variant, Vascular Function, and Insulin Sensitivity in Type 2 Diabetes

Fernández-Real¹,

Peñarroja²,

Richart³

et al. 2003

Hypertension

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Abstract-A common polymorphism (825 C/T) in exon 10 of the GNB3 gene, that encodes for the ␤-3 subunit, has been associated with different degrees of activation of heterotrimeric guanine nucleotide binding proteins (G proteins). Many hormones and neurotransmitters use specific receptors that interact noncovalently with G proteins in the transmembrane signaling process. Among them, insulin uses an inhibitory G protein-sensitive mechanism that is involved in metabolic and vascular events, leading to enhanced glucose transport and vasodilation. We hypothesized differences in peripheral and vascular insulin sensitivity according to GNB3 gene polymorphism in type 2 diabetic patients. To address this issue, we used an intervention-optimization protocol to examine whether diabetic patients with the variant show a different response in terms of insulin-sensitivity. Interindividual differences in baseline insulin sensitivity and vascular dysfunction (vasodilatory response to glyceryl trinitrate) were not attributable to this polymorphism of the GNB3 gene. However, in contrast to normal homozygotes, insulin sensitivity (S I ) significantly improved (Pϭ0.01) in carriers of the 825T variant. Parallel to these findings, stimulated C-peptide tended to decrease, and the response to glyceryl trinitrate significantly improved (Pϭ0.004) among 825T carriers. Body mass index, systolic and diastolic blood pressure, heart rate, or serum lipid levels did not significantly change in either group. Our findings suggest an effect of GNB3 gene polymorphism on important phenotypic variations in type 2 diabetes mellitus. The GNB3 gene polymorphism might be an example of pharmacogenetics, with the underlying etiological genetic defect altering the response to treatment. Key Words: G protein Ⅲ endothelium Ⅲ vascular resistance Ⅲ nitric oxide Ⅲ polymorphism Ⅲ insulin Ⅲ diabetes mellitus M any hormones and neurotransmitters use specific receptors that interact noncovalently with guanine nucleotide binding proteins (G proteins) in the transmembrane signaling process. 1 G proteins comprise a family of ubiquitous signal-transducing proteins. The large G proteins are heterotrimers of alpha, beta, and gamma subunits. The ␤-3 subunit preferentially links to the inhibitory G protein (G i ). A common polymorphism (825 C/T) in exon 10 of the GNB3 gene, which encodes for the ␤-3 subunit, has been recently identified. 2 The 825T allele was associated with a splice variant, which shortens the protein by 41 amino acids and one domain. In vitro studies showed that this truncated protein was associated with increased activation of heterotrimeric G proteins. The GNB3 825T homozygous genotype has been associated with increased body mass index (BMI) among different populations. 3,4 One of the proposed mechanisms is increased signaling by pertussis toxin-sensitive G proteins, which have been shown to stimulate adipogenesis. 5 Increased G i activity could also attenuate G s -mediated lipolysis, leading to impaired adrenergic-mediated lipolysis and obesity. 6 In fac...

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Section: Discussionmentioning

confidence: 83%

G Protein β3 Gene Variant, Vascular Function, and Insulin Sensitivity in Type 2 Diabetes

Fernández-Real¹,

Peñarroja²,

Richart³

et al. 2003

Hypertension

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“…The key mediator of erection NO leads to an activation of the guanylate cyclase catalysing the formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate, which results in the relaxation of smooth muscle cells promoting the blood flow into the corpora cavernosa (Rajfer et al, 1992;Andersson & Wagner, 1995). One study alludes to the fact that cGMP exerts its smooth muscle relaxing effect partially via Gprotein coupled signal transduction (Torfgard et al, 1990). This might explain the improved response of patient's genotype TT to sildenafil .…”

Section: Discussionmentioning

confidence: 97%

Genetic association study of the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms and the risk to develop erectile dysfunction in a German ED population

et al. 2010

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Erectile dysfunction (ED) is often associated with cardiovascular disorders such as hypertension, coronary heart disease, hypercholesterolaemia and diabetes mellitus. The genotypes in the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms have been identified as genetic risk factors for cardiovascular disorders. The association between the genotypes in these polymorphisms and the risk to develop ED was analysed. In 455 German ED patients and 111 age-matched healthy controls genotyping in the candidate polymorphisms was performed after DNA extraction from whole blood. Association studies between the genotype distribution in the control group in comparison with the ED-group and age of onset of the disease as well as erectile response to intracorporal prostaglandin injection in dependence of candidate polymorphism genotype were performed using the SPSS-Software(R). Genotype distribution of the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms was similar in the ED population and the healthy control group. The age of onset of the disease as well as the erectile response to intracorporal prostaglandin injection was independent of the genotypes in the three candidate polymorphisms. In contrast to the previous studies in this analysis, the risk to develop ED is not influenced by the genotypes in the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms.

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“…Several reports have documented enhanced G protein-mediated signal transduction in patients carrying the T allele of GNB3 (18). Torfgard et al reported that glycerol trinitrate (GTN) relaxes vascular smooth muscle cells partially via G protein-dependent mechanisms (19). The nitric oxide (NO)/cyclic GMP pathways are altered in diabetic patients who carry the T allele (20), and the degree of improved insulin sensitivity and the vasodilatory response to GTN are much larger in T allele carriers (14).…”

Section: Discussionmentioning

confidence: 99%

Polymorphism of the G Protein β3 Subunit Gene Influences the Efficacy of Sildenafil in Patients with Pulmonary Hypertension

et al. 2014

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Objective The C825T polymorphism in the G protein β3 subunit gene (GNB3) influences the efficacy of sildenafil in patients with erectile dysfunction. The effects of this polymorphism on the therapeutic response to sildenafil in patients with pulmonary hypertension remains unknown. To investigate whether the GNB3 C825T polymorphism is associated with the clinical efficacy of sildenafil in patients with pulmonary hypertension. Methods Fifty-nine patients (age: 55.6±13.3 [SD] yrs., mean pulmonary arterial pressure (Ppa): 52±11 mmHg) with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension were treated with sildenafil. The pre-and post-treatment parameters, including pulmonary hemodynamics measured using right heart catheterization, the systolic pulmonary arterial pressure estimated on Doppler echocardiography (sPA), the six-minute walk distance (6MWD) and freedom from clinical worsening, were compared between the patients with the TT and CT/CC genotypes. Results The pretreatment parameters were not significantly different between the two groups, with the exception of a lower mean Ppa in the TT group. The post-treatment World Health Organization (WHO) class was significantly better (p=0.03) and the 6MWD values trended toward improvement in the TT genotype patients compared with that observed in the CC/CT genotype patients (p=0.05). The time to clinical worsening was significantly longer in the TT genotype patients than in the CC/CT genotype patients (3-year freedom from clinical worsening: 83.1% vs. 46.0%, p=0.02), while the TT genotype was found to be a significant predictor of freedom from clinical worsening, even after adjusting for the baseline mean Ppa. Conclusion The GNB3 C825T polymorphism influences the efficacy of sildenafil in patients with pulmonary hypertension.

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Relaxation of Bovine Mesenteric Arteries by Glyceryl Trinitrate and Other Nitro‐Compounds: Evidence for Partly Different Mechanisms of Action

Cited by 24 publications

References 29 publications

G Protein β3 Gene Variant, Vascular Function, and Insulin Sensitivity in Type 2 Diabetes

G Protein β3 Gene Variant, Vascular Function, and Insulin Sensitivity in Type 2 Diabetes

Genetic association study of the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms and the risk to develop erectile dysfunction in a German ED population

Polymorphism of the G Protein β3 Subunit Gene Influences the Efficacy of Sildenafil in Patients with Pulmonary Hypertension

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