Genetic aspects of variability in superficial vein responsiveness to norepinephrine

Luthra, Atul; Borkowski, K. R.; Carruthers, S. George

doi:10.1038/clpt.1991.41

Cited by 30 publications

(20 citation statements)

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“…Samples were assayed by reversed-phase high-performance liquid chromatography with electrochemical detection. 9 Dihydroxybenzylamine was used as the internal standard. The mobile phase was a citrate/ acetate buffer containing 5% (vol/vol) MeOH, pH 4.4.…”

Section: Determination Of Isoproterenol Concentrations In Organ Bath mentioning

confidence: 99%

Human insulin-mediated enhancement of vascular beta-adrenergic responsiveness.

1994

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Insulin may play an important role in the physiological and/or pathophysiological regulation of the cardiovascular system. Defects in insulin secretion and insulin receptor responsiveness have been associated with increased peripheral resistance and hypertension. The mechanisms linking these events remain unclear. To assess the effect of insulin on 0-adrenergic-mediated vasodilation, we examined aortic ring segments obtained from normotensive male Wistar and spontaneously hypertensive rats. Vessels were maximally preconstricted with phenylephrine (3 junol/L). Relaxation was induced by either isoproterenol (10 jtmol/L) or sodium nitroprusside (10 nmol/L), and the relaxant response was followed for 20 minutes. Insulin exposure did not alter phenylephrine-mediated constriction. However, insulin mediated I nsulin may play an important role in the physiological and/or pathophysiological regulation of the cardiovascular system. Insulin augments sympathetic activity, 1 increases renal sodium retention, 2 and increases forearm blood flow.3 Furthermore, hyperinsulinemia and insulin resistance have been associated with elevated blood pressure. 4-5 However, a causal relation has yet to be established.Recent studies have focused on the role of insulin as an endogenous vasodilator. In humans, insulin increases blood flow and reduces vascular resistance despite augmentation of sympathetic activity.1 Further insulin-mediated increases in blood flow were suggested to occur via a /3-adrenergic mechanism (ie, were blocked by /3-adrenergic receptor antagonists) in both canine 6 and human 3 studies. However, the mechanism for this effect remains unexplained. Therefore, to determine whether insulin might have a role in regulating vascular responsiveness through alterations in adrenergic responsiveness, we examined the effect of insulin on tension development in isolated rat thoracic aortic ring segments. Data indicated that insulin enhances /3-adrenergic responsiveness in vessels from normotensive animals, that this effect is endothelium dependent, and that this enhancement is lost in spontaneously hypertensive rats (SHR). Methods DrugsPhenylephrine hydrochloride, (±)isoproterenol hydrochloride, sodium nitroprusside, and acetylcholine chloride were obtained from Sigma Chemical Co. Human insulin was obReceived August 23,1993; accepted in revised form January 19, 1994.From the Departments of Medicine and Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada.Correspondence to Dr R.D. Feldman, Room 6-L13, University Hospital, PO Box 5339, London, Ontario, Canada N6A 5A5. a dose-dependent increase in isoproterenol-induced relaxation, to a maximum of 120±4% of baseline isoproterenolmediated relaxation, with an EC*, for insulin of 32 pmol/L in aortic rings from Wistar rats. Insulin exposure also did not alter nitroprusside-mediated relaxation. In contrast to the results obtained in rings from Wistar rats, insulin did not enhance isoproterenol-mediated responses in rings from spontaneously hypertensiv...

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Section: Determination Of Isoproterenol Concentrations In Organ Bath mentioning

confidence: 99%

Human insulin-mediated enhancement of vascular beta-adrenergic responsiveness.

1994

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“…Table i shows the characteristics of the IDDM diabetic and non-diabetic subjects studied. The control subjects were significantly younger (p < 0.02) than the normoalbuminuric diabetic group but not the microalbuminuric group, and there was no difference in age between the two diabetic groups; age has previously been shown not to affect hand-vein reactivity [13]. Mean arterial blood pressure was higher in both diabetic groups in comparison to the control subjects (p < 0.01), but there was no difference between the two diabetic groups (p = 0.8).…”

Section: Discussionmentioning

confidence: 87%

“…Therefore, although there is clearly an association between peripheral nerve dysfunction and vascular reactivity to NA (with approximately 50 % interdetermination, r 2 = 0.43 for the microalbuminuric group), it is unlikely that this alone can be responsible for the exaggerated vascular reactivity found in our previous study. It may be that the microalbuminuric IDDM patients also have other factors, such as genetic predisposition [13,22], which are responsible for their exaggerated responses.…”

Section: Discussionmentioning

confidence: 99%

Asymptomatic peripheral nerve dysfunction and vascular reactivity in IDDM patients with and without microalbuminuria

et al. 1994

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SummaryAbnormal vascular reactivity has been implicated in the aetiology of diabetic microvascular disease and we have previously demonstrated enhanced contractility of hand veins to noradrenaline in insulin-dependent diabetic (IDDM) patients with microalbuminuria. We have now assessed the possible contribution of subclinical peripheral nerve dysfunction to exaggerated vascular reactivity in microalbuminuric patients. Twenty-five IDDM patients (15 with microalbuminuria), none of whom had symptomatic neuropathy, and 10 control subjects were studied. Vasoconstrictor responses were measured in dorsal hand veins using noradrenaline and phenylephrine. Conduction in median, peroneal and sural nerves was assessed using electrophysiology, and autonomic function using standard cardiovascular reflex tests. The noradrenaline dose causing 50 % vasoconstriction was significantly lower in the microalbuminuric diabetic subjects compared with normoalbuminuric (3.6(1.7) mean (SEM) ng/min vs 20.1(6.0) ng/min, p = 0.0002) and non-diabetic subjects (35.1(5.0) ng/min; p < 0.0001). However, reactivity to phenylephrine did not differ between the groups. Median nerve motor conduction velocity was significantly slower in microalbuminuric (48.4(1.4) m/s) than in normoalbuminuric (52.7(1.2) m/s, p = 0.04) and non-diabetic subjects (56.7(0.9) m/s, p = 0.0001). In the diabetic group overall, there was a strongly positive linear correlation between vascular response to noradrenaline and conduction velocity in both the median nerve (r = 0.62, p = 0.0009) and peroneal nerve (r = 0.53, p = 0.006). There was no correlation between phenylephrine-induced responses and motor conduction velocity in either nerve, nor were indices of autonomic function correlated with vascular reactivity to either agent. Enhanced vascular reactivity to noradrenaline ((x 1-and a2-agonist), but not phenylephrine (ch-agonist only), in subclinical neuropathy is correlated with severity of nerve damage. This suggests that damage to presynaptic inhibitory a2-adrenoceptors is in part responsible for the exaggerated vascular responses found in microalbuminuric subjects. [Diabetologia (1994) Vascular tone is determined by neural and hormonal influences, including noradrenaline (NA) [1], which acts on vascular smooth muscle (x-adrenoceptors to cause vasoconstriction. These receptors can be stimulated by NA released locally from sympathetic nerve endings, and into the circulation from nerve endings and the adrenal medulla. We have previously reported that vascular reactivity to NA is exaggerated in normotensive insulin-dependent diabetic (IDDM) patients with incipient nephropathy [2]. We measured vascular responses in veins on the dorsum of

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“…α 2 -ARs have been shown to have importance in the regulation of vascular tone in humans at least in digital [22] and coronary [23] arteries and in large superficial veins [6]. Family studies on the inter-individual variability in DHV constriction responses to norepinephrine have suggested that multiple genetic polymorphisms may be involved [9,10], but the genetic determinants of DHV responsiveness to α 2 -AR activation have not been identified.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic factors may contribute significantly, as DHV sensitivity to constrict after infusion of norepinephrine is a familial trait [9,10]. Studies with mono- and dizygotic twin pairs and parents and their children have clearly demonstrated that genetic factors contribute significantly to the inter-individual differences in the responses of DHVs to norepinephrine, but did not further examine the genes involved [9,10]. …”

Section: Introductionmentioning

confidence: 99%

A polymorphism in the protein kinase C gene PRKCB is associated with α2-adrenoceptor-mediated vasoconstriction

Posti

Salo²,

Ruohonen

et al. 2013

Pharmacogenetics and Genomics

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Objectives α2-Adrenoceptors (α2-AR) mediate both constriction and dilatation of blood vessels. There is substantial inter-individual variability in dorsal hand vein (DHV) constriction responses to α2-AR agonist activation. Genetic factors appear to contribute significantly to this variation. The present study was designed to identify genetic factors contributing to the inter-individual variability in α2-AR-mediated vascular constriction induced by the selective α2-AR agonist dexmedetomidine. Methods DHV constriction responses to local infusion of dexmedetomidine were assessed by measuring changes in vein diameter with a linear variable differential transformer. The outcome variable was log-transformed dexmedetomidine ED50 for constriction. A genome-wide association study (GWAS) of 433,378 single nucleotide polymorphisms (SNPs) was performed for the sensitivity of DHV responses in 64 healthy Finnish subjects. 20 SNPs were selected based on the GWAS results and their associations with the ED50 of dexmedetomidine were tested in an independent North American study population of 68 healthy individuals. Results In both study populations (GWAS and replication samples), the SNP rs9922316 in the gene for protein kinase C type β was consistently associated with dexmedetomidine ED50 for dorsal hand vein constriction (unadjusted p = 0.00016 for the combined population). Conclusions Genetic variation in protein kinase C type β may contribute to the inter-individual variation in dorsal hand vein constriction responses to α2-AR activation by the agonist dexmedetomidine.

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Genetic aspects of variability in superficial vein responsiveness to norepinephrine

Cited by 30 publications

References 0 publications

Human insulin-mediated enhancement of vascular beta-adrenergic responsiveness.

Human insulin-mediated enhancement of vascular beta-adrenergic responsiveness.

Asymptomatic peripheral nerve dysfunction and vascular reactivity in IDDM patients with and without microalbuminuria

A polymorphism in the protein kinase C gene PRKCB is associated with α2-adrenoceptor-mediated vasoconstriction

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