High-Dose, Not Low-Dose Insulin Increases the Vasoconstrictor Effect of Norepinephrine in Spontaneously Hypertensive Rats: Effects of Antihypertensive Treatment

Rizzoni, Damiano; Porteri, Enzo; Piccoli, Alfonso; Castellano, Maurizio; Pasini, Giancarlo; Guelfi, Daniele; Muiesan, María Lorenza; Rosei, Enrico Agabiti

doi:10.1159/000025679

Cited by 4 publications

(5 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results are partly different in respect to what we have previously observed in an animal model of genetic hypertension (an increased response to norepinephrine in hypertensive rats but not in normotensive ones) [7]. However, in both cases, insulin elicits a prohypertensive effect in pathological conditions (hypertension, diabetes), and not in normal controls.…”

Section: Discussioncontrasting

confidence: 99%

“…Therefore, endothelin-1 might be responsible for insulin-induced changes in vascular contractility [40]. In fact, an endothelin-1-mediated increase of the norepinephrine response was previously demonstrated, at least in rats [7]. Finally, as previously mentioned, it is also possible that interactions between insulin and leptin may be impaired in pathological conditions with consequent loss of nitric oxide-induced vasodilatation.…”

Section: Discussionmentioning

confidence: 99%

“…In aortic rings of Wistar-Kyoto normotensive rats (WKY), low-concentration insulin (715 pmol/l) reduces the vasoconstrictor effect of norepinephrine; however, this effect is not present in young, prehypertensive spontaneously hypertensive rats (SHR) [6]. We have previously demonstrated that high-concentration insulin (715 nmol/l) may induce an increase in the reactivity to norepinephrine in mesenteric small resistance arteries of adult SHR but not in normotensive, age-matched WKY [7]. …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of Insulin on Endothelial and Contractile Function of Subcutaneous Small Resistance Arteries of Hypertensive and Diabetic Patients

et al. 2008

Self Cite

View full text Add to dashboard Cite

The effect of insulin on the vasoconstriction induced by norepinephrine is at present controversial. We have previously demonstrated that high-concentration insulin may induce an increased reactivity to norepinephrine in mesenteric small resistance arteries of spontaneously hypertensive rats. The aim of the present study was to evaluate the effects of low- and high-concentration insulin on the concentration-response curves to norepinephrine and acetylcholine in subcutaneous small resistance arteries of hypertensive and diabetic patients. Twelve normotensive subjects (NT), 11 patients with essential hypertension (EH), 8 patients with non-insulin-dependent diabetes mellitus (NIDDM), and 8 patients with both EH and NIDDM (EH + NIDDM) were included in the study. Subcutaneous small resistance arteries were dissected and mounted on an isometric myograph. Concentration-response curves to norepinephrine (from 10^–8 to 10^–5 mol/l) and acetylcholine (from 10^–9 to 10^–5 mol/l) were performed in the presence or absence of insulin 715 pmol/l (low concentration) and 715 nmol/l (high concentration). A significant reduction in the contractile response to norepinephrine was observed in NT after preincubation of the vessels with both low- and high-concentration insulin. No reduction was observed in NIDDM and EH + NIDDM, while a significant decrease was obtained in EH with high-concentration insulin. Moreover, a significant difference in reduction in contractile response at maximal concentration of norepinephrine in the presence of low-concentration insulin was observed in NT compared to EH (p = 0.03), NIDDM (p = 0.02), and EH + NIDDM (p = 0.05), whereas no difference was observed with high-concentration insulin. No differences in the concentration-response curves to acetylcholine before or after precontraction with either low- or high-concentration insulin were observed in any group. In conclusion, insulin at low (physiological) concentrations seems to induce a decreased reactivity to norepinephrine in subcutaneous small resistance arteries of NT, but this effect was lost in EH, NIDDM and EH + NIDDM. This effect does not seem to involve acetylcholine-stimulated nitric oxide release.

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of Insulin on Endothelial and Contractile Function of Subcutaneous Small Resistance Arteries of Hypertensive and Diabetic Patients

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…Dose-dependent effects of insulin on endothelin-mediated vasoconstriction have been reported in arterioles isolated from normal rats during concurrent NOS synthase antagonism (9) and in vascular rings from spontaneously hypertensive rats (43). These observations suggest that a second source of vascular dysfunction may be necessary to demonstrate insulinstimulated vasoconstriction via endothelin.…”

Section: Discussionmentioning

confidence: 78%

Hyperinsulinemia fails to augment ET-1 action in the skeletal muscle vascular bed in vivo in humans

Lteif

Fulford

Considine³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Endogenous endothelin action is augmented in human obesity and type 2 diabetes and contributes to endothelial dysfunction and impairs insulin-mediated vasodilation in humans. We hypothesized that insulin resistance-associated hyperinsulinemia could preferentially drive endothelin-mediated vasoconstriction. We applied hyperinsulinemic-euglycemic clamps with higher insulin dosing in obese subjects than lean subjects (30 vs. 10 mU.m(-2).min(-1), respectively), with the goal of matching insulin's nitric oxide (NO)-mediated vascular effects. We predicted that, under these circumstances, insulin-stimulated endothelin-1 (ET-1) action (assessed with the type A endothelin receptor antagonist BQ-123) would be augmented in proportion to hyperinsulinemia. NO bioactivity was assessed using the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine. Insulin-mediated vasodilation and insulin-stimulated NO bioavailability were well matched across groups by this approach. As expected, steady-state insulin levels were approximately threefold higher in obese than lean subjects (109.2 +/- 10.2 pmol/l vs. 518.4 +/- 84.0, P = 0.03). Despite this, the augmentation of insulin-mediated vasodilation by BQ-123 was not different between groups. ET-1 flux across the leg was not augmented by insulin alone but was increased with the addition of BQ-123 to insulin (P = 0.01 BQ-123 effect, P = not significant comparing groups). Endothelin antagonism augmented insulin-stimulated NO bioavailability and NOx flux, but not differently between groups and not proportional to hyperinsulinemia. These findings do not support the hypothesis that insulin resistance-associated hyperinsulinemia preferentially drives endothelin-mediated vasoconstriction.

show abstract

“…A recent study has indeed demonstrated that incubation with a high dose (715 nmol/L) but not a low dose (715 pmol/L) of insulin increases the vasoconstrictor effect of NE in resistance vessels of spontaneously hypertensive rats. 35 This effect was attenuated by ET-receptor blockade, suggesting that enhanced NE responses were at least partially mediated by ET. Accordingly, ET-1 has been reported to enhance adrenergic vasoconstriction, 36 suggesting that sympathetic activation in hyperinsulinemic states could be linked to ET.…”

Section: Discussionmentioning

confidence: 96%

Insulin-Induced Biphasic Responses in Rat Mesenteric Vascular Bed

Misurski

McNeill

et al. 2001

Hypertension

View full text Add to dashboard Cite

Abstract-The vasodilatory capacity of insulin has been widely reported, yet some investigators have not noted this effect.Because insulin has been shown to enhance endothelin release, we speculated that endothelin could be attenuating insulin-evoked vasodilation. We examined the effect of ex vivo insulin perfusion on vascular resistance by using the Sprague-Dawley rat mesenteric vascular bed. In methoxamine-preconstricted preparations, insulin (3.0 pmol/L to 10 nmol/L) evoked a concentration-dependent decrease in perfusion pressure (PP) with a maximal response of 42.0Ϯ9.2%, whereas continuous exposure to 10 nmol/L insulin induced a 51.8Ϯ3.5% relaxation. Further exposure to 10 nmol/L insulin resulted in the generation of endothelin and a subsequent loss of the vasodilatory response. Indomethacin had no effect on vascular responses. The vasodilatory response was significantly inhibited by nitric oxide synthase inhibition (20.5Ϯ4.2%; PϽ0.01) and calcium-activated potassium channel blockade (28.5Ϯ3.7%; PϽ0.05). Endothelial denudation attenuated the vasodilatory component (20.3Ϯ7.1%; PϽ0.01) and altered the biphasic pattern of the response. The decline in insulin-evoked vasodilation was significantly prevented by an endothelin-A antagonist (BQ123), an endothelin-B antagonist (BQ788), and nonselective endothelin blockade with both BQ123 and BQ788. These results demonstrate that the endothelium is intimately involved in regulating the vascular response to insulin. Insulin promotes the release of nitric oxide and endothelium-derived hyperpolarizing factor. During sustained exposure to higher concentrations, this vasodilatory effect is countered by the pathological generation of endothelin. Key Words: insulin Ⅲ nitric oxide Ⅲ vasodilation Ⅲ endothelin Ⅲ endothelium Ⅲ mesenteric arteries T he ability of insulin to induce vasodilation is integral to the regulation of skeletal muscle blood flow and glucose delivery. [1][2][3] Insulin-mediated vasodilation is impaired in insulin-resistant patients, suggesting a close relation between insulin resistance and hypertension. 4,5 However, despite the potential significance, the mechanism(s) underlying direct vascular effects of insulin remain controversial. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Several studies in animals and humans attribute the vasodilatory effect of insulin to enhanced generation of endotheliumderived nitric oxide (EDNO). 2,[11][12][13][14][15][16] On the contrary, there have been reports supporting an endothelium-independent mechanism. 5-10 Incubation with insulin has been shown to reduce cytosolic-free calcium levels 6 and to increase the expression of the sodium pump gene, leading to hyperpolarization of vascular smooth muscle (VSM) cells. 7 Insulin enhancement of vascular ␤-adrenergic responsiveness has also been reported in normotensive animals and humans. 8,9 In the perfused rat mesenteric vascular bed (MVB), insulinevoked vasodilation has been linked to the activation of calcitonin gene-related peptide receptors on the VSM cells. 10 Inte...

show abstract

High-Dose, Not Low-Dose Insulin Increases the Vasoconstrictor Effect of Norepinephrine in Spontaneously Hypertensive Rats: Effects of Antihypertensive Treatment

Cited by 4 publications

References 44 publications

Effects of Insulin on Endothelial and Contractile Function of Subcutaneous Small Resistance Arteries of Hypertensive and Diabetic Patients

Effects of Insulin on Endothelial and Contractile Function of Subcutaneous Small Resistance Arteries of Hypertensive and Diabetic Patients

Hyperinsulinemia fails to augment ET-1 action in the skeletal muscle vascular bed in vivo in humans

Insulin-Induced Biphasic Responses in Rat Mesenteric Vascular Bed

Contact Info

Product

Resources

About