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Biomedical subjects

G Iaccarino

Publications and source records attributed to G Iaccarino.

At least 19 recordsLinked to original sources
PubMed1998

Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade.

BACKGROUND: Impaired myocardial beta-adrenergic receptor (betaAR) signaling, including desensitization and functional uncoupling, is a characteristic of congestive heart failure. A contributing mechanism for this impairment may involve enhanced myocardial beta-adrenergic receptor kinase (betaARK1) activity because levels of this betaAR-desensitizing G protein-coupled receptor kinase (GRK) are increased in heart failure. An hypothesis has emerged that increased sympathetic nervous system activity associated with heart failure might be the initial stimulus for betaAR signaling alterations, including desensitization. We have chronically treated mice with drugs that either activate or antagonize betaARs to study the dynamic relationship between betaAR activation and myocardial levels of betaARK1. METHODS AND RESULTS: Long-term in vivo stimulation of betaARs results in the impairment of cardiac +betaAR signaling and increases the level of expression (mRNA and protein) and activity of +betaARK1 but not that of GRK5, a second GRK abundantly expressed in the myocardium. Long-term beta-blocker treatment, including the use of carvedilol, improves myocardial betaAR signaling and reduces betaARK1 levels in a specific and dose-dependent manner. Identical results were obtained in vitro in cultured cells, demonstrating that the regulation of GRK expression is directly linked to betaAR signaling. CONCLUSIONS: This report demonstrates, for the first time, that betaAR stimulation can significantly increase the expression of betaARK1 , whereas beta-blockade decreases expression. This reciprocal regulation of betaARK1 documents a novel mechanism of ligand-induced betaAR regulation and provides important insights into the potential mechanisms responsible for the effectiveness of beta-blockers, such as carvedilol, in the treatment of heart failure.

Animals↗
PubMed1998

Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice.

Heart failure is accompanied by severely impaired beta-adrenergic receptor (betaAR) function, which includes loss of betaAR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of betaAR function is agonist-stimulated receptor phosphorylation by the betaAR kinase (betaARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in betaAR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of betaARK1 or the beta2AR were mated into a genetic model of murine heart failure (MLP-/-). In vivo cardiac function was assessed by echocardiography and cardiac catheterization. Both MLP-/- and MLP-/-/beta2AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP-/-/betaARKct mice had normal LV chamber size and function. Basal LV contractility in the MLP-/-/betaARKct mice, as measured by LV dP/dtmax, was increased significantly compared with the MLP-/- mice but less than controls. Importantly, heightened betaAR desensitization in the MLP-/- mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), was completely reversed with overexpression of the betaARK1 inhibitor. We report here the striking finding that overexpression of this inhibitor prevents the development of cardiomyopathy in this murine model of heart failure. These findings implicate abnormal betaAR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit betaARK1 as a novel mode of therapy.

Animals↗
PubMed1998

Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy.

Hormones and neurotransmitters may mediate common responses through receptors that couple to the same class of heterotrimeric guanine nucleotide-binding (G) protein. For example, several receptors that couple to Gq class proteins can induce cardiomyocyte hypertrophy. Class-specific inhibition of Gq-mediated signaling was produced in the hearts of transgenic mice by targeted expression of a carboxyl-terminal peptide of the alpha subunit Galphaq. When pressure overload was surgically induced, the transgenic mice developed significantly less ventricular hypertrophy than control animals. The data demonstrate the role of myocardial Gq in the initiation of myocardial hypertrophy and indicate a possible strategy for preventing pathophysiological signaling by simultaneously blocking multiple receptors coupled to Gq.

Angiotensin II↗
PubMed1998

Myocardial overexpression of GRK3 in transgenic mice: evidence for in vivo selectivity of GRKs.

Transgenic mice were generated with cardiac-specific overexpression of the G protein-coupled receptor kinase 3 (GRK3) to explore the in vivo role of this GRK in cardiac function. GRK3 is expressed in the heart along with the beta-adrenergic receptor kinase (beta-ARK1) and GRK5. We have previously demonstrated that myocardial-targeted overexpression in transgenic mice of beta-ARK1 (Koch, W.J., H. A. Rockman, P. Samama, R. A. Hamilton, R. A. Bond, C. A. Milano, and R. J. Lefkowitz. Science 268: 1350-1353, 1995) or GRK5 (Rockman, H.A., D.-J. Choi, N. U. Rahman, S. A. Akhter, R. J. Lefkowitz, and W. J. Koch. Proc. Natl. Acad. Sci. USA 93: 9954-9959, 1996) results in significant attenuation of beta-adrenergic signaling and in vivo cardiac function and selective desensitization of angiotensin (ANG) II-mediated cardiac responses. Surprisingly, myocardial overexpression of GRK3 resulted in normal biochemical signaling through beta-adrenergic receptors (beta-ARs), and in vivo hemodynamic function in response to a beta-AR agonist was indistinguishable from that in nontransgenic controls. Furthermore, in vivo signaling and functional responses to ANG II were unaltered. However, myocardial thrombin signaling, as assessed by p42/p44 mitogen-activated protein (MAP) kinase activation, was significantly attenuated in GRK3 transgenic mouse hearts, indicating a distinct in vivo substrate specificity for GRK3.

Adenylyl Cyclases↗
PubMed1998

Adenoviral-mediated inhibition of G beta gamma signaling limits the hyperplastic response in experimental vein grafts.

BACKGROUND: Vein graft intimal hyperplasia is associated with changes in G protein expression. The carboxyl terminus of the beta-adrenergic receptor kinase-1 (beta ARKCT) is known to inhibit G beta gamma-mediated mitogen-activated signaling pathways. This study examines the effects of adenoviral-mediated beta ARKCT infection on the development of intimal hyperplasia in vein grafts. METHODS: New Zealand White rabbits underwent bypass grafting of the carotid artery with the jugular vein. Vein grafts were infected with adenoviral vectors encoding for beta ARKCT (n = 19), beta-galactosidase (n = 3), or empty viral constructs (n = 12). In control animals, vein grafting was performed without infection (n = 10). RESULTS: The efficacy of beta ARKCT infection in vein grafts was verified by reverse transcriptase-polymerase chain reaction. X-gal staining of beta-galactosidase-infected vein grafts demonstrated the transgene in cells throughout the vessel wall. Adenoviral infection of vein grafts without gene transfer did not alter wall thicknesses or sensitivities to contractile agonists, compared with control grafts. beta ARKCT infection, however, reduced intimal thickness by 36% (P < .001) and medial thickness by 24% (P < .001), compared with empty viral infection. beta ARKCT-infected vein grafts also demonstrated increased sensitivity in response to contractile agonists. CONCLUSIONS: These results show that inhibition of G beta gamma signaling with adenoviral-mediated beta ARKCT in vivo infection effectively modifies the structural and functional hyperplastic abnormalities in vein grafts.

Adenoviridae↗
PubMed1997

Insulin modulation of an endothelial nitric oxide component present in the alpha2- and beta-adrenergic responses in human forearm.

We explored in 51 normal subjects, distributed in various series of experiments, whether endothelium nitric oxide may play a role in insulin modulation of alpha2- and beta-adrenergic- evoked vascular responses. In particular, we examined the forearm blood flow response (FBF, ml.min-1.dl-1) to intrabrachial infusion of BHT-933 (0.5, 1, and 2 microg.min-1.dl-1) or isoproterenol (1, 3, and 6 ng. min-1.dl-1) in control conditions, during intrabrachial infusion of insulin alone (0.05 mU.kg-1.min-1) and associated with l-N-monomethylarginine (L-NMMA) (0.05 microg.min-1.dl-1), a nitric oxide synthase inhibitor. In control conditions both BHT-933 and isoproterenol induced a dose-dependent vascular response. Local hyperinsulinemia (deep venous plasma insulin 68.5+/-4 microU/ml) did not change basal FBF whereas attenuated BHT-933 vasoconstriction and enhanced isoproterenol vasodilation. L-NMMA reduced basal FBF and abolished the insulin effect on BHT-933 and isoproterenol response. To clarify whether a nitric oxide component is included in alpha2- and beta-adrenergic response and may be responsible for insulin vascular effect, we further examined BHT-933 and isoproterenol responses during nitric oxide inhibition. Interestingly, L-NMMA potentiated the BHT-933 vasoconstriction and attenuated the isoproterenol vasodilation and, in these conditions, insulin was no more able to exhibit its vascular effects. Finally, to rule out the possibility that the conteracting effect of L-NMMA may not be specifically related to insulin action, dose-response curves to phenylephrine (0.5, 1, and 2 microg.min-1.dl-1) or sodium nitroprusside (1, 2, and 4 microg.min-1.dl-1) were also performed. Both insulin and L-NMMA were unable to alter the phenylephrine-induced vasoconstriction and the sodium nitroprusside vasodilation. In conclusion, our data demonstrate an endothelial nitric oxide component in the alpha2- and beta-adrenergic vascular responses which is the target of the insulin vascular action.

Adrenergic alpha-Agonists↗
PubMed1997

Correction of erythrocyte shape abnormalities in familial hypercholesterolemia after LDL-apheresis: does it influence cerebral hemodynamics?

It is well known that red blood cells incubated in low-density lipoprotein (LDL)-rich medium show shape abnormalities that revert to normal after reincubation in normal plasma. Patients with homozygous familial hypercholesterolemia (HFH) have an increased percentage of abnormally-shaped erythrocytes (mostly stomatocytes, knisocytes, and crenated cells) compared to normocholesterolemic controls: 7.73+/-0.96 versus 3.52+/-0.52 (mean+/-SEM; P = 0.001). To confirm the role of high LDL concentration in inducing red cell shape abnormalities we determined the percentage of abnormally shaped erythrocytes in seven HFH patients 1 day after the procedure of LDL-apheresis with a 40% cholesterol decrease. A reduction in kniscocytes, stomatocytes, and crenated cells was observed in the patients treated by LDL-apheresis (P < 0.01). To investigate the possible benefit of a reduction in erythrocyte shape abnormality on cerebral hemodynamics, cerebral flow velocity, as evaluated by transcranial Doppler, was evaluated concomitantly and found to be remarkably increased after apheresis (P < 0.01). No significant change in hematocrit, plasma viscosity, blood viscosity, mean pressure, or cardiac output was detected, 1 day after apheresis. An inverse correlation was demonstrated (r = 0.55; P = 0.04) between changes in the percentage of knisocytes+stomatocytes +crenated cells and percent changes in middle cerebral artery peak systolic velocity. The correction of erythrocyte shape abnormalities after LDL-apheresis might be related to dramatic changes in plasma phospholipid concentration and proportion occurring after this procedure in HFH patients. The reduction of erythrocyte shape abnormalities could contribute, together with other hemorheological factors, to the improvement of cerebral hemodynamics after LDL-apheresis.

Blood Component Removal↗
PubMed1997

Insulin enhances endothelial alpha2-adrenergic vasorelaxation by a pertussis toxin mechanism.

To investigate whether insulin effect on endothelium is related to a specific signal transduction pathway or reflects a more generalized action of the hormone, we studied in aortic rings of Wistar-Kyoto (WKY) rats the effects of the hormone on endothelium-dependent relaxations generated by acetylcholine, adenosine diphosphate, the selective alpha2-adrenergic agonist UK 14,304, and the calcium ionophore ionomycin. The responses were evaluated both in control conditions and after 30 minutes of exposure to three different levels of insulin (30, 100, and 500 microU/mL). Insulin failed to modify the phenylephrine aortic contractions and the relaxations induced by acetylcholine, adenosine diphosphate, and ionomycin. In contrast, both 100 and 500 microU/mL insulin were able to potentiate the UK 14,304-induced vasorelaxation (+96+/-19% and +91+/-12%, respectively). Pertussis toxin, which causes alpha2-adrenergic receptor Gi uncoupling, reduced the alpha2-adrenergic vasorelaxation and prevented the insulin potentiation of the response to UK 14,304. Furthermore, in primary cultured aortic endothelial cells from WKY, we evaluated the conversion of [3H]arginine to [3H]citrulline in response to acetylcholine, ionomycin, and UK 14,304, both in control conditions and during insulin exposure. Again, insulin did not affect basal citrulline production or the increase induced by acetylcholine and ionomycin, whereas it potentiated the response to UK 14,304. Finally, in aortic rings of spontaneously hypertensive rats, insulin treatment (100 and 500 microU/mL) was unable to enhance the alpha2-adrenergic vasodilator response; in vascular endothelial cells from spontaneously hypertensive rats, insulin did not potentiate the increase in citrulline production evoked by UK 14,304. In conclusion, insulin selectively enhances alpha2-adrenergic endothelial vasorelaxation through a pertussis toxin-sensitive mechanism, by potentiating endothelial nitric oxide production. This vasorelaxant mechanism is altered in spontaneously hypertensive rats.

Adrenergic alpha-Agonists↗
PubMed1996

Association and cosegregation of stroke with impaired endothelium-dependent vasorelaxation in stroke prone, spontaneously hypertensive rats.

While hypertension is a major risk factor for stroke, it is not its sole determinant. Despite similar blood pressures, spontaneously hypertensive rats (SHR) do not share the predisposition to cerebrovascular disease typical of stroke-prone spontaneously hypertensive rats (SHRSP). We investigated vascular function in male SHR and SHRSP as well as in SHRSP/SHR-F2 hybrid animals. Animals were maintained on the appropriate dietary regimen necessary for the manifestation of stroke. Among the hybrid animals, a group of stroke-prone and a group of stroke-resistant rats were selected. Blood pressure was similar in all groups. Endothelium-independent vascular reactivity tested on isolated rings of thoracic aorta and basilar artery after death showed similar contractile and dilatory responses to serotonin and nitroglycerin, respectively, in all groups. In contrast, endothelium-dependent relaxation, in response to acetylcholine or substance P, was markedly reduced in SHRSP compared with SHR. Similarly, reduced vasodilatory responses were present in aortae of F2 rats that had suffered a stroke when compared with SHR or F2 rats resistant to stroke. The observed association and cosegregation of stroke with significant and specific impairment of endothelium-dependent vasorelaxation among SHRSP and stroke-prone F2 hybrids, respectively, suggest a potential causal role of altered endothelium-dependent vascular relaxation in the pathogenesis of stroke.

Acetylcholine↗
PubMed1996

Insulin modulation of beta-adrenergic vasodilator pathway in human forearm.

BACKGROUND: Insulin modulates sympathetic vasoconstriction, but the mechanisms underlying this effect are not completely elucidated. We have recently investigated the insulin effect on the alpha 1- and alpha 2-adrenergic vasoconstriction pathway, where it is still conflicting with the possible insulin influence on the beta-adrenergic vasodilator pathway. The aim of the present study was to investigate this issue. METHODS AND RESULTS: The study was performed on the forearm of healthy humans, and all test substances were infused into the brachial artery at systemically ineffective rates. In five subjects, we evaluated isoproterenol-induced vasodilation (1, 3, 6, and 9 ng. kg-1. min-1) both under control conditions and during insulin infusion (0.05 mU. kg-1. min-1). In another group of five subjects, we tested whether the vasorelaxant effect of sodium nitroprusside (1, 2, 4, and 8 ng . kg-1 . min-1) was modified by insulin. Moreover, to explore whether the interaction between insulin and forearm beta-adrenergic pathway participates in insulin modulation of sympathetic-evoked vasoconstriction, we measured in six normal subjects the forearm vascular response to lower-body negative pressure under control conditions and during intrabrachial infusion of insulin alone and in combination with a selective beta-adrenergic blocking agent (propranolol 10 micrograms/100 mL per minute). Finally, to verify whether insulin interaction with the beta-adrenergic pathway may also account for insulin modulation of alpha 2-adrenergic vasoconstriction, we assessed the vascular response to a selective alpha 2-adrenergic agonist before and after propranolol administration. Insulin exposure potentiated the vascular responsiveness to isoproterenol but did not affect the vasodilator response to sodium nitroprusside. Furthermore, the insulin-induced attenuation of sympathetic vasoconstriction was partially corrected by propranolol. In contrast, the insulin modulation of alpha 2-adrenergic vasoconstriction was not influenced by beta-adrenergic blockade. CONCLUSIONS: Taken together, our results suggest that insulin modulation of sympathetic-induced vasoconstriction is carried out through an interaction of the hormone with the pathways of both alpha 2-and beta -adrenergic receptors.

Adrenergic beta-Antagonists↗
PubMed1996

Influence of digitalis on left ventricular functional response to exercise in congestive heart failure.

This was a double-blind, placebo-controlled, crossover study designed to determine the influence of digitalis treatment on left ventricular (LV) response to physical exercise in patients with congestive heart failure (CHF). In 10 patients with CHF (ejection fraction 29 +/- 2%), LV function was assessed during upright bicycle exercise using an ambulatory radionuclide detector for continuous noninvasive monitoring of cardiac function. Exercise was performed during control conditions and after a 3-week treatment with digoxin (0.25 mg/day orally) or placebo. Ten normal volunteers matched for sex and age constituted the control group. In normals, exercise ejection fraction and end-diastolic volume increased (both p <0.001), while end-systolic volume decreased progressively (p <0.001). In control conditions, patients with CHF had a sharp increase in heart rate during exercise, while ejection fraction did not change; both end-diastolic and end-systolic volumes increased significantly (both p <0.001) during exercise. During digoxin treatment, heart rate response to exercise recorded in patients with CHF was comparable to that recorded in normal subjects. In addition, a significant increase in ejection fraction during exercise was detected (P <0.001), and the increase in end-systolic volume was significantly smaller than that observed in control conditions (p <0.05). When patients received placebo, the responses of LV function to exercise were comparable to those observed in control conditions. These findings demonstrate that digitalis has a favorable influence on LV functional adaptation to exercise in CHF.

Adult↗
PubMed1996

Effects of tissue factor induced by oxygen free radicals on coronary flow during reperfusion.

Tissue factor is a transmembrane protein that activates the extrinsic coagulation pathway by binding factor VII. Endothelial cells, being in contact with circulating blood, do not normally express tissue factor. Here we provide evidence that oxygen free radicals induce tissue factor messenger RNA transcription and expression of tissue factor procoagulant activity in endothelial cells in culture. Isolated, perfused rabbit hearts exposed to exogenous oxygen free radicals also showed a marked increase in tissue factor activity within the coronary circulation. Furthermore, in ex vivo and in vivo hearts subjected to ischemia and reperfusion, a condition associated with a production of oxygen free radicals in large amounts, a marked increase in tissue factor activity occurred. This phenomenon could be abolished by oxygen radical scavengers. This increase in tissue factor activity during postischemic reperfusion was accompanied by a significant decrease in coronary flow, suggesting that increase in tissue factor activity with the consequent activation of the coagulation cascade might impair coronary flow during reperfusion and possibly contribute to the occurrence of reperfusion injury.

Animals↗
PubMed1996

Macula study with standardized echography.

At an early clinical stage, patients with cystoid macular oedema show no significant changes in their vision. This phase is described as angiographic cystoid macular oedema. Echographic macular studies have in the past years shown that the macular thickness is increased in the early stages of cystoid macular oedema. In these patients there was no evidence of cystoid macular oedema with the visual acuity test, B-scan echography and fluorescein angiography. In this paper an echographic macular study by standardized A-scan echography was performed in 537 patients before extracapsular cataract extraction and intraocular lens implantation in posterior chamber (ciliary sulcus). The results showed that this method is very sensitive in detecting patients with high risk of cystoid macular oedema.

Adult↗
PubMed1996

The crosstalk between insulin and the sympathetic nervous system: possible implications in the pathogenesis of essential hypertension.

Patients with non-insulin dependent diabetes mellitus and obesity show an elevated risk for development of arterial hypertension, while many non-obese, non-diabetic patients with essential hypertension display resistance to insulin-induced glucose disposal, accompanied by hyperinsulinaemia. This close association has lead some investigators to postulate that insulin resistance could be implicated in the pathogenesis of essential hypertension. Among the various factors considered as potential links between insulin resistance and high blood pressure, the sympathetic nervous system can be considered a prime candidate. In particular, our recent data in hypertensive patients have documented that the muscle sympathetic response evoked by insulin is about threefold greater than that observed in normal subjects. Such finding is well in agreement with previous observations in hypertensives obtained with experimental maneuvers and extends them by showing an abnormal sympathetic response to a physiological stimulus like insulin, so important in every day life. Recent data both from our and other laboratories have clearly established that an acute activation of sympathetic nervous system is able to antagonize insulin-mediated glucose uptake in the skeletal muscle, making very real the possibility that a primary defect in insulin sensitivity in hypertension may be further aggravated by the greater sympathetic response evoked by episodic stimuli, such as postprandial hyperinsulinaemia. However, while insulin evokes an increase in sympathetic nervous activity, at same time it is able to blunt the vasoconstrictive effects caused by the reflex sympathetic activation. Such vascular modulating effect of insulin is lost in essential hypertension, indicating that the resistance to insulin effect in this disease is not only present in skeletal muscle metabolism but it is also evident at the vascular level.

Blood Glucose↗
PubMed1995

Insulin modulation of vascular reactivity is already impaired in prehypertensive spontaneously hypertensive rats.

Hyperinsulinemia reduces the vasoconstrictive response to norepinephrine in Wistar-Kyoto rats (WKY) but not in spontaneously hypertensive rats (SHR). It has been hypothesized that this difference in the vascular effect of insulin could be a hallmark of the hypertensive state. To test this hypothesis we studied SHR before (5 weeks old, n = 10) and after (15 weeks old, n = 10) the establishment of hypertension as well as two groups of age- and sex-matched WKY (5 weeks old, n = 14; 15 weeks old, n = 13). Blood pressure was significantly higher in SHR compared with WKY (181 +/- 5 versus 118 +/- 6 mm Hg, respectively, P < .001) in the 15-week-old rats but not in the 5-week-old rats (121 +/- 5 versus 117 +/- 3 mm Hg, P < NS). We tested vascular reactivity using increasing amounts of norepinephrine (from 10(-10) to 10(-5) mmol/L) on isolated aortic rings in control conditions and after 30 minutes of exposure to 715 pmol/L insulin. In WKY insulin reduced the vascular response to norepinephrine in both the 5-week-old (repeated-measures ANOVA with grouping factor: F = 2.443, P < .05) and 15-week-old (F = 9.667, P < .01) groups. In SHR at both ages insulin failed to modify the vascular response to norepinephrine (5 weeks: F = 0.107, P < NS; 15 weeks: F = 0.075, P < NS). Sodium nitroprusside was able to attenuate the vascular response to norepinephrine in WKY and SHR at 5 and 15 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1994

Acute noradrenergic activation induces insulin resistance in human skeletal muscle.

We assessed in normal subjects the effects of an acute increase in forearm norepinephrine (NE) release, evoked by -20 mmHg lower body negative pressure (LBNP), on insulin-mediated muscle glucose uptake. Seven normal subjects underwent the following two insulin euglycemic clamps in random sequence: one during application of LBNP and the other without LBNP (control study). In the control study, hyperinsulinemia (approximately 60 microU/ml) produced a significant increment in forearm NE release, measured by using the forearm perfusion technique combined with infusion of tritiated NE (from 4.91 +/- 1 to 7.94 +/- 1.33 ng.l-1.min-1; P < 0.05). Forearm glucose uptake rose from 0.97 +/- 0.13 to 5.2 +/- 0.2 mg.l-1.min-1 in response to insulin infusion. When the insulin clamp was performed during LBNP, forearm NE release rose to significantly higher values than those of the control study (from 4.33 +/- 0.52 to 12.7 +/- 1.46 ng.l-1.min-1; P < 0.01 vs. control). Under these conditions, the stimulatory effect of insulin on forearm glucose uptake was markedly reduced (from 0.78 +/- 0.10 to 3.2 +/- 0.7 mg.l-1.min-1; P < 0.02 vs. control). Forearm blood flow and plasma epinephrine and free fatty acid concentrations were comparable in the two study sessions. These data demonstrate that an acute activation of endogenous NE release antagonizes insulin-mediated glucose uptake in forearm skeletal muscle, probably accounted for by a direct metabolic effect of NE.

Adult↗
PubMed1994

Insulin blunts sympathetic vasoconstriction through the alpha 2-adrenergic pathway in humans.

We investigated the mechanisms underlying the insulin-induced attenuation of sympathetic forearm vasoconstriction in healthy humans. In 5 subjects, we applied 20 mm Hg lower body negative pressure for 30 minutes in control conditions and during a 60-minute infusion of insulin (0.05 mU/kg per minute) in the brachial artery and measured forearm norepinephrine kinetics and hemodynamics. In 11 subjects, we applied graded lower body negative pressure at 5, 10, 15, and 20 mm Hg for 5 minutes each in control conditions and during the simultaneous intrabrachial administration of insulin (0.05 mU/kg per minute) (5 subjects) or insulin plus ouabain (3.5 micrograms/min per liter) (6 subjects) to investigate whether insulin acts through a potentiation of the vascular smooth muscle Na+,K(+)-ATPase. To assess a possible effect of insulin on a specific adrenergic receptor pathway, in a further study group we evaluated (1) the forearm vascular response to intrabrachial infusion of the alpha 1-adrenergic receptor agonist phenylephrine (0.5, 1, and 2 micrograms/kg per minute; n = 7) and of the alpha 2-adrenergic receptor agonist BHT-933 (0.5, 1, 2, and 4 micrograms/kg per minute; n = 9), and (2) the effects of intra-arterial infusion of prazosin (0.5 microgram/100 mL per minute) alone or combined with insulin on the forearm vascular response to graded lower body negative pressure (7 subjects). Insulin blunted the peak increase in forearm vascular resistance (from 13 +/- 2 to 6 +/- 2 U, P < .05) but not the rise in forearm norepinephrine spillover induced by 20 mm Hg lower body negative pressure (from 8.3 +/- 1.8 to 11.1 +/- 3.5 pmol/min per liter, P = NS). Ouabain administration did not prevent the insulin-induced attenuation of the forearm vasoconstrictive response to graded lower body negative pressure. Insulin infusion in the brachial artery did not modify the forearm vasoconstriction induced by intra-arterial infusion of phenylephrine but significantly reduced the increase in forearm vascular resistance induced by BHT-933 (F = 6.111, P < .001). Finally, intra-arterial infusion of prazosin significantly attenuated the forearm vasoconstriction induced by graded lower body negative pressure. The residual vasoconstrictive response was abolished by insulin infusion. Taken together, these findings suggest that insulin interacts with the sympathetic nervous system at the vascular level predominantly through the alpha 2-adrenergic vasoconstrictive pathway.

Adrenergic alpha-Agonists↗