Scientific Contributions Insulin Blunts Sympathetic Vasoconstriction Through the e * 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 brachiaJ 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 fig/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 a,-adrenergic receptor agonist phenylephrine (0.5, 1, and 2 jig/kg per minute; n=7) and of the a2-adrenergic receptor agonist BHT-933 (0.5, 1, 2, and 4 jtg/kg per minute; n=9), and (2) the effects of intra-arterial infusion of prazosin (0.5 ^g/100 mL per minute) alone or combined with insulin on the forearm vascular response to It is now clearly demonstrated that an important cross talk exists between insulin and the sympathetic nervous system. In humans, physiological hyperinsulinemia evokes a net reflex increase in both muscle sympathetic nervous activity' and norepinephrine release. The interplay between insulin and the sympathetic nervous system occurs at different levels. In the skeletal muscle the sympathetic nervous system modulates insulin action on glucose metabolism,and at the vascular level insulin attenuates the vasoconstrictive effects of reflex sympathetic activation. This latter observation, obtained in an in vivo study, extends the results of in vitro studies showing that insulin is able to blunt vascular reactivity. The mechanisms through which insulin exerts this short-term and direct effect on sympathetic-induced vasoconstriction still remain unclear. On the basis of in vitro studies it is possible to suggest several hypotheses: (1) Insulin may act at the neurojunctional level, causing a decrease in the amount of norepinephrine reaching the adrenergic receptors; (2) insulin may act at the vascular smooth muscle level, Received December 16, 1993; accepted in revised form July 14, 1994. From the Department of Internal Medicine, School of Medicine, Federico II University, Naples, Italy. Correspondence to Bruno Trimarco, MD, Medicina Interna, Via S. Pansini 5, 80131 Napoli, Italy. © 1994 American Heart Association, Inc. 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 insulininduced 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 a2-adrenergic vasoconstrictive pathway. (Hypertension. 1994;24:429-438.)