Effect of age on cutaneous vasoconstrictor responses to norepinephrine in humans

Abstract

. Effect of age on cutaneous vasoconstrictor responses to norepinephrine in humans. Am J Physiol Regul Integr Comp Physiol 287: R1230 -R1234, 2004 doi:10.1152/ajpregu.00467. 2004.-To test the hypothesis that cutaneous vasoconstrictor responsiveness to exogenous norepinephrine is reduced in older compared with young subjects, dose-response relations between norepinephrine and skin blood flow were established. Seven doses of norepinephrine (1 ⅐ 10 Ϫ8 to 10 Ϫ2 log M) were perfused (2 l/min) intradermally (4 min/dose) using cutaneous microdialysis (2 probes/subject). To account for possible differences in endogenous norepinephrine between groups, one microdialysis probe was perfused with bretylium tosylate to locally block noradrenergic vesicle release before establishing the norepinephrine dose-response relations. Skin blood flow was indexed via laser-Doppler flowmetry directly over both microdialysis probe sites and is expressed as cutaneous vascular conductance (laserDoppler flux/mean arterial blood pressure). Local skin temperature was maintained at 34°C at both sites throughout the protocol. Doseresponse relation between norepinephrine and cutaneous vascular conductance was similar between control and bretylium-pretreated sites in young subjects (EC 50 ϭ Ϫ5.18 Ϯ 0.27 and Ϫ5.03 Ϯ 0.27 log M, respectively). In contrast, the dose-response relation was significantly shifted to the right (i.e., a higher dose of norepinephrine was needed to produce the same vasoconstrictor response) in the bretylium-pretreated site in older subjects (EC 50 ϭ Ϫ5.46 Ϯ 0.23 and Ϫ4.53 Ϯ 0.23 log M, respectively). Significant increases in EC 50 were observed in older compared with young subjects at the bretylium-pretreated but not the control sites. These data indicate that cutaneous vasoconstrictor responsiveness is decreased in older subjects when endogenous release of norepinephrine is antagonized. Furthermore, these findings suggest that differences in presynaptic norepinephrine release between older and younger subjects are profound enough to affect dose-response relations between norepinephrine and cutaneous vascular conductance. intradermal microdialysis; ␣-adrenergic receptors; cold stress AGING modulates autonomic thermoregulatory responses during environmental stress (14,34,35). Reduced cutaneous vasodilation and sweating during heat stress are well established in older subjects (10,12,17,19,24). However, the effects of age on autonomic responses to cold stress are less clear. This lack of clarity is especially apparent when assessing age-related cutaneous vasoconstrictor responses.Kenney and Armstrong (13) have identified impaired rate and extent of forearm vasoconstriction in older subjects during a 120-min cold air stress. Although the mechanisms responsible for this vasoconstrictor deficit were not identified in this study, one possible mechanism for this impaired vasoconstrictor response in older adults could involve blunted end-organ responsiveness. Supporting this concept, Dinenno et al. (4) observed blunted vasoconstri...

Tetrahydrobiopterin does not affect end-organ responsiveness to norepinephrine-mediated vasoconstriction in aged skin

“…Thus, supplementation of BH 4 did not alter the VC response postsynaptically via sympatholytic mechanisms, thereby indicating that BH 4 acts independently of NOS coupling and increases in NO bioavailability during cutaneous VC. Additionally, we verified that VC in aged skin is blunted at various physiological (10 Ϫ12 -10 Ϫ8 M) and supraphysiological (10 Ϫ4 -10 Ϫ2 M) concentrations of NE (36,40). This result occurred even when controlling for endogenous NE release with bretylium (40).…”

“…Additionally, we verified that VC in aged skin is blunted at various physiological (10 Ϫ12 -10 Ϫ8 M) and supraphysiological (10 Ϫ4 -10 Ϫ2 M) concentrations of NE (36,40). This result occurred even when controlling for endogenous NE release with bretylium (40).…”

“…Deficits in noradrenergic function have also been identified in adrenoreceptor and second messenger systems of vascular smooth muscle (7,18,26,34,36). Conflicting accounts exist regarding the effect of age on the cutaneous VC response to NE: one study showed no difference (40) and another demonstrated a blunted VC response in aged skin (36). Compared with these studies, we extended the dose-response range to include the 10 Ϫ12 M concentration and verified that the VC response to these doses of NE was attenuated in aged skin even after controlling for presynaptic adrenergic function with bretylium tosylate.…”

Decreased Microvascular Nitric Oxide–Dependent Vasodilation in Postural Tachycardia Syndrome

“…21 Blockade was followed by escalating norepinephrine iontophoresis (dose response) to test for a defect in norepinephrine binding or response. 24 …”

Implications for burn shock resuscitation of a new in vivo human vascular microdosing technique (microdialysis) for dermal administration of noradrenaline

“…The dose of noradrenaline that we chose is well established [16][17][18] and is thought to be in the physiological and therapeutic ranges. However, we found long-lasting effects, including ischaemia and reduced glucose uptake, which implies that the dose was too high and that giving the drug to tissue with reduced blood flow might create a deposition of noradrenaline in the tissue.…”