bibp-3226 and Ischemia

Cryotherapy is a therapeutic technique using ice or cold water applied to the skin to manage soft tissue trauma and injury. While beneficial, there are some potentially detrimental side effects, such as pronounced vasoconstriction and tissue ischemia that are sustained for hours post-treatment. This study tested the hypothesis that this vasoconstriction is mediated by 1) activation of post-synaptic α-adrenergic receptors and/or 2) activation of post-synaptic neuropeptide Y1 (NPY Y1) receptors. 8 subjects were fitted with a commercially available cryotherapy unit with a water perfused bladder on the lateral portion of the right calf. Participants were instrumented with four intradermal microdialysis probes beneath the bladder. The following conditions were applied at the four treatment sites: 1) control (Ringer solution), 2) combined post-synaptic β-adrenergic receptors and neuropeptide (NPY) Y

Topics: Administration, Cutaneous; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adrenergic Fibers; Adult; Arginine; Blood Vessels; Cryotherapy; Female; Humans; Ischemia; Leg; Male; Microdialysis; Propranolol; Receptors, Adrenergic, alpha; Receptors, Neuropeptide Y; Skin; Time Factors; Vasoconstriction; Yohimbine

This study evaluated the role of alpha-adrenergic receptor- and neuropeptide Y (NPY) Y1 receptor-mediated vasoconstriction in the collateral circuit of the hind limb. Animals were evaluated either the same day (Acute) or 3 weeks following occlusion of the femoral artery; the 3-week animals were in turn limited to cage activity (Sed) or given daily exercise (Trained). Collateral-dependent blood flows (BFs) were measured during exercise with microspheres before and after alpha-receptor inhibition (phentolamine) and then NPY Y1 receptor inhibition (BIBP 3226) at the same running speed. Blood pressures (BPs) were measured above (caudal artery) and below (distal femoral artery) the collateral circuit. Arterial BPs were reduced by alpha-inhibition (50-60 mmHg) to approximately 75 mmHg, but not further by NPY Y1 receptor inhibition. Effective experimental sympatholysis was verified by 50-100% increases (P < 0.001) in conductance of active muscles not affected by femoral occlusion with receptor inhibition. In the absence of receptor inhibition, vascular conductance of the collateral circuit was minimal in the Acute group (0.13 +/- 0.02), increased over time in the Sed group (0.41 +/- 0.03; P < 0.001), and increased further in the Trained group (0.53 +/- 0.03; P < 0.02). Combined receptor inhibition increased collateral circuit conductances (P < 0.005), most in the Acute group (116 +/- 37%; P < 0.02), as compared to the Sed (41 +/- 6.6%; P < 0.001) and Trained (31 +/- 5.6%; P < 0.001) groups. Thus, while the sympathetic influence of the collateral circuit remained in the Sed and Trained animals, it became less influential with time post-occlusion. Collateral conductances were collectively greater (P < 0.01) in the Trained as compared to Sed group, irrespective of the presence or absence of receptor inhibition. Conductances of the active ischaemic calf muscle, with combined receptor inhibition, were suboptimal in the Acute group, but increased in Sed and Trained animals to exceptionally high values (e.g. red fibre section of the gastrocnemius: approximately 7 ml min(-1) (100 g)(-1) mmHg(-1)). Thus, occlusion of the femoral artery promulgated vascular adaptations, even in vessels that are not part of the collateral circuit. The presence of active sympathetic control of the collateral circuit, even with exercise training, raises the potential for reductions in collateral BF below that possible by the structure of the collateral circuit. However, even with release of

Topics: Acetylcholine; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Arginine; Blood Pressure; Blood Vessels; Body Weight; Collateral Circulation; Heart Rate; Hindlimb; Ischemia; Male; Muscle, Skeletal; Phentolamine; Phenylephrine; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Regional Blood Flow; Vasoconstriction; Vasodilator Agents

We have investigated the effects of ischaemia on neuropeptide Y (NPY) mechanisms involved in sympathetic vascular control of the pig kidney in vivo. Reperfusion after 2 h of renal ischaemia was associated with local overflow of noradrenaline (NA) but not of NPY-like immunoreactivity (-LI). Renal sympathetic nerve stimulation 10 min into reperfusion evoked markedly reduced vasoconstrictor effects and significantly less overflow of NA (reduced by 70% from the pre-ischaemic conditions), whereas NPY-LI overflow was unaltered. Renal vasoconstrictor responses to exogenous peptide YY (PYY), phenylephrine and angiotensin II were strongly attenuated after this ischaemic period, while vasoconstriction to alpha, beta-methylene ATP was maintained to a larger extent. The renal vascular responses and NA overflow had become partially normalized within a 2 h recovery period. In contrast, the renal vasoconstrictor response and the overflow of NPY-LI upon sympathetic nerve stimulation were enhanced after 15 min of renal ischaemia. In parallel, the PYY-evoked renal vasoconstriction was selectively and markedly prolonged after the 15 min of ischaemia. In the presence of the NPYY1 receptor antagonist BIBP 3226, the augmented vascular response to nerve stimulation was significantly attenuated. We conclude that reperfusion after 2 h of renal ischaemia is associated with local overflow of NA, whereas the sympathetic nerve-evoked release of NA and the reactivity of the renal vasculature to vasoconstrictor stimuli are reversibly reduced. Furthermore, possibly due to an impaired local degradation, the role of neurogenically released NPY in renal sympathetic vasoconstriction is enhanced after short-term (15 min) ischaemia compared with control conditions.

Topics: Adrenergic alpha-Agonists; Animals; Arginine; Electric Stimulation; Female; Ischemia; Male; Neuropeptide Y; Norepinephrine; Peptide YY; Phenylephrine; Receptors, Neuropeptide Y; Renal Circulation; Reperfusion Injury; Swine; Sympathetic Nervous System; Time Factors; Vasoconstriction