Autonomic and cardiovascular consequences resulting from experimental hemorrhagic stroke in the left or right intermediate insular cortex in rats


      Damage to the insular cortex (IC) results in serious cardiovascular consequences and evidence indicates that the characteristics are lateralized. However, a study comparing the effects of focal experimental hemorrhage between IC sides was never performed. We compared the cardiovascular, autonomic and cardiac changes produced by focal experimental hemorrhage (ICH) into the left (L) or right (R) IC. Wistar rats were submitted to microinjection of autologous blood (ICH) or saline (n = 6 each side/group) into the R or L IC. Blood pressure (BP), heart rate (HR) and renal sympathetic activity (RSNA) were recorded. Measurements of calcium transient and sarcoplasmic Ca2+ ATPase expression in cardiomyocytes were performed. ICH increased baseline HR (Δ:L-ICH 452 ± 13 vs saline 407 ± 11 bpm; R-ICH 450 ± 7 vs saline 406 ± 8 bpm, P < 0.05) without changing BP. HR was restored to baseline levels after i.v. atenolol. Strikingly, ICH rats presented a reduced baseline RSNA (Δ:L-ICH 122 ± 4 vs saline 148 ± 11 spikes/s; R-ICH 112 ± 5 vs saline 148 ± 7 spikes/s, P < 0.05). After 24 h of ICH we observed a marked increase in cardiac ectopies and this number was greater after ICH R-IC. Heart weight, calcium amplitude and SERCA expression were reduced only in ICH R-IC. Focal stroke into IC can alter the cardiac and renal autonomic control. Damage to the R-IC produces a greater number of arrhythmias and changes in calcium dynamics in cardiac cells indicating that the cardiovascular consequences are hemisphere-dependent. These findings confirm asymmetry for cardiac autonomic control at the IC and help to understand the cardiac and renal implications observed after specific side cortical damage.

      Graphical abstract


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Autonomic Neuroscience: Basic and Clinical
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Abboud H.
        • Berroir S.
        • Labreuche J.
        • Orjuela K.
        • Amarenco P.
        Insular involvement in brain infarction increases risk for cardiac arrhythmia and death.
        Ann. Neurol. 2006; 59: 691-699
        • de Almeida P.W.M.
        • de Freitas Lima R.
        • de Morais Gomes E.R.
        • Resende C.R.
        • Roman-Campos D.
        • Gondim A.N.S.
        • Gavioli M.
        • Lara A.
        • Parreira A.
        • de Azevedo Nunes S.L.
        Functional cross-talk between aldosterone and angiotensin-(1–7) in ventricular myocytes.
        Hypertension. 2013; 61: 425-430
        • Bisceglia C.
        • Mazzetti A.
        Pre-excitation syndrome.
        in: Sports Cardiology. Springer, 2012: 179-183
        • Colivicchi F.
        • Bassi A.
        • Santini M.
        • Caltagirone C.
        Cardiac autonomic derangement and arrhythmias in right-sided stroke with insular involvement.
        Stroke. 2004; 35: 2094-2098
        • Fontes M.A.P.
        • Limborço Filho M.
        • Machado N.L.S.
        • de Paula C.A.
        • Cordeiro L.M.S.
        • Xavier C.H.
        • Marins F.R.
        • Henderson L.
        • Macefield V.G.
        Asymmetric sympathetic output: the dorsomedial hypothalamus as a potential link between emotional stress and cardiac arrhythmias.
        Auton. Neurosci. 2017; 207: 22-27
        • Green A.R.
        • Odergren T.
        • Ashwood T.
        Animal models of stroke: do they have value for discovering neuroprotective agents?.
        Trends Pharmacol. Sci. 2003; 24: 402-408
        • Guatimosim S.
        • Sobie E.A.
        • dos Santos Cruz J.
        • Martin L.A.
        • Lederer W.J.
        Molecular identification of a TTX-sensitive Ca2+ current.
        Am. J. Phys. Cell Phys. 2001; 280: C1327-C1339
        • Hasenfuss G.
        • Reinecke H.
        • Studer R.
        • Meyer M.
        • Pieske B.
        • Holtz J.
        • Holubarsch C.
        • Posival H.
        • Just H.
        • Drexler H.
        Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+-ATPase in failing and nonfailing human myocardium.
        Circ. Res. 1994; 75: 434-442
        • Hua Y.
        • Keep R.F.
        • Hoff J.T.
        • Xi G.
        Brain injury after intracerebral hemorrhage: the role of thrombin and iron.
        Stroke. 2007; 38: 759-762
        • Laowattana S.
        • Zeger S.L.
        • Lima J.A.C.
        • Goodman S.N.
        • Wittstein I.S.
        • Oppenheimer S.M.
        Left insular stroke is associated with adverse cardiac outcome.
        Neurology. 2006; 66: 477-483
        • Luczak E.D.
        • Leinwand L.A.
        Sex-based cardiac physiology.
        Annu. Rev. Physiol. 2009; 71: 1-18
        • Marins F.R.
        • Limborço-Filho M.
        • Xavier C.H.
        • Biancardi V.C.
        • Vaz G.C.
        • Stern J.E.
        • Oppenheimer S.M.
        • Fontes M.A.P.
        Functional topography of cardiovascular regulation along the rostrocaudal axis of the rat posterior insular cortex.
        Clin. Exp. Pharmacol. Physiol. 2016; 43: 484-493
        • Nagai M.
        • Dote K.
        • Kato M.
        • Oda N.
        Atrial fibrillation after acute intracerebral hemorrhage: how would the insular cortex damage interact?.
        Eur. J. Neurol. 2018; 25: e58
        • Nakamura T.
        • Kuroda Y.
        • Yamashita S.
        • Zhang X.
        • Miyamoto O.
        • Tamiya T.
        • Nagao S.
        • Xi G.
        • Keep R.F.
        • Itano T.
        Edaravone attenuates brain edema and neurologic deficits in a rat model of acute intracerebral hemorrhage.
        Stroke. 2008; 39: 463-469
        • Oppenheimer S.
        • Cechetto D.
        The insular cortex and the regulation of cardiac function.
        Compr. Physiol. 2011; 6: 1081-1133
        • Paxinos G.
        • Watson C.
        The Rat Brain in Stereotaxic Coordinates.
        Academic Press Australia, 1986
        • Pieske B.
        • Maier L.S.
        • Piacentino III, V.
        • Weisser J.
        • Hasenfuss G.
        • Houser S.
        Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium.
        Circulation. 2002; 106: 447-453
        • Qureshi A.I.
        • Ali Z.
        • Suri M.F.K.
        • Shuaib A.
        • Baker G.
        • Todd K.
        • Guterman L.R.
        • Hopkins L.N.
        Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: an in vivo microdialysis study.
        Crit. Care Med. 2003; 31: 1482-1489
        • da Silva A.Q.G.
        • Xavier C.H.
        • Campagnole-Santos M.J.
        • Caligiorne S.M.
        • Baltatu O.C.
        • Bader M.
        • Santos R.A.S.
        • Fontes M.A.P.
        Cardiovascular responses evoked by activation or blockade of GABAA receptors in the hypothalamic PVN are attenuated in transgenic rats with low brain angiotensinogen.
        Brain Res. 2012; 1448: 101-110
        • Singh K.
        • Xiao L.
        • Remondino A.
        • Sawyer D.B.
        • Colucci W.S.
        Adrenergic regulation of cardiac myocyte apoptosis.
        J. Cell. Physiol. 2001; 189: 257-265
        • Svigelj V.
        • Grad A.
        • Tekavcic I.
        • Kiauta T.
        Cardiac arrhythmia associated with reversible damage to insula in a patients with subarachnoid hemorrhage.
        Stroke. 1994; 25: 1053-1055
        • Sykora M.
        • Diedler J.
        • Steiner T.
        Repetitive asystole in right insular hemorrhage.
        J. Neurol. Neurosurg. Psychiatry. 2007; : 1282-1283
        • Wagner K.R.
        Modeling intracerebal hemorrhage: glutamate, nuclear factor-κB signaling and cytokines.
        Stroke. 2007; 38: 753-758
        • Wilson M.E.
        Stroke: understanding the differences between males and females.
        Pflügers Arch.-Eur. J. Physiol. 2013; 465: 595-600
        • Xavier C.H.
        • Beig M.I.
        • Ianzer D.
        • Fontes M.A.P.
        • Nalivaiko E.
        Asymmetry in the control of cardiac performance by dorsomedial hypothalamus.
        Am. J. Phys. Regul. Integr. Comp. Phys. 2013; 304: R664-R674
        • Yahalom G.
        • Schwartz R.
        • Schwammenthal Y.
        • Merzeliak O.
        • Toashi M.
        • Orion D.
        • Sela B.-A.
        • Tanne D.
        Chronic kidney disease and clinical outcome in patients with acute stroke.
        Stroke. 2009; 40: 1296-1303