Regulatory Mechanism Of Ang-(1-7) Within Midbrain Periaqueductal Gray Responsible For Sympathetic Nerve Activity In Rats With Heart Failure

Heart failure (HF) caused by various cardiovascular diseases is a clinicalcomplication of cardiac dysfunction. Mostly, HF is a chronic condition that ischaracterized by impaired cardiac contractility that leads to a decrease in blood supplyto metabolizing tissues and organs, and then the pulmonary and/or systemiccirculation appear(s) congestive. Because HF often is accompanied by the passiveblood obstruction of the pulmonary circulation and/or systemic circulation, it is oftencalled the chronic congestive heart failure (CHF). CHF is a progressive andcomplicated clinical situation that results from cardiac and vascular diseases thatdamage myocardial systolic and diastolic functions. Every year millions of patientsare hospitalized because of CHF and with increasing in the aging population and rateof survival for the acute myocardial infarction, hypertension as well as othercardiovascular diseases the prevalence rate of CHF likely raises in the future.The amplified activity of the sympathetic nervous system (SNS) is a hallmark ofCHF. Overactive sympathoexcitation can worsen clinical symptoms of CHF. Manyfactors cause the exaggerated SNS activity, including abnormal inputs of peripheralbaroceceptor and chemo-receptor, and neurotransmitters-elevated output of SNS etc.Recently, increasing researches have greatly focused on the role of the CNS inregulating enhanced sympathoexcitation in CHF, such as abnormalities in activationof SNS, renin-angiotensin aldosterone system (RAAS), cerebral inflammation, nitricoxide (NO) and so on. Among them, RAAS is considered as a primary factor inregulating SNS activity.In CHF, the RAAS is activated due to decreased cardiac output and impairedrenal blood flow. This increases cardiac contractility, and peripheral vascularresistance to maintain arterial blood pressure. Also, this can adjust redistribution ofblood flow to supply blood sufficiently to critical organs such as heart and brain etc;whereas an increase in the levels of aldosterone elevates systemic fluid volume thereby leading to heightened cardiac preloading. Overall, activation of the RAAS isbeneficial and plays a compensatory role in the early stage of CHF. Angiotensinogenis broken down into angiotensin I by renin and then angiotensin converting enzyme(ACE) converts angiotensin I to angiotensin II (Ang II), which is a key bioactivesubstance to combine and stimulate its receptors to cause vasoconstriction andcardiovascular remodeling as well as to retain sodium via the release of aldosterone.Ang II has a regulatory effect on sympathetic function at the multiple levels,including that it increases the releases of norepinephrine from presynaptic terminalsand regulates postsynaptic effects of norepinephrine. Blocking AT1receptors candecrease sympathetic tone and thus investigators have made a great effort to look forsubstances to antagonize Ang II since ACE/AngII/AT1is a central axis to play a rolein regulating sympathetic activation.For the last ten years, as a new member of RAAS angiotensin converting enzyme2(ACE2) has been discovered and investigators found that there is anangiotensin-(1-7)[Ang (1-7)], which has the opposite effects of Ang II. There arethree biochemical pathways to generate Ang-1-7. First, prolyl carboxypeptidase orprolyl peptide chain endonuclease can cleave Ang I to Ang (1-7). Second, Ang II is amain resource of Ang (1-7) via ACE2and prolyl carboxypeptidase. Third, ACE2indirectly converts Ang I to Ang (1-9) and then Ang (1-9) is converted to Ang (1-7)via ACE or prolyl peptide chain endonuclease. Ang-(1-7) exerts its action and plays arole in vasodilatation via Mas receptor. More and more evidence indicates thatACE2/Ang (1-7)/Mas axis has counter-effect to ACE/Ang II/AT1axis and hasbeneficial effects on cardiovascular system. As endogenous substance, Ang (1-7)exists within the brain tissues and studies have found that endogenous Ang (1-7) andAng II have opposite effects on arterial baroreceptor function. Also, administration ofAng-(1-7) can attenuate Ang II-mediated release of norepinephrine.The midbrain periaqueductal gray (PAG) is divided into four sub-regions andengaged in pain modulation, autonomic and cardiovascular activities and othersurvival related critical functions. Studies have shown that dosolateral PAG (dl-PAG)is a sympathetic excitatory center. Ang II can stimulate presynaptic AT1receptors anddecrease the release of GABA to affect neuronal activities within the dl-PAG.However, the role of Ang (1-7) and its receptors in the dl-PAG, especially, centraleffects of Ang (1-7) on SNS in CHF are unclear.Therefore, in the current investigation, the left descending coronary artery of rats was ligated to obtain a model of myocardial infarction. Echocardiographicmeasurement was performed to determine functions of CHF. Western blot analysiswas used to examine the protein levels of Ang (1-7) receptors and NOS expressionand electrophysiological methods were employed to examine neuronal activities ofthe dl-PAG of control and CHF rats. In addition, renal sympathetic nerve activity(RSNA) was recorded to determine engagement of Ang (1-7) within the dl-PAG insympathetic nerve activity in CHF rats.Overall, results of this investigation have demonstrated:⑴Mas receptors appear within the dl-PAG neurons and as compared with control,expression of Mas receptor is significantly less in CHF (P<0.05, CHF vs. control).⑵Among three NOS subtypes, greater expression of neuronal NOS (nNOS)appears in the dl-PAG and nNOS is decreased in CHF as compared with control(P<0.05, CHF vs. control).⑶Ang (1-7) from10nM to1μM can decrease frequency rate of neuronaldischarge within dl-PAG and attenuating effects of Ang (1-7) are significantly smallerin CHF than in control (P<0.05, CHF vs. control).⑷Antagonists to Mas, nNOS and GABAa can diminish effects of Ang (1-7) onneuronal activities of the dl-PAG.⑸Microinjection of GABAa antagonist into dl-PAG of CHF rats augmentsRSNA compared with control rats.We made following conclusions based on our results:⒈Ang (1-7) of the dl-PAG is involved in regulating amplified sympathetic nerveactivity in CHF.⒉In healthy rats, Ang (1-7) stimulates Mas receptors and activates nNOSproduction, and then NO decreases presynaptic releases of inhibitory GABA.Thus, overall, dl-PAG neuronal activities are attenuated by Ang (1-7).⒊In CHF, due to less expression of Mas receptors and nNOS within the dl-PAG,Ang (1-7)-Mas-R-nNOS-GABA pathways are impaired. This leads to adecrease in the release of GABA and thereby de-inhibition of dl-PAG neuronsand sympathetic nerve activity is amplified in CHF.