Ivabradine Dr.Rajesh Rajan M.D.,D.Card,FACC,FAHA,FESC PRESIDENT – IACC www.accindia.org 1

Elevated Resting Heart Rate Accelerates production of atherosclerosis (Int J Cardiol 2008;126:302-12) Associated with coronary plaque disruption (Circulation 2001;126:1477-82) Framingham Study progressive increase in all cause and cardiovascular mortality in relation to antecedent HR (Am Heart J 1987; 113:1489-94) Continuous increase in death rates in survivors of Acute MI starting at HR > 70 (J Am Coll Cardiol 2007;50:823-30) Circ journal: Heart rates greater than 80. 2

Beta-Adrenoceptors Endogenous catecholamines activate B-receptors (Adenylate Cyclase) Increased cAMP Increased Ca++ influx B-receptors, located on cardiac nodal tissue, the conducting system, and contracting myocytes Inotropic effects due to several methods including increased calcium availability to Troponin-C in cardiac myocytes Chronotropic, in part at least, to activation of L-type calcium channels, and their effect on the action potential. Inotropic Chronotropic 3

Beta Blockers (BB) B1negative chronotropy and inotropy AV conduction delay Reduced atrial and ventricular arrythmias B2Bronchoconstriction Peripheral unopposed alpha constriction Decrease glycogenolysis (contribute to hypoglycemic events) Other antagonize release of renin reduces intraocular pressures Alpha constriction, which at least initially increases peripheral resistance, but also of potential concern in cocaine users. Glycogenolysis, particularly in Type I diabetics Renin, thereby altering the renin-angiotensin pathway 4

Impact of BB Acute MI CHF Norwegian Multicenter Study Group Timolol * CAPRICORN † ISIS-1 ‡ CHF COPERNICUS £ MERIT-HF € Norwegion: AMI, given Timilol for up to 33 months, showing reduced mortality in the Timolol group. CAPRICORN, AMI and EF lower than 40% BB reduced all cause mortality ISIS-1, Atenolol vs placebo during hospitalization for AMI (16,000 patients). Showed reduced in-hospital mortality. COPPERNICUS, Carvedilol in patients with EF less than 25%, reduced severity of HF and hospitalizations MERIT-HF: Metoprolol XL vs placebo, 4000 patients with Class II-IV HF, EF of less than 40%, stopped early due to mortality benefit with Metoprolol 5

Intolerence of BB Side effects Bronchoconstriction, AV delay, hypoglycemia Weight gain, depression, fatigue BB may not be tolerated in high enough doses to attain heart rates below 70bpm Acute setting (Acute MI, or CHF), the negative inotropic effect could be deleterious This has been shown in dogs (Eur Heart J (2004) 25 (7): 579-586 Target doses for many studies are between 150 to 200mg of metoprolol daily. 6

If Current The funny current is highly expressed in spontaneously active cardiac regions, such as the sinoatrial node (SAN, the natural pacemaker region), the atrio-ventricular node (AVN) and the Purkinje fibres of conduction tissue. Particularly unusual, the funny current is a mixed sodium-potassium current, inward and slowly activating on hyperpolarization at voltages in the diastolic range (normally from -60/-70 mV to -40 mV). When at the end of a sinoatrial action potential the membrane repolarizes below the If threshold (about -40/-50 mV), the funny current is activated and supplies inward current, which is responsible for starting the diastolic depolarization phase (DD); By this mechanism, the funny current controls the rate of spontaneous activity of sinoatrial myocytes, hence the cardiac rate.

If Current Another unusual feature of If is its dual activation by voltage and by cyclic nucleotides. Cyclic adenosine monophosphate (cAMP) molecules bind directly to f-channels and increase their open probability. cAMP dependence is a particularly relevant physiological property, Since it underlies the If –dependent autonomic regulation of heart rate. Sympathetic stimulation raises the level of cAMP molecules which bind to f-channels and shift the If activation range to more positive voltages; This mechanism leads to an increase of the current at diastolic voltages and therefore to an increase of the steepness of DD and heart rate acceleration. Parasympathetic stimulation (which acts to increase probability of potassium channels opening but decreases the probability of calcium channel opening) decreases the heart rate by the opposite action, that is by shifting the If activation curve towards more negative voltages.

Ivabradine Does not alter… Specifically binds the Funny channel Reduces the slope for diastolic depolarization Prolongs diastolic duration Does not alter… Ventricular repolarization Myocardial contractility Blood pressure Because it binds to the F channel in the open position, it has greatest activity when there is greater open-close cycling of the F channel. Hence it exhibits is greatest effect when heart rates are highest. In that sense it has a partial self limiting capability. 9

Ivabradine Trials Reduces atherosclerosis (Circ 2008;117:2377-87) Decreases vascular oxidative stress Improves endothelial function Increases exertional tolerance and time to ischemia in patients with > 3 months angina (Circ 2003;107:817-23) Non-inferior to Atenolol (Eur Heart J 2005;26:2529-36) Exercise tolerance, time to angina or ischemia Non-inferior to Amlodipine (Drugs 2007;67(3):393-405) Atherosclerosis, Male apolipoprotein E-deficient mice fed a high-cholesterol diet, Ivabradine decreased atherosclerotic plaque size in the ascending aorta by >70% in 6 weeks. Exertional tolerance: Using bicycle Exercise Tolerence test, there was an increased time to ST depression and time to exercise limiting angina. NOTE, this was after a 2-7 day washout of all anti-anginals, including betablockers. Compared to atenolol for 12 weeks of administration 10

MorBidity-mortality EvAlUation of The I f inhibitor Ivabradine in patients with coronary disease and left ventricULar dysfunction BEAUTIFUL Trial

RATIONALE In CAD patients, high heart rate is associated with higher mortality1 CAD patients with associated LVD are at higher risk of mortality2 Heart rate reduction could reduce mortality in CAD patients3 Ivabradine is a pure heart rate reducing agent with proven antianginal and anti-ischemic efficacy 4,5,6 1- Diaz A,et al. Eur Heart J. 2005;26:867-874. 2- Emond M. Circulation. 1994;90:2645–2657. 3- Cucherat Ml. Eur Heart J. 2007;28:3012-3019. 4- Borer JS et al. Circulation. 2003;107:817-823. 5- Tardif JC,et al. Eur Heart J. 2009;30:540-548 6- Tardif JC et al. Eur Heart J. 2005;26:2529-2536.

Pathophysiological objective MorBidity-mortality EvAlUation of The I f inhibitor Ivabradine in patients with coronary disease and left ventricULar dysfunction Clinical objective To examine the effects of ivabradine on cardiovascular events in coronary patients with left ventricular dysfunction Pathophysiological objective To examine the effects of elevated HR (>70 bpm) on cardiovascular events in these coronary patients

781 sites in 33 countries across 4 continents Worldwide study 10 917 participants with documented coronary artery disease and left ventricular dysfunction 781 sites in 33 countries across 4 continents

Inclusion criteria Male or female Nondiabetic 55 years, diabetic 18 years Documented coronary artery disease Sinus rhythm and resting heart rate 60 bpm Documented left ventricular systolic dysfunction (<40%) Clinically stable for 3 months with regards to angina or heart failure symptoms or both Therapeutically stable for 1 month (appropriate or stable doses of conventional medications) K. Fox et al. Am Heart J. 2006;152:860-866.

Follow-up for 12 to 35 months–median 19 months Design of the study Ivabradine 5 mg  7.5 mg bid Multicenter (781 centers / 33 countries) randomized trial 10 917 patients with stable CAD and left ventricular dysfunction (EF <40%) Already receiving appropriate conventional cardiovascular medical therapy Placebo bid Visits Follow-up for 12 to 35 months–median 19 months Fox K et al. Lancet. 2008;372:807-816.

12 138 screened 10 917 randomized 5479 to ivabradine 5438 to placebo Patients and follow-up 12 138 screened 10 917 randomized 5479 to ivabradine 5438 to placebo 5479 analyzed 5438 analyzed Median study duration: 19 months Maximum: 35 months Fox K et al. Lancet. 2008;372:807-816.

Baseline characteristics Placebo Ivabradine All Time since CAD diagnosis (years) 8.2 (7.1) 8.1 (7.0) 8.2 (7.0) Previous MI (%) 89 88 88 Time since last MI (years) 6.2 (6.0) 5.9 (5.7) 6.0 (5.9) History of diabetes (%) 37 37 37 History of hypertension (%) 71 71 71 Previous coronary revascularization (%) 52 51 52 Values in parentheses are standard deviations Fox K et al. Lancet. 2008;372:807-816.

Concomitant treatment -blockers (%) Statins (%) Antithrombotic agents (%) Renin-angiotensin blockers (%) 87 74 94 90 Placebo Ivabradine All Fox K et al. Lancet. 2008;372:807-816.

Results

Heart rate above 70 bpm increases risk of myocardial infarction by 46% Prospective data from the BEAUTIFUL placebo arm 8 Hazard ratio = 1.46 (1.11 – 1.91) P=0.0066 Heart rate ≥70 bpm 6 % with hospitalization for fatal and nonfatal MI 4 Heart rate <70 bpm 2 0.5 1 1.5 2 Years Fox K et al. Lancet. 2008;372:817-821.

Heart rate above 70 bpm increases risk of coronary revascularization by 38% % with coronary revascularization 6 P=0.037 Hazard ratio = 1.38 (1.02 – 1.86) Heart rate ≥70 bpm 4 2 Heart rate <70 bpm 0.5 1 1.5 2 Years Fox K et al. Lancet. 2008;372:817-821

Effect of ivabradine on primary endpoint (Overall population) % with primary composite end point of CV death, hospitalization for acute MI, or for new-onset or worsening heart failure Ivabradine Placebo P=0.94 Hazard ratio = 1.00 (0.91 – 1.10) 5 10 15 20 25 Years 0.5 1 1.5 2 Fox K et al. Lancet. 2008;372:807-816.

fatal or nonfatal MI (%) Ivabradine reduces fatal and nonfatal myocardial infarction (HR ≥70 bpm) 8 P=0.001 Hazard ratio = 0.64 (0.49 – 0.84) Placebo (HR >70 bpm) RRR 36% fatal or nonfatal MI (%) Hospitalization for 4 Ivabradine 0.5 1 1.5 2 Years RRR: relative risk reduction Fox K et al. Lancet. 2008;372:807-816.

Ivabradine shifts the patients from high risk to low risk 8 HR >70 bpm in placebo (mean HR = 79 bpm) -36%* 4 HR <70 bpm in placebo (mean HR = 64 bpm) fatal or nonfatal MI (%) Hospitalization for HR > 70 bpm with Procoralan (mean HR = 66 bpm after treatment) Procoralan eliminate the excess risk of MI in CAD patioents with HR above 7à who are at higher risk of CV events, and restore that risk to a low level by reducing specifically HR below 70 bpm. *P=0.001 **P=0.0066 0.5 1 1.5 2 Years Fox K et al. Lancet. 2008;372:807-816.

Ivabradine reduces the need for revascularization (HR ≥70 bpm) 8 Hazard ratio = 0.70 (0.52 – 0.93) P=0.016 Placebo (HR >70 bpm) RRR 30% Coronary revascularization (%) 4 Ivabradine 0.5 1 1.5 2 Years RRR: relative risk reduction Fox K et al. Lancet. 2008;372:807-816.

Ivabradine reduces all coronary events in coronary patients with HR ≥70 bpm Predefined end point Hazard ratio Risk reduction P value 0.114 31% 0.69 Fatal MI 0.001 36% 0.64 Fatal and nonfatal MI 0.023 22% 0.78 Fatal and nonfatal MI or unstable angina 0.009 23% 0.77 Fatal and nonfatal MI, unstable angina, or revascularization 0.016 30% 0.70 Coronary revascularization Fox K et al. Lancet. 2008;372:807-816. 27 27

Optimal reduction in heart rate in coronary patients with HR ≥70 bpm 90 80 Placebo 70 Heart rate (bpm) 60 Ivabradine 50 15 30 90 180 360 540 720 Follow-up (days) Fox K, et al. Lancet. 2008;372:807-816.

New Results In angina patients

New results in angina patients Rationale Angina is the most common clinical manifestation of coronary artery disease (CAD). Ivabradine has established anti-ischemic and antianginal efficacy. In the large BEAUTIFUL trial, Ivabradine demonstrates that it reduces coronary events in CAD patients. Objective To explore the effects of Ivabradine on cardiovascular outcomes in BEAUTIFUL patients with limiting angina at baseline.

12 138 patients with CAD and LVD screened Design and methodology New results in angina patients 12 138 patients with CAD and LVD screened 10 917 randomized 1507 randomized with angina 773 to placebo 734 to Ivabradine 734 analyzed 773 analyzed Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Data on file.

New results in angina patients Total BEAUTIFUL population Baseline treatment New results in angina patients   Patients with angina Total BEAUTIFUL population Ivabradine (n=734) Placebo (n=773) Ivabradine Placebo   Aspirin or antithrombotic agent 92% 92% 94% 94% Statin 67% 64% 74% 74% ACE inhibitor and/or ARB 88% 86% 90% 90% β-Blocker 89% 90% 87% 87% Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line.

-24% Ivabradine reduces primary end point in angina patients New results in angina patients Primary end point(PEP) : CV death + hospitalization for HF or MI n=1507 P=0.05 Years 5 10 15 20 0.5 1 1.5 2 Cumulative incidence for PEP* (%) -24% Placebo Ivabradine Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line.

Ivabradine reduces myocardial infarction in patients with angina New results in angina patients All patients with angina Patients with angina and heart rate >70 bpm Placebo Ivabradine Hospitalization for fatal and nonfatal MI HR (95% CI), 0.58 (0.37–0.92); P=0.021 Years 5 10 15 0.5 1 1.5 2 Event rate (%) 42% Placebo Ivabradine Hospitalization for fatal and nonfatal MI HR (95% CI), 0.27 (0.11–0.66); P=0.002 Years 5 10 15 0.5 1 1.5 2 Event rate (%) 73% Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line.

Summary of observed cardiovascular risk reduction in angina patients New results in angina patients 24% 0.76 Primary composite end point 12% 0.88 CV death 42% 0.58 16% 0.84 Hospitalization for HF 13% 0.87 All-cause mortality Risk reduction Hazard ratio Predefined end point 30% 0.70 Coronary revascularization Hospitalization for MI (n=1507) Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line.

In brief Ivabradine, the first selective and specific If inhibitor, has already demonstrated antianginal and anti-ischemic efficacy and improvement of cardiac performance BEAUTIFUL, the first morbidity-mortality trial with ivabradine, includes 10 917 patients with documented stable coronary artery disease and left ventricular dysfunction receiving optimal guidelines-based therapy. In patients with coronary artery disease and left ventricular dysfunction, those with a heart rate >70 bpm have a higher risk of cardiovascular mortality, hospitalization for myocardial infarction, and heart failure. In patients with heart rate >70 bpm, ivabradine reduces the composite of fatal and nonfatal myocardial infarction and reduces the need for revascularisation. In angina patients, ivabradine reduces the primary end point of cardiovascular death, hospitalization for heart failure, or for myocardial infarction.

Systolic Heart failure treatment with the If inhibitor ivabradine Trial SHIFT Trial http://www.lancet.com published online August 29, 2010 DOI:10.1016/S0140-6736(10)61198-1

Background Elevated heart rate is associated with poor outcome in a number of cardiovascular conditions including heart failure Heart rate remains elevated in many heart failure patients despite treatment by beta-blockers Ivabradine is a novel heart rate-lowering agent acting by inhibiting the If current in the sino-atrial node We hypothesized that the addition of ivabradine to recommended therapy would be beneficial in heart failure patients with elevated heart rate

Primary objective To evaluate whether the If inhibitor ivabradine improves cardiovascular outcomes in patients with 1. Moderate to severe chronic heart failure 2. Left ventricular ejection fraction 35% 3. Heart rate 70 bpm and 4. Recommended therapy

6505 patients, 37 countries, 677 centres Multinational study Bulgaria Czech Republic Estonia Hungary Europe Germany Portugal Belgium Greece Spain Denmark Ireland Sweden Finland Italy Turkey France The Netherlands UK Latvia Lithuania Norway Poland Romania Russia Slovakia Slovenia Ukraine North America Canada Asia China Hong Kong India South Korea Malaysia South America Argentina Brazil Chili Australia 6505 patients, 37 countries, 677 centres

Class II to IV NYHA heart failure Ischaemic/non-ischaemic aetiology Inclusion criteria 18 years Class II to IV NYHA heart failure Ischaemic/non-ischaemic aetiology LV systolic dysfunction (EF 35%) Heart rate 70 bpm Sinus rhythm Documented hospital admission for worsening heart failure 12 months Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81. 41

Ivabradine 7.5/5/2.5 mg bid according to Study design Ivabradine 5 mg bid Ivabradine 7.5/5/2.5 mg bid according to HR and tolerability Screening 7 to 30 days Matching placebo, bid D0 D14 D28 M4 Every 4 months 3.5 years Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81. 42

Primary composite endpoint Study endpoints Primary composite endpoint Cardiovascular death Hospitalization for worsening heart failure Other endpoints All-cause / CV / HF death All-cause / CV / HF hospitalization Composite of CV death, hospitalization for HF or non-fatal MI NYHA class / Patient & Physician Global Assessment In total population and in patients with at least 50% target dose of beta-blockers Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81. 43

7411 screened 6558 randomized 3268 to ivabradine 3290 to placebo Patients and follow-up 7411 screened 6558 randomized 3268 to ivabradine 3290 to placebo Excluded: 27 Excluded: 26 3241 analysed 2 lost to follow-up 3264 analysed 1 lost to follow-up Median study duration: 22.9 months; maximum: 41.7 months

Baseline characteristics Ivabradine 3241 Placebo 3264 Mean age, y 60.7 60.1 Male, % 76 77 Ischaemic aetiology, % 68 67 NYHA II, % 49 NYHA III/IV, % 51 Previous MI, % 56 Diabetes, % 30 31 Hypertension, % 66

Baseline characteristics Ivabradine 3241 Placebo 3264 Mean heart rate, bpm 80 Mean LVEF, % 29 Mean SBP, mm Hg 122 121 Mean DBP, mm Hg 76 eGFR, mL/min/1.73 m2 75

Chronic HF background treatment Patients (%) 100 91 91 89 90 90 84 83 Ivabradine 80 Placebo 70 61 59 60 50 40 30 22 22 20 10 3 4 Beta-blockers ACEIs and/or Diuretics Aldosterone Digitalis ICD/CRT ARBs antagonists

Background beta-blocker treatment Patients (%) 100 Ivabradine 10 20 30 40 50 60 70 80 90 89 89 Placebo 56 56 26 26 BB at randomization At least 50% target daily dose Target daily dose

Mean heart rate reduction Mean ivabradine dose: 6.4 mg bid at 1 month 6.5 mg bid at 1 year Heart rate (bpm) 90 Ivabradine Placebo 80 80 75 75 70 67 64 60 50 2 weeks 1 4 8 12 16 20 24 28 32 Months

Primary composite endpoint Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY) HR = 0.82 [95% CI 0.75-0.90] p<0.0001 Cumulative frequency (%) 40 Ivabradine Placebo - 18% 30 20 10 6 12 18 24 30 Months

Hospitalization for heart failure Ivabradine n=514 (9.4%PY) Placebo n=672 (12.7%PY) HR = 0.74 [95% CI 0.66-0.83] p<0.0001 Cumulative frequency (%) 30 Ivabradine Placebo - 26% 20 10 6 12 18 24 30 Months

Cardiovascular death HR = 0.91 p=0.128 Ivabradine n=449 (7.5%PY) Placebo n=491 (8.3%PY) HR = 0.91 p=0.128 Cumulative frequency (%) 30 Ivabradine Placebo 20 10 6 12 18 24 30 Months

Effect of ivabradine on outcomes Endpoints Hazard ratio 95% CI p value Primary composite endpoint 0.82 [0.75;0.90] p<0.0001 All-cause death 0.90 [0.80;1.02] p=0.092 Death from HF 0.74 [0.58;0.94] p=0.014 Hospitalisation for any cause 0.89 [0.82;0.96] p=0.003 Hospitalisation for CV reason 0.85 [0.78;0.92] p=0.0002 CV death/hospitalisation for HF or non-fatal MI [0.74;0.89]

Effect of ivabradine in prespecified subgroups Test for interaction Age <65 years ≥65 years Sex Male Female Beta-blockers No Yes Aetiology of heart failure Non-ischaemic Ischaemic NYHA class NYHA class II NYHA class III or IV Diabetes No Yes Hypertension No Yes Baseline heart rate <77 bpm ≥77 bpm p=0.029 0.5 1.0 1.5 Hazard ratio Favours ivabradine Favours placebo

Patients with at least 50% BB target dose (n=3181) p value Ivabradine Placebo Hazard ratio Primary composite endpoint ns 330 (11.9 PY) 362 (13.3 PY) 0.90 Cardiovascular death ns 176 (5.9 PY) 175 (5.9 PY) 1.00 Hospitalisation for worsening HF 213 (7.7 PY) 260 (9.6 PY) 0.81 p=0.021 0.5 1.0 1.5 Hazard ratio Favours ivabradine Favours placebo

NYHA class changes p=0.0003 Ivabradine Placebo 70 68 28 24 6 5 Patients (%) 70 68 p=0.0003 70 60 Ivabradine 50 Placebo 40 28 30 24 20 10 5 6 Improvement Stability Worsening

Incidence of selected adverse events (N = 6492) Patients with an event Ivabradine N=3232, % (n) Placebo N=3260, % (n) p value All serious adverse events 45% (1450) 48% (1553) 0.025 All adverse events 75% (2439) 74% (2423) 0.303 Heart failure 25% (804) 29% (937) 0.0005 Symptomatic bradycardia 5% (150) 1% (32) <0.0001 Asymptomatic bradycardia 6% (184) 1% (48) Atrial fibrillation 9% (306) 8% (251) 0.012 Phosphenes 3% (89) 1% (17) Blurred vision <1% (7) 0.042

Conclusion Heart failure with systolic dysfunction and elevated heart rate is associated with poor outcomes (primary composite endpoint in the placebo group is 18%/year) Ivabradine reduced CV mortality or heart failure hospitalization by 18% (p<0.0001). The absolute risk reduction was 4.2% This beneficial effect was mainly driven by a favourable effect on heart failure death/hospital admission (RRR 26%) Overall, treatment with ivabradine was safe and well tolerated

ESC - 2012 Should be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤35%, a heart rate remaining ≥70 b.p.m., and persisting symptoms (NYHA class II–IV) despite treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose below that), ACE inhibitor (or ARB), and an MRA (or ARB). - IIa B May be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤35% and a heart rate ≥70 b.p.m. who are unable to tolerate a beta-blocker. Patients should also receive an ACE inhibitor (or ARB) and an MRA (or ARB). ] - IIb C

Autonomic Nervous System ACh = acetylcholine; AC = adenylate cyclase; β-AR = β-adrenoceptor receptor; Gi = inhibitory G-protein (inhibits AC); Gs = stimulatory G-protein (stimulates AC); M2-R= type-2 muscarinic receptor; NA = noradrenaline (norepinephrine). 60

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Autonomic Nervous System ACh = acetylcholine; AC = adenylate cyclase; β-AR = β-adrenoceptor receptor; Gi = inhibitory G-protein (inhibits AC); Gs = stimulatory G-protein (stimulates AC); M2-R= type-2 muscarinic receptor; NA = noradrenaline (norepinephrine). 62