BPS 337 Vasodilators and adrenergic antagonists 2023 PDF

Vasodilators and adrenergic antagonists 11/29/2023 BPS 337 Richard Clements  Outline Background: Blood pressure: vasodilation and contraction Drugs that induce vasodilation Direct Vasodilators Nitrates Hydralazine...

Vasodilators and adrenergic antagonists 11/29/2023 BPS 337 Richard Clements  Outline Background: Blood pressure: vasodilation and contraction Drugs that induce vasodilation Direct Vasodilators Nitrates Hydralazine PDE5i K+ channel agonists Calcium Channel blockers. Alpha2 agonists Alpha1 antagonists Beta blockers Blood Pressure basics CO = DP/SVR DP ~ Mean Arterial Pressure MAP = CO * SVR CO = Stroke Volume (SV) * HR What are the determinants of SV? Preload: basically venous return. Increases SV Afterload: blood pressure and cardiac wall stress: Decreases SV Contractility: force of the heart contracting: Increases SV Blood pressure is dependent on vascular resistance (SVR) and CO. CO is dependent on HR, preload, afterload and contractility.  Vasoconstriction and vasodilation In the most simplistic terms: Vasoconstriction decreases the radius and thus cross-sectional area for flow increased resistance higher pressure Vasodilation increases the cross-sectional area less resistance lower pressure R = DP / Q Remember P a R4  Molecular Basis of Contraction – Smooth Muscle Agonists activate receptors which turn on plasma membrane Ca++ channels Depolarization of smooth muscle and/or signaling causes release of Ca++ in intracellular stores through IP3 receptor on SR. Ca++ activates MLCK to phosphorylate MLC. Rho Kinase is activated in parallel to MLCK to shut off MLC dephosphorylation MLC phosphorylation causes activation of myosin and subsequent vessel contraction Molecular Basis of VSMC Dilation In endothelial cells: Receptor activated signaling cascades activate nitric oxide synthase (eNOS) NO diffuses to VSMC eNOS activated by both receptor and mechanical signal cascades (shear stress, pressure) In VSMC KCa NO activates soluble guanylate cyclase (sGC) K + sGC makes cyclic-GMP cGMP activates PKG PKG has a coordinated response to limit VSMC contraction: Decrease Ca++ influx/release MYP Decrease MLC phosphorylation via active MYPT ML T Increase K+ efflux C  PKA and smooth muscle dilation In smooth muscle: Vasodilators can activate adenylate cyclase Makes cAMP cAMP activates PKA PKA has negative effects on MLCK as well as activates MLCP to reduce contraction This is the complete opposite effect from PKA in the heart  Summary of VSMC signaling Vessel dilation/contraction can cause huge changes in flow (radius4) Signaling mechanism of vessel contraction and dilation 1 Signal (smooth muscle receptor) 2 Plasma membrane Ca++ channels 3 Intracellular Ca store release 4 MLCK activation 5 MLC phosphorylation Signaling mechanisms of vessel dilation: 1 Signal (endothelial/VSMC receptor etc..) 2 activation of Nitric Oxide 3 Diffusion of NO to VSMC guanylate cyclase 4 generation of cGMP 5 Activation of PKG 6 activation of myosin phosphatase (limits MLC-phosphorylation) and K+ channels  Nitrates Nitrites are potent vasodilators. Nitrates cause release of the gasotransmitter Nitric Oxide (NO). One major effect of NO donors is venous dilation: reduces venous return and reduces preload : NO donors cause dilation of systemic and coronary conduit vessels (>200 uM) : may increase flow across partially blocked conduit vessels. Minimal effect on resistance arterioles, thus systemic pressure and afterload only mildly effected  Nitrates: compounds GTN: Nitroglycerin: glyceryl trinitrate Dependent on cysteine (GSH) / ALDH2 for NO liberation Rapid onset and t1/2 of 1-3 min: most often sublingual tablet Isosorbide dinitrate: ISDN Not ALDH2 dependent Rapid onset and t1/2 ~ 45min, active metabolites t1/2 of (3- 6h). Acute and sustained therapy NTG Isosorbide-5-mononitrate (ISMN) Not ALDH2 dependent Slower onset, longer half-life, not for acute angina treatment Sodium Nitroprusside: SNP – IV only NO donor for emergency treatment Inhaled NO gas Main effect on pulmonary circulation. Rapidly inactivated for systemic effects. ISDN  NO in smooth muscle cells NO promotes vasodilation Produced in the endothelium by eNOS and diffuses to smooth muscle Damaged endothelium may not generate sufficient NO. Stimulates guanylate cyclase in smooth muscle: generates cGMP cGMP activates Protein Kinase G (cGMP- dependent protein kinase) KCa PKG promotes a coordinated response to promote dilation. K Inhibit Ca+ channels and Ca++ release and + hyperpolarizes cells (K+ channels) Activate Myosin phosphatase to reduce myosin phosphorylation All of these responses of NO happen relatively quickly (~ 1 min) to promote vasodilation  Reduced NO and endothelial dysfunction In many diseases NO availability is thought to be reduced leading to impaired dilation Diabetes, hyperlipidemia, metabolic syndrome, atherosclerosis, other inflammatory conditions Reduced NO bioavailability may be due to: Endothelial dysfunction and disruption in eNOS (uncoupling) Increases in endothelial and inflammatory ROS ROS can scavenge NO and turn it into a powerful antioxidant ONOO (peroxynitrite) Nitrates and areas of action Nitrates major effect to increase dilation of veins and decrease preload Promotes dilation of larger conduit vessels Does lower afterload but not great compared to other agents as milder effects on resistance vessels (needs higher dose)  Nitrate tolerance Prolonged/ frequent use of nitrates (GTN) can cause tolerance and ineffectiveness May involve changes in processing enzymes (ALDH2:NTG) Damage to relaxation signaling via nitroso radicals ONOO-, HNO2, N2O3 Therapy should be administered to prevent tolerance: Avoid high doses Interrupt therapy at night 8-12 hours Effectiveness restored after short term withdrawal.  Summary: Nitrates Used for treatment of angina in SIHD: Major effect by dilating large veins which reduces preload on heart and thus wall stress leading to less O2 use. Additional effect by dilating systemic vessels which can decrease afterload (although small because nitrates have limited effect on resistance vessel DHP Will decrease CO and reduce pressure Non-DHP: Decreases cardiac rate and conduction via effects on SA and AV node. Will decrease CO and lower pressure via effects on HR MAP = CO * R Types of Ca++ channel blockers. Dihydropyridines vs non-dihydropyridines  Ca channel blockers: side effects DHP’s especially can cause reflex tachycardia due to drops in blood pressure. Vasodilation elicits a baroreceptor reflex to increase HR and normalize blood pressure. DHP’s have minimal direct effect on HR that do not overcome this Formulations with delayed release drugs with slower onset help mitigate Not as big problem with Verapamil or Diltiazem as they have direct effects to lower HR and conduction. This is also a function of the baroreceptor reflex and increased SNS activity!  Summary: CCB Ca++ channel blockers reduce Ca++ entry into vascular smooth muscle and cardiomyocytes Reduce vasoconstriction by limiting Ca++ dependent MLC phosphorylation Decrease afterload Reduce cardiomyocyte contraction by Ca++ initiated contraction Decrease contractility Diltiazem and Verapamil (non-DHP): reduce HR via blocking recovery of Ca++ channels necessary for propagation of action potential in SA and AV node Decrease HR: we will cover heart rate effects in detail in later lectures Know the difference between DHP (more vascular) and non- DHP (more cardiac) effects  K+ channels and vasodilation K+ channels on vascular smooth muscle plasma membrane promote vasodilation In vasoconstriction cascades Ca++ channel activation causes Ca++ to enter the cell and make it more positive – “depolarize” Opening of K+ channels causes K+ leave and the cell becomes more negative – “hyperpolarize” Keeping the cell hyperpolarized promotes dilation and limits constriction Both PKA and PKG which promote vasodilation in smooth muscle also work to activate K+ channels on the plasma membrane There are also mitochondrial K+ channels which do not modulate dilation/constriction Different than the K+ channels involved in action potentials K+ channels in vasomotor regulation  K+ channels openers Drugs that are K+ channel openers: minoxidil , diazoxide Minoxidil: older drug only used in severe hypertension when resistant to other drugs. 5 mg up to 100 mg/day major risk of hypotension: adverse myocardial effects. Diazoxide: KATP channel opener: not used in hypertension: hyperinsulinemic hypoglycemia There are many other agents and pathways that activate K+ channels as part of vasodilatory cascades Currently no specific drugs to target vascular K+ channels directly for treatment of blood pressure  a2-AR agonists a2-AR agonists decrease blood pressure Why? a2-AR in the vasculature often initiate constriction directly? These drugs have major effects to stimulate a2 receptors in the brain which causes a decrease in SNS outflow and increases vagal tone: Brain stimulation wins out and: Decreased vascular constriction due to less SNS Decreased HR due to increased PNS and decreased SNS pressure is reduced due to decreased SVR and decreased CO  a2-AR agonists Two main drugs in this category are clonidine and methyldopa Clonidine: older drug: not a first line hypertensive agent: Used in patients who require additional blood pressure lowering medications (First line agents: ACEi/ARB: Diuretics: CCB : b- blockers) Methyldopa: generally used in pregnancy-induced hypertension, preferred Major side effects associated with use: Sodium and water retention (methyldopa>clonidine) Orthostatic hypotension Rebound hypertension: major increase in blood pressure if stopped abruptly.  a1-AR antagonists a1 activation causes vasoconstriction via standard vasoconstrictive signaling a1-AR Ca++ influx IP3R mediated Ca++ release Ca/CaM activation of MLCK RhoA/ Rho kinase MLC phosphorylation SNS and norepinephrine/epinephrine (high dose) initiate vasoconstriction via a1-AR activation. This is straightforward compared to a2-agonists.  a1-AR antagonists Doxazosin and prazosin, Doxazosin Tested in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial – ALLHAT (1994-2002). More adverse events than thiazide diuretics: removed treatment arm early. Doxazosin and Prazosin can still be used as alternative blood pressure lowering agents but as second/third line with diuretic use. Can cause water and sodium retention: edema Effective in lowering BP Major adverse effects include orthostatic hypotension: especially initial or increasing dose.  a-AR agents and BP summary a2 agonists are used to decrease BP as an alternative to first line agents These act centrally in the brain to reduce SNS signaling (negative feedback) a1-AR antagonists can potently reduce SVR and thus MAP. Not a preferred first line medication due to increased adverse events versus other agents Useful as an alternative if patient resistant/unresponsive to other medications Work by blocking NE/EPI activation of a1-AR and subsequent MLC phosphorylation cascades.  beta-blockers Recall: b1 adrenergic receptors are on the heart and cause increases in HR and contractility when activated b2 adrenergic receptors are on the vasculature and cause vasodilation. Beta blockers can be nonspecific: or Beta 1 specific. Or mixed beta and alpha1 specific  Sympathetic stimulation of heart rate Activation of b1 receptors Increased Na current through “funny channels” Increased + charge allows Ca++ channels to open HR is increased Parasympathetic stimulation decreases funny currents  b-blocker effect on heart rate B-blockers cause slower Na+ influx through funny b- channels by limiting PKA- blocker dependent increases in channel opening The slower Na++ influx makes it take longer to reach threshold for opening of Ca+ + channels B-blockers result in slower HR and decreased CO MAP = CO * SVR  B1-AR PKA activation promotes Ca++ release PKA can increase Ca++ release through direct modulation of Ca+ + release through RyR, and external Ca++ channels. However, Ca++ stores need to be replenished and increased so PKA phosphorylates and inhibits PLB PLB normally inhibits SERCA. pPLB no longer inhibits SERCA and SR Ca++ stores increase Subsequent Ca++ release from SR is increased. b-blockers inhibit this and thus limit contractility and CO Adrenergic Antagonists  b-blockers Do Beta-blockers cause vasodilation? - not really. b-blockers can reduce blood pressures by: Decreasing HR Decreasing contractility Both of these effects can greatly reduce CO: MAP = CO * SVR CO = HR * SV What are the major types of B-blockers to use to reduce pressure? b1 selective: leaves Beta 2 mediated dilation intact (2nd / 3rd generation) Although non-specific drugs still decrease pressures (minimal effect B2 overall) Metoprolol/atenolol etc… Mixed antagonists: a/b1 selective: Allows alpha1 and beta1 blocking to decrease CO and SVR: carvedilol (3rd generation) Labetalol a1 and b1>b2 Newer drugs: Nebivolol: b1 –specific and has an NO donor moiety (promotes dilation)  Reflex Tachycardia One major use of beta-blockers in combination therapy to lower blood pressure is limiting reflex tachycardia. When vasodilators cause a drop in blood pressure the baroreceptor will increase SNS signaling to increase HR and CO to restore pressure b-blockers can limit this response Also reflex tachycardia if too extreme can damage the heart  Summary b-blockers and BP Pure b-blockers don’t really cause vasodilation or directly decrease SVR b-blockers do decrease SNS stimulation of the heart Decrease HR which decreases CO Decrease contractility which decreases CO MAP = CO * SVR Decrease reflex actions to raise BP b1- selective blockers are preferred to leave intact beneficial B2-AR receptor responses, ex metoprolol If necessary a1 and b1 mixed antagonists can be used to provide additional BP lowering: ex carvedilol Know these cascades! PDE 5 Preferred Combinations for Hypertension  A note about the upcoming test Read the question thoroughly. There may be answer choices that are accurate as a standalone 28. SNS activity increases blood statement. volume via: But are completely incorrect a. decrease in PNS signaling to when in the context of the increase BP question b. increase in oxytocin This is where a lot of students *c. activation of B1-AR on can screw up, because they juxtaglomerular cells to make chose an accurate but renin inappropriate (wrong) answer! d. Activation of alpha1 adrenergic ~30% have gotten this wrong to increase peripheral constriction (chose d). Similar pattern in other questions