Term
| What is venous capacitance? |
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Definition
| Regulation of volume of blood returning to the heart, which is a major determinant of end-diastolic volume of the heart |
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Term
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Definition
| End-diastolic ventricular wall stress Or the stress on the ventricular fibers just before contraction |
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Term
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Definition
Chest pain is termed as angina pectoris is a symptom of myocardial ischemia (not always)
Angina at work (exercise)
Common treatment of angina pectoris is nitroglycerin |
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Term
| What does nitroglycerine do? How does it work? |
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Definition
Agent that decreases vascular tone
Decreases the O2 supply and demand |
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Term
| Preload is directly related to ______________. |
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Definition
Venous capacitance
Not:
Arterial resistance
Contractility
tone |
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Term
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Definition
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Term
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Definition
Afterload
Myocardial O2 demand
Regional myocardial perfusion |
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Term
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Definition
Venous pooling
Preload
Myocardial O2 demand |
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Term
| Sources of Ca2+ for Contraction of Vascular Smooth Muscle Cells |
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Definition
| The cytosolic concentration of Ca2+ is low (10–7 M), while the extracellular and sarcoplasmic reticulum concentrations of Ca2+ are high (2 × 10–3 M). Ca2+ can enter the cytoplasm of the vascular smooth muscle cell from the extracellular space or from the sarcoplasmic reticulum via Ca2+-selective channels. The increased concentration of Ca2+ in the cytosol initiates contraction by promoting the formation of actin–myosin cross-bridges. |
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Term
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Definition
Activation of guanylyl cyclase in SMC -> Cyclic guanosine 3’,5’-monophosphate (cGMP)-> cGMP dependent protein kinase
-> Myosin light chain phosphatase
-> Dephosphorylation of myosin light chain -> Inhibits interaction of myosin head with actin -> SMC relaxation |
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Term
| Mechanism of Vascular Smooth Muscle Cell Contraction and Relaxation |
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Definition
| Vascular smooth muscle cell contraction and relaxation are controlled by the coordinated action of several intracellular signaling mediators. Ca2+ entry through L-type voltage-gated Ca2+ channels (left panel) is the initial stimulus for contraction. Ca2+ entry into the cell activates calmodulin (CaM). The Ca2+-CaM complex activates myosin light chain kinase (MLCK) to phosphorylate myosin light chain (myosin-LC). The phosphorylated myosin-LC interacts with actin to form actin–myosin cross-bridges, a process that initiates vascular smooth muscle cell contraction. Relaxation (right panel) is a coordinated series of steps that act to dephosphorylate (and hence inactivate) myosin-LC. Nitric oxide (NO) diffuses into the cell and activates guanylyl cyclase. The activated guanylyl cyclase catalyzes the conversion of guanosine triphosphate (GTP) to guanosine 3′,5′-cyclic monophosphate (cGMP). cGMP stimulates cGMP-dependent protein kinase (not shown), which activates myosin-LC phosphatase, which dephosphorylates myosin light chain, preventing actin–myosin cross-bridge formation. As a result, the vascular smooth muscle cell relaxes. The active form of each enzyme is italicized and blue. |
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Term
Vascular smooth muscle cell contraction is a direct result of NO
release from the endothelium |
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Definition
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Term
| Endothelial Regulation of Nitric Oxide-Mediated Vascular Smooth Muscle Relaxation |
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Definition
Endothelial-cell production of nitric oxide (NO) controls the extent of vascular smooth muscle cell relaxation. Production of NO is stimulated by agonists such as acetylcholine or bradykinin. Stimulation of receptors by these agonists activates Ca2+ second messenger systems and promotes direct entry of Ca2+ into the cytosol. The increased cytosolic Ca2+ activates a Ca2+-calmodulin complex that stimulates endothelial nitric oxide synthase (eNOS), an enzyme that catalyzes the formation of NO from L-arginine (L-Arg, an amino acid). NO diffuses from the endothelial cell into subjacent vascular smooth muscle cells, where it activates guanylyl cyclase, promoting smooth muscle cell relaxation (see Fig. 21-3). NO can also directly activate Ca2+-dependent K+ channels. This parallel signaling pathway contributes to relaxation by hyperpolarizing the smooth muscle cell. The active form of each enzyme is italicized and blue.
L-Arg –(THB + Ca2+/eNOS)-> L-Citrullin |
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Term
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Definition
Acetyl choline (Ach) causes vasorelaxation in intact vasculature (with endothelium)
De-endothealized blood vessels fail to relax with Ach
Hypothesis: Ach causes muscarinergic stimulation and releases substance called as EDRF
(Endothelium derived relaxing factor)
Later it was found that EDFR is NO
NO can be stimulated by a variety of other mediators:
Shear stress, acetyl choline, histamine, bradykinin, sphingosine-1-phosphate,
serotonin, substance P, and ATP |
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Term
| Additional vasorelaxation pathways: |
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Definition
Activation of Ca2+ dependent K+ channels in vascular smooth
muscle cells
NO activates K+ channels (Ca2+ activated K+ channels) via
cGMP independent pathway
This cause hyperpolarization of cells and vasodilation |
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Term
| Acetyl choline will cause relaxation in a denuded vessel |
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Definition
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Term
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Definition
What is Endothelin?
21 amino acid vasoconstrictor peptide
Most Potent vasoconstrictor
Opposing effects to that of NO (endothelin is a constrictor)
Physiological properties:
Positive inotropic and positive chronotropic actions on heart
Remodeling in heart and cardiovascular system
Also, plays important role in lungs, kidneys and brain
Proposed mechanism -Neointimal proliferation and increased collagen deposition-> Fibrosis |
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Term
| Endothelin’s have two receptors |
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Definition
ETA and ETB
G protein coupled receptors
ET-1 binds to ETA and ETB receptors on VSMC and endothelial cells
ETA are located on VSMC
ETB are predominantly on Vascular endothelial cells control vasodilatation
via release of prostacyclin and NO
ETB on VSMC control vasoconstriction |
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Term
| Isoforms of Endothelin and main actions: |
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Definition
1)Endothelin 1 (ET-1): involved in cardiovascular actions, produced by endothelial cells , VSMC, under inflammation
2) Endothelin 2 (ET-2):
3) Endothelin 3 (ET-3) |
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Term
| Endothelin causes ____________. |
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Definition
Vasoconstriction
Not:
Vasorelaxation
Dilatation
hyperplasia |
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Term
| Sites of Action of Vasodilators |
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Definition
| Vasodilators act at several sites in the vascular smooth muscle cell. Left panel: Ca2+ channel blockers and K+ channel openers inhibit the entry of Ca2+ into vascular smooth muscle cells by decreasing activation of L-type Ca2+ channels. ACE inhibitors, AT1 antagonists, α1-antagonists, and endothelin receptor (ETA, ETB) antagonists all decrease intracellular Ca2+ signaling. The decreased cytosolic Ca2+ results in decreased vascular smooth muscle cell contraction, and, hence, in relaxation. Right panel: ACE inhibitors inhibit kininase II (KII), leading to increased levels of bradykinin. Nitrates release NO. Sildenafil and other PDE5 inhibitors inhibit phosphodiesterase (PDE). These agents all cause an increase in cGMP, an effect that promotes vascular smooth muscle relaxation. The active form of each enzyme is italicized and blue. α1, α1-adrenergic receptor; ACE, angiotensin converting enzyme; AT-I, angiotensin I; AT-II, angiotensin II; AT1, angiotensin II receptor; CaM, calmodulin; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; MLCK, myosin light chain kinase; myosin-LC, myosin light chain. |
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Term
| NO Donors ( Organic nitrates, sodium nitroprusside) |
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Definition
| MOA: activating guanylyl cyclase and increasing deposhorylation of myosin light chain |
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Term
| cGMP phosphodiesterase type V (PDE5) inhibitors |
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Definition
| MOA: prevent cGMP hydrolysis and promote dephosphorylation of MLC |
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Term
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Definition
| MOA: reducing intracellular calcium levels |
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Term
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Definition
| MOA: opening ATP sensitive potassium channels |
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Term
| Endothelial receptor antagonists |
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Definition
| MOA: Block endothelin mediated vasoconstriction |
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Term
| α1 adrenergic antagonists |
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Definition
| MOA: inhibits vasoconstrictive action of epi and norepinephrine |
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Term
| ACE inhibitors or Angiotensin II receptor subtype 1 antagonists |
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Definition
| MOA: inhibit vasoconstrictive effects of angiotensin II or blocking of AT1 receptor |
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Term
| Hydralazine and β-adrenergic antagonists |
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Definition
| MOA: modulate vascular tone |
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Term
| Biotransformation of Organic Nitrates and Sodium Nitroprusside |
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Definition
| Organic nitrates and sodium nitroprusside increase local levels of NO by different mechanisms. Organic nitrates have the chemical structure RNO2. The nitro group is reduced to form NO in the presence of specific enzymes and extracellular and/or intracellular reductants (e.g., thiols). In comparison, sodium nitroprusside releases NO spontaneously without enzymatic aid. Both agents effect relaxation via the formation of NO. However, the requirement of organic nitrates for specific cellular enzymes and/or reductants may result in tissue selectivity. Because sodium nitroprusside spontaneously converts to NO, it does not dilate vascular beds selectively. |
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Term
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Definition
Oldest cardiac therapies
-also called as nitroglycerin (used for angina symptoms for over 100 years)
-Used for stable and unstable angina, myocardial infraction, hypertension,
acute and chronic heart failure
Organic Nitrates can be catalyzed in tissues
Mitochondrial aldehyde dehydrogenase and may allow targeting of effects to
Specific vascular tissues
Nonenzymatic: related to thiol pool
NO can dilate both arteries and veins: venous dilatation
predominates at therapeutic doses |
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Term
| Cardiovascular and peripheral effects of NO |
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Definition
NO causes venous dilatation->Increases venous capacitance->Decrease in the venous return of blood to right side of heart->Causing a decrease in the right and left ventricular end-diastolic
pressure and volume->Decrease in preload causes decrease in myocardial O2 demand |
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Term
| Decrease in afterload will cause increase in O2 consumption. |
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Definition
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Term
| Sites of Action of Organic Nitrates |
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Definition
| Organic nitrates exert the majority of their vasodilator action on venous capacitance vessels. This selectivity results in greatly decreased preload, with resulting decreased myocardial O2 demand. Organic nitrates also mildly dilate arteriolar resistance vessels, with resulting decreased afterload and decreased myocardial O2 demand. Myocardial O2 supply is mildly increased by dilation of large epicardial arteries. |
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Term
| Chemical Structures and Metabolism of Nitroglycerin and Isosorbide Dinitrate |
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Definition
| Nitroglycerin and isosorbide dinitrate are biologically active nitrates that are metabolized into active molecules with longer half-lives than their parent compounds. Nitroglycerin is denitrated into glyceryl 1,2-dinitrate and glyceryl 1,3-dinitrate; these active metabolites have a half-life of approximately 40 minutes. Isosorbide dinitrate is denitrated into isosorbide 2-mononitrate and isosorbide 5-mononitrate; these active metabolites have half-lives of 2 and 4 hours, respectively. |
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Term
| Chemical Structure and Metabolism of Sodium Nitroprusside |
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Definition
| A. Sodium nitroprusside is a complex of iron, cyanide (CN), and a nitroso (NO) group. B. Sodium nitroprusside spontaneously decomposes to release NO and cyanide. NO effects vasodilation; cyanide is metabolized in the liver to thiocyanate, which undergoes renal excretion. Cyanide toxicity can result from prolonged administration of the drug or in the presence of renal insufficiency. |
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Term
| A 64 year old man with stable angina has been doing well on isosorbide dinitrite, 20 mg Bid. Recently he increased his dose to four times daily, thinking more is better. Soon after he noted that the symptoms were worsening. What might be the reason? |
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Definition
Worsening angina secondary to progression of his coronary artery disease
Nitrate tolerance
Studies with stable angina show that persistent anti-anginal effects when
nitrate free interval of 10-12 hours is provided. Many patients experience an attenuation
or complete loss of anti-anginal effects when long acting agents are used 3-4 times daily.
Similarly long acting NTG patches should be removed for 10 12 hours |
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Term
| Pharmacological Tolerance: |
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Definition
Important and clinically relevant phenomenon
Limits the efficacy of this class of vasodilators
Workers at the munitions exposed to volatile nitrates in work place
Monday morning head aches and faded during week however, over week end
recovered
Returned to work and suffered from headache again...
-Nitrate free intervals
-Patients may experience rebound angina during nitrate free hours
-Oral isosorbide 5-mononitrate has clear advantages for some of these issues |
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Term
| Oral isosorbide 5-mononitrate |
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Definition
Advantages:
The pharmacokinetic properties make this preparation attractive for
nitrate tolerance and angina rebound
2) High bioavailability and high half life periods produce high therapeutic plasma
concentrations of plasma
3) High periods of plasma concentration is followed by low levels rather than “Zero” levels
4) Transdermal NTG or oral isosorbide 5-mononitrate illustrate how pharmacokinetic
properties of similar acting drugs can have different therapeutic utility
Mechanism of tolerance:
Sulfhydryl hypothesis
Formation of peroxynitrite
Contraindications:
Contraindicated in patients with hypotension
In patients with elevated intracranial pressure
(because can further dilate vessels and increase pressure)
Used with caution in diastolic heart failure patients
Recent discovery: Use of nitrates with sildenafil (PDE5 inhibitors) |
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Term
| Concomitant use of NO donors with PDE5 inhibitors… |
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Definition
NO donors increase levels of nitric oxide
PDE5 inhibitors restrict degradation of cGMP which is effector
if NO induced vasodilation
Therefore the NO response is amplified |
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Term
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Definition
Mechanism:
Act both on vasculature and myocardium
Ca2+ channel blockers are arteriolar dilators
Treatment of hypertension, arrhythmias, some forms of angina
Main MOA: Ca2+ blockers act by blocking the entry of Ca2+ by L-type
calcium channels
In cardiomyocytes: decrease Ca2+ influx decreases contractility,
SA node pacemaker rate,
AV node conduction velocity
Chemical classes:
Dihydropyridines: nifedipine, amlidipine, felodipine
Benzothiazipines: diltiazem
Phenylalkylamines: verapamil |
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Term
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Definition
| nifedipine, amlidipine, felodipine |
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Term
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Definition
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Term
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Definition
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Term
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Definition
Vasodilation (peripheral arterioles and coronary arteries)
5
Depression of cardiac contractility
1
Depression of automaticity (SA node)
1
Depression of conduction( AV node)
0
Nifedipine is the most selective drug for peripheral vasodilation |
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Term
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Definition
Vasodilation (peripheral arterioles and coronary arteries)
3
Depression of cardiac contractility
2
Depression of automaticity (SA node)
5
Depression of conduction( AV node)
4
Diltiazem and verapamil more selective in the heart |
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Term
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Definition
Vasodilation (peripheral arterioles and coronary arteries)
4
Depression of cardiac contractility
4
Depression of automaticity (SA node)
5
Depression of conduction( AV node)
5
Diltiazem and verapamil more selective in the heart |
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Term
| Toxicity and Contraindications of Ca2+ channel blockers |
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Definition
Patients taking β-blockers are advised not to take Ca2+ blockers
Because they are both negative inotropes (cardiac depression)
Major indication based secondary to mechanism: smooth muscle relaxation, constipation
Increase the risk of mortality in heart failure patients |
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Term
| Sites of Action of Ca2+ Channel Blockers |
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Definition
| Ca2+ channel blockers dilate coronary arteries and peripheral arterioles, but not veins. They also decrease cardiac contractility, automaticity at the SA node, and conduction at the AV node. Dilation of the coronary arteries increases myocardial O2 supply. Dilation of systemic (peripheral) arterioles decreases afterload and thereby decreases myocardial O2 demand. However, some Ca2+ channel blockers (especially dihydropyridines) cause reflex tachycardia, which can paradoxically increase myocardial O2 demand (not shown). Decreased cardiac contractility and decreased SA-node automaticity also decrease myocardial O2 demand. The inhibition of AV-node conduction by some Ca2+ channel blockers makes them useful as antiarrhythmic agents. Note that the effects diagrammed here are representative effects of the class of drugs; individual agents are more or less selective for each of these effects (see Table 21-2). |
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Term
Among Ca2+ channel blockers, what is the first choice of drug for
peripheral vasodilatation? |
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Definition
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Term
| K+ channel openers (Modulators of K+ ATP channel) |
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Definition
Opening of K+ATP channels hyperpolarizes the membrane
As sufficient number of K+ channels remain open then the normal
excitatory stimuli would not be able to cause depolarization
Examples and mode of action
Minoxidil
Cromakalim
Pinacidil
Nicorandil
Primarily act on SMC->Decrease
arterial pressure |
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Term
| Endothelial Receptor antagonists |
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Definition
Used in treatment of pulmonary hypertension
Major adverse effects: Elevation in serum transaminase levels
(Therefore monitor liver function tests every month) |
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Term
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Definition
Bosentan: Competitive antagonists of ETA and ETB receptors
Used in treatment of pulmonary hypertension |
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Term
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Definition
Used in treatment of pulmonary hypertension
Relative specificity for ETA receptor
Less hepatotoxicity than bosentan |
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Term
| The Renin-Angiotensin–Aldosterone Axis |
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Definition
| Angiotensinogen is a prohormone secreted into the circulation by hepatocytes. Renin, an aspartyl protease secreted by juxtaglomerular cells of the kidney, cleaves angiotensinogen to angiotensin I. Angiotensin converting enzyme (ACE), a protease expressed on pulmonary capillary endothelium (and elsewhere), cleaves angiotensin I to angiotensin II. Angiotensin II has four actions that increase intravascular volume and maintain tissue perfusion. First, angiotensin II stimulates zona glomerulosa cells of the adrenal cortex to secrete aldosterone, a hormone that increases renal NaCl reabsorption at multiple segments along the nephron. Second, angiotensin II directly stimulates renal proximal tubule reabsorption of NaCl. Third, angiotensin II causes efferent arteriolar vasoconstriction, an action that increases intraglomerular pressure and thereby increases GFR. Fourth, angiotensin II stimulates hypothalamic thirst centers and promotes ADH secretion. |
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Term
| Renin Angiotensin system blockers |
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Definition
Used for vasorelaxation effect
ACE inhibitor: Hypotensive effect by decreased catabolism of
bradykinin (vasorelaxant released in response to inflammation)
ACE inhibitors and AT1 receptor blockers are considered
“balanced” vasodilators because they effect both arteriolar and
venous tone
Used for hypertension and heart failure |
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Term
How do nitrates achieve their anti-anginal affects?
What kind of nitrate therapy are available?
How is nitrate tolerance manifested?
) Which vasodilators are common in clinical use?
2) Is there a role for the association between ARB’s (Angiotensin Receptor Blockers)
and ACE inhibitors?
3) What are calcium channel blockers?
4) How do K channel openers work as vasodilators? |
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Definition
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