Vasoactive drugs act on vascular smooth muscle to cause vasoconstriction or vasodilation. Vasoconstrictors such as endothelin, angiotensin II, and ADH cause contraction through increasing calcium levels or sensitivity. Vasodilators such as calcium channel blockers, ACE inhibitors, and nitrates cause relaxation through decreasing calcium, increasing cGMP/cAMP, or inhibiting phosphodiesterases. The vascular endothelium releases various mediators like prostanoids, nitric oxide, and C-type natriuretic peptide that regulate vascular tone. RAAS activation leads to vasoconstriction and sodium retention through angiotensin II, while drugs blocking RAAS cause indirect vasodilation.

1. Vasoactive Drugs
HDT 2:2 – Semester 2

2. Vascular Structure
• Muscular arteries and arterioles are the main resistance vessels, thus determining afterload, whilst
veins are the main capacitance vessels, determining preload.
• Two important systems regulate vascular tone, these are; the RAAS system, and vascular
endothelium. As well as acting as a physical barrier between plasma and ECF, the vascular
endothelium acts as a source of many potent vasoactive substances. These are; prostanoids, NO,
peptides, endothelium-derived hyperpolarization factors (EDHFs) and endothelin.

3. Mechanisms of Action
• The state of vascular smooth muscle is affected by sympathetic innervation, vascular endothelium
and hormones circulating in the blood.
• Contraction of smooth muscle cells causes vasoconstriction and can be the result of increased
intracellular calcium ions which increase contraction through activation of myosin-light chain
kinases (phosphorylating myosin), or through increasing the sensitivity of myofilaments to calcium
(by inhibiting myosin phosphatase).
• Those agents that cause contraction will either release intracellular calcium via inositol
trisphosphate, cause membrane depolarisation allowing calcium influx through voltage-gated
channel, or through increasing sensitivity (via myosin-light chain kinases or inhibition of myosin
phosphatases).
• Those agents that cause relaxation will so do via inhibition of calcium entry via voltage-gated
channels, directly or through hyperpolarisation, or they may also work through increasing
intracellular cGMP and cAMP concentrations, which inactivate myosin-light chain kinases and
increase calcium efflux.

4. The Endothelium - Mediators
• Below are examples of three classes of mediator released in vascular endothelium that help
regulate the dilation and constriction of vasculature. C-NP stands for C-natriuretic peptide.
• Endothelin is a vasoconstricting substance made in vascular endothelial cells in response to
mediators of inflammation and trauma, such as cytokines, endotoxins, hypoxia, activated
platelets, angiotensin-II, ADH, adrenaline and insulin. It’s production is inhibited by prostaglandins,
natriuretic peptides and NO.
• Endothelin acts on ETA and ETB receptors, primarily causing vasoconstriction. There are three
variants of endothelin; ET-1, ET-2 and ET-3.
Class of Mediator Mediator Effect Vascular
Prostanoid PGI2 Activation of adenylate cyclase Dilation
PGE2 Direct, also inhibits NAd release from sympathetic terminals Dilation
Nitric oxide NO Activation of guanylate cyclase Dilation
Peptide C-NP Activation of cGMP pathways Dilation

5. Effect of RAAS
• Renin is secreted from justaglomerular cells of the afferent arteriole, in response to a decrease in
calcium influx experienced through the gap junctions of mesangial, juxtaglomerular and macula
densa cells of the JGA, which is caused when MD cells detect a fall in luminal sodium
concentration.
• Renin converts angiotensinogen (produced in the liver) into the decapeptide, angiotensin I. This is
then converted to the ocapeptide, angiotensin II via ACE, which then acts on AT1 and AT2
receptors.
• Via AT-1 receptors, angiotensin-II causes general vasoconstriction, especially in the glomerular
efferent, increase NAd release from sympathetic nerve terminals, increasing heart rate (and force
of contraction), proximal tubular Na+ reabsorption, secretion of aldosterone, ADH, cell growth in
heart and arteries and also stimulates feeling of thirst.

6. Vasoconstrictors
• Alpha-adrenoceptor agonists and other drugs that release NAd from sympathetic nerve terminals
have a vasoconstrictor effect, as do endothelins, angiotensin-II and ADH peptides.
• Angiotensin-II is a vasoconstrictor that is 40 times more potent than NAd at increasing ABP. It has
constrictor effects mainly on cutaneous, splanchnic and renal beds and avoids cerebral and
skeletal muscle vascular contraction. It doesn’t have any clinical uses, indeed many drugs have
been developed to oppose it’s function.
• ADH is a posterior pituitary hormone that acts on V1 and V2 receptors. Signaling via the latter
receptor occurs in the kidney and at low plasma concentrations, where it promotes the migration
of AQP2 to the apical surface of CD cells in the nephron via activation of intracellular adenylate
cyclase. The vasoconstriction effect occurs at higher plasma concentrations via the former of the
two receptor types, and causes constriction of many vascular beds, including mesenteric,
coronary and coeliac vessels. It also affects smooth muscle and so can cause cramps.
• Endothelins have some vasodilatory but mainly vasoconstriction effects, where they are more
potent than angiotensin-II and have a much longer and pronounced duration of action. They are
not used clinically and will likely be targeted for antagonism by some drugs in the future.

7. Vasodilators
• Vasodilators have three main actions; reduce central venous pressure, reduce arterial pressure,
increase local tissue blood flow.
• The main therapeutic effect is to reduce preload (reduced filling pressure) and afterload (reduced
peripheral resistance), therefore reducing cardiac work.
• Clinically, they can be used to treat hypertension (ARBs, calcium channel blockers, α1 blockers),
angina (calcium channel blocker, nitrates) and heart failure (ACE inhibitors, ARBs).
• Hydralazine is a drug that can be used short term in some very rare cases to treat hypertension
as is relaxes arteries and arterioles, though causes reflex tachycardia and is associated with
causing lupus.

8. Direct Vasodilators
• Calcium channel blockers can cause vasodilation and reduced contractility of the heart through
reducing the inward flow of calcium through L-type calcium channels. Dihydropyridines (i.e.
nifedipine) act preferentially on vascular smooth muscle and have less of an effect on contractility,
whereas verapamil is a drug that acts on the heart, and diltiazem is in between the two. Because
lowering blood pressure alone will cause increased HR (baroreceptor reflex), then DHPs can
cause reflex tachycardia, whereas the others do not as they act both on the heart and vasculature.
• Potassium-channel activators are rarely used clinically due to their side effects, and work through
binding to intracellular ATP that otherwise blocks KATP channels, thus increasing K+ permeability,
hyperpolarising cells and thus reducing contractility of smooth muscle. They also cause reflex
tachycardia (can use beta-antagonist to prevent), hirsuitism and sodium and water retention
(usually prescribed with a diuretic). Cromakalim, nicorandil and levosimendan are examples.
• Cyclase activation to increase intracellular cGMP or cAMP will cause relaxation of smooth muscle
through inhibition of contraction. Examples of drugs which act via this mechanism include
nitroprusside and nesiritide, though these aren’t used clinically. β2 agonists, dopamine,
prostaglandins and adenosine increase cAMP levels.
• Inhibition of phosphodiesterases can reduce cyclic nucleotide breakdown and thus prolong
vasodilation. Methylxanthines have a non-selective PDE inhibition and so aren’t used for this,
though sildenafil is an example of a PDE type-V inhibitor that can be used to potentiate and
prolong local vasodilation in the penis and lungs.

9. Indirect Vasodilators
• ACE inhibitors (captopril, ramipril, enalapril, lisinopril, perindopril and trandolapril) reduce cardiac
load and arterial pressure, and increase cardiac output. They act preferentially on beds supplying
the brain, heart and kidneys which maintains perfusion to these vital areas. However, in renal
artery stenosis ACE inhibitors in fact reduce GFR.
• Angiotensin-II receptor antagonists (candesartan, losartan, valsartan and irbesartan) block the
action of ang-II at AT1 receptors and are not associated with the side effects of ACE inhibitors
such as dry cough, due to the avoidance of accumulating bradykinins (due to inhibition of their
degradation). The drugs work by opposing the action of ang-II, which are; increasing ADH and
aldosterone release, causing peripheral vasoconstriction, glomerular efferent constriction,
increasing sympathetic activity and stimulating thirst receptors (and inhibiting renin release).
• All drugs blocking the RAAS system can have the potential to cause hyperkalaemia, as they
inhibit a major pathway of aldosterone production, which causes the renal secretion of potassium
in the DCT and enhances sodium reabsorption.