smooth muscle pharmacology Flashcards
how is smooth muscle contraction regulated
an increase in intracellular calcium concentration by release from the SR or opening of L-type calcium channels
intracellular calcium binds to calmodulin forming a calcium-calmodulin complex which activates MLCK to phosphorylate MLC which causes contraction
how is smooth muscle relaxation regualted
cGMP activates protein kinase C whihc activates additional MLCP to dephosphorylate MLC(P) which causes relaxation
what is endothelium-dependent vasodilation
in the vascular lumen
= vasodilating substances (e.g. bradykinin, ADP, serotonin or sheer stress)
in the endothelial cell
= increase in intracellular calcium concentration forming a calcium-calmodulin complex
= binds to endothelial nitric oxide synthase to form nitric oxide and citrulline
in the smooth muscle cell
= formation of nitric oxide which activates guanylate cyclase which catalyses the converstion of GTP to cGMP which activates protein kinase G causing relaxation
how does protein kinase G cause relaxation
stimulates myosin light chain phosphatase
stimulates plamsa membrane Ca2+ATPase
stimulates sarcoplasmic/endoplasmic reticulum Ca2+ATPase
activates K+ channels that cause hyperpolarisation and inactivate calcium channels
what is angina
inadequate myocardial oxygen supply by fixed vessel narrowing or endothelial dysfunction
what is stable angina
episodic
brought on by exertion
relieved by rest
what is unstable angina
symptomatic, even at rest
what is the pharmacological management of angina
organic nitrates act directly on the smooth muscle cell to increase nitric oxide production
leads to smooth muscle relaxation and therefore vasodilation
acts primarily on veins to reduce preload and oxygen demand in the myocardium
secondary action on the coronary collaterals to improve oxygen delivery to the ischaemic myocardium
what are the effects of organic nitrates on venodilation
the primary action of organic nitrates is to induce venodilation
venodilation reduces venous pressure and the venous return to the heart
this reduces work of the heart by starlings law
reduces oxygen demand
↓ venous pressure = ↓ cardiac output = ↓ arterial pressure = ↓ total peripheral resistance
what are the effects of organic nitrates on the coronary collaterals
nitrate dilates collateral
blood flow to ischaemic myocardium increased
what is glyceryl trinitrate (GTN)
do not directly release nitric oxide
GTN > NO2 > NO > guanylate cyclase
biologically inactive
half life = ≈40 minutes
low bioavailability if given orally
what is isosorbide dinitrate or isosorbide mononitrate
do not directly release nitric oxide
isosorbide dinitrate/mononitrate > NO2 > NO > guanylate cyclase
biologically inactive
half life = ≈2-4 hours
bioavailability varies
what is hypertension
diastolic blood pressure = 90mmHg
systolic blood pressure = 140mmHg
same modifiable and non-modifiable causes
consequences = left ventricular hypertrophy, renal failure, stroke
how is hypertension manage pharmacologically
calcium channel blockers
KATP channel openers
⍺-blockers
how do calcium channel blockers manage hypertension
act at L-type calcium channels on vascular smooth muscle and in cardia myocytes
are administered orally
bioavailability of 10-30%
half life = 2-4 hours
dihydropyridines - nifedipine and amlodipine
benzothiazepines - diltiazem
phenylalkylamines - verapamil
how do KATP channel openers manage hypertension
in severe hypertension can be used with beta blocker and diuretics
open KATP channels in the smooth muscle cell membrane and hyperpolarise the smooth muscle cell
e.g. minoxidil and nicorandil
how do ⍺-blockers manage hypertension
⍺1 adrenoceptors are the first part of the signalling cascade that ultimately leads to smooth muscle contraction following activation of the sympathetic nervous system
⍺1 antagonists prevent this signalling cascade and therefore lead to vasodilation
e.g. prazozin
