DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

794
sympathetic
stimulation
Bradykinin
X
Inactive
peptides
X
β 1 receptor
antagonists
J-g cells
of kidney
Renin
ACE inhibitors
ACE
(Kininase II)
Angiotensinogen
X
Angiotensin I
X
Angiotensin II
renin inhibitors
ACE-independant
pathways, (e.g., chymase)
AT 1 receptor
antagonists
X
SECTION III
Bradykinin
receptors
NO
PGI 2
AT 1 receptors
Aldosterone
AT 2 receptors
vasoconstriction
sympathetic stimulation
cellular hypertrophy
renovascular effects
MODULATION OF CARDIOVASCULAR FUNCTION
Figure 28–3. The renin–angiotensin–aldosterone axis. Renin, excreted in response to β adrenergic stimulation of the juxtaglomerular
(J- g) cells of the kidney, cleaves plasma angiotensinogen to produce angiotensin I. Angiotensin- converting enzyme (ACE) catalyzes
the conversion of angiotensin I to angiotensin II (AngII). Most of the known biologic effects of AngII are mediated by the type 1
angiotensin (AT 1
) receptor. In general, the AT 2
receptor appears to counteract the effects of AngII that are mediated by activation of
the AT 1
pathway. AngII also may be formed through ACE- independent pathways. These pathways, and possibly incomplete inhibition
of tissue ACE, may account for persistence of Ang II in patients treated with ACE inhibitors. ACE inhibition decreases bradykinin
degradation, thus enhancing its levels and biologic effects, including the production of NO and PGI 2
. Bradykinin may mediate some
of the biological effects of ACE inhibitors.
Table 28–2
Potential Roles of Aldosterone in the
Pathophysiology of Heart Failure
MECHANISM
PATHOPHYSIOLOGIC EFFECT
Increased Na + and Edema, elevated cardiac filling
water retention pressures
K + and Mg 2+ loss Arrhythmogenesis and risk of
sudden cardiac death
Reduced myocardial Potentiation of NE affects:
NE uptake
myocardial remodeling
and arrhythmogenesis
Reduced baroreceptor Reduced parasympathetic
sensitivity
activity and risk of sudden
cardiac death
Myocardial fibrosis, Remodeling and ventricular
fibroblast proliferation dysfunction
Alterations in Na + Increased excitability and
channel expression contractility of cardiac
myocytes
to NO • or bioactive S- nitrosothiols. The activities of
specific enzyme(s) and cofactor(s) required for this biotransformation
appear to differ by target organ and even
by different vasculature beds within a particular organ
(Münzel et al., 2005).
Organic Nitrates. As discussed in Chapter 27, organic
nitrates are available in a number of formulations that
include rapid- acting nitroglycerin tablets or spray for
sublingual administration, short- acting oral agents such
as isosorbide dinitrate (ISORDIL, others), long- acting oral
agents such as isosorbide mononitrate (ISMO, others),
topical preparations such as nitroglycerin ointment and
transdermal patches, and intravenous nitroglycerin.
These preparations are relatively safe and effective;
specifically, their principal action in CHF is reducing
LV filling pressure. This occurs, in part, by augmentation
of peripheral venous capacitance that results in preload
reduction. Additional effects of organic nitrates
include pulmonary and systemic vascular resistance