Bradykinin
is a vasodilator peptide released from
clotting factor XII by a tissue protease called kallikrein. It plays little role
in the regulation of normal blood flow, but becomes more important following
injury or infection.
Kaplan et al (2002) Pathways for bradykinin formation and
inflammatory disease J. Allergy & Clinical Immunology 109(2) 195-209.
This excellent article is available electronically, but only via OVID. 'Orrid
OVID. You can get to it (with patience & persistence) using the
library catalogue.
The library will shortly switch to a more convenient source.
Brain natriuretic peptide
(BNP, nesiritide) has
recently been approved for clinical use. This peptide is released naturally from
overstretched ventricular muscle.
Tremblay et al (2001)
Biochemistry and
physiology of the natriuretic peptide receptor guanylyl cyclases Mol.
Cell. Biochem. 230(1-2), 31 - 47. [Write down the reference, click the
link and then select the article from the publishers' website.]
Calcium sensitisers
allegedly increase the efficiency
of cardiac muscle by modifying calcium binding to troponin and they are claimed
to increase cardiac output without increasing oxygen consumption. There is
dispute about their mode of action, and levosimendan also activates the ATP
sensitive potassium channel in vascular smooth muscle plasmalemma, leading to an
increase in coronary flow. These compounds are only just starting clinical
trials and it will be several years before their efficacy can be properly
assessed.
Kaheinen et al (2001)
Levosimendan Increases
Diastolic Coronary Flow in Isolated Guinea-Pig Heart by Opening ATP-Sensitive
Potassium Channels J. Cardiovasc. Pharmacol. 37(4), 367 - 374.
[Write down the reference, click the link and then select Contents on the
publishers' website.]
Pro-inflammatory cytokines (TNF-a,
IL-1b, IL-6) and chemokines (MCP-1 & IL-8) are
produced by macrophages and many other cell types. They are raised in CHF, and
there is increased expression within the failing myocardium. They are implicated
in the pathogenesis of dilated cardiomyopathy (DCM). These peptides act on the
hypothalamus to increase body temperature, reduce food intake and result in the
mobilisation of energy and protein stores. They stimulate the liver to secrete
C-reactive protein and mannan-binding lectin as part of the acute phase
response. Various anti-cytokine trials have so far yielded disappointing
results.
Endothelin
is a potent vasoconstrictor and smooth
muscle mitogen secreted by endothelial cells lining the blood vessel walls. The
endothelin system is activated in several disease states including hypertension
and heart failure. There are two classes of endothelin receptor: ETAR located
mainly on vascular smooth muscle cells and ETBR located mainly on the
endothelial cells themselves. ETAR signaling causes both vasoconstriction and
myoproliferation. ETBR signals vasodilation when expressed on endothelial cells
but vasoconstriction when expressed on smooth muscle cells. Selective and
non-selective endothelin receptor antagonists (ETRA) have been developed.
Pre-clinical studies have shown limited effects on hypertension, but these drugs
have an excellent ability to prevent end organ damage
Growth hormone
is an experimental drug for the
treatment of CHF and a growth hormone releasing peptide from stomach also
appears to be effective. Physical exercise and sleep are physiological stimuli
for growth hormone release, and it is also produced in response to fasting. Many
of the actions of growth hormone are mediated indirectly by locally-produced
insulin-like growth factors. So far most of this work has been carried out
with animals and as yet (April 2002) there are no results available from large
scale clinical trials.
Vasopeptidase inhibitors
simultaneously inhibit both
neutral endopeptidase and angiotensin-converting enzyme (ACE). Neutral
endopeptidase is responsible for the breakdown of both bradykinin and the
natriuretic peptides, so inhibition of this enzyme should produce valuable
clinical effects. Early results have been very promising and omapatrilat, the
most studied drug in this class, is currently in phase II clinical trials.
Vasopressin
is a powerful vasoconstrictor that also
activates water uptake from the kidney collecting ducts, producing a
concentrated urine and retaining water within the body. There are three classes
of vasopressin receptors. V1 receptors are found in the vascular
system, V2 receptors are on the kidney collecting ducts and V3
receptors are in the posterior pituitary. Both V1 and V2
are targets for drug development work. Vasopressin antagonists are only just
starting clinical trials, but have already been shown to produce a powerful
aquaretic effect in human volunteers. They displace vasopressin from V2
receptors in the renal collecting ducts, leading to a large increase in water
(but not salt) excretion. In subjects given free access to water, plasma
osmolarity is unchanged.
Surgical Interventions:
These lectures have concentrated on new cardiovascular drugs,
but there have also been important advances in surgical techniques.
Revascularisation and stenting can yield considerable benefits in ischaemic
heart failure, although there is a tendency for coronary occlusion to re-appear
where the underlying metabolic defects are still in existence. In addition, the
MIRACLE trial [Hare (2002)
Cardiac-Resynchronization Therapy for Heart Failure NEJM 346,
1902-1905] indicates that bi-ventricular pacing may be of benefit in
cardiomyopathic heart failure. Encouraging results have also been obtained with
mechanical devices to assist the acutely failing heart. In some cases patients
who were being prepared for transplantation have recovered sufficient function
to continue with their own hearts after weaning from the mechanical pump. See,
for example, Farrar et al (2002)
Long-term follow-up of thoratec ventricular assist device bridge-to-recovery
patients successfully removed from support after recovery of ventricular
function J. Heart & Lung Transplantation 21(5), 516-521.
|
