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One of the important steps leading to more widespread use of salvia
was the development of a concept new to the Chinese system:
microcirculation. Since ancient times, Chinese doctors have known
the importance of blood circulation. Indeed, the whole system of
meridians (jingluo; major and branch vessels) was based on an
attempt to map the blood vessels (see: Drawing a concept: jing), and
to influence the circulation within them by using acupuncture,
moxibustion, and herb therapies. A well-known saying regarding the
circulation is: "The qi moves the blood; the blood carries the qi."
Put another way, the qi and blood flow together through the vessels,
including the major vessels (jing, mainly arteries) and the minor
vessels (luo, mainly veins). Within this flow of qi and blood, one
can distinguish two types of qi: the nutritive qi (yingqi) and the
defensive qi (weiqi). The nutritive qi is said to flow within the
vessels intermingled with the blood, while the defensive qi is said
to flow at the surface of the vessels. The concept of
microcirculation merely adds yet another dimension to the
description, and refers primarily to the flow of blood through tiny
vessels invisible to the naked eye, such as the capillaries. Since
these tiny vessels could not be visualized by examiners in the past,
they were only described as part of modern scientific investigations
into human physiology. Western research into the dynamics of
capillary bed flow was undertaken during the 1960s; Chinese
investigations began about a decade later.
Capillaries are the part of the vascular system that distributes
blood carried within the large vessels (arteries) to the tissues of
the body. The capillaries are so fine that they generally permit no
more than one blood cell through at a time, and are linked to the
large vessels through intermediaries, called arterioles. The
capillary walls, unlike those of arteries and veins, are permeable:
nutrients, oxygen, and other blood constituents are able to leave
the capillaries and enter the surrounding cells, while waste
materials (including carbon dioxide) are able to enter the
capillaries and be flushed away from the surrounding cells. A
capillary can only provide these services to a depth of a few cells,
so the body is completely enmeshed in a system of capillaries. The
characteristics of fluid flow through these capillaries are
different than through the major vessels due to their small size and
their permeability.
At a Chinese herb conference held in Hong Kong in 1984, there was a
special session devoted to microcirculation, following up on the new
research on the subject in China. A collaborating team of Dr. R.J.
Xiu of the Research Center for Microcirculation (Chinese Academy of
Medical Science, Beijing) and M. Intaglietta, of the Department of
Applied Mechanics, Engineering Sciences, and Bioengineering
(University of California, San Diego), provided an overview. They
introduced the subject by describing the capillary bed system and
arterioles without mentioning them by name:
The microcirculation is the principal avenue for the delivery and
exit of the substances involved in the metabolism of every cell of
the tissues. In normal physiological conditions, the optimal
regulation of this process is accomplished through the control of
the state of tension of the smooth muscle cells present in the
vascular wall, which ultimately determines the maintenance of three
different homeostatic processes, namely the maintenance of fluid
balance, the delivery of blood to each microscopic domain of the
tissues, and the maintenance of the systemic blood pressure.
In normal conditions, the controls of the homeostatic processes act
in concert, causing the simultaneous adjustment of all variables in
such a fashion that local blood pressure, flow, and fluid balance
are, on the average, kept within the narrow range characteristic and
necessary for the successful long-term survival of the organism.
The control of the state of smooth muscle constriction, or tone, is
provided by three fundamentally different mechanisms, namely the
numerous chemicals present in the blood stream, the regulatory
activity of the nervous system, and the special characteristic of
these [smooth muscle] cells to react to changes in pressure, termed
myogenic property. It is important to note that when the smooth
muscle ceases to be active-as a consequence of diseases, or because
it has reached an extreme limiting condition of constriction and
dilation-flow, pressure, and exchange become regulated solely by the
fluid mechanical characteristics of the microvasculature.
This somewhat obtuse description focuses on the concern that the
microvasculature (i.e., capillaries) can become constricted and
unresponsive to vasodilation signals, thus limiting their ability to
regulate blood flow. In the absence of regulation, especially when
there are constricted vessels that do not allow the optimal flow of
blood, the surrounding tissues can become damaged. From the
traditional Chinese perspective, the authors are describing a
syndrome of blood stasis that is secondary to a disorder of the qi
circulation, particularly of the weiqi, which is responsible for
regulating the vessel walls (the yingqi carries the substances that
can induce changes in the vascular walls, such as the vasodilation
signals these authors mentioned).
One of the therapeutic substances of great interest in relation to
microcirculation was an alkaloid that had been recently isolated:
anisodamine (from Anisodus tanguticus, an herb found primarily in
the Tibetan region). This compound was introduced into clinical use
in China as a synthetic drug in 1965, initially for treatment of
epidemic meningitis, a problem that was causing widespread
disability and deaths. Later, anisodamine was shown to produce
favorable results in treatment of numerous serious ailments,
including shock, glomerular nephritis, rheumatoid arthritis,
hemorrhagic necrotic enteritis, eclampsia, and lung edema. The
mechanism of its actions were sought and traced to a vasodilating
action that affected the microcirculation.
Unfortunately, potent alkaloid drugs can be dangerous, and
anisodamine fell into the category of a drug therapy requiring
careful monitoring (the whole herb also contains the alkaloids
hyoscyamine, anisodine, scopalamine, and cuscohygrine, all
potentially toxic). Adverse effects of the whole herb include dry
mouth, dizziness, headache, blurred vision, lassitude, drowsiness,
palpitation, and dysuria; the isolated anisodamine has fewer side
effects, but may still cause these symptoms. The main method of
administration of anisodamine in Chinese hospitals was by injection,
using just 50 mg or less, a relatively tiny amount.
The interest in microcirculation that was spurred by the use of
anisodamine turned out to have positive implications for salvia. At
the same conference, Dr. A. Koo, from the Department of Physiology
at the Chinese University of Hong Kong, described widely used
Chinese herbs that had good potential for treating microcirculation
disorders by their vasodilation activity: salvia, ilex (maodongqing),
and capillaris (yinchenhao). Dr. Koo described the nature and
importance of microcirculation, reflecting the description by Xiu
and Intaglietta, but mentioning the specific vessels explicitly:
Microcirculation has been demonstrated as occupying a key position
in the cardiovascular system. Thus, in classical description,
structural components of a microvascular bed include a network of
microvessels and terminal capillaries. Among several types of
microvessels, terminal arterioles (20-50 micrometers in diameter)
are distinctly different from others by the presence of a profusely
reactive circumferential layer of vascular smooth muscle cells. The
function of arterioles in the circulatory system is indeed the
myogenic reactivity of these vascular smooth muscle cells. Hence,
active changes in dimension of arterioles not only regulate local
blood flow to downstream capillaries supplying organs and tissues,
but also alter total peripheral resistance to flow as well as
control systemic arterial pressure. Usually, two types of myogenic
activities of arterioles are observed: sustained constriction or
dilation, and rhythmic alterations of contraction and relaxation (vasomotion).
Such sustained or rhythmic myogenic activities are either responses
of vascular smooth muscle to endogenous neural and humoral effects,
or induced by exogenously administered drugs, including vasoactive
agents from Chinese medicinal herbs.
The implications for medical research and application seemed very
promising, so a search through the range of Chinese herbs for active
constituents that are vasoactive-and that specifically effect
microcirculation-was undertaken. This time, the emphasis was on
herbs of low toxicity that would allow widespread and regular use.
To observe the effects of herb components on the small vessels, Koo
developed a video microscope (first reported by him in 1977), which
he used in laboratory animal studies to view internal tissues
(exposed by surgery). The development of laser technology around
that time permitted improved observation of blood pulsing through
the microvessels, by utilizing on a doppler flowmetric technique (in
essence, observing light reflected from a moving object to determine
its speed). This procedure worked well for laboratory animal
studies, but in order to move on to clinical evaluations, it was
necessary to examine the blood flow non-surgically.
A clinical microscopic viewing technique was developed in mainland
China, first reported in 1979, in which circulation in burned skin
was evaluated so as to monitor the healing effects of herbal
therapies. It was found that blood clots (thrombosis) within the
capillaries in the area of burn damage led to necrosis of the
underlying skin; vasoconstriction and slow blood flow were the key
conditions leading to thrombosis. Therefore, if a substance could
counter vasoconstriction and, thereby, free up the blood flow, the
level of necrosis could be lower, so long as it was administered
(internally or topically) very soon after the burn. A traditional
burn remedy, huzhang (Polygonum cuspidatum), was confirmed by this
method to be a useful agent that prevents thrombosis. It is still
relied on for this purpose today.
The same basic observation technique was applied to examination of
capillaries in the finger nail beds. The nail bed is easy to view
and is richly endowed with capillaries very close to the skin
surface beneath the nail. It was theorized that the condition of the
capillaries at this site would reflect the condition of the
capillaries elsewhere in the body. One of the first applications of
the nail bed measurements was reported at the Hong Kong conference.
A group of researchers at the Huashan Hospital of the Shanghai First
Medical College reported that nail bed circulation in patients with
chronic viral hepatitis was abnormal, and that as treatment of
hepatitis with Chinese herbs progressed, with reduction of symptoms
and liver inflammation, the nail bed circulation improved. Salvia
was a featured herb in the treatment for hepatitis in these studies.
The authors concluded their presentation thus:
Salvia has been tried clinically in our hospital. The results
suggest that promoting blood circulation will be beneficial to
microcirculatory perfusion, hasten the development of collateral
circulation, and lower the lactic acid content within the
microcirculation. With the improvement in microcirculation,
deficiency of blood and anoxia in liver tissues could be relieved,
these in turn will be beneficial to the recovery and regeneration of
liver cells. Repeated liver biopsies had been done in 5 patients, 3
of them were treated with medicines activating blood circulation and
eliminating blood stasis. Pathologic findings were improved, but not
completely recovered in 2 cases. Their microcirculation was also
improved. Thus, the use of blood activating and sludge eliminating
medicines is worth studying.
These findings led to widespread use of microscopic studies of nail
bed circulation and intensive use of salvia for treatment of
conditions thought to be associated with microcirculation disorders,
especially hepatitis, a disease that affects many millions of
Chinese. In the same year as the Hong Kong conference, the Journal
of Traditional Chinese Medicine (English language version) offered
its first report on microcirculation: it involved use of salvia for
the prevention and treatment of experimental cirrhosis. The authors,
working at the Laboratory of Hepatic Diseases at the Shanxi Medical
College, pointed out that salvia was already being widely used in
China for treatment of chronic liver disease. Some of the substances
used for treating hepatitis (e.g., glycyrrhizin from licorice and
oleanolic acid from ligustrum) previously tested by the authors,
showed good results in inhibiting liver damage due to fibrosis, but
did not have an effect on existing fibrosis. The findings with
salvia indicated that, after three weeks treatment of laboratory
animals with induced liver damage, the fibrous septa were thinner or
disappeared. The authors wrote:
Cirrhosis is characterized by connective tissue septa and
hyperplastic liver nodules. The excess fibrous tissue between the
hepatic nodules result from the collapse of the existing fibrous
frame after necrosis of the liver cells. Fibrosis is therefore the
consequence of liver cell necrosis....In our experiments, we
observed that the disturbances of hepatic microcirculation affected
metabolic exchange between the blood and the liver cells resulting
in degeneration [necrosis] of the liver cells. The vicious cycle of
necrosis-fibrosis-necrosis thus aggravated cirrhosis of the liver.
Salvia treatment reduces these pathological changes, speeds blood
circulation, and opens up a larger capillary network.
Microcirculation of the liver is thus improved by salvia, breaking
the vicious cycle and preventing occurrence of cirrhosis.
Nearly 20 years later, salvia has become the main herb recommended
for prevention and treatment of liver damage due to viral hepatitis
(see: Hepatitis C: update 2001). The mechanism of action of salvia
on preventing fibrosis in the liver has been tentatively elucidated.
Fibrous collagens are released by hepatic stellate cells (fat
storage cells) that have been activated and transformed into
myofibroblasts rich in alpha-actin. This transformation occurs when
the cells are exposed to activators such as hepatic viral infection,
excess iron or alcohol, liver-damaging drugs, tumor invasion of the
liver, or excess bile due to cholestasis. The myofibroblasts are
then responsible for excess collagen deposition resulting in
fibrosis and cirrhosis of the liver. As described in one laboratory
animal study: "The extract of Salvia miltiorrhiza markedly reduced
protein expression of alpha-smooth muscle cell-like actin, which
indicates that hepatic stellate cell activation was inhibited during
liver fibrosis." The inhibition of hepatic stellate cell activation
was also suggested to be the mechanism of salvia action found in an
in vitro study . The vasodilating activity of salvia may relax the
stellate cells (actin is one of the components that contracts the
stellate cells) and aid bile flow and hepatic blood circulation.
Spontaneous resolution of liver fibrosis occurs mainly as the result
of the action of collagenases, known as matrix metalloproteinases
(enzymes incorporating heavy metals; these are partly induced by
zinc), that breakdown the accumulated collagen. When new liver
fibrosis is inhibited by salvia, it is possible that natural
processes slowly reverse the existing fibrosis. Although not yet
studied, it is also possible that salvia helps induce collagenase or
reduces collagenase inhibitors so that fibrosis recovery is speeded
up. It has been proposed that liver regeneration is promoted by
salvia through general mechanisms of improving hepatic
microcirculation, reducing lipid peroxidation, elevating plasma
levels of fibronectin (an antifibrotic agent), and regulating immune
responses.
While treatment of angina and hepatitis remain the most common
clinical applications of salvia in modern Chinese clinical practice,
the herb has been shown to have other valuable applications, based
on its effects on microcirculation. For example, laboratory
experiments with bone fracture healing at the Shanghai Institute of
Traumatology and Orthopedics have indicated that salvia helps
mobilize calcium and aid deposition of calcium to the fracture zone.
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