Classifications of OH vary. Some research on the subclassification of instantaneous OH, postural tachycardia syndrome, neurally-mediated syncope, and delayed OH has been conducted . However, if there are symptoms of an underlying condition, selective α1-agonists are used for treatment of OH, and such therapy improves sympathetic nerve function .
We have already reported that in SART-stressed rats, HUT test-induced OH develops more frequently than in unstressed rats, and can be classified into four types on the basis of BP fluctuations that resemble the four types of OH observed in man as noted above . In the present study, stress-induced OH in rats was improved by the selective α1-agonist phenylephrine. These symptoms were previously reported to be improved by a selective M2-receptor antagonist, AF-DX 116 [9, 12]. M2-receptors contribute to persistent hypotension but M1-receptors do not. Increased sensitivity of M2-receptors located on sympathetic nerve endings in the heart and decreased sensitivity of myocardial M2-receptors have been suggested as probable etiologies for the phenomenon . Involvement of M2 receptors in the manifestation of OH in SART-stressed rats has been demonstrated . We applied the isoproterenol-treated HUT test, which is used for diagnosis of neurally-mediated syncope, on SART-stressed rats. Effects of β-blockers on OH show involvement of a cardiac β1-receptors and vascular β2-receptors. When expression of OH is strong, an accommodative disorder of the sympathetic nervous system is thought to be involved . The primary cause of OH is considered to be autonomic dysfunction but secondary causes include dehydration, malnutrition (vitamin deficiency) or hypometabolism secondarily. SART-stressed rats do not show abnormalities in the electrolytes (Na+, K+), GOT (AST) and GPT (ALT) in serum , and dehydration. SART-stressed animals have a voracious appetite . It is thought that dehydration and a suppression of metabolism do not occur in SART-stressed rats, although further study is needed regarding vitamins.
SART-stressed rats are associated with hypotension and tachycardia [6, 9, 12, 13], and severe OH is easily induced by postural manipulation . Compared with unstressed rats, SART-stressed rats show large MD and smaller %reflex, but show no compensatory tachycardia caused by the fall in BP. MD is the maximal fall in MBP with the HUT test and is used diagnosing OH. Percentage reflex is a value reflecting a compensation of sympathetic function that normalizes BP after the decrease caused by the HUT test. AUC reflects MD and %reflex, and can indicate the intensity of OH. SART-stressed baseline tachycardia, and reflex systems regulating HR are considered to be inhibited.
To investigate improvement effects on OH, the dose of phenylephrine without influence on resting MBP in both unstressed and SART-stressed rats was determined as 1 μg/kg/min. Continual infusion of this dose gives similar OH indices that indicate improvement effects from 15 to 105 min and therefore values at 15 min were used as representative figures.
Phenylephrine improved OH in SART-stressed rats and showed effects on MD, %reflex, and AUC after the HUT test. Because MD decreased in SART-stressed rats, a decrease in sympathetic tone and peripheral vessel vasoconstriction was speculated. During the continuous infusion of phenylephrine, the improvements in sympathetic tone and peripheral vessel vasoconstriction were similar to those from continuous infusion of the adrenalin β-receptor agonist isoproterenol.
It is known that vascular resistance in peripheral arteries such as mesenteric arteries is strongly related to BP [18–23]. OH occurs after a change to the standing position from the resting position: because of a combination of three factors, arteriolar hyposystolic failure in the resistance vessels, decrease in hemoperfusion volume and cardiac output by weakness of the inferior limb muscles and abdominal muscles, and reduction of venoconstriction. In our study, the constriction reaction of various vascular smooth muscles to phenylephrine in SART-stressed rats decreased in the thoracic aorta and carotid arteries and increased in the mesenteric arteries. In vivo, after phenylephrine infusion, the contraction of the mesenteric arteries in SART-stressed rats decreased the blood pooled in the vascular bed. The constrictive balance of the carotid and mesenteric arteries circulated blood to the brain more efficiently. It is thought that these results greatly contribute to improvement in SART stress-induced OH. It is already known that blood flow in SART-stressed rats decreases in the carotid artery but increases in the abdominal and mesenteric arteries , and plasma noradrenaline (NA) levels are several times higher than those in unstressed rats . The plasma NA level increased to several fold in people who were changed to a standing position. In other words, in SART-stressed rats, blood flow in the carotid artery and vasoconstriction of the thoracic aorta remarkably decreased along with the sympathetic tone during the HUT test. Furthermore, it is thought that OH is strongly manifested, and a transient cerebral ischemia is caused by an increase in blood flow to the mesenteric arteries during the HUT test.
Today, selective α1-agonists increase BP by predominantly causing vascular smooth muscle constriction, and are the therapeutic drugs for various types of hypotension including OH. Many of these drugs cause tachycardia to increase BP instantly. This can cause discomfort and a stressful sensation. In pharmacotherapy of OH, it is important to assist the sympathetic nerve function to develop a substitutive reflection caused by standing.
Stress and the autonomic nervous system strongly influence the development of hypotension and OH. Sympathetic hypoactivity is considered a cause of these diseases, and most pharmacotherapeutic options for these diseases target the sympathetic nervous system. However, BP is regulated not only by the sympathetic nervous system but also by the parasympathetic nervous system. We have already reported that the parasympathetic nervous system has an important role in the pathogenesis of OH (12). Our understanding of the role played by the parasympathetic nerve in OH is still poor, but we are paying more attention to this area and plan to study it further.