The annual meeting on "Catecholamines and the Cardiovascular System" in Japan has reached its third decade. Last year, we celebrated the 20th anniversary of this meeting and published a supplement in the Journal of Cardiovascular Pharmacology. After summarizing the meetings held over the past two decades, we decided to expand the research field to include the physiological and pathophysiological cardiovascular effects of substances such as angiotensins, endothelins, natriuretic peptides, and adrenomedullins, which act alone or in conjunction with catecholamines.
As a result, we received 17 papers this year, which covered topics over a large area of research from genetics and molecular biology to in vivo or in situ preparations and clinical studies. The papers have been divided into three categories: basic pharmacology, the role of catecholamines in the pathogenesis of cardiovascular diseases, and clinical studies. These three categories are closely related to each other. For example, the mechanism of norepinephrine (NE) release from sympathetic nerves has been studied in intact preparations, in animal models, and in patients with cardiovascular diseases.
In basic pharmacology studies, Yang and Chiba (Matsumoto) showed that adrenergic sympathetic transmission was pharmacologically and physiologically different from purinergic transmission in the isolated canine splenic artery. Both types of transmission were equally affected by N-type Ca channel blockade (with ω-conotoxin), but adrenergic transmission was more sensitive to Na channel blockade (with tetrodotoxin). Chu and Endoh (Yamagata) reported that, in isolated canine ventricular myocardium, endothelin (ET)-1 alone did not elicit an inotropic response, while it caused a biphasic inotropic response in the presence of NE that depended on the concentration of NE. They suggested that cross-talk between ET-1 and NE may play a crucial role in pathophysiological regulation of the contractility of intact dog ventricular myocardium. Ozawa et al. (Tokushima) reported that the long-term treatment with ouabain increased catecholamine synthesis by cultured bovine adrenal chromaffin cells through stimulation of the rate-limiting enzyme, tyrosine hydroxylase, in a Ca-dependent manner, suggesting a partial contribution to the positive inotropic effect of ouabain in addition to the direct effect via inhibition of Na+,K+ ATPase and the release of norepinephrine. Ohta et al. (Niigata) reported that there was a myocardial protective effect of carvedilol, a β-blocker, in the rat heart related to the effect on the natriuretic peptide system. At high and low concentrations, carvedilol increased plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels, along with the upregulation of ANP and BNP mRNA expression and the downregulation of natriuretic peptide receptor C mRNA expression.
The pathogeneses of various cardiovascular diseases in relation to catecholamines was analyzed using animal models of myocardial injury, heart failure, and hypertension. Xi et al. (Tokyo) reported that dystrophin, which stabilizes the sarcolemma, was disrupted in rats with acute myocardial injury induced by isoproterenol overload, suggesting that excessive β-adrenergic stimulation caused breakdown of dystrophin followed by apoptosis. Kawada et al. (Osaka) used microdialysis to show that local catecholamine release from cardiac sympathetic nerve terminals was impaired in rabbits with chronic adriamycin-induced cardiomyopathic heart failure. Ohtsuka et al. (Tsukuba) reported that NE release from cardiac sympathetic nerves was increased in dog hearts with hibernating myocardium induced by chronic ischemia. Matsui et al. (Kanazawa) induced autoimmune cardiomyopathy in rabbits with an autoantibody to a peptide corresponding to the sequence of the second extracellular loop of the human β1-adrenoceptor. Lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, protects the myocardium from injury induced by autoimmunity directed against the β1-adrenoceptor. Watanabe et al. (Niigata) investigated the effects of endothelin-1 and TAK-044 (ETA and ETB receptor antagonists, respectively) in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Although the ET-1-induced increase of mean arterial pressure was completely abolished by TAK-044 in the controls, higher doses of TAK-044 were needed to block the pressor response to ET-1 in the cardiomyopathy model. Natori et al. (Asahikawa) reported that the positive inotropic effect of catecholamines (isoproterenol and NE) was not altered by inhaled nitric oxide, even in dogs with procainamide-induced heart failure. Inhaling nitric oxide decreased the pulmonary vascular resistance in heart failure but increased left ventricular preload in the presence of additional catecholamine stress, indicating the aggravation of heart failure.
In spontaneous hypertensive rats, accentuated antagonism of parasympathetic stimulation might be enhanced in the early phase of the development of hypertension when compared with Wistar-Kyoto rats, as reported by Masuda (Yamaguchi). Tsuda et al. (Wakayama) reported that the inhibitory effect of β-endorphin, an endogenous opioid, on NE release in the medulla oblongata was weaker in spontaneous hypertensive rats than in Wistar-Kyoto rats, suggesting that opioid peptides could be involved in the regulation of central sympathetic activity in hypertension. Murakami et al. (Sendai) developed β3-null mice, lacking the β3 subunit of the voltage-dependent calcium channel. These mice showed no apparent changes of smooth muscle contraction and sensitivity to dihydropyridine Ca channel blockers. Also, blood pressure was normal when the mice were fed a normal diet. However, when the mice were fed a high-salt diet, the blood pressure increased along with significant reduction of plasma catecholamine levels. They suggested that the β3 subunit of the voltage-dependent calcium channel might play a role in the onset of salt-sensitive hypertension in mice.
In clinical studies, Yasunari et al. (Osaka) reported a patient with a dopamine-secreting pheochromocytoma, in whom excessive dopamine production caused hypotension and diarrhea. Decreased dopamine β-hydroxylase expression in the tumor was considered as a possible mechanism. After surgical resection, dramatic cessation of the diarrhea and elevation of blood pressure were noted. Abe et al. (Kitakyushu) reported on postural orthostatic tachycardia syndrome, which is more prevalent in young women. Oral β-blocker therapy was effective, suggesting that β-adrenergic hypersensitivity may play a role in the mechanism of this syndrome. Minami et al. (Tochigi) demonstrated that the plasma concentrations of adrenomedullin, ANP, and BNP in obese patients with essential hypertension could be decreased by a low-calorie diet. These vasodilatory peptides may prevent further elevation of blood pressure in obese patients with essential hypertension. Mabuchi et al. (Shiga) reported that the release of interleukin-6 (IL-6) into the peripheral circulation increased along with the severity of congestive heart failure, and was associated with activation of the endogenous sympathetic nervous system. Intravenous dopamine increased the IL-6 level in patients with dilated cardiomyopathy at the deteriorating phase of congestive heart failure, but oral β-blocker therapy decreased the plasma IL-6 level along with improvement of symptoms and the left ventricular ejection fraction.
The lecturer invited to the 21st meeting was Prof. Toshio Tanaka (Department of Molecular and Cellular Pharmacology, Mie University School of Medicine, Japan). He discussed novel methods for the treatment of cerebral vasospasm through pharmacogenomics. He used transcriptome analysis to study changes of gene expression in a rat model of cerebral vasospasm and found that heme oxygenase-1 mRNA was prominently induced in the basilar artery. There was a significant correlation between heme oxygenase-1 mRNA levels and the severity of vasospasm in the basilar artery exhibiting vasospasm. Tanaka reported a protective effect of endogenous or exogenous gene induction in cerebral vasospasm after subarachnoid hemorrhage.
As guest editors, we found that all of the papers were of high quality with sufficient priority and originality for the Journal of Cardiovascular Pharmacology, and we would like to thank the authors for sending their manuscripts in due time.
The symposium and the publication of this supplement were supported by an educational grant from Novartis Pharma K.K. Tokyo, Japan.