Synthetic Salusins as Cardiac Depressors in Rat

Abstract

Abstract-Using bioinformatic analyses of full-length, enriched human cDNA libraries, we recently identified salusins, multifunctional related peptides ubiquitously expressed in major human tissues. Salusins cause transient and profound hypotension when injected intravenously to rats, the hypotensive effect of salusin-␤ being especially striking. However, the mechanisms of this hypotensive action remain elusive. To determine whether salusins modulate cardiac function in rats, we studied serial changes of systemic hemodynamics and functions of isolated perfused working and nonworking hearts before and after salusin administration. Intravenous salusin-␤ administration to intact anesthetized rats caused a temporary rapid, profound decrease in aortic blood flow concomitantly with hypotension and bradycardia without affecting systemic vascular resistance. Salusin-␤-induced hypotension and bradycardia were completely blocked by pretreatment with atropine, a muscarinic receptor antagonist, but not by propranolol. In isolated perfused working rat hearts, salusin-␤ significantly decreased cardiac output, aortic flow, and stroke work. However, it did not affect coronary flow in isolated working and nonworking hearts. Our results indicate that salusins induce potent hypotension via negative inotropic and chronotropic actions. Salusin-␤ promotes its actions by facilitating vagal outflows to the heart, whereas the negative inotropism of salusin-␤ is also mediated via a direct myotropic effect. Key Words: cardiac output Ⅲ heart rate Ⅲ blood pressure Ⅲ vascular resistance T he availability of a massive amount of information on human genome sequences has allowed for the faster elucidation of gene functions. Functional characterization of putative bioactive proteins is an indispensable process in elucidating the roles of secretory proteins. Very recently, we identified 2 novel multifunctional peptides of 28-and 20-residues that we designated as salusin-␣ and salusin-␤, respectively, 1 after screening a number of secretory proteinencoding cDNAs using receptor ligand-facilitated gene transfer protocols. 2,3 These salusins are considered to be generated simultaneously through proteolytic processing of prosalusin, a commonly occurring alternatively spliced product of the TOR2A gene, which has structural homologies to torsion dystonia genes (DYT1 and DQ1). 4,5 Alternative splicing responsible for biosynthesis of salusin peptides is probably not a rare event, and salusins are expressed ubiquitously throughout human tissues. 1 Systemic administration of salusins to rats is associated with rapid and profound hypotension and bradycardia; the maximal hypotensive response to salusin-␤ in rats is almost equivalent to or even exceeds those of the hypotensive peptide hormones identified thus far. Further, other potent endogenous hypotensive peptides do not induce hypotension and concomitant bradycardia with such a time course, implying an as yet undescribed mechanism for salusins. Although the expression of preprosalusin in heart is very limit...

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