ABSTRACT
ProAngiotensin-12 (PA12) is the most recent peptide to be identified as a functional component of the renin-angiotensin system (RAS). PA12 is reported to constrict rat coronary arteries and the aorta, dependent upon angiotensin II-converting enzyme 1 (ACE1) and chymase. The current study employed myography to determine the direct vascular effects of PA12 on a range of isolated rat arteries extending from the core to periphery. PA12 significantly constricted the descending thoracic aorta, right and left common carotid arteries, abdominal aorta and superior mesenteric artery, with little effect on the femoral and renal arteries. AngII was found to produce similar responses to PA12 when administered at the same dose. A potency gradient in response to PA12 was clearly apparent, with vessels in closest proximity to the heart responding with the greatest constriction; while constrictive potency was lost further form the heart. Inhibition of ACE1 and chymase both significantly attenuated PA12-induced vasoconstriction, with chymostatin displaying lesser potency. We postulate ACE1 primarily regulates RAS activity within the circulation, while chymase may have an important role in local, tissue-based RAS activity.
Subject(s)
Angiotensinogen/pharmacology , Arteries/drug effects , Peptide Fragments/pharmacology , Vasoconstrictor Agents/pharmacology , Angiotensin II/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensinogen/antagonists & inhibitors , Animals , Antihypertensive Agents/pharmacology , Captopril/pharmacology , Chymases/antagonists & inhibitors , Chymases/physiology , Drug Stability , Hypertension/drug therapy , Hypertension/physiopathology , In Vitro Techniques , Male , Oligopeptides/pharmacology , Organ Specificity , Peptide Fragments/antagonists & inhibitors , Peptidyl-Dipeptidase A/physiology , Rats , Rats, Sprague-Dawley , Serine Proteinase Inhibitors/pharmacology , Time Factors , Vasoconstriction/drug effects , Vasoconstrictor Agents/antagonists & inhibitorsABSTRACT
Circulating urotensin II (UII) concentrations and the tissue expression of its cognate receptor (UT) are elevated in patients with cardiovascular disease (CVD). The functional significance of elevated plasma UII levels in CVD is unclear. Urotensin-related peptide (URP) is a paralog of UII in that it contains the six amino acid ring structures found in UII. Although both peptides are implicated as bioactive factors capable of modulating cardiovascular status, the role of both UII and URP in ischemic injury is unknown. Accordingly, we provide here the first report describing the direct cardiac effects of UII and URP in ischemia-reperfusion injury. Isolated perfused rat hearts were subjected to no-flow global ischemia for 45 min after 30min preconditioning with either 1nM rUII or 10nM URP. Both rUII- and URP-induced significant vasodilation of coronary arteries before (both P<0.05) and after ischemia (both P<0.05). Rat UII alone lowered contractility prior to ischemia (P=0.053). Specific assay of perfusate revealed rUII and URP both significantly inhibited reperfusion myocardial creatine kinase (CK) release (P=0.012 and 0.036, respectively) and atrial natriuretic peptide (ANP) secretion (P=0.025). Antagonism of the UT receptor with 1muM palosuran caused a significant increase in perfusion pressure (PP) prior to and post-ischemia. Furthermore, palosuran significantly inhibited reductions in both PP and myocardial damage marker release induced by both rUII and URP. In conclusion, our data suggests rUII and URP reduce cardiac ischemia-reperfusion injury by increasing flow through the coronary circulation, reducing contractility and therefore myocardial energy demand, and inhibiting reperfusion myocardial damage. Thus, UII and URP present as novel peptides with potential cardioprotective actions.
Subject(s)
Myocardial Reperfusion Injury/metabolism , Peptide Hormones/metabolism , Reperfusion Injury/metabolism , Urotensins/metabolism , Animals , Atrial Natriuretic Factor/metabolism , Coronary Vessels/metabolism , Creatine Kinase, MB Form/metabolism , Humans , Male , Myocardial Contraction/physiology , Myocardial Reperfusion Injury/pathology , Peptide Hormones/genetics , Quinolines/metabolism , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/metabolism , Reperfusion Injury/pathology , Urea/analogs & derivatives , Urea/metabolism , Urotensins/genetics , Vasodilation/physiologyABSTRACT
Urotensin II (UII) was first discovered in the urophyses of goby fish and later identified in mammals, while urotensin II-related peptide (URP) was recently isolated from rat brain. We studied the effects of UII on isolated heart preparations of Chinook salmon and Sprague-Dawley rats. Native rat UII caused potent and sustained, dose-dependent dilation of the coronary arteries in the rat, whereas non-native UII (human and trout UII) showed attenuated vasodilation. Rat URP dilated rat coronary arteries, with 10-fold less potency compared with rUII. In salmon, native trout UII caused sustained dilation of the coronary arteries, while rat UII and URP caused significant constriction. Nomega-nitro-(l)-arginine methyl (l-NAME) and indomethacin significantly attenuated the URP and rat UII-induced vasodilation in the rat heart. We conclude that UII is a coronary vasodilator, an action that is species form specific. We also provide the first evidence for cardiac actions of URP, possibly via mechanisms common with UII.
