Document Detail

Effects of a neutral endoprotease enzyme inhibitor, thiorphan, on hemodynamics and renal excretory function in four models of experimental hypertension.
MedLine Citation:
PMID:  10685724     Owner:  NLM     Status:  MEDLINE    
Thiorphan, a neutral endoprotease (NEP) enzyme inhibitor, has been shown to enhance the effects of atrial natriuretic peptide (ANP) in vivo. In this study, we examined the effects of an intravenous (iv) infusion of thiorphan on cardiovascular hemodynamics and excretion of urine volume (UV), sodium (U(Na)V) and potassium (UKV) in four different models of experimental hypertension, namely: 1) SHR, 2) two-kidney, one clip (2K1C),3) one-kidney, 1 clip (1K1C) and. 4) 70% reduced renal mass-salt (RRM-S) hypertensive rats. SHR has normal plasma renin activity, 2K1C is renin dependent, and 1K1C and RRM-S are low renin volume dependent models of hypertension. Rats were divided into experimental and control groups. Under inactin (120 mg/kg, body weight) anesthesia, rats were instrumented to record blood pressure and dP/dt (Millar catheter) and urine was collected through a suprapubic urinary bladder catheter. Experimental animals received an iv infusion of thiorphan, 0.5 mg/kg/min for 120 minutes. Control animals received vehicle only. In some animals, vascular smooth muscle cell membrane potentials (Em) was measured in vivo. In another series of experiments, using the identical protocol, cardiac output was recorded. The thiorphan infusion produced a similar progressive decrease in blood pressure in all models of hypertension. Cardiac output did not change relative to vehicle infused control animals. Thus pressure decreased because of a decrease in total peripheral resistance. The contractility index (dP/dt/P, where P = left ventricular pressure) did not change but vascular smooth muscle cells in tail arteries hyperpolarized in all four models. In spite of a significant decrease in blood pressure, thiorphan infusion either increased or produced no change in urinary volume (UV) and sodium (U(Na)V) excretion. These data show that thiorphan, an NEP inhibitor, decreases the blood pressure of hypertensive rats due to a decrease in total peripheral resistance, perhaps by hyperpolarizing vascular smooth muscle cells. These effects are independent of the mechanism of the hypertension. Increased UV and U(Na)V in the face of decreased pressure suggests a direct renal effect.
M B Pamnani; S Chen; H J Bryant; J F Schooley; F J Haddy; R D Ghai
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Clinical and experimental hypertension (New York, N.Y. : 1993)     Volume:  22     ISSN:  1064-1963     ISO Abbreviation:  Clin. Exp. Hypertens.     Publication Date:  2000 Jan 
Date Detail:
Created Date:  2000-03-15     Completed Date:  2000-03-15     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9305929     Medline TA:  Clin Exp Hypertens     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  45-62     Citation Subset:  IM    
Department of Physiology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
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MeSH Terms
Atrial Natriuretic Factor / blood
Biological Markers / blood,  urine
Blood Pressure / drug effects*
Cyclic GMP / urine
Hypertension / drug therapy,  metabolism*
Infusions, Intravenous
Kidney / drug effects*
Potassium / urine
Protease Inhibitors / pharmacology*
Rats, Inbred SHR
Sodium / urine
Thiorphan / pharmacology*
Urodynamics / drug effects
Reg. No./Substance:
0/Biological Markers; 0/Protease Inhibitors; 7440-09-7/Potassium; 7440-23-5/Sodium; 7665-99-8/Cyclic GMP; 76721-89-6/Thiorphan; 85637-73-6/Atrial Natriuretic Factor

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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