Effects of a Neutral Endoprotease Enzyme Inhibitor, Thiorphan, on Hemodynamics and Renal Excretory Function in Four Models of Experimental Hypertension

Abstract

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.

Omapatrilat in Subtotal Nephrectomy-Salt Hypertension

“…8 Furthermore, it appears that the BPlowering effect of OM is greater than that seen with ACE or NEP inhibitors alone. 8,12 However, one must be cautious when interpreting the results between different studies using this model. Several variables must be taken into account, including the severity of hypertension, which is dependent on the duration of the protocol and the degree of renal mass reduction; the route of drug administration; and whether the drug is given acutely (hours) or chronically (days to weeks).…”

Vagal reflex actions of atrial natriuretic peptide survive physiological but not pathological cardiac hypertrophy in rat

“…Chronic 1K‐1C hypertension has its primary aetiology in the kidney, is volume‐dependent and has less elevation of sympathetic and plasma renin activity (e.g. Oparil, 1986; Pamnani et al 2000) than other hypertensive models such as the SHR. Despite the distinctly different causes and characteristics of hypertension in SHRs and 1K‐1C rats, ANP was similarly ineffective in both.…”