Susumu Niimura

Effects of losartan, a nonpeptide angiotensin II receptor antagonist, on cardiac hypertrophy and the tissue angiotensin II content in spontaneously hypertensive rats

Losartan, a recently developed nonpeptide angiotensin II (Ang II) receptor antagonist, was administered orally to 10-week-old spontaneously hypertensive rats (SHR) for 2 weeks. Cardiac weight and tissue Ang II, as well as plasma renin activity (PRA) and Ang II, were determined. Treatment with Losartan (10 mg/kg per day) lowered blood pressure markedly. Losartan reduced significantly the left ventricular weight by 11% compared with control rats. The left ventricular Ang II content was lowered by Losartan (18.6 +/- 0.9 pg/tissue; 21.9 +/- 0.9 pg/tissue, control, p less than 0.05), whereas PRA and plasma Ang II concentration were increased by the treatment. With the control and Losartan-treated animals, there was a significant positive correlation between the left ventricular weight and the tissue Ang II content (r = 0.563, p less than 0.05). These results provide evidence that cardiac tissue Ang II, rather than circulating Ang II, plays an important role in the pathophysiology of left ventricular hypertrophy of this animal model of human hypertension.

Hypotensive activity of TCV-116, a newly developed angiotensin II receptor antagonist, in spontaneously hypertensive rats

TCV-116, a recently developed angiotensin II (Ang II) receptor antagonist, was administered orally (1 mg/kg per day) to 10-week-old spontaneously hypertensive rats (SHR) for 2 weeks. Blood pressure and plasma components of the renin-angiotensin-aldosterone system were determined in these rats. TCV-116 produced a marked reduction in blood pressure without altering heart rate. Whereas plasma renin concentration (PRC), angiotensin I (Ang I) and angiotensin II (Ang II) all were significantly increased, plasma aldosterone was decreased by approximately 70% compared with control animals. These results not only indicate therapeutic efficacy of this agent in the chronic treatment of human hypertension, but support also the concept that the renin-angiotensin system plays an important role in the control of blood pressure in this animal model of human essential hypertension.

Antihypertensive and hormonal activity of MK 954 in spontaneously hypertensive rats

MK 954 (DuP 753), a recently developed angiotensin II (Ang II) receptor antagonist, was administered orally for 2 weeks to spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY). Whereas the basal levels of plasma Ang II were lower in SHR than in WKY, treatment with MK 954 markedly reduced blood pressure in SHR but not in WKY. Plasma renin activity, Ang I and Ang II were increased, while plasma aldosterone was decreased in both strains. These results no only indicate therapeutic efficacy of this agent in the chronic treatment of human hypertension, but also support the idea that the renin-angiotensin system plays an important role in the control of blood pressure in SHR.

Direct evidence for local generation and release of angiotensin II in human vascular tissue

A direct measurement of both angiotensins I and II immunoreactive substances was made in the perfusate from isolated human umbilical vein perfused with Krebs-Ringer solution which was free of any component of the renin-angiotensin system. The identity of the immunoreactive peptides was confirmed as angiotensin I and angiotensin II by high-performance liquid chromatography in reference to standard compounds. The rate of release of angiotensins was 41.9 +/- 7.4 and 63.4 +/- 12.0 pg for angiotensins I and II, respectively, during the first perfusion period of 30 min, and it remained stable at least for 3 hours. Angiotensin-converting enzyme inhibitor captopril, added to the perfusion medium (10(-9) to 5 x 10(-6) M), suppressed immunoreactive angiotensin II release in a dose-dependent fashion; the maximal percent inhibition of angiotensin II release evoked by captopril (5 x 10(-6) M) was approximately 56%. These results taken together with the previous observations of presence of essential components of the renin-angiotensin system in vascular tissue provide direct evidence for local generation and subsequent release of angiotensin II in vascular beds of human beings.

TCV−116, a newly developed angiotensin II receptor antagonist, induces regression of cardiac hypertrophy through suppression of the tissue renin-angiotensin system in spontaneously hypertensive rats

Previously, we reported that an orally active angiotensin II (Ang II) receptor antagonist Losartan induces regression of left ventricular hypertrophy with reduction in the tissue Ang II contents in spontaneously hypertensive rats (SHR). To further address the role of the cardiac renin-angiotensin system in the pathophysiology of hypertensive left ventricular hypertrophy, we examined the effects of TCV-116, a newly developed, highly specific nonpeptide Ang II receptor antagonist, on cardiac hypertrophy and the tissue angiotensin I (Ang I) and Ang II, as well as plasma renin activity (PRA) and Ang II, were determined. Treatment with TCV-116 (1 mg/kg per day) lowered blood pressure markedly. TCV-116 reduced significantly the left ventricular weight by about 11% compared with control animals. The left ventricular Ang I and Ang II contents were lowered by TCV-116 (12.9 +/- 1.4 vs. 30.4 +/- 2.5 pg/tissue, control, p < 0.01, for Ang I; 15.1 +/- 0.6 vs. 18.7 +/- 0.4 pg/tissue, control, p < 0.01, for Ang II), whereas PRA and plasma Ang II concentration were increased by the treatment. With the control and TCV-116-treated animals, there was a significant positive correlation between the left ventricular weight and the tissue Ang II content (r = 0.681, p < 0.01). These results not only further support the view that cardiac Ang II, rather than circulating Ang II, plays an important role in the pathophysiology of left ventricular hypertrophy of this animal model of human hypertension, but imply also that TCV-116 induces regression of hypertensive left ventricular hypertrophy through suppression of the tissue renin-angiotensin system.

Urinary Endothelin and Sodium Excretion in Essential Hypertension

Dr. Iku-e Saito, MD, Third Department of Internal Medicine, Fukushima Medical College, 1 Hikari-ga-oka, Fukushima 96012 (Japan) used was 250% with ET-2, 14% with human big ET and less than 0.01% with ET-3. Whereas no significant differences in the plasma irET-1 were observed among the normal-, lowand high-sodium intakes, urinary excretion of irET-1 was 20.1 + 2.5 (mean ± SE), 11.8 ± 3.8 and 29.6 ± 3.5 ng/g creatinine with the respective sodium diets. A similar change in fractional excretion of irET-1 (FEET) was observed with these different sodium intakes (1.2 ± 0.2, 0.7 ± 0.1 and 7.0-, 6.05.0 4.0Ui 3.0 2.01.0Fig.1. .Relationship between FEET and FENa of low-, normaland high-sodium intakes. 0.0 0.0 Dear Sir, Endothelin (ET), a potent vasoconstrictor known today, has been suggested to play multiple roles in cardiovascular diseases. Although ET was first isolated from vascular endothelial cells, recent studies have provided evidence which suggests that ET is widely distributed in renal tissue compatible with important autocrine and paracrine actions in the kidney [1]. Indeed, several reports demonstrated that increased ET production within the kidney may contribute to the intense intrarenal vasoconstriction characteristic of acute renal failure [2], endotoxin shock [3] and cyclosporin nephrotoxicity [4]. However, knowledge concerning the precise role of ET in the kidney tissue is still scanty. We have, therefore, examined the effect of sodium intake on

Losartan, a specific angiotensin II receptor antagonist, increases angiotensin I and angiotensin II release from isolated rat hind legs: Evidence for locally regulated renin-angiotensin system in vascular tissue

The effect of Losartan (10(-9) to 10(-6) M) on angiotensins I and II release was examined in isolated hind legs perfused with Krebs-Ringer solution from normal and bilaterally nephrectomized rats. Losartan increased dramatically both angiotensins I (Ang I) and II (Ang II) release in a dose-dependent fashion; the maximal percent increment in Ang I and Ang II release evoked by Losartan (10(-6) M) was about +380% and +160%, respectively, in normal rat hind legs. In nephrectomized animals, Losartan elicited a marked increase in both peptides dose-dependently. There was a highly positive correlation between the released amounts of Ang I and that of Ang II altered by Losartan in either normal (r = 0.954) or nephrectomized rats (r = 0.923). These results not only confirm the existence of a functional renin-angiotensin system in vascular tissues, but also suggest that the system is regulated by locally generated Ang II.

EFFECT OF DELAPRIL ON THE VASCULAR ANGIOTENSIN II RELEASE IN ISOLATED HIND LEGS OF THE SPONTANEOUSLY HYPERTENSIVE RAT: EVIDENCE FOR POTENTIAL RELEVANCE OF VASCULAR ANGIOTENSIN II TO THE MAINTENANCE OF HYPERTENSION

1. In view of a recent interesting hypothesis that the vascular renin‐angiotensin system (RAS) plays an important role in the maintenance of hypertension, we examined the effect of delapril (DP), a newly developed angiotensin converting enzyme inhibitor (ACEI), on angiotensin II (Ang II) release from isolated perfused hind legs of spontaneously hypertensive rats (SHR) in comparison with normotensive rats of Wistar‐Kyoto strain (WKY).

Atrial natriuretic factor (ANF) increases urinary protein excretion in patients with essential hypertension: A possible role of ANF for renal handling of protein

Low dose iv infusion (0.01 and 0.03 micrograms/kg per min, for 30 min each) of alpha-human atrial natriuretic factor (alpha-hANF) produced a significant increase (+300%) in urinary protein excretion in patients with essential hypertension but not in normotensive controls, when their renal function was normal. The major component of excreted proteins induced by alpha-hANF infusion was presumed to be albumin on the basis of molecular weight (69,000) analyzed by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. Urine output and sodium and potassium excretion rates were increased dose-dependently by alpha-hANF infusion in the hypertensive patients in a similar fashion to those in the controls. Glomerular filtration rate (GFR) remained unchanged in the controls but was slightly increased in the patients (+33%) during the infusion. These results suggest that besides its previously recognized physiological functions such as natriuresis and diuresis, ANF plays an important role in the regulation of renal handling of proteins in patients with essential hypertension.

The effect of docarpamine, a dopamine pro-drug, on blood pressure and catecholamine levels in spontaneously hypertensive rats.

We studied the effects of bolus intravenous injection of the dopamine prodrug, docarpamine (200 μg/kg), on mean arterial pressure (MAP) and heart rate (HR) in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs). In WKY rats (n=18), MAP and HR increased 5 min after docarpamine and then returned to baseline levels within 15 min. In contrast, in SHRs (n=15), MAP and HR gradually decreased, reaching a nadir 20 min after injection. Five min after docarpamine, plasma dopamine and 3,4-dihydroxy phenyl acetic (DOPAC) levels increased in both WKY rats (n=5) and SHRs (n=5). The docarpamine-induced changes in MAP and HR in both rat strains (n=5/strain) were blocked by the D1-like antagonist, SCH23390. α-Adrenergic (n=4) and vasopressin V1 (n=3) receptor blockade also abrogated the effects of docarpamine in WKY rats. We conclude that docarpamine differentially affects MAP and HR in WKY and SHRs. In SHRs, the depressor and bradycardiac effects of docarpamine are mediated by D1-like receptors. In WKY rats, the pressor and tachycardiac responses are caused by an interaction among D1-like, α-adrenergic, and V1 receptors.