Masao Hiwatari

PHARMACOLOGICAL PROFILE OF A NEW CORONARY VASODILATOR DRUG, 2‐NICOTINAMIDOETHYL NITRATE (SG‐75)

1. In anaesthetized, open‐chest dogs, 2‐nicotinamidoethyl nitrate (SG‐75) administered intravenously (0.3–1 mg/kg) or intraduodenally (3 mg/kg) produced decreases in systemic blood pressure, coronary resistance, heart rate and an increase in coronary sinus outflow, but virtually no change in myocardial oxygen consumption and atrioventricular conduction. The effects of SG‐75 administered intraduodenally emerged within a few minutes after dosing and lasted over about 1 h.

NO EFFECT OF ATRIAL NATRIURETIC FACTOR ON CARDIAC RATE, FORCE AND TRANSMITTER RELEASE

1. The effects of atrial natriuretic factor (ANF, 1‐300 nmol/l) on cardiac rate, force and neurotransmitter release were examined in guinea‐pig isolated heart preparations.

Involvement of vasopressin in the cardiovascular effects of intracerebroventricularly administered alpha 1-adrenoceptor agonists in the conscious rat.

To determine the interaction between central adrenergic and vasopressinergic mechanisms in the regulation of cardiovascular function, the effects of intracerebroventricular (i.c.v.) administration of the alpha 1-agonists, methoxamine and phenylephrine, in conscious Long-Evans (LE) rats were compared with those in Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI). In LE rats, both i.c.v. methoxamine and phenylephrine increased mean arterial pressure (MAP) and decreased heart rate (HR) in a dose-related manner, while they had no effect on MAP and HR in DI rats within the dose range of 3-30 micrograms/kg. Both i.c.v. methoxamine (10 micrograms/kg) and phenylephrine (30 micrograms/kg) also increased plasma levels of arginine vasopressin (AVP) in LE rats from 2.6 +/- 0.4 (n = 9) to 22.4 +/- 3.5 (n = 6, P less than 0.01) and 37.0 +/- 4.0 pg/ml (n = 6, P less than 0.01), respectively, without affecting plasma renin activity (PRA) and plasma angiotensin II (ANG II) levels. Central alpha 1-adrenoceptor stimulation increases vasopressin release from the posterior pituitary, which in part is responsible for the hypertensive and bradycardic responses. However, central vasopressinergic pathways have also been shown to be involved in these cardiovascular effects. Neither i.c.v. nor intravenous (i.v.) infusion of AVP restored the cardiovascular response to i.c.v. alpha 1-agonists in DI rats. In LE rats, however, i.v. pretreatment with the specific vascular antagonist to the pressor effect of AVP, d(CH2)5Tyr(Me)AVP (VP-ANT; 10 micrograms/kg), significantly attenuated, but did not completely block the hypertensive and bradycardic effects of i.c.v. methoxamine and phenylephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Morning home blood pressure may be a significant marker of nephropathy in Japanese patients with type 2 diabetes : ADVANCED-J study 1

A 3-year multicenter, prospective, randomized, open-label trial (ADVANCED-J) compared the effect of an increased dose of angiotensin-II receptor blocker (ARB) with that of a maintenance dose of ARB plus calcium channel blocker (amlodipine) on blood pressure (BP) control, nephropathy and atherosclerosis in patients with type 2 diabetes and hypertension in whom the usual ARB dose failed to control BP. A cross-sectional analysis using baseline data was conducted. Of 316 patients (recruited between September 2004 and December 2005), 228 patients were evaluated by multiple regression analysis using two models after randomization and exclusions. Model 1 assessed 13 baseline variables (age, sex, estimated diabetes duration, estimated hypertension duration, HbA1c, brain natriuretic peptide (BNP), high-sensitive C-reactive protein (hsCRP), triglycerides (TGs), total cholesterol (TCHO), diabetic retinopathy (DMR), systolic morning home BP (HBP), diastolic morning HBP and brachial-ankle pulse wave velocity (baPWV)) for correlation with the urinary albumin creatinine excretion rate (UACR). In model 2, systolic and diastolic morning HBP was replaced by systolic and diastolic office BP. The systolic morning HBP and systolic office BP or diastolic morning HBP and diastolic office BP correlations were weak, but significant (r=0.43 and 0.48, respectively). BNP, HbA1c, DMR and estimated diabetes duration were significantly correlated with UACR in both models 1 and 2. Although systolic office BP did not show a significant correlation with UACR in model 2, systolic morning HBP showed a significant correlation with UACR in model 1. Morning HBP, but not office BP, may be a significant marker of nephropathy in Japanese patients with type 2 diabetes.

Expression of the renal kallikrein gene in mineralocorticoid-treated and genetically hypertensive rats

On the basis of both clinical observations and experimental studies it has been proposed that renal kallikrein is a mineralocorticoid regulated protein. In other studies, changes in renal kallikrein activity have been implicated in the genesis of, and/or response to, hypertension. Using a cloned complementary DNA (cDNA) to rat pancreatic kallikrein (pcXP39) for hybridization histochemistry, and both Northern and dot blot analysis, we studied expression of the kallikrein gene in steroid-treated control animals, and in three strains of genetically hypertensive rats. No differences in renal kallikrein messenger RNA (mRNA) levels were found between adrenalectomized rats and those treated for 5-14 days with 9 alpha-fludrocortisone, corticosterone or dexamethasone, or between hypertensive rats and their appropriate controls. Since mRNA levels appear essentially invariant under such circumstances, the change in renal kallikrein activity/immunoreactivity after chronic mineralocorticoid elevation, or in hypertensive rats, presumably reflects modulation at the post-transcriptional level.

Evaluation of the chronotropic property of captopril in hypertensive patients

Captopril was administered (50 mg orally) to 88 untreated hypertensive patients (70 with essential hypertension, eight with renal arterial disease, 10 with renal parenchymal disease) and to 25 hypertensive patients treated with sympatholytic or beta-blocking agent (20 with essential hypertension, five with renal arterial disease). In the former group, captopril caused a decrease in heart rate (HR) in 18 patients and an increase in only two. As a whole, captopril caused significant decreases in blood pressure without increase in HR. Significant negative correlation was observed between change in HR and plasma renin activity obtained before captopril administration (n = 79, r = -0.425, p less than 0.0001). Hypotensive and chronotropic effects of captopril were almost identical in untreated and treated patients. Hypotensive effects caused by captopril and nifedipine (20 mg orally) were almost identical. Nifedipine caused reflex tachycardia, while captopril caused slight bradycardia. Absence of compensatory tachycardia appears to be related to reduction of endogenous angiotensin II by captopril.U

Effect of dietary sodium intake on the metabolism of prostaglandins in the kidney in hypertensive patients

To investigate the role of renal prostaglandins (PGs) in the renal handling of sodium, urinary excretion of PGE, PGF2 alpha and PGF2 alpha MUM (main urinary metabolite of PGF2 alpha) were measured after various manipulations of dietary sodium intake in 8 hypertensive patients. A low sodium intake increased urinary excretion of PGF2 alpha MUM (p less than 0.05), but failed to change urinary excretion of PGE and PGF2 alpha. In contrast, a high sodium intake increased urinary excretion of PGE (p less than 0.01) and decreased urinary excretion of PGF2 alpha MUM (p less than 0.02). A low sodium intake decreased the ratio of urinary PGE/PGF2 alpha MUM and high sodium increased it (both p less than 0.001). There was a significant positive correlation between urinary excretion of sodium and that of PGE (p less than 0.001). Additional oral administration of potassium chloride did not change urinary excretion of PGs. These results may suggest that dietary sodium intake may be one of the regulators of the metabolism of PGs in the kidney, supporting the hypothesis that renal PGE has a natriuretic action in humans.

Reduced urinary excretion of prostaglandin E in essential hypertension.

To ascertain whether renal prostaglandin (PG) E synthesis is decreased in patients with essential hypertension (EH), urinary PGE excretion (UPGEV) was measured in 47 normal females and 62 female patients with EH. In order to avoid contaminations of urine by seminal fluids, only female subjects were studied. UPGEV was also measured in female patients with renovascular hypertension (RVH) as well as primary aldosteronism (PA) or idiopathic hyperaldosteronism (IHA). As a whole, UPGEV was lower in patients with EH (226.9 +/- 13.7 ng/day) than that in normal females (317.3 +/- 22.1 ng/day, p less than 0.001). Younger patients (15 to 39 years) had significantly lower UPGEV than normal females of corresponding ages. However, there was no significant difference in UPGEV between older patients (over 40 years) with EH and normal females of the same age range. There were no significant differences in UPGEV among patients with low renin EH, normal renin EH, RVH, PA and IHA. We reconfirmed the decrease in UPGEV in patients with EH as compared with normal controls by studying female subjects. Further, it is suggested that renal PGE synthesis is not influenced by the renin-angiotensin system in these hypertensive states.

The Role of Renal Prostaglandin E in the Mechanism of the Exaggerated Fractional Na Excretion in Hypertensive Patients with Advanced Renal Disease

Prostaglandin E (PGE) is a vasodilatory and natriuretic substance which is synthesized in the renomedullary interstitial cell and collecting tubule.1–3 Previous experimental and theoretical studies have shown a reduced clearance of sodium and water in renal hypertension.4 On the other hand, it is well known that sodium excretion per nephron varies inversely with the number of constituent nephrons, and that reduction of renal excretory function due to renal parenchymal disease is associated with exaggerated fractional sodium excretion.5 Since PGE can induce natriuresis, there is a possibility that renal PGE may contribute to the mechanism of exaggerated fractional sodium excretion in hypertensive patients with end-stage renal disease. The present study was performed to investigate this possibility.

Renal kallikrein activity in spontaneously hypertensive rats

To assess possible roles of the renal kallikrein-kinin system in the development of spontaneous hypertension, we determined daily excretion of urinary total and active kallikrein in 6-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats for up to 2 weeks. We also evaluated the effect of aprotinin, a reversible inhibitor of kallikrein and other serine proteases, on the development of hypertension in the 6-week-old SHR on ordinary intakes of sodium or on sodium loading with 1% NaCl for up to 2 weeks. Active kallikrein was determined by its kininogenase activity, and the generated kinins were radio-immunologically measured. Total kallikrein was also determined by measuring kininogenase activity after inactive kallikrein had been activated with trypsin (200 micrograms/ml). Urinary active kallikrein excretion was significantly reduced in 7-week-old SHR (1.5 +/- 0.2 microgram/day compared to 2.8 +/- 0.3 micrograms/day in WKY, P less than 0.05) and in 8-week-old SHR (1.6 +/- 0.2 microgram/day compared to 3.2 +/- 0.4 micrograms/day in WKY, P less than 0.01). Urinary total kallikrein excretion was also reduced in the 7- and 8-week-old SHR whereas the ratio of active to total kallikrein did not change. In addition, renal contents of total and active kallikrein were significantly lower in the 8-week-old SHR than in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)