Defect of the potassium transport process in the kidney of spontaneously hypertensive rats.

We investigated the natriuretic and kaliuretic effect of distal tubular diuretics in saline-loaded spontaneously hypertensive Wistar rats (SHR) from three different sources and normotensive Wistar rats (NWR). Orally administered early distal tubular diuretics (hydrochlorothiazide, chlorthalidone, metolazone, indapamide and cicletanine) caused much less potassium excretion in SHR than in NWR, whereas the magnitude of concurrent natriuresis was similar in both NWR and SHR. The intriguing renal handling of potassium excretion was exemplified by hydrochlorothiazide, for which enhanced kaliuresis was dose dependent in NWR but not in SHR. The doses tested ranged from 1 to 100 mg/kg, p.o. Amiloride, a late distal tubular diuretic, was also evaluated for its effect on sodium and potassium excretion in NWR and SHR. Amiloride produced potassium retention more effectively in NWR than in SHR, although the magnitude of natriuresis was similar. The difference between SHR and NWR with regard to potassium-retaining activity of amiloride was consistent at all doses tested (1-30 mg/kg, p.o.). In conclusion, it was suggested that SHR appear to have a genetic defect in potassium transport in the distal nephron.     

Antihypertensive effect of a novel calcium antagonist, SD-3211, in experimental hypertensive rats.

The antihypertensive effect of SD-3211, a structurally novel type of nondihydropyridine calcium antagonist, was assessed using several types of experimental hypertensive rats. Oral administration of SD-3211 (10, 20, and 30 mg/kg) to conscious spontaneously hypertensive rats (SHR), deoxycorticosterone acetate-salt hypertensive rats (DHR) and 2-kidney, 1-clip renal hypertensive rats (RHR) resulted in a dose-dependent decrease in systolic blood pressure (SBP). The hypotensive effect of SD-3211 in these hypertensive rats was more pronounced than in normotensive rats (NR). The potencies of SD-3211 for the hypotensive effect in the hypertensive rats and NR were 5-7 times greater than that of diltiazem but 2-3 times less than that of nicardipine. Furthermore, SD-3211 showed longer-lasting hypotensive action than diltiazem and nicardipine, at the respective equihypotensive dose. During the course of hypotension, SD-3211 did not exert any influence on heart rate (HR) in any type of hypertensive rats or NR, in contrast to the appearance of tachycardia with nicardipine in SHR, DHR, and NR and of bradycardia with diltiazem in DHR. At doses of 10 and 30 mg/kg, the hypotensive doses, SD-3211 elicited a dose-dependent natriuresis but no kaliuresis in SHR. In the chronic study using SHR, SD-3211 at 10 mg/kg/day showed an antihypertensive effect during an administration period of 12 consecutive weeks. These results allow us to conclude that SD-3211 has a potent and long-lasting hypotensive action with little cardiac effect.     

Antihypertensive effect of naftopidil (KT-611), a novel alpha 1-adrenoceptor antagonist, in freely moving experimental hypertensive rats and dogs

The antihypertensive effect of naftopidil (KT-611) following single oral administration was investigated in normotensive Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), DOCA-Salt hypertensive rats (DHR), 2-kidney 1-clip renal hypertensive rats (RHR) and Grollman type renal hypertensive dogs with 1-kidney (RHD); and it was compared with that of the selective alpha 1-adrenoceptor antagonist prazosin. The blood pressure and heart rate were measured under the unanesthetized, unrestrained state through an arterial catheter that was chronically implanted into the abdominal aorta. In SHR and WKY, both KT-611 (10 and 30 mg/kg, p.o.) and prazosin (1 and 3 mg/kg, p.o.) markedly inhibited the pressor response to the alpha 1-adrenoceptor agonist phenylephrine (3 micrograms/kg, i.v.). KT-611 (10 to 100 mg/kg, p.o.) showed a dose-dependent hypotensive effect in SHR, DHR and RHR but not in WKY. The hypotensive effect of KT-611 reached maximum at 0.5-1 hr, lasted for 4-6 hr and was more potent in DHR and RHR than in SHR. The potency of KT-611 was 1/10-1/30 weaker than that of prazosin. In RHD, single oral administration of KT-611 (1 to 10 mg/kg) caused a dose-dependent and long-lasting hypotensive effect. These results suggest that KT-611 has a long-lasting hypotensive effect in experimental hypertensive animal models.     

Decreased renal excretory capacity of uric acid in rats fed a low sodium diet under consecutive administration of thiazide diuretics

The effect of consecutive treatments with thiazide diuretics on renal handling of uric acid was investigated with clearance experiments using rats. Two weeks of oral administration of trichlormethiazide (2 mg/kg, twice a day) in rats fed an ordinary diet caused no change in the uric acid excretory capacity. However, a week of oral administration of trichlormethiazide (0.1, 0.5 and 2 mg/kg, twice a day) in rats maintained on a purified diet containing low sodium amounts decreased the fractional excretion of uric acid. At 2 mg/kg, the decrease of inulin clearance developed clearly. Similar treatments with hydrochlorothiazide (10 mg/kg) and cyclopenthiazide (0.5 mg/kg) also decreased the inulin clearance and the fractional excretion of uric acid. Administration of the above diuretics during sodium deprivation resulted in a marked rise of the hematocrit and hypokalemia. Purified diet containing low sodium amounts alone did not change the uric acid excretory capacity as compared to the ordinary diet. Trichlormethiazide treatment and continued sodium deprivation caused marked losses of body weight and food intake and promotions of urine output and water intake. Histologically, hyperplasia of the cells and tubular dilatation at macula densa were slightly developed during sodium deprivation. With these severe changes, dilatation of the proximal tubules with flattened and regenerated epithelium was shown by the trichlormethiazide treatment (0.5 mg/kg). From these results, the characteristics of chronic treatment with thiazide diuretics acting on renal uric acid retention could be understood in the rat under sodium deprivation.     

Acute effects of candesartan on rat renal haemodynamics and proximal tubular reabsorption

1. The effects of the specific angiotensin II receptor type I (AT1) antagonist candesartan on renal proximal tubular sodium transport were studied using lithium clearance. The effects of candesartan on mean arterial blood pressure (MABP), renal plasma flow (RPF), glomerular filtration rate (GFR) and sodium and potassium excretion were also investigated. 2. Male Wistar rats were anaesthetized with Inactin (thiobutabarbital sodium; Sigma, St Louis, MO, USA). Clearance markers (8% polyfructosan, 1% para-aminohippuric acid and 4 mmol/l lithium chloride) were given into a jugular vein at the rate of 1.6 mL/h per 100 g bodyweight. Candesartan was given as bolus injection (0.01, 0.1, 0.2, 0.5 and 1.0 mg/kg) followed by 60 min continuous infusion at a rate of 0.5, 5, 10, 25 and 50 microg/min per kg, respectively. 3. The non-depressor dose of candesartan (0.01 mg/kg) did not alter RPF or GFR, whereas diuresis, natriuresis and kaliuresis were observed. The higher doses of candesartan reduced MABP, RPF and GFR, although diuresis, natriuresis and kaliuresis were still observed. 4. Renal tubular sodium and water reabsorption were inhibited after intravenous administration of candesartan independently of an alteration in arterial pressure. Lithium clearance data indicate that the site of inhibition was in the proximal nephron segment.     

A new diuretic that does not reduce renal handling of uric acid in rats, S-8666

The uric acid-retaining effects of diuretics were studied using sodium-restricted spontaneously hypertensive rats. Test agents were administered orally once a day for two weeks. Diuretic thiazides such as trichlormethiazide and hydrochlorothiazide and loop diuretics such as furosemide and indacrinone clearly reduced the renal function for uric acid excretion in treatment which produced major effects such as diuresis, saluresis and hypotension. However, a new diuretic with uricosuric activity, S-8666, developed in our laboratories, had no effect on the renal handling of uric acid at doses which showed major effects similar to those of other diuretics. The results should aid the understanding of the utility of S-8666 as a new diuretic antihypertensive which does not cause hyperuricemia during therapy.     

Long-lasting hypotensive and antihypertensive effects of a new 1,5-benzothiazepine calcium antagonist in hypertensive rats and renal hypertensive dogs

The hypotensive effect of a new 1,5-benzothiazepine derivative, TA-3090 ((+) (2S,3S)-3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2, 3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one maleate), was studied in various models of experimental hypertension. In conscious spontaneously hypertensive rats (SHR), TA-3090 at a dose of 3 mg/kg p.o. or more caused significant hypotension. The effect was long-lasting, being observed for more than 8 h and 24 h at doses of 30 and 100 mg/kg p.o., respectively. Heart rate was not increased with doses up to 30 mg/kg p.o. TA-3090 like diltiazem, showed more potent hypotensive effect in SHR than in Wistar Kyoto rats (WKY). The enhancement of the hypotensive effect in SHR was more evident with TA-3090 and diltiazem than with 1,4-dihydropyridine calcium antagonists (1,4-DHPs). The enhanced hypotensive effect of TA-3090 was also observed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats in which the minimum hypotensive dose of TA-3090 was 1 mg/kg p.o. In SHR, reflex tachycardia induced by TA-3090 was smaller than those induced by 1,4-DHPs, while diltiazem decreased the heart rate. In WKY, all calcium antagonists except diltiazem at a low dose (30 mg/kg p.o.) increased the heart rate. Development of hypertension in young SHR was significantly suppressed by chronic treatment with TA-3090 at a daily dose of 10 mg/kg p.o. or more. The antihypertensive effect of TA-3090 was also observed by administration in the diet in matured SHR. In addition, TA-3090 exhibited a dose-related natriuretic but not kaliuretic effect in SHR at doses slightly higher than the hypotensive ones.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological properties of the novel highly potent diuretic 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid potassium salt.

7-Chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid potassium salt (M17055, CAS 114417-20-8) showed potent diuretic and saluretic effects dose-dependently, in rats (p.o.), mice (p.o.) and dogs (i.v.), at doses of 0.1-100 mg/kg, 0.3-100 mg/kg and 0.01-30 mg/kg, respectively. The efficacy of M17055 for diuresis, natriuresis and chloruresis was much higher than that of hydrochlorothiazide and almost the same as that of furosemide. These results indicate that this compound may be classified as a "high ceiling diuretic". The potencies of M17055 for natriuresis in rats (p.o.), mice (p.o.) and dogs (i.v.) calculated with ED50 values were 38, 34 and 24 times, respectively, more potent than those of furosemide. Urinary excretions of sodium, chloride and potassium increased in parallel with urinary volume with the administration of M17055 or furosemide, whereas an apparent dissociation with urinary calcium and sodium excretion was observed with M17055 alone. In rats, the increase of urinary calcium excretion with M17055 was significantly lower than that with furosemide under comparable conditions of natriuresis. Moreover, in mice, M17055 decreased urinary calcium excretion at doses with low effectiveness. In clearance studies using anesthetized dogs, M17055 suppressed negative free water clearance (CH2O) under saline loaded conditions, and it decreased positive CH2O under water diuretic conditions. These changes in the effects on CH2O induced by M17055 resemble those of loop diuretics. However, M17055 could not shift negative CH2O to positive, while furosemide was able to do so. Moreover, positive CH2O decreased to nearly zero with M17055, while urine remained dilute with furosemide even at 30 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypotensive and hemodynamic effects of the new non-sulfhydryl angiotensin converting enzyme inhibitor N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline

The hypotensive effects of N-[8-amino-1(S)-carboxyoctyl] -L-alanyl-L-proline (AB-47, CAS 120008-53-9) were examined in normotensive rats and various hypertensive rat models. The hemodynamic effect of AB-47 was also examined in anesthetized spontaneously hypertensive rats (SHR). In 2-kidney, 1-clip renal hypertensive rats (2K, 1C-RHR) and SHR, the single administration of AB-47 (10 mg/kg, p.o.) induced potent and long-lasting hypotensive effects. The repeated administration of AB-47 (1 to 10 mg/kg, p.o.) to SHR for 29 days produced a dose-dependently and sustained hypotensive effect of 20 to 70 mmHg. AB-47 (10 mg/kg, p.o.) had a weak hypotensive effect in DOCA-salt hypertensive rats but no effects in normotensive and 1-kidney, 1-clip renal hypertensive rats (1K, 1C-RHR). AB-47 (3 mg/kg, p.o.) reduced blood pressure in intact SHR but not in bilateral nephrectomized SHR. The single intravenous injection of AB-47 (10 to 100 micrograms/kg) dose-dependently lowered systemic blood pressure, left ventricular systolic pressure (LVSP) and dp/dtmax without affecting heart rate (HR) and these effects of AB-47 were more potent than those of captopril and enalaprilat. These results suggest that AB-47 is a potent and long-lasting hypotensive agent and may be useful for the therapy of both hypertension and congestive heart failure.     

Blood pressure lowering and renal hemodynamic effects of fosinopril in conscious animal models.

The blood pressure lowering and renal hemodynamic effects of fosinopril, the chemically novel inhibitor of angiotensin I converting enzyme (ACE), was assessed in conscious animal models. In conscious dogs, intravenous infusion of SQ 27,519 [0.5 mg/kg (1.1 mumol/kg) bolus plus 0.1 mg/kg/min (0.22 mumol/kg/min)], the active moiety of the prodrug fosinopril, increased PAH clearance and GFR by 25 and 16%, respectively (p less than 0.05, each) without changing arterial pressure (AP). Urine volume, sodium excretion, and potassium excretion were elevated, although not significantly increased. In sodium-depleted cynomolgus monkeys, 1.5 and 5.0 mumol/kg (0.88 and 2.9 mg/kg) p.o. of fosinopril lowered arterial pressure from 115 +/- 5 to 99 +/- 5 mm Hg and from 116 +/- 3 to 87 +/- 4 mmHg, respectively (p less than 0.05, each). When given orally to SHR at 10 and 30 mg/kg (5.9 and 17.6 mumol/kg), fosinopril lowered AP by 23 (183 +/- 4 to 160 +/- 5 mm Hg) and 20 mm Hg (176 +/- 4 to 156 +/- 4 mm Hg), respectively. The combination of fosinopril [10 mg/kg (5.9 mumol/kg)] plus hydrochlorothiazide (10 mg/kg) reduced AP from 206 +/- 4 to 167 +/- 2 mm Hg when given orally to SHR. Fosinopril was more effective in two-kidney, one-clip hypertensive rats relative to SHR; AP fell from 201 +/- 9 to 160 +/- 7 mm Hg after 10 mg/kg (5.9 mumol/kg), and from 205 +/- 7 to 145 +/- 7 mm Hg after 30 mg/kg (17.6 mumol/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the calcium channel blocker AE0047 on renal function in conscious spontaneously hypertensive rats: Focus on renal proximal tubules

The hypotension induced by peripheral vasodilators is occasionally accompanied by diminished urine formation induced via various anti-diuretic mechanisms. The question of whether an antihypertensive agent has diuretic action is therefore relevant to its usefulness. In the present study, conducted in conscious, spontaneously hypertensive rats (SHR), the lithium clearance technique was used to investigate the effect of intravenously administered AE0047 on renal function; the effect of orally administered AE0047 on uric acid excretion was also investigated. Intravenous injection of AE0047 (10 and 30 μg/kg) produced potent hypotension, accompanied by diuresis and natriuresis. The diuretic action was accompanied by an elevation of FE_Na and FE_Li levels, with minimal change in GFR. Oral administration of AE0047 (1 and 3 mg/kg) led to a dose-related increase in urine volume and in urinary excretion of sodium and uric acid (U_UAV). Simultaneous administration of pyrazinamide, an inhibitor of uric acid secretion in proximal tubules, mitigated the increase in U_UAV. These findings indicate that systemically administered AE0047 produces diuresis and natriuresis, in part via an inhibition of sodium and water reabsorption in the proximal tubules. The action of AE0047 at renal proximal tubular sites thus offers benefit in hypertension therapy. Drug Dev. Res. 41:91–98, 1997. © 1997 Wiley-Liss, Inc.     

Renal and cardiovascular effects of acute and chronic administration of felodipine to SHR

Renal function and salt and water turnover were studied in SHR during acute and chronic administration of felodipine, which is an efficient antihypertensive vasodilating Ca2+ antagonist. In conscious SHR acute administration of felodipine in hypotensive doses increased renal sympathetic nerve activity but caused renal vasodilation, increases in GFR and a 2-3 fold increase in urinary flow rate and sodium excretion. The fraction of filtered sodium excreted (FENa) was approximately doubled. The diuretic and natriuretic effects of felodipine are therefore suggested to be due to a direct inhibitory action on the renal tubular cells, resulting in reduced sodium reabsorption. Nifedipine also induced diuresis and natriuresis in this system, while minoxidil reduced water and sodium excretion. Throughout 6 months of felodipine treatment, the mean arterial pressure (MAP), remained 25-20 per cent reduced. Felodipine in combination with metoprolol reduced MAP 25-30 per cent and also caused regression of left ventricular hypertrophy, while felodipine alone prevented its further progression. Also during chronic administration, felodipine induced diuresis but had no effect on plasma volume and on sodium or potassium excretion in SHR. It is concluded that in SHR felodipine induces diuresis; on acute treatment this is secondary to reduced tubular sodium reabsorption, although during chronic treatment the sodium loss is compensated for while the diuresis remains. Thus, the cardiovascular and renal effects of Ca2+ antagonists like felodipine differ substantially from those of other potent antihypertensive vasodilators e.g. minoxidil.     

Regional hemodynamic effects of betaxolol, a new selective beta 1-blocker, and atenolol in conscious spontaneously hypertensive rats.

Betaxolol is a new beta-blocker that has been reported to have beta 1-selectivity, and it is devoid of both membrane stabilizing action and intrinsic sympathomimetic action. The effects of betaxolol on systemic and regional hemodynamics were examined in conscious spontaneously hypertensive rats (SHR) by a microsphere method and compared with the effects of atenolol. A single oral administration of betaxolol at 1 and 10 mg/kg decreased the mean arterial pressure in a dose-dependent manner. At the same doses, atenolol also showed a similar but weak hypotensive effect. Both of these drugs at the high dose decreased cardiac output and heart rate and at the low dose, did not. Total peripheral resistance decreased by only betaxolol at the low dose. Betaxolol showed a tendency to normalize the hemodynamic abnormalities which were observed in the kidney, spleen and gastrointestinal tract of SHR, while atenolol did not. It should be noted that betaxolol increased the flow rate in the kidney, which may be explained by its direct vasodilatory action on renal blood vessels. In conclusion, betaxolol showed an antihypertensive action at the doses of 1 and 10 mg/kg, exhibited the characteristics of a beta 1-blocker and produced preferable effects on regional hemodynamics in SHR.     

Effect of acebutolol, a cardioselective beta-adrenoceptor blocking agent, on the blood pressure in rats (author's transl)]

The effects of acebutolol, a cardioselective beta-adrenoceptor blocking agent, on the systolic blood pressure and heart rate were investigated in conscious Kyoto Wistar normotensive rats (WKY), spontaneously hypertensive rats (SHR) and DOCA-NaCl hypertensive rats (DOCA rats) and the results compared with those of propranolol and practolol. In WKY and DOCA rats, the intraperitoneal administration of acebutolol, propranolol and practolol (0.5 approximately 20 mg/kg) produced a hypotensive action, however, these effects were observed only with restricted doses and there was no evidence of a dose-dependency. The heart rate was decreased by acebutolol and propranolol, but was increased by practolol which possesses an intrinsic sympathomimetic activity. In SHR, propranolol produced a dual action, a slight rise followed by a slight fall, the change not being significant, while practolol induced a slight hypertension. On the other hand, acebutolol in high doses induced a dose-dependent hypotensive action. The heart rate was markedly and dose-dependently decreased by these three agents. Thus, while propranolol and practolol produced hypotensive effects in WKY and DOCA rats, acebutolol produced hypotensive effects in WKY, SHR and DOCA rats. These results suggest that acebutolol is a beta-adrenoceptor blocking agent which possesses hypotensive activity in hypertensive rats.     

Involvement of the renal kallikrein-kinin system in furosemide-induced natriuresis in rats

This study examined whether the renal kallikrein-kinin system (KKS) is involved with furosemide-induced natriuresis in rats. Intravenous administration of furosemide (10 mg/kg) to anesthetized rats infused with physiological saline (saline) increased renal KK excretion as well as urine volume and urinary excretions of sodium, chloride and potassium. The change in the increase of renal KK excretion by furosemide at a dose of 1.0 mg/kg relative to the control was larger than that of urine volume. Pretreatment with a B2-receptor antagonist, 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (FR173657, 100 mg/kg), significantly inhibited the furosemide-induced natriuresis by 58.6%. The effect of FR173657 on the furosemide-induced natriuresis was also examined in hypotonic saline-loading rats. Similar to the saline-loading rats, urinary excretion of sodium collected during the first 8 h in metabolic cages significantly reduced by 22.4% when FR173657 (100 mg/kg) was given concurrently with furosemide (100 mg/kg) and hypotonic saline (5% of body wt.). These results indicate that furosemide increased renal KK excretion through a mechanism different from a washout mechanism and induced natriuresis partly through an augmentation of the renal KKS following the increase in renal KK excretion in both the saline- and hypotonic saline-loading rats.     

Effects of intracerebroventricular administration of magnesium sulphate on blood pressure and heart rate in anesthetized normotensive and hypertensive rats

Intracerebroventricular (i.c.v.) injection of magnesium sulphate (MgSO4:2.5, 5 and 10 mumol in 5 microliters) decreased blood pressure and heart rate in both anesthetized normotensive (WKY) and hypertensive rats (SHR). The effects were greater in WKY than in SHR. Moreover, a pretreatment with hexamethonium (2 mg/kg, i.v.) significantly blunted the hypotensive and bradycardic effects induced by i.c.v. injection of 10 mumol of MgSO4 in both WKY and SHR. Our data suggest that MgSO4 produces hypotensive and bradycardic effects when injected i.c.v. in both WKY and SHR.     

Reduction in blood pressure and vascular reactivities to pressor substances by chronic treatment with piretanide in spontaneously hypertensive rats

1. Effects of treatment with piretanide (10 and 30 mg/kg per day p.o.) for 9 weeks on blood pressure, urinary excretion of electrolytes, and vascular reactivities to pressor substances were investigated in 10-week-old spontaneously hypertensive (SHR) rats. 2. Piretanide (30 mg/kg) prevented development of hypertension and produced a significant reduction in blood pressure from the 2nd week of the treatment. A slight decrease in blood pressure was observed in rats treated with the lower dose of piretanide. 3. Piretanide produced significant and dose-dependent diuresis throughout the experiment. Although significant natriuresis was observed in the 1st and 4th week of the treatment, natriuresis disappeared in the 8th week. Urinary excretion of potassium was decreased significantly by piretanide throughout the experiment. 4. Attenuation of pressor responses to phenylephrine and angiotensin II was observed after chronic administration of piretanide (30 mg/kg). 5. These data demonstrate the contribution of attenuated vascular reactivities to pressor substances as well as a diuretic action to the antihypertensive effect of piretanide during its long-term administration in SHR rats.     

Bumetanide and frusemide: a comparison of dose-response curves in healthy men

1 Log dose-responses for the loop diuretics bumetanide and frusemide in healthy subjects deviated significantly from parallelism as regards urine volume and sodium excretion. Ignoring the nonparallelism the best estimate of natriuretic potency (bumetanide: frusemide) was 46:1 in the bumetanide dose range 0.5-2 mg. 2 For a given natriuresis the urinary potassium excretion following bumetanide was significantly lower than that for frusemide within this dose range. 3 The data illustrate the limitations of studies comparing diuretics at a single dose level. Extrapolation of the observed log dose-response curves provides one possible explanation for the relative potency (bumetanide: frusemide) of 20:1 reported when the drugs are used at high dosage in patients with renal failure.     

Role of the alpha-adrenergic blocking effect in the acute hypotensive effect of beta-adrenergic blocking drugs with alpha-blocking activities in conscious SHR

Acute hypotensive effects and the mechanisms of three beta-adrenergic blocking drugs with alpha-blocking activity were studied in comparison with those of prazosin, propranolol and hydralazine in the conscious spontaneously hypertensive rat (SHR). Prazosin lowered the blood pressure dose-dependently and inhibited the pressor response to phenylephrine. Three beta-adrenergic blocking drugs with alpha-blocking activity, labetalol (30 mg/kg), arotinolol (100 mg/kg) and nipradilol (100 mg/kg) also lowered the blood pressure to the same extent as prazosin (0.3 mg/kg), but the inhibition of the pressor response to phenylephrine produced by them was disproportionately slight. Propranolol (100 mg/kg) did not lower the blood pressure. These results suggest that the acute hypotensive effects of three beta-adrenergic blocking drugs with alpha-blocking activity were attributable only partially to the alpha-adrenergic blocking effect; a mechanism or mechanisms other than the alpha-adrenergic blocking effect must be invoked to explain the acute hypotensive effect produced by lower doses of these drugs in the conscious SHR.     

Comparison of the severity of the chronic cardiotoxicity produced by doxorubicin in normotensive and hypertensive rats

A comparison was made of the severity of chronic doxorubicin cardiotoxicity in adult male spontaneously hypertensive rats (SHR) and in genetically related normotensive Wistar-Kyoto rats (WKY). Groups of SHR and WKY were given 12 weekly iv injections of doxorubicin at 0.25, 0.5, or 1.0 mg/kg. When the study was concluded, mean arterial pressure was 127 to 161 nm Hg in doxorubicin-treated SHR compared with 74 to 87 mm Hg in similarly treated WKY. Lesions, consisting mainly of cytoplasmic vacuolization and myofibrillar loss, were noted in the hearts from both types of rats given the 1.0-mg/kg dose and were considerably more severe in SHR than in WKY (average scores 3.8 and 2.0). Renal lesions (glomerular vacuolization and dilatation of tubules with accumulations of proteinaceous material) were of comparable severity in both types of rats at the 9- and 12-mg/kg cumulative doses; however, they were more severe in SHR at the 6-mg/kg cumulative dose. Moderate cardiac alterations were present in all SHR (average score 1.6) given 0.5 mg doxorubicin/kg; at the same dose, lesions were minimal in two and absent in three WKY. In a second study, groups of rats were killed 1 week after 3,6,9, or 12 weekly iv injections of doxorubicin (1.0 mg/kg). Myocardial lesions were noted initially in SHR after six doses and in WKY after nine doses. Three of five SHR were dead by the 12th dose. These results indicate that spontaneously hypertensive rats are much more sensitive than normotensive rats to the cardiotoxic effects of doxorubicin.