J. S. Hutchinson

INCREASED SODIUM PERMEABILITY OF ERYTHROCYTES IN SPONTANEOUSLY HYPERTENSIVE RATS

1. The Na permeability of red cells from spontaneously hypertensive rats (SHR) has been studied. In the Japanese Wistar‐Kyoto strain, a significant increase of 30% in 22Na influx for male SHR was found compared with normotensive male controls. In contrast the Na influx for genetically hypertensive and normotensive New Zealand rats did not differ. Normotensive Wistar‐Kyoto rats rendered hypertensive by unilateral renal artery clipping, did not show any difference in Na influx from control animals.

IMMUNOREACTIVE β‐ENDORPHIN LEVELS IN PLASMA AND PITUITARY TISSUE FROM GENETICALLY HYPERTENSIVE AND NORMOTENSIVE RATS

1. Levels of immunoreactive β‐endorphin were measured in neurointermediate lobes, anterior lobes and plasma from the Japanese and New Zealand strains of genetically hypertensive rats and their normotensive controls.

HYPOTENSIVE EFFECTS OF CAPTOPRIL ADMINISTERED CENTRALLY IN INTACT CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS AND PERIPHERALLY IN ANEPHRIC ANAESTHETIZED SPONTANEOUSLY HYPERTENSIVE RATS

1. The hypotensive response to captopril in anaesthetized spontaneously hypertensive rats (SHR) is not modified by bilateral nephrectomy performed 1 or 24 h previously.

Angiotensin converting enzyme in the brain of spontaneously hypertensive rats.

1. Angiotensin converting enzyme (ACE) was measured in homogenates of regions of rat brain using the substrate Hip‐His‐Leu.

Exaggerated hypotensive responses to calcium antagonists in spontaneously hypertensive rats.

The hypotensive effects of intravenous injection and infusion of diltiazem, l- and d-verapamil were investigated in conscious and anaesthetized rats with spontaneous hypertension (SHR) and normal blood pressure (NT-WKY). The inhibitory actions of these calcium-influx blockers on the pressor responses to angiotensin II (AII) and noradrenaline (NA) were also examined in anaesthetized SHR and NT-WKY. The intravenous injections of these three drugs (0.03, 0.1, 0.3, 1.0 mg/kg) lowered mean arterial pressure (MAP) in a dose related manner in conscious NT-WKY and SHR. The small dose of the blockers administered by intravenous infusion (0.02 mg/kg per min) also decreased MAP in both groups. The potency of the antihypertensive action was in the order l-verapamil greater than d-verapamil = diltiazem. The fall in blood pressure expressed as percentage of the initial MAP produced by the compounds was significantly enhanced in SHR compared to NT-WKY. The pressor responses to AII (0.03, 0.1, 0.3, 1.0 micrograms/kg i.v.) were suppressed by the intravenous infusion of 20 micrograms/kg per min with l-verapamil but not with d-verapamil, diltiazem and vehicle in NT-WKY, while no calcium blocker significantly diminished the vasopressor action of AII in SHR. The pressor effects of NA (0.3, 1.0, 3.0, 10.0 micrograms/kg i.v.) were inhibited by the same doses of l-verapamil and diltiazem but not with d-verapamil and vehicle in NT-WKY. Diltiazem reduced the response to NA in SHR but the other compounds (l- and d-verapamil) did not alter the pressor response to NA in SHR. The pressor responses to arginine vasopressin (3, 10, 30 and 100 mU/kg i.v.) were not altered by diltiazem infusion in either SHR or NT-WKY. It is concluded that these compounds are different in the potency of their hypotensive action and also the inhibition of the pressor responses to AII and NA. Calcium entry blockers are more effective antihypertensive agents in SHR than in NT-WKY. It appears that their inhibitory effects on the responses to AII and NA do not explain the exaggerated hypotensive responses in SHR.

Captopril potentiates the vasodepressor action of Met‐enkephalin in the anaesthetized rat

1 The transient vasodepressor action of Met‐enkephalin (10–80 μg kg−1, i.v.) in anaesthetized rats was significantly potentiated by the angiotensin‐converting enzyme inhibitor, captopril (2 mg kg−1, i.v.); at this dose, it failed to modify the transient vasodepressor action of the non‐specific vasodilator, nitroprusside (2.5, 5.0, 10 μg kg−1, i.v.). 2 Captopril (2 mg kg−1, i.v.) caused a slow, progressive fall in the blood pressure of anaesthetized spontaneously hypertensive (SH) rats when compared to vehicle‐treated controls. Pretreatment with naloxone (1.5 mg kg−1, i.v.) 30 min earlier failed to alter significantly the hypotensive action of captopril in anaesthetized SH rats. 3 It was concluded that although captopril potentiated the vasodepressor action of Met‐enkephalin in anaesthetized normotensive rats, potentiation of endogenous opioids does not appear to be involved in the hypotensive action of captopril in anaesthetized SH rats.

Central angiotensin converting enzyme blockade and thirst.

The role of endogenous brain angiotensin II (AII) in various thirst states was examined in the rat using the angiotensin converting enzyme inhibitor, captopril. Intracerebroventricular (ICV) captopril (7 micrograms) significantly attenuated the dipsogenic response to centrally administered angiotensin I (AI) (200 ng) for up to 2 hours. The same dose of captopril significantly potentiated the dipsogenic response to ICV AII (100 ng) but failed to alter the dipsogenic response to ICV carbachol (200 pmoles). Central pretreatment with captopril (7 micrograms), for 30 minutes, failed to alter markedly the cumulative water intake of 24 hour water deprived rats. However, a small, significant 8% decrease in water intake was noted in ICV captopril treated rats 60 minutes following the return of water. The same dose of captopril, administered intraperitoneally, significantly potentiated the cumulative water intake of 24 hour water deprived rats. Central pretreatment with captopril (7 micrograms), for 30 minutes, failed to alter the cumulative water intake of rats treated intraperitoneally with hypertonic saline (0.75 M given at a dose of 1% of the body weight). From these studies it would appear that central angiotensin converting enzyme plays only a minor role in thirst induced by water deprivation.

Evidence for a functional central dopaminergic insufficiency in the spontaneously hypertensive rat.

1. Several neuroendocrine abnormalities reported in the spontaneously hypertensive rat (SHR) suggest that the function of the dopaminergic tuberoinfundibular tract is impaired in this strain.

Failure of aspirin to modify the hypotensive action of captopril in spontaneously hypertensive rats.

1. Oral administration of the angiotensin converting enzyme inhibitor, captopril (30 mg/kg per day) to spontaneously hypertensive rats of the Okamoto strain progressively reduced arterial blood pressure by 60 mmHg over 4–5 days.

A COMPARISON OF THE ACTIVITY OF THE ANGIOTENSIN CONVERTING ENZYME INHIBITORS SQ 14 225, SA 446, AND MK 421

This study was designed to compare the activity of three structurally different drugs (SQ 14 225, SA 446, and MK 421) as inhibitors of angiotensin converting enzyme in vivo and to compare their effects in two experimental models of hypertension.