THE EFFECT OF HYPERTENSIVE EPISODES AND CARDIAC HYPERTROPHY ON THE CANINE CARDIAC BAROREFLEX

1. Left ventricular (LV) hypertrophy has been implicated in the reduction of baroreflex sensitivity present in hypertension. The aim of the current study was to investigate the mean arterial pressure-heart rate reflex (MAP-HR) in a model which induced left ventricular hypertrophy but no sustained blood pressure elevation. 2. Five mongrel dogs were exposed to transient blood pressure elevation of between 20 and 30 mmHg, through hindlimb compression using a pneumatic pressure suit, for 7 h per day, 6 days per week for 6 weeks. Resting blood pressure was not altered by the 6 week hindlimb compression intervention. 3. Echocardiographically determined LV mass (mean ± s.e.m.) was 116.0 ± 7.4 g prior to hindlimb compression (baseline) and elevated to 125.4 ± 8.1 g (P= 0.003) after 6 weeks of compression. A reduction in the early (E) to late (A) transmitral diastolic flow ratio (E/A) from 1.80 ± 0.06 at baseline to 1.54 ± 0.09 (P = 0.037) after the 6 week intervention suggested that cardiac compliance was reduced. 4. The maximum gain of the MAP-HR reflex, studied using the ‘steady-state’ drug technique, when blood pressure was normal, showed a trend for reduction from 3.85 ± 0.43 beats/min per mmHg at baseline to 3.10 ± 0.45 beats/min per mmHg (P= 0.067) after 6 weeks of compression. This gain reduction became significant after β-adrenoceptor blockade with propranolol (3.13 ± 0.55 vs 2.32 ± 0.25 beats/min per mmHg; P= 0.039). Covariant analysis showed a significant inverse correlation between LV mass and maximum gain (r= 0.96; P<0.001) during the 6 week compression period. 5. The MAP-HR reflex changes in this model mimic those present in hypertension and implicate cardiac hypertrophy as one possible mediator.     

AUGMENTATION OF ANGIOTENSIN II RELEASE FROM ISOLATED MESENTERIC ARTERIES OF WISTAR-KYOTO AND SPONTANEOUSLY HYPERTENSIVE RATS FOLLOWING NEPHRECTOMY

1. We previously reported that angiotensin II release from the mesenteric arteries of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) increased in a time-dependent manner as a result of the isolation of the arteries and perfusion. This phenomenon appeared to be due to the withdrawal of circulating angiotensin II (AII). 2. The purpose of the present study was to test the hypothesis that vascular AII generation may be negatively regulated by circulating AII in WKY and SHR, and to clarify the role of this vascular angiotensin II in the sustained hypertension of SHR following nephrectomy. 3. The mesenteric arteries from kidney-intact and nephrectomized WKY and SHR were perfused and the amount of AII released into the perfusate was measured. The effects of the angiotensin converting enzyme inhibitor, captopril, and the effects of supplementation of renal renin and circulating angiotensins to nephrectomized rats, by blood exchange between kidney-intact and nephrectomized rats, on AII release were examined to clarify the pathway of vascular AII generation after nephrectomy. 4. Nephrectomy caused augmentation of vascular AII release both in WKY and SHR in spite of the abolishment of circulating renin. Captopril reduced this enhanced release of AII, but blood exchange did not affect it. There was no significant difference in these responses between WKY and SHR. 5. These results suggest that WKY and SHR have in common a potent pathway for production of vascular AII in response to the withdrawal of circulating AII, although this pathway is not responsible for the sustained hypertension of SHR after nephrectomy. The precise pathophysiological role of this pathway remains to be elucidated.     

DIFFERENCES IN ENDOTHELIUM-DEPENDENT RELAXATION IN VARIOUS ARTERIES FROM WATANABE HERITABLE HYPERLIPIDAEMIC RABBITS WITH INCREASING AGE

1. Endothelium-dependent relaxation in response to acetylcholine (ACh) and the calcium ionophore A 23187 was examined in aorta, coronary, basilar and renal arteries isolated from Watanabe heritable hyperlipidaemic (WHHL) rabbits of 2, 6 and 12 months of age, with normolipidaemic heterozygous WHHL rabbits as controls. 2. In the rings of WHHL rabbit aortae and coronary arteries preconstricted with vasoconstrictors, endothelium-dependent relaxation in response to ACh was attenuated with age compared to the heterozygous WHHL rabbits. A significant negative correlation was found between the total cholesterol content and the relaxation response to ACh in the aortae or coronary arteries from 6 and 12 month old WHHL rabbits. 3. In the rings of basilar arteries, endothelium-dependent relaxations to ACh were not modified with age. Similarly, in the rings of renal arteries, the relaxation response to ACh was not changed with age, but in the 6 and 12 month preparations, after the age of 6 months, a contraction following the relaxation appeared at higher concentrations of ACh (10^?7 to 10^?6 mol/L). The contraction was endothelium-dependent and inhibited by indomethacin. 4. A 23187-induced endothelium-dependent relaxations were also markedly attenuated in the aorta and significantly in the coronary artery with age. 5. Endothelium-independent relaxation to sodium nitroprusside was not changed in all arteries from WHHL rabbits of different ages. 6. These findings indicate that in the aorta and coronary artery of the WHHL rabbit, the endothelium-dependent relaxation to ACh and A 23187 becomes impaired with increasing age (i.e., with the progression of cholesterol deposition in the arterial wall) but is preserved in the basilar and renal artery.     

REPERFUSION FOLLOWING MYOCARDIAL ISCHAEMIA ENHANCES INOSITOL PHOSPHATE RELEASE IN THE ISOLATED PERFUSED RAT HEART

1. Global myocariial ischaemia (MI) for periods greater tan 5 min caused an inhibition of phosphatidylinositol specific phospholipase C (PtdIns-PLC) activity. 2. Two min reperfusion following a 20 min MI period, a time point associated with reperfusion-induced arrhythmias, resulted in an activation of PtdIns-PLC activity, dependent on endogenous noradrenaline and mediated via al-adrenoceptors. 3. This 2 min reperfusion response, in contrast to healthy myocardium, resulted in: (i) enhanced PtdIns-PLC activity; (ii) increased sensitivity to endogenous noradrenaline; (iii) rapid increases in inositol(1,4,5)trisphosphate (Ins(1,4,5)P3); and (iv) PLC hydrolysis primarily of PtdIns(4,5)P₂, such that the majority of InsP isomers derive from Ins(1,4,5)P₃. 4. Together, these data suggest a functional role for Ins(1,4,5)P3 under postischaemic reperfusion conditions, and provide a possible link between al-adrenoceptor stimulation of the PtdIns turnover pathway and reperfusion injury.     

LYSOSOMAL IRON ACCUMULATION AND TUBULAR DAMAGE IN RAT PUROMYCIN NEPHROSIS AND AGEING

1. Energy dispersive X-ray spectrometry was used to examine the relationship between proteinuria and increased urinary iron excretion, and structural and functional damage in puromycin nephrosis. 2. After 11–12 days rats treated with puromycin (10 mg/100g, i.v.i.) had greater proteinuria (211.6 ± 35.7 mg/day, mean ± s.e.m.) and urinary iron excretion (15.4 ± 2.2 μg/day) than salinetreated controls (14.5 ± 1.4 mg/day and 1.1 ± 0.2 μg/day, respectively, both P<0.001). 3. On day 13, mean lysosomal iron concentration of proximal tubular cells (306.6 ± 64.5 vs 11.9 ± 8.6 mg%, P<0.001), and proximal tubular cell damage assessed semi-quantitively (1.17 ± 0.10 vs 0.62 ± 0.10, P<0.001) were higher and creatinine clearance (0.15 ± 0.01 vs 0.29 ± 0.02 mL/min perg kidney weight, P<0.001) lower than in control rats. 4. At days 35, 60 and 360 there were no differences in any of the measured parameters between rats treated with puromycin or saline, and in both groups proteinuria, tissue damage and lysosomal iron concentration increased with time. 5. Lysosomal iron accumulation was the only independent predictor of both functional and structural damage. 6. In conclusion, the apparent association between proteinuria and tubulo-interstitial damage in puromycin nephrosis, and with ageing, is best explained by factors associated with accumulation of iron within lysosomes of proximal tubule cells.     

RENIN GENE POLYMORPHISM ASSOCIATED WITH ALDOSTERONE RESPONSIVENESS TO THE RENINANGIOTENSIN SYSTEM IN PATIENTS WITH ALDOSTERONE-PRODUCING ADENOMAS

1. Aldosterone levels in patients with unilateral aldosterone-producing adenomas may be responsive or unresponsive to the renin-angiotensin system, with the former often previously misdiagnosed as bilateral adrenal hyperplasia. 2. In tumours from patients in the responsive subgroup, renin mRNA is expressed in greater amounts than in tumours from patients in the unresponsive subgroup, or in normal adrenals. 3. We compared the frequency of four renin gene polymorphisms in peripheral blood DNA from the two subgroups and found significant associations between BglI, TaqI and HinfI restriction fragment length polymorphisms (RFLP) and aldosterone responsiveness. 4. Allelic variation in the constitutive renin gene was associated with a specific cause of hypertension.     

VASOCONSTRICTOR RESPONSES TO COMPONENTS OF THE RENIN-ANGIOTENSIN SYSTEM IN CYCLOSPORIN-INDUCED HYPERTENSION IN THE RAT

1. Since plasma renin activity is increased in cyclosporin A (CsA)-induced hypertension in the rat, the role of the vascular renin-angiotensin system (RAS) in CsA-induced hypertension was investigated in rat mesenteric resistance vessels. 2. Female Wistar rats received CsA (10 mg/kg per day, s.c.) or vehicle for 30 days. CsA treatment increased tail-cuff systolic blood pressure (CsA treated 135 ± 3 mmHg vs control 125 ± 1 mmHg, P<0.0001). 3. Mesenteric resistance arteries (200–300 μm) were isolated and mounted in a microvessel myograph. Concentration-response curves to tetradecapeptide renin substrate (10-¹¹-10^?6 mol/L), angiotensin I (10-^l1-10^?6 mol/L) and angiotensin II (10-¹²-10^?6 mol/L) showed no differences between CsA-treated and control groups. 4. Mesenteric vascular angiotensin-converting enzyme (ACE) characteristics were determined by radioligand binding. There were no differences in the content or affinity of ACE between CsA-treated and control rats. 5. These results suggest that the mesenteric vascular RAS does not play a major role in CsA-induced hypertension in the rat.     

INTERACTION BETWEEN EPIDERMAL GROWTH FACTOR AND ARGININE VASOPRESSIN IN RENAL MEDULLARY MEMBRANES

1. Epidermal growth factor is a potent mitogen that causes natriuresis, diuresis and inhibition of arginine vasopressin-induced water reabsorption. 2. The aim of this study was to determine any interaction between epidermal growth factor and the V1 (vascular) and/or V2 (antidiuretic) arginine vasopressin receptor subtypes. 3. Radioligand binding displacement assays demonstrated that although arginine vasopressin related peptides displaced both radioligands from renal medullary membranes at low concentrations epidermal growth factor displaced neither. 4. Arginine vasopressin V2 receptor second messenger cyclic adenosine monophosphate (CAMP) production was inhibited by epidermal growth factor (IC₅₀ 2 ± 10^?7 mol/L) as was sodium fluoride cAMP production but only at much higher concentrations. 5. Therefore the diuretic effect of epidermal growth factor is not via direct antagonism of arginine vasopressin receptors but seems mediated via inhibition of the V2 second messenger system.     

INTERACTIONS BETWEEN THE CIRCULATORY EFFECTS OF CENTRAL HYPOVOLAEMIA AND ARTERIAL HYPOXIA IN CONSCIOUS RABBITS

1. Eight conscious rabbits were repeatedly subjected to progressive reduction in central blood volume by gradually inflating a thoracic inferior vena caval-cuff so cardiac index (CI) fell at a constant 8.5% of baseline/min. 2. Caval-cuff inflations were performed after 10 min exposure to 100, 21, 12–14 and 8–10% O₂, with and without the addition of 3–4% CO₂, in randomized order. 3. The haemodynamic response to progressive reduction in central blood volume was biphasic. In Phase I, systemic vascular conductance index (SVCI) fell linearly, supporting mean arterial pressure (MAP). When CI had fallen to a critical level, Phase II occurred in which SVCI rose abruptly, MAP plummeted and respiratory drive progressively increased. 4. During Phase I, there were independent linear relationships between Pao₂ (but not Pao₂) and the rates at which SVCI and MAP changed during the progressive fall of CI. The higher the level of Pao₂, the greater was the rate of fall of SVCI and the less the rate of fall of MAP. 5. There was an inverted U-shaped effect of Pao₂, on the level of CI at which Phase II occurred: (a) during hyperoxia (100% O₂), Phase II occurred later than during normoxia (21% O₂); and (b) across the normoxic and hypoxic gas mixtures (21–8% O₂, with and without added CO₂), there was an independent linear relationship between Pao₂ (but not Pao₂ or Pao₂×Pao₂) and the level of CI at which Phase II occurred. That is, the lower the level of Pao₂, the later was the onset of Phase II. This interaction is best explained by an increased level of central sympathetic vasoconstrictor drive during hypoxia.     

THE INTERACTION BETWEEN ENALAPRILAT AND SELECTED α-ADRENOCEPTOR ANTAGONISTS IN ISOLATED RAT TAIL ARTERIES

1. Isolated perfused rat tail artery preparations were used to investigate the effects of the angiotensin converting enzyme inhibitor enalaprilat on the actions of a series of α-adrenoceptor antagonists. The agonist used was phenylephrine. 2. Enalaprilat (1 μmol/L) potentiated the competitive α₁-adrenoceptor antagonist actions of phentolamine (10–100 nmol/L) and yohimbine (0.3–3.0 μmol/L) as well as the non-competitive antagonist action of phenoxybenzamine (50–100 pmol/L). 3. The competitive α₁-adrenoceptor antagonist action of prazosin (1–10 nmol/L) was not affected by enalaprilat. 4. For the competitive α₁-adrenoceptor antagonists, including prazosin, there appeared to be an inverse relationship between antagonist potency and the extent of potentiation by enalaprilat. 5. The results support the hypothesis and angiotensin II modulates vascular smooth muscle α₁-adrenoceptor function.