ENDOGENOUS VASOPRESSIN MODULATES THE BAROREFLEX SENSITIVITY IN RATS

The effect of endogenous vasopressin on the baroreceptor reflex has been examined by comparing baroreflex function in Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI rat) with that in Long-Evans rats (LE rat). Baroreflex function was assessed in conscious unrestrained rats during increases in blood pressure with phenylephrine. The slope of the baroreflex function line in LE rats [(19.0, s.e.m. = 1.4) X 10(-4), n = 34] was significantly steeper than that in DI rats [(6.9, s.e.m. = 0.6) X 10(-4), n = 44, P less than 0.0001]. A subpressor infusion of arginine8-vasopressin (2 ng/kg per min for 2 h i.v.) and an equidose of DDAVP caused bradycardia and increased the baroreflex function slope significantly. Acute volume expansion in DI rat did not change the baroreflex sensitivity. A specific vasopressin vascular receptor antagonist, d(Ch2)5Tyr(Me)AVP, did not alter the baroreflex sensitivity in LE rats. These results suggest that endogenous vasopressin is an important physiological regulator of the baroreflex sensitivity in normal rats.     

VASCULAR LESIONS AND ANGIOTENSIN IN MALIGNANT HYPERTENSION IN THE ABSENCE OF VASOPRESSIN

1 Vasopressin deficient homozygous Brattleboro rats develop malignant renal hypertension following complete aortic-ligature between the renal arteries. 3 The levels of PRA and AH in the malignant hypertensive Brattleboro rats were not different from those in Long-Evans rats with malignant hypertension.     

PREVENTION OF ARTERIAL DISEASE IN EXPERIMENTAL RENAL HYPERTENSION

1. This study examined the effect of various antihypertensive agents on the development of polyarteritis nodosa lesions along the mesenteric artery system over a 10 week period after renal artery clipping in uninephrectomized rats (lKlC). 2. Of the agents, only hydralazine, enalapril and diltiazem significantly inhibited systolic blood pressure (SBP) rise over the 10 week period (P less than 0.001). 3. All agents except hydralazine reduced the severity of arteritic lesions compared with lKlC rats, but only with enalapril (P less than 0.001), nifedipine (P less than 0.001), diltiazem (P less than 0.005), propranolol (P less than 0.001) and reserpine (P less than 0.05) was this reduction statistically significant. 4. There was a positive correlation between the degree of arteritic change and SBP, but the correlation coefficient was neither high (r = 0.68) nor highly significant (P = 0.03, d.f. = 9). On examining the data, this was due on the one hand to nifedipine, propranolol and reserpine reducing the severity of lesions without significantly inhibiting SBP, and on the other to hydralazine reducing SBP without significantly affecting the extent of arteritic change. 5. These findings suggest that factors other than mere SBP alone are involved in the pathogenesis of these arteritic lesions.     

SYSTEMIC AND REGIONAL HAEMODYNAMICS IN EXPERIMENTAL RENAL HYPERTENSION IN CONSCIOUS RABBITS

1. The radioactive microsphere method was used to measure the distribution of cardiac output, regional flows and resistances in conscious normotensive and hypertensive rabbits implanted with an electromagnetic flow probe on the ascending aorta or pulmonary artery. Hypertension was induced by wrapping one kidney with cellophane and removing the other, and studies were performed about 5 weeks later. 2. Heart rate, stroke volume, cardiac output and total renal mass were reduced in the hypertensive animals, while the weight of, and the cardiac output distribution to left ventricle and the remaining kidney were increased. 3. In renal hypertensive rabbits, the weight normalized regional blood flow was diminished in a number of tissues, including the kidney, and, except for some organs in the splanchnic area (stomach, small intestine, mesentery and pancreas) and the fat, there was a rather uniform increase in tissue vascular resistance.     

IMPORTANCE OF ENDOGENOUS VASOPRESSIN IN THE HYPERTENSIVE AND BRADYCARDIC RESPONSE TO CENTRAL α1-ADRENERGIC STIMULATION

To determine the interaction between alpha 1-adrenergic and vasopressinergic mechanisms in the central regulation of cardiovascular functions, the effects of intracerebroventricular (i.c.v.) administration of the alpha 1-agonists, methoxamine and phenylephrine, were examined in conscious Long-Evans (LE) rats and Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI). In LE rats, i.c.v. methoxamine and phenylephrine (3-30 micrograms/kg) increased blood pressure and decreased heart rate in a dose-related manner, while they had no detectable cardiovascular effects in DI rats. Neither i.c.v. (0.5 ng/kg per min, 1 h) nor intravenous (i.v., 2 ng/kg per min, 2 h) infusion of vasopressin (AVP) restored the cardiovascular response to i.c.v. phenylephrine in DI rats. In LE rats, however, i.v. pretreatment with the specific antagonist to the pressor effect of AVP, d(CH2)5Tyr(Me)AVP (10 micrograms/kg), attenuated the hypertensive and bradycardic effects of i.c.v. phenylephrine, while i.c.v. pretreatment with AVP antagonist (300 ng/kg) did not alter the cardiovascular response to i.c.v. alpha 1-agonist. The cardiovascular response to i.c.v. phenylephrine was blocked by i.c.v. pretreatment with the alpha 1-antagonist, prazosin (2 micrograms/kg). Intracerebroventricular phenylephrine increased plasma AVP levels 14-fold without affecting plasma angiotensin II levels. The present study clearly demonstrated that endogenous AVP plays a significant role in the cardiovascular response to i.c.v. alpha 1-agonist.     

SAMPLE SIZE REQUIREMENTS FOR CLINICAL TRIALS OF ISOLATED SYSTOLIC HYPERTENSION

1. This study investigated components of blood pressure variability in elderly subjects with isolated systolic hypertension (ISH) using both ambulatory blood pressure monitoring (ABPM) and casual clinic blood pressure measurement. These were then used to determine sample size requirements for clinical trials of different designs. 2. Eleven elderly subjects not receiving antihypertensive medication were seen on four occasions at weekly intervals. On each occasion blood pressure was measured in the clinic and then for 24 h using a non-invasive ABPM device. Nested analysis of variance was used to calculate the 'between subject' and 'between subject within occasion' components of blood pressure variability. 3. Increasing the number of readings or occasions where measurement was performed in a parallel group trial only reduced the variability substantially when the number of subjects involved was less than 50. Use of a cross-over design substantially reduced the sample size required. 4. ABPM appears most useful as a strategy for reducing sample size in parallel group trials in ISH involving small numbers of subjects measured on one occasion.     

IS ISOLATED SYSTOLIC HYPERTENSION A WHITE COAT’ PHENOMENON IN THE ELDERLY?

1. Repeated clinic blood pressure measurement was compared with non-invasive ambulatory blood pressure (ABP) monitoring in 10 elderly subjects with isolated systolic hypertension (ISH) and 11 normotensive controls (NT). 2. Subjects were assessed on four occasions at weekly intervals. None was receiving antihypertensive or vasoactive medication. 3. Mean clinic blood pressure was consistently higher than mean daytime ABP in both clinical groups. This effect was greater for systolic (SBP) than diastolic blood pressure (DBP) and in the ISH group compared with the NT group. The reproducibility of the clinic minus ABP difference was high in both groups; the mean +/- s.d. of the differences was 26 +/- 15/9 +/- 2 mmHg in the ISH group and 7 +/- 18/8 +/- 9 mmHg in the controls. 4. ABP readings were normally distributed for both SBP and DBP in both groups. In the ISH group, the frequency distribution of SBP readings was shifted to the right whilst the distribution of DBP readings overlapped that of the NT subjects. 5. These results suggest a pressor response may largely account for the elevated SBP seen in elderly subjects with sustained ISH based on casual readings.     

ISOLATED SYSTOLIC HYPERTENSION: DOES IT REALLY EXIST ON AMBULATORY BLOOD PRESSURE MONITORING?

1. The diagnosis of isolated systolic hypertension, diastolic hypertension and normotension in elderly subjects, as defined by casual office blood pressure measurement, was compared with 24 h ambulatory blood pressure monitoring using an Accutracker II. 2. Mean day-time ambulatory blood pressure monitoring underestimated the casual systolic blood pressure in all three clinical groups. Diastolic pressure was not underestimated to the same extent. 3. Ambulatory blood pressure monitoring best reflected casual blood pressure determination for normotensive subjects. In subjects with isolated systolic hypertension ambulatory blood pressures were only consistent with that diagnosis for 8% of the day time period. For 34% of the day time, their ambulatory blood pressures were consistent with diastolic/mixed hypertension. 4. It is concluded that isolated systolic hypertension may not be a sustained condition, but rather an isolated response to office measurement of blood pressure.     

IMPORTANCE OF CENTRAL SEROTONIN NEURONS IN THE HYPOTENSIVE ACTION OF METHYLDOPA IN THE RAT

1. Normotensive (WKY) and stroke prone spontaneously hypertensive (SHR-SP) rats were given methyldopa (200 mg/kg i.p.) daily for five days and their brains were then sectioned and processed with the Faglu method for catecholamine fluorescence. 2. This treatment with methyldopa induced a green fluorescence not seen in control animals, in cells coinciding with the B1–B9 groups of serotonin neurons in the brainstem. 3. Pretreatment with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT, i.c.v.), which is relatively specific for serotonin neurons, prevented the appearance of this green fluorescence in the serotonin cell groups of rats given methyldopa. 4. Pretreatment with 5,7-DHT, i.c.v. approximately halved the magnitude of the hypotensive response to a single dose of methyldopa (80 mg/kg i.p.). 5. We suggest that central serotonin nerves contribute to the hypotensive action of methyldopa. 6. It is our hypothesis that methyldopa is taken up by these serotonin cells and that the green fluorescence reflects the production of α-methyldopamine, as a result of decarboxylation by the ubiquitous enzyme, L-aromatic amino acid decarboxylase.     

GENES OF STRESS IN EXPERIMENTAL HYPERTENSION

1. A significant portion of blood pressure variance is modified by the environment. 2. The present report summarizes evidence that: (i) the environmental response is genetically determined; (ii) various stressors can evoke a differential response in hypertensive animals and constitute its intermediate phenotypes; (iii) the response to heat stress can be assigned to a single ‘thermosensitivity’ locus; (iv) candidate genes of susceptibility to environmental stresses are member(s) of the heat stress gene (HSP) gene families; (v) a restriction fragment length polymorphism ofhsp70 and a single base mutation in the 3′-untranslated region of hsp27 are associated with hypertension in recombinant inbred strains. 3. In conclusion, HSP gene variants may be causative in susceptibility to hypertension.     

THE EFFECT OF RENAL DENERVATION ON ACTH-INDUCED HYPERTENSION IN SHEEP

1. The effect of renal denervation on ACTH-induced hypertension in sheep has been examined. 2. Both intact and renally denervated sheep showed similar rises in blood pressure following ACTH treatment. 3. Following renal denervation, the initial urinary sodium retention and ACTH-withdrawal natriuresis typical of ACTH administration in intact sheep were absent, and the fall in blood pressure was delayed.     

ROLE OF THE RENIN-ANGIOTENSIN SYSTEM IN HYPERTENSION PRODUCED BY UNILATERAL RENAL ARTERY CONSTRICTION IN THE RAT

1. Conscious rats which had undergone unilateral renal artery constriction were infused for 1 h with a specific antagonist of angiotensin II, 1-Sar-8-Ala-angiotensin II (P-113). 2. There was a highly significant correlation between the change in blood pressure induced by P-113 and the pre-infusion plasma renin concentration (PRC), regardless of initial blood pressure or the duration of stenosis. However, the blood pressure fall was not significantly greater in nineteen hypertensive rats than in eleven which remained normotensive. P-113 did not abolish the hypertension. 3. The extent to which angiotensin II supports blood pressure in rats with renal artery constriction is directly related to the PRC.     

A RANDOMIZED CONTROL TRIAL OF A VEGETARIAN DIET IN THE TREATMENT OF MILD HYPERTENSION

The effect of an ovo-lacto-vegetarian (OLV) diet on blood pressure was assessed in a randomized, controlled, crossover trial in 58 mild untreated hypertensive subjects recruited from the Perth Centre for the 1983 NHF Risk Factor Prevalence Survey. Subjects were randomly allocated to one of three groups; the first maintained their usual diet throughout 12 weeks; the other two were given an OLV diet for either the first or second 6 weeks of the 12-week trial. Introduction of an OLV diet was associated with a significant fall in systolic blood pressure, on average of the order of 5 mmHg, which was unrelated to change in urinary sodium, potassium or body weight. It was concluded that a vegetarian diet may have an adjunctive role in control of mild hypertension, but that in view of likely problems with acceptability those dietary components responsible for the blood pressure differences need to be identified.     

ACTH HYPERTENSION IN THE RAT: ROLE OF KIDNEY AND GONADS

1. Adrenocorticotrophin (ACTH) administration produces an adrenally dependent rise in blood pressure in rats. 2. The haemodynamic and metabolic effects of ACTH were examined in nephrectomized, 5/6 nephrectomized and orchidectomized male Sprague-Dawley rats and sham operated controls. 3. Reduction in renal mass did not increase the blood pressure rise produced by ACTH. 4. Gonadectomy did not reduce the blood pressure rise produced by ACTH, which was slightly higher in castrated animals.     

EFFECTS OF PROPRANOLOL ON DEVELOPMENT AND MAINTENANCE OF SEVERE RENAL HYPERTENSION IN RATS

1. The effect of chronic administration of propranolol on the development and maintenance of severe renal hypertension in rats subjected to unilateral renal artery constriction was studied in relation to possible changes in peripheral PRA and the blood and tissue levels of propranolol. Propranolol was administered s.c. twice daily in doses of 1, 10 and 25 mg/kg, starting 2 days before operation. 2. Contrary to expectations, not only did the initial rise in systolic blood pressure become accelerated, but the established level of hypertension attained in the propranolol treated rats was of the same severity as that attained in placebo treated rats. Moreover, the progressive rise in peripheral plasma renin activity following unilateral renal artery constriction was not affected by propranolol administration. 3. The same doses of propranolol were also administered daily for 8 days to rats with established severe hypertension. A slight further rise in blood pressure occurred initially, followed by a moderate decrease of 15–25 mmHg. Propranolol failed to exert this minor hypotensive effect in hypertensive rats treated concomitantly with furosemide. No suppressive effect on the markedly increased levels of plasma renin activity was observed in these severely hypertensive rats in the presence or absence of furosemide administration. 4. These results indicate that in severely renal hypertensive rats propranolol has only a minor hypotensive effect and no blocking action on renin release under the conditions of study.     

RENAL HYPER-RESPONSIVENESS TO BLOOD VOLUME EXPANSION IN BRATTLEBORO RATS IS NOT RELATED TO PLASMA ANF IMMUNOREACTIVITY

1. Anaesthetized homozygous Brattleboro (DI) rats were used to study the renal response to iso-oncotic blood volume expansion. 2. With the same degree of hypervolaemia DI rats had exaggerated diuresis, natriuresis, and chloriuresis, but not kaliuresis, compared with heterozygous control rats. This increased excretion resulted in negative water balance by the end of the experiment in DI rats, whereas the controls showed restoration of normal balance. The control rats retained significant amounts of sodium and chloride, the Brattleboro rats, however, did not. 3. The lithium clearance method was used to localize the defect in sodium reabsorption. As judged from this method, there was a significantly lower sodium reabsorption in the proximal tubules as well as in the distal parts of the nephron of DI rats. 4. Plasma immunoreactivity of atrial natriuretic factor (ANF) was not different between groups before volume expansion. ANF levels rose and fell similarly in both groups during and after the iso-oncotic infusion. 5. Our results demonstrate that DI rats respond to acute hypervolaemia with an exaggerated diuresis and saluresis. The mechanism of the increased salt excretion may involve inhibition of sodium transport in the proximal tubules as well as in the distal parts of the nephron. These transport defects are not dependent on differing plasma ANF levels.