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Biomedical subjects

A E Doyle

Publications and source records attributed to A E Doyle.

At least 55 records · Page 3Linked to original sources
PubMed1988

Angiotensins II and III prevent captopril-induced renin release in the rat.

1. The effects of exogenous angiotensins II and III (50 pmol/min i.v.) on plasma renin release following captopril injection (5 mg/kg, i.v.) were studied in anaesthetized Sprague-Dawley rats, to determine whether angiotensin II blockade is the major mechanism by which captopril induces renin release. 2. Captopril produced a 12-fold increase in plasma renin concentration compared with saline-injected controls. This was completely reversed by pre-infusion of angiotensin II or III. 3. The fall in blood pressure following captopril treatment was also abolished by angiotensins II and III pre-infusion. Noradrenaline pre-infusion (200-800 ng/min, i.v.) also prevented the captopril-induced hypotension but did not alter the rise in plasma renin. 4. Ureteric ligation did not significantly reduce captopril-induced renin release suggesting that acute changes in sodium excretion or delivery of electrolyte to the macula densa were not involved in renin release. 5. These findings suggest that captopril induces renin release by inhibiting angiotensin II feedback control of renin secretion and that angiotensin III may also modulate renin release.

Angiotensin II↗
PubMed1988

The relevance of serotonin antagonism in the treatment of hypertension.

The role of serotonin in the pathogenesis of hypertension is not clear. Serotonin is produced by the enterochromaffin cells of the gut; the greater part of this is metabolised in the liver and lungs and nearly all of the remainder is taken up by the platelets. Consequently, circulating levels of serotonin are extremely low. The arterial wall possesses S2-serotonergic receptors, stimulation of which by serotonin leads to vasoconstriction. There are also serotonergic neurons in the central nervous system, particularly in the medulla, which are concerned with the neurogenic control of the circulation. Ketanserin has a high affinity for the S2-receptors, and thus it will antagonise the stimulating effect of serotonin at these receptors. It also has a weaker affinity for alpha 1-adrenoceptors and may act in part by antagonising the pressor effects of norepinephrine, either directly, or indirectly through a link between serotonin S2-receptors and alpha 1-receptors. Experimental evidence suggests that atheromatous lesions lead to increased sensitivity to the vasoconstricting effects of serotonin. This may be due in part to platelet adhesion to areas of endothelial damage, with an associated reduced presence of endothelial relaxing factor. In human hypertension, ketanserin appears to lower blood pressure more effectively in older patients, an effect which may be due to associated atheroma of the aorta and large arteries of these patients. Serotonin antagonism offers a novel approach to the treatment of the hypertensive patient. The increased effectiveness of ketanserin in elderly patients may be of particular importance.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamics↗
PubMed1988

Why are the antihypertensive effects of ketanserin age-related?

Ketanserin induces larger falls of blood pressure in patients above the age of 60 years, both following acute intravenous and chronic oral administration. Although there is no clear explanation for these findings, it is possible that the age-related effects of ketanserin are due to antagonism of serotonin-induced vasoconstriction occurring in elderly patients with atheroma.

Adult↗
PubMed1988

Do hybrid drugs offer an additional benefit over pure alpha 1-blockade for hypertensive patients?

Alpha-blocking drugs, although effective antihypertensive agents, often cause tachycardia, faintness and postural hypotension. Hybrid drugs such as labetalol, which has beta- as well as alpha-blocking action, ketanserin, which has 5-hydroxytryptamine (5HT)-blocking as well as alpha-blocking action, and urapidil, which appears to have a central effect as well as an alpha-blocking action, produce fewer side effects attributable to alpha-blockade. Urapidil appears to be an effective antihypertensive drug with a wide spectrum of action and few side effects.

Adrenergic alpha-Antagonists↗
PubMed1987

Rapid eye movement sleep and the associated cardiovascular changes during and after continuous 10-day infusion of clonidine in normotensive rats: comparison with lofexidine and S3341.

The centrally acting alpha-adrenoceptor agonists clonidine, lofexidine, and S3341 vary in their selectivity for the alpha 2-adrenoceptor subtype (S3341 greater than clonidine greater than lofexidine). The aim of this study was to examine the frequency and duration of rapid eye movement (REM) sleep episodes, and the cardiovascular changes associated with these episodes, during and after the continuous (10-day) infusion of saline (0.9% wt/vol), clonidine (10 micrograms/kg/h), lofexidine (10 micrograms/kg/h), or S3341 (50 or 100 micrograms/kg/h) in unrestrained, chronically instrumented rats. During a typical 24-h period, the saline infusion animals (n = 4) had 46 +/- 3 REM sleep episodes of 2.4 +/- 0.1 min duration. The majority of these episodes were associated with relatively minor phasic and tonic changes in arterial blood pressure and heart rate. During infusion, the three drugs markedly reduced the cardiovascular and behavioural signs of REM sleep. On cessation of the clonidine and lofexidine infusions, rebound increases (i.e., to values greater than controls) in the frequency and duration of REM sleep episodes were observed. These episodes were associated with markedly exaggerated fluctuations in arterial blood pressure and heart rate. The REM sleep rebound and associated cardiovascular responses were greater during the post-lofexidine infusion phase. A relatively minor rebound increase in total REM sleep time was observed after cessation of the 100-micrograms/kg/h, but not the 50-micrograms/kg/h, infusion rate of S3341. The cardiovascular responses during the REM sleep episodes were mildly exaggerated after cessation of the higher infusion rate of S3341.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

The Australian Therapeutic Trial in Mild Hypertension.

In the Australian Therapeutic Trial in Mild Hypertension treated patients had significantly lower cardiovascular mortality and a significantly lower incidence of cerebrovascular complications than patients given placebos. There was, however, no difference in the incidence of nonfatal myocardial infarction or other new manifestations of ischaemic heart disease. Although the evidence of benefit from treatment was clear-cut, the number of cardiovascular complications in the control group was small. This was due to several factors. Patients admitted to the trial had no preceding evidence of cardiovascular complications, the blood pressure fell spontaneously to below 95 mm Hg in almost half the control group, and patients whose blood pressures rose to levels above 110 mm Hg were given treatment, but remained in the placebo group for analysis. In both treated and placebo groups, trial end-points occurred more frequently in persons whose average diastolic blood pressure during the study remained raised. Ischaemic heart disease and many cases of stroke are due to atherosclerotic arterial disease. This appears not to be favourably influenced by antihypertensive drug therapy.

Adult↗
PubMed1986

Usefulness of early exercise testing after non-Q-wave myocardial infarction in predicting prognosis.

The value of an early symptom-limited maximal exercise test in predicting coronary anatomy, left ventricular ejection fraction and hemodynamics was assessed prospectively in 64 patients after an acute non-Q-wave myocardial infarction (MI). Exercise tests and cardiac catheterization were performed at a median of 6 and 7 days, respectively, after non-Q MI. Forty-one percent of the patients had a negative exercise test response (no angina, less than 1 mm of ST depression and normal blood pressure responses). Twenty-five percent had a positive response (1 to 1.9 mm of ST depression or angina); 34% had a "strongly positive" exercise test response (at least 2 mm of ST depression or abnormal blood pressure responses). A negative response predicted the absence of 3-vessel disease (at least 70% stenosis) or critical stenoses (at least 90% stenosis) involving major coronary arteries (negative predictive accuracy 92%), whereas a strongly positive response predicted their presence (positive predictive value 77%, specificity 88%). Cardiac index and mean pulmonary artery wedge pressure did not vary significantly among the 3 exercise groups, whereas left ventricular ejection fraction was slightly higher in the exercise test group with a positive response (p less than 0.025). Thus, in patients who have had a non-Q MI, early exercise testing can be used to predict the extent and severity of coronary artery disease, and the decision to perform coronary angiography should be guided by the exercise test results.

Adult↗
PubMed1986

Comparison of calcium antagonists with other antihypertensive agents.

The demonstration that antihypertensive drug treatment reduces mortality and morbidity in persons with mild hypertension has extended the indications for treatment. Verapamil, nitrendipine, angiotensin converting enzyme inhibitors and beta-adrenoceptor blocking drugs are equally effective in reducing blood pressure. The choice of which drug to use depends on the presence or absence of specific contraindications and the occurrence of adverse effects in the individual patient.

Adrenergic beta-Antagonists↗
PubMed1986

Pressor sensitivity to angiotensin I and angiotensin II during the development of experimental renal hypertension in the rat.

Treatment with the potent angiotensin converting enzyme inhibitor perindopril completely prevented any rise in blood pressure in the 2-kidney, 1-clip (2K1C) model of renal hypertension in rats. Withdrawal of this inhibitor was followed by a slow rise in blood pressure. In 2K1C rats treated with perindopril, pressor responses to angiotensin I fell during the treatment period, but returned to normal after the inhibitor was stopped. Pressor responses to angiotensin II (AII) increased during treatment with perindopril; this was presumably due to increased receptor sensitivity consequent on the falls in endogenous AII levels. Responses to AII fell to control levels after the inhibitor was stopped. It is concluded that an increased pressor sensitivity to AII is not the cause of the slowly developing hypertension in the 2K1C model of hypertension, and that the slow pressor response to AII must be due to other factors.

Angiotensin I↗
PubMed1986

Accelerated progression of diabetic nephropathy in the spontaneously hypertensive streptozotocin diabetic rat.

Streptozotocin (STZ)-diabetes was induced in spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats with their litter mates serving as controls. The animals were studied for 6 months and blood pressure, weight, urinary and serum glucose, creatinine clearance, total proteinuria and albuminuria were measured monthly. With induction of diabetes, there was a significant rise in creatinine clearance in the hypertensive diabetic animals (SHR-STZ). SHR-STZ (n = 6) developed higher levels of total proteinuria than WKY-STZ (n = 5) although the rise from basal levels was only apparent after 20 weeks of diabetes. All SHR-STZ developed albustix positive proteinuria after 6 months of diabetes. In the first 12 weeks after onset of diabetes, albuminuria increased to a greater degree in SHR-STZ than in WKY-STZ. This occurred before there was a detectable rise in total proteinuria. The SHR-STZ model of genetic hypertension and diabetes may be suitable for the evaluation of antihypertensive therapy in human diabetic renal disease.

Albuminuria↗
PubMed1986

Renal haemodynamics and total body sodium in immature spontaneously hypertensive and Wistar-Kyoto rats.

We have investigated the renal haemodynamics and sodium metabolism in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats during the first 10 weeks of life. Using constant infusion clearance measurements of 51Cr-EDTA and 125I-hippuran in unrestrained, conscious, 4-week-old rats we found a significant reduction in glomerular filtration rate (GFR) and renal blood flow (RBF), respectively, in SHR compared with WKY. The arterial blood pressure (BP) and renal vascular resistance were also significantly elevated in SHR at this age. Acute oral treatment with hydralazine increased SHR GFR and RBF to equal that of WKY, but acute angiotensin converting enzyme inhibition with oral MK 421 caused the GFR and RBF of SHR to exceed that of WKY. In addition, the plasma renin activity of 4-week-old SHR was significantly elevated compared with WKY. Total body sodium was measured from 1 to 10 weeks of age by determining the whole-body radioactivity of rats equilibrated on 22Na-labelled NaCl of constant specific activity. Indirect blood pressure and sodium intake were measured from weeks 4 to 10 inclusive. Relative sodium retention was observed in SHR both before and during the early developmental phase of hypertension. The sodium intake and BP of SHR were consistently higher than WKY throughout weeks 4 to 10. We propose that increased renal vascular resistance in immature SHR alters the pressure natriuresis relationship to cause sodium retention, with the subsequent development of hypertension.

Animals↗
PubMed1986

Evaluation of verapamil in the treatment of hypertension.

Two separate randomized double-blind, crossover trials were carried out in hypertensive patients to evaluate the antihypertensive efficacy and safety of verapamil. In the first study, verapamil, in doses of 120 mg three times daily, was compared with pindolol, in doses of 7.5 mg twice daily. A thiazide diuretic was given with both drugs. In another study, verapamil, in doses of 160 mg twice daily, was compared with 200 mg twice daily of labetalol in hypertensive patients with coexisting chronic obstructive lung disease. Blood pressure fell equally with these drugs, and neither of the drugs caused significant side effects. Labetalol significantly reduced both forced expiration volume at 1s (FEV1) and forced vital capacity (FVC), suggesting a bronchoconstrictor effect. Verapamil was devoid of any such effect. Verapamil did not affect plasma renin concentration.

Adult↗
PubMed1985

Cardiovascular morbidity and mortality in mild hypertension: the Australian Trial.

The Australian Therapeutic Trial in Mild Hypertension was a controlled trial in which mildly hypertensive patients, aged between 35 and 65 years (diastolic blood pressure 95-109) were randomly assigned to take antihypertensive drugs or matched placebos for periods of up to 6 years. The overall data showed that the treated group had a lower incidence of both death and of nonfatal cardiovascular events. The differences in the incidence of noncardiovascular deaths did not differ significantly between the two groups. Univariate analysis of possible prognostic factors at the time of entry into the study showed a higher incidence of trial endpoints--mostly events due to ischemic heart disease and cerebrovascular disease--in older subjects, men, cigarette smokers and those with higher systolic blood pressures, and in thinner subjects than in others. There was a lower incidence of these events in actively treated persons than in control subjects at each level of incidence of each covariate measured. Treatment benefit was greatest in persons with lower systolic blood pressures and lower serum cholesterol levels. Multivariate regression analyses confirmed that the incidence of trial endpoints increased with age and with systolic blood pressures. There was a higher incidence in smokers than in nonsmokers, especially in those with low body weights. Treatment benefited thin smokers most, and the effects of treatment seemed to be reduced in those with higher serum cholesterol levels. There was a substantial fall in blood pressure in many of the placebo group.

Adult↗
PubMed1985

Comparison of calcium antagonists with other antihypertensive agents.

The demonstration that antihypertensive drug treatment reduces mortality and morbidity in mild hypertension has extended the indications for treatment. Verapamil, nitrendipine, angiotensin converting enzyme inhibitors and beta-adrenoceptor blocking drugs are all equally effective in reducing blood pressure. The choice of drug depends on the presence or absence of specific contra-indications and the occurrence of side effects in individual patients.

Adrenergic beta-Antagonists↗