Treating hypertension in older patients.
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Age Factors↗
Biomedical subjects
A E Doyle
Publications and source records attributed to A E Doyle.
Role of angiotensin-converting enzyme inhibitors in preventing or reducing end-organ damage in hypertension.
Angiotensin-converting enzyme inhibitors have been shown to be effective therapy for hypertension, and also for severe congestive heart failure, whether due to hypertension or to other causes. The reduction in cardiac hypertrophy that follows the use of these drugs is undoubtedly due in part to their favorable hemodynamic effects of reducing peripheral resistance and inducing venodilation. The same factors reduce cardiac dilation and left ventricular remodeling after myocardial infarction. The prevention of the hemodynamic effects of angiotensin II (Ang II) is probably the major factor in preventing end-organ damage, but there are some indications that Ang II may have an effect independent of blood pressure in promoting vascular hypertrophy. The separation of vasoconstrictor effects from any metabolic effects of Ang II is not easy, and final elucidation of the mechanisms involved is not yet available.
Angiotensin-Converting Enzyme Inhibitors↗
Hypertension and vascular disease.
The use of antihypertensive drug treatment has altered the natural history of hypertension. Whereas congestive heart failure, cerebral hemorrhage, and renal failure were the major complications of untreated severe hypertension, myocardial infarction and thrombotic stroke have emerged as major problems in treated hypertensive patients. None of the major therapeutic trials in hypertension have provided evidence that reducing blood pressure reduces the risk of atherosclerotic complications of hypertension. Hypertension certainly aggravates the severity of atheromatous lesions in experimental animals, and may do so in humans. However, atherosclerosis is more closely related to disturbances in lipoprotein metabolism than to other factors. The common finding that serum cholesterol is raised in hypertensive patients may be due to atherosclerosis being the primary lesion, and hypertension a secondary complication rather than hypertension being the primary lesion.
Antihypertensive Agents↗
Hypertension and vascular disease.
The use of antihypertensive drug treatment has altered the natural history of hypertension. Whereas congestive heart failure, cerebral hemorrhage, and renal failure were the major complications of untreated severe hypertension, myocardial infarction and thrombotic stroke have emerged as the major problems in treated hypertensives. None of the major therapeutic trials in hypertension have provided evidence that reducing blood pressure reduces the risk of atherosclerotic complications of hypertension. Hypertension certainly aggravates the severity of atheromatous lesions in experimental animals and, thus, may do so in humans. However, atherosclerosis is more closely related to disturbances in lipoprotein metabolism than to other factors. The common finding that serum cholesterol is raised in hypertensive patients may be due to atherosclerosis being the primary lesion, with the hypertension as a secondary complication rather than the primary lesion.
Arteriosclerosis↗
Sir Horace Smirk. Pioneer in drug treatment of hypertension.
Sir Horace Smirk deserves much of the credit for establishing the benefits of reducing blood pressure. He was one of the main early proponents of the idea that it was the raised intra-arterial pressure itself that caused many of the cardiac and vascular complications of hypertension. His training in both pharmacology and internal medicine enabled him to devise practical methods for successful treatment of hypertension with ganglion blocking drugs such as hexamethonium. The major clinical benefits that followed such drug treatment proved a great stimulus to the development of drugs with fewer disadvantages and to widespread acceptance of the beneficial effects of antihypertensive drug treatment.
Antihypertensive Agents↗
Age-related effects of 5-HT2 antagonists.
Ketanserin, an S2 antagonist, has been shown to be an effective antihypertensive drug. Carefully controlled clinical trials have demonstrated that ketanserin is as effective as both metoprolol and thiaside diuretics in reducing blood pressure. However, unlike the beta-blocking drug metoprolol and the diuretics, the response rate to ketanserin is significantly greater in older patients, reflecting perhaps the greater vasoconstrictor effects of 5-hydroxytryptamine in patients with atherosclerotic disease. This enhanced vasoconstrictor response to serotonin in elderly patients may be matched by an increased effect on platelet aggregation, which is also blocked by ketanserin. There is very suggestive evidence from the PACK study that ketanserin may reduce vascular thrombotic episodes in patients with extensive atherosclerosis. This unique characteristic, combined with effectiveness as an antihypertensive agent, makes ketanserin a particularly useful drug in the treatment of elderly patients with hypertension and vascular disease.
Adult↗
Serotonin antagonists and vascular protection.
There is very suggestive evidence for a role of serotonin release from platelets in the mechanisms for platelet aggregation, arterial thrombosis, and arterial spasm. These effects are mediated via the 5HT2 receptor and are specifically antagonized by ketanserin. The recently published PACK study was a randomized controlled trial of the effects of ketanserin in patients with intermittent claudication. The purpose of the trial was to discover whether ketanserin treatment would reduce the incidence of atherosclerotic complications such as myocardial infarction or stroke. An unexpected adverse interaction between ketanserin and potassium-losing diuretics was observed, causing an excess of deaths in the group taking this combination of drugs. The "intention-to-treat" analysis showed no overall difference between ketanserin and placebo in terms of cardiovascular complications. Withdrawal of patients taking potassium-losing diuretics left insufficient numbers of patients in the study to answer the original question. However, the "on-treatment" analysis excluding those taking the combination suggested strongly, although did not prove, that ketanserin reduced thrombotic episodes by about 25%. It is concluded that the risks of interactions between many drugs and potassium-losing diuretics make the use of the latter undesirable. Further studies on ketanserin, possibly combined with thromboxane A2 inhibitors, seem highly desirable.
Animals↗
Nephropathy in model combining genetic hypertension with experimental diabetes. Enalapril versus hydralazine and metoprolol therapy.
We compared the effects of the angiotensin-converting enzyme inhibitor enalapril and a conventional antihypertensive regimen (hydralazine and metoprolol) on kidney function, albuminuria, and glomerular ultrastructure in hypertensive diabetic and nondiabetic rats. Diabetes was induced with streptozocin at 8 wk of age in spontaneously hypertensive (SHR) rats. Antihypertensive drugs were administered in drinking water from the time of induction of diabetes in all groups. Blood pressure reduction was equal in the diabetic and nondiabetic SHR rats receiving either enalapril or hydralazine plus metoprolol. In diabetic SHR rats, there was a rise in serum creatinine after 32 wk, which did not occur in diabetic rats treated with either antihypertensive regimen or in nondiabetic rats. Both drug regimens reduced albuminuria in diabetic and nondiabetic SHR rats to a similar degree. Enalapril and the combination of hydralazine and metoprolol were associated with decreased glomerular basement membrane thickness and glomerular volume in diabetic and nondiabetic SHR rats without significant effect on fractional mesangial volume. Thus, antihypertensive therapy retards the development of albuminuria, glomerular basement membrane thickening, and glomerular hypertrophy in the rat in the presence or absence of diabetes. No specific benefit of angiotensin-converting enzyme inhibition was observed in these hypertensive models of nephropathy. Human studies comparing the effects of different classes of antihypertensive drugs on kidney function, proteinuria, and glomerular morphology are warranted.
Administration, Oral↗
Stroke as a clinical problem in hypertension.
Stroke is a major clinical problem in hypertension. Cerebral hemorrhage has become considerably less frequent since treatment of hypertension has become more widely used. Antihypertensive treatment has also reduced the incidence of lacunar stroke, which is a result of hypertensive vascular disease of small arteries. Cortical cerebral infarction due to embolus from extracranial arterial atheromatous plaques is now the most common clinical cause of stroke. Drug treatment for hypertension has probably not reduced the incidence of this type of stroke. Cigarette smoking is also associated with an increased incidence of stroke; the incidence is related to the amount smoked, and former smokers continue to be at increased risk for up to 10 years.
Animals↗
Smoking as a risk factor for cerebral ischaemia.
To assess whether a rigorous clinical classification, based on computerised tomography, of patients with cerebral ischaemia would identify subgroups at higher or lower risk with respect to cigarette smoking habits, a case-control study was carried out on 422 cases of first-episode cerebral ischaemia matched for age and sex with 422 community-based neighbourhood controls. Patients with ischaemic stroke due to extracranial or intracranial vascular disease were at higher risk from smoking than has previously been reported for stroke (relative risk 5.7, 95% confidence interval 2.8, 12.0) whereas those with stroke due to cardiac emboli had no excess risk associated with smoking (relative risk 0.4 [0.1, 1.8]). After cessation of smoking, the relative risk declined gradually over 10 years, at the end of which time a significant risk was still evident. This finding may imply that the risk incurred by smoking is due mainly to atheroma formation, rather than transient haematological effects. Exposure to smoking by a spouse was an independent risk factor for the whole group of cerebral ischaemia patients (relative risk 1.7 [1.1, 2.6]), but this was not so for smoking by either parent (relative risk 1.2 [0.8, 1.8]). These findings suggest that smoking is a more potent risk factor for the most common form of ischaemic stroke than has previously been appreciated. The persistent nature of the risk even after cessation of smoking and the possible risk associated with passive exposure strengthens public health arguments against smoking.
Adult↗
Enalapril retards glomerular basement membrane thickening and albuminuria in the diabetic rat.
This study has evaluated the effects of the angiotensin converting enzyme inhibitor Enalapril on glomerular ultrastructure and albuminuria in normotensive and hypertensive diabetic rats. Streptozotocin-diabetes was induced in Wistar Kyoto and spontaneously hypertensive rats. Enalapril was administered in drinking water in diabetic normotensive, control hypertensive and diabetic hypertensive rats. Enalapril therapy prevented an increase in glomerular basement membrane thickness in diabetic normotensive, control hypertensive and diabetic hypertensive rats without any significant effect on fractional mesangial volume. Enalapril decreased albuminuria in diabetic normotensive, control hypertensive and diabetic hypertensive rats. Thus, enalapril retards the development of glomerular basement membrane thickening and albuminuria in the rat, in the presence or absence of hypertension.
Albuminuria↗
Effects of continuous infusions (10 days) and cessation of infusions of clonidine and rilmenidine (S 3341) on cardiovascular and behavioral parameters of spontaneously hypertensive rats.
Clonidine is a centrally acting antihypertensive drug that acts in vivo at both alpha 1- and alpha 2-adrenoceptor sites, whereas rilmenidine (S 3341) is more selective for alpha 2 adrenoceptors. The present study compared the effects of continuous 10-day infusions of clonidine (5 micrograms/kg/hour) with those of rilmenidine (100 micrograms/kg/hour) on various cardiovascular and behavioral parameters in the spontaneously hypertensive rat. The changes in these parameters after cessation of the infusions were also compared. At these rates of infusion, clonidine and rilmenidine produced quantitatively similar reductions in mean arterial pressure (MAP), lability of MAP and cardiovascular responsiveness during normal behaviors such as eating and grooming. Neither drug infusion affected heart rate. The cessation of the clonidine infusion resulted in a "withdrawal" syndrome characterized by prominent rapid eye movement-sleep rebound, and cardiovascular and behavioral disturbances including an increased lability of MAP, exaggerated cardiovascular responses during normal behaviors, tachycardia, and an "opiate abstinence-like" syndrome including head and body shakes. Cessation of rilmenidine infusion resulted in somewhat similar cardiovascular and behavioral disturbances, but unlike clonidine there was a return to normal rapid eye movement sleep without rebound.
Adrenergic alpha-Agonists↗
The Australian Tobacco Research Foundation.
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Australia↗
Genetic co-segregation of renal haemodynamics and blood pressure in the spontaneously hypertensive rat.
1. To determine the relevance of renal circulatory abnormalities found in the immature spontaneously hypertensive rat (SHR) to the genetic hypertensive process, glomerular filtration rate and renal blood flow were measured in conscious F2 rats, derived from cross-breeding SHR and normotensive Wistar-Kyoto rats (WKY), at 4, 11 and 16 weeks of age by determining the renal clearances of 51Cr-ethylenediaminetetra-acetate and 125I-hippuran respectively. Plasma renin activity was measured at 11 and 16 weeks of age. 2. Mean arterial pressure, glomerular filtration rate and renal blood flow increased between 4 and 11 weeks of age. Between 11 and 16 weeks the mean glomerular filtration rate and renal blood flow did not alter, although the mean arterial pressure rose significantly. At 11 weeks of age, during the developmental phase of hypertension, a significant negative correlation between mean arterial pressure and both glomerular filtration rate and renal blood flow was noted. However, by 16 weeks when the manifestations of genetic hypertension were more fully expressed, no correlation between mean arterial pressure and renal blood flow or glomerular filtration rate was observed. Plasma renin activity was negatively correlated with both glomerular filtration rate and renal blood flow, but the relationship was stronger at 11 than at 16 weeks of age. 3. These results suggest that the reduction in renal blood flow and glomerular filtration rate, found in immature SHR, is genetically linked to the hypertension and may be of primary pathogenetic importance. It is proposed that the increased renal vascular resistance in these young animals stimulates the rise of systemic arterial pressure which returns renal blood flow and glomerular filtration rate to normal.
Animals↗
Genetic hypertension accelerates nephropathy in the streptozotocin diabetic rat.
To evaluate whether hypertension is a cause or just an association with diabetic renal disease, diabetes was induced in both normotensive Wistar-Kyoto and spontaneously hypertensive rats (WKY and SHR). Animals were assessed monthly for 8 months before sacrifice. When compared to normotensive diabetic rats (WKY-STZ), hypertensive diabetic rats (SHR-STZ) had an earlier and more rapid rise in urinary albumin excretion. In addition, SHR-STZ had increased glomerular basement membrane thickness when compared to WKY-STZ or SHR. In a separate experiment, Enalapril therapy (35 mg/L) was administered in drinking water to WKY-STZ and SHR-STZ. Enalapril significantly reduced blood pressure in both animal groups, and this was associated with a decrease in urinary albumin excretion. The SHR-STZ model has accelerated nephropathy as determined by both functional and structural parameters. Angiotensin-converting enzyme inhibition is associated with a reduction in albuminuria in both hypertensive and normotensive models of diabetic nephropathy.
Albuminuria↗
Does hypertension predispose to coronary disease? Conflicting epidemiological and experimental evidence.
Hypertension is associated with an increased risk of coronary events. Treatment of hypertension in controlled trials has not reduced the incidence of coronary events, although the risk of stroke is reduced. In untreated hypertension, about one-half the deaths were due to hypertensive heart failure, whereas myocardial infarction caused 10%-12% of deaths. In treated hypertension, coronary events cause about 40% of deaths. Although in autopsy serious coronary atherosclerosis is commonly found in hypertension, in severe hypertension, dilated coronary vessels free of atheroma were a common finding. No correlation was noted between the height of blood pressure and degree of coronary atherosclerosis. The relationship between coronary disease and hypertension is consistent with an association between them rather than hypertension being a causal factor. The factors that cause acute myocardial infarction may differ from those which predispose to coronary atherosclerosis.
Coronary Disease↗
Institutional and home-based long-term care alternatives: the 1965-1985 Swedish experience.
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Aged↗
Effects of genetic hypertension on diabetic nephropathy in the rat--functional and structural characteristics.
Streptozotocin (STZ) diabetes was induced in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Body weight, blood pressure, renal function, glycaemic control and proteinuria were assessed monthly for 32 weeks. At 32 weeks, the animals were killed and glomerular basement membrane (GBM) thickness and fractional mesangial volume were measured. There was no significant difference in renal function between diabetic SHR and diabetic WKY. Diabetic SHR showed an earlier and larger rise in total proteinuria and urinary albumin excretion than diabetic WKY. Urinary albumin excretion was increased more than tenfold in diabetic SHR compared to diabetic WKY after 32 weeks of diabetes. GBM thickness was significantly increased in diabetic SHR compared with diabetic WKY. Both diabetic WKY and diabetic SHR showed mesangial expansion when compared to their nondiabetic counterparts. On the other hand, both hypertensive models showed increased glomerular volume, which was not influenced by the presence of diabetes. The diabetic SHR model has features of accelerated nephropathy, as evidenced by increased albuminuria and GBM thickness. This suggests that pre-existing hypertension may play an important role in the progression of diabetic renal disease.
Animals↗