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Biomedical subjects

T D Giles

Publications and source records attributed to T D Giles.

At least 73 records · Page 4Linked to original sources
PubMed1989

Myocardial disease in hypertensive-diabetic patients.

Experimental and clinical evidence points to the existence of a cardiomyopathy associated with diabetes mellitus that is not due to coronary atherosclerosis. The condition is characterized by distinct clinical presentations and physiologic and biochemical abnormalities. Potential mechanisms for the development of diabetic cardiomyopathy are complex but are probably associated, in part, with hyperglycemia and hyperlipidemia. Primary hypertension is also associated with the development of myocardial abnormalities. Many of these changes are similar to those seen in diabetic cardiomyopathy. It is now clear that the co-existence of hypertension and diabetes mellitus produces a more severe cardiomyopathy than that produced by hypertension or diabetes alone. Potential mechanisms for interaction are numerous. Treatment of hypertension in diabetic patients must be targeted to more specific needs. Antihypertensive drugs should not worsen cardiac risk factors or glucose control and should have favorable effects on left ventricular function. The calcium antagonists and angiotensin-converting enzyme inhibitors have pharmacologic profiles that make them attractive as monotherapy for diabetic patients.

Animals↗
PubMed1989

Interactions between circulating peptides and the central nervous system in hemodynamic regulation.

Enkephalins and endothelins are endogenous peptides, which, at least at pharmacologic doses, produce complex hemodynamic responses after intravenous administration. The enkephalins, when injected into conscious animal models and humans, increase blood pressure, heart rate and minute ventilation. This response occurs by activation of specific opiate receptors located outside the bloodbrain barrier; the actual mechanism involves an increase in adrenergic autonomic nervous system tone and a decrease in cholinergic tone. These opiate receptors may activate afferent fibers, perhaps nicotinic cholinoceptors; in many ways their properties are suggestive of chemoreceptors. Furthermore, enkephalin responses appear to be modulated by gamma-aminobutyric acid complexes, in that the reversal of the excitatory hemodynamic responses seen in the conscious state to vasodepressor responses after barbiturate anesthesia may result from alteration of the state of activation of the gamma-aminobutyric acid complex. The enkephalin receptors are localized to the vertebral artery vascular distribution; the specific site may be the area postrema, a blood-brain barrier-deficient circum-ventricular organ demonstrated to modulate heart rate and blood pressure and to represent a target site for circulating angiotensin II. Endothelin increases heart rate and blood pressure when infused slowly into conscious or anesthetized dogs, although barbiturates do blunt the increase in heart rate. The mechanism appears to involve modification of autonomic tone, but also some element of direct vasoconstrictor activity. Interestingly, rapid bolus doses of endothelin produce only vasodepressor responses, suggesting that the rate and concentration at which circulating endothelin reaches afferent receptors or vasoconstrictor sites on vascular smooth muscle may determine the net hemodynamic response observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Short- and long-acting angiotensin-converting enzyme inhibitors: a randomized trial of lisinopril versus captopril in the treatment of congestive heart failure. The Multicenter Lisinopril-Captopril Congestive Heart Failure Study Group.

A randomized, parallel, double-blind study was performed with lisinopril, a long-acting angiotensin-converting enzyme inhibitor, versus captopril, a shorter-acting angiotensin-converting enzyme inhibitor, in the treatment of congestive heart failure. All patients were in New York Heart Association class II, III or IV and had remained symptomatic despite therapy with digoxin and diuretics. After a 4 to 14 day placebo baseline period, patients were randomized to receive either lisinopril, 5 mg orally once per day (n = 94), or captopril, 12.5 mg orally three times per day (n = 95), in addition to continuation of digoxin and diuretics. The dose of study drug could be doubled at 4 week intervals for a total of 12 weeks of double-blind therapy. The maximal dose was 20 mg once per day of lisinopril or 50 mg three times per day of captopril. The addition of either lisinopril or captopril to a regimen of diuretics or digoxin, or both, caused an increase in exercise duration as assessed on a motorized treadmill. When protocol violators were excluded, patients receiving lisinopril had a statistically greater increase in exercise duration than that of patients receiving captopril. In patients with renal impairment (serum creatinine greater than 1.6 mg/dl at baseline), lisinopril was superior to captopril in improving exercise duration. Lisinopril, but not captopril, increased left ventricular ejection fraction in patients with moderately to severely (less than 35%) decreased function (p less than 0.05). Improvement in functional capacity and quality of life, as assessed by the Yale Scale dyspnea/fatigue index, was significantly greater for the lisinopril group.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Carteolol, an antihypertensive beta-blocker with intrinsic sympathomimetic activity, reduces ECG evidence of left ventricular hypertrophy.

Effective treatment of chronic hypertension may be accompanied by a decrease, increase, or no change in the extent of LVH, depending on the pharmacologic properties of the antihypertensive agents employed. Unlike beta-adrenoceptor blockers without ISA, beta-adrenoceptor blockers with ISA have been reported to increase left ventricular mass despite favorable reductions in blood pressure. To assess further the potential effect of ISA on LVH, we retrospectively evaluated the effect of carteolol, a nonspecific beta-adrenoceptor antagonist with strong ISA, upon ECG evidence of LVH. In 12 patients with LVH, carteolol treatment for one year reduced mean arterial blood pressures from 120 +/- 2 mm Hg to 100 +/- 2 mm Hg and mean hypertrophy scores from 5.2 +/- 0.6 to 2.6 +/- 0.8. Therefore, ISA does not preclude the regression of ECG evidence of LVH during the treatment of hypertension.

Aged↗
PubMed1989

Lisinopril in the treatment of congestive heart failure.

In a series of studies, lisinopril, a new, once-daily, non-sulphydryl-containing ACE inhibitor, has been evaluated for the treatment of congestive heart failure (CHF). Lisinopril significantly improved exercise duration, left ventricular ejection fraction (LVEF) and the clinical signs and symptoms of CHF when compared with placebo in a 12-week prospective, randomised, double-blind trial involving 130 patients (NYHA Class II-IV) who were also receiving digitalis and diuretics. In another study involving 10 patients with CHF, lisinopril was found to increase maximal oxygen uptake. Lisinopril has also been compared with captopril in a 12-week randomised, double-blind, parallel trial in 189 patients with CHF (Class II-IV) on digoxin and diuretics. Both lisinopril and captopril increased treadmill exercise times. However, lisinopril was equally effective in patients with renal impairment whereas captopril was not. Also, lisinopril, but not captopril, improved LVEF. In all studies, lisinopril was well tolerated in a manner similar to captopril. Lisinopril produces more frequent increases in serum creatinine than captopril, but these changes are rarely of significant consequence. These results confirm those of previous studies, from which it is concluded that lisinopril is an important addition to the ACE inhibitor class for the treatment of CHF.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Lisinopril and captopril in the treatment of heart failure in older patients. Comparison of a long- and short-acting angiotensin-converting enzyme inhibitor.

Heart failure is a common cardiovascular disorder that increases in prevalence with age. Older patients may respond differently than younger patients to the various classes of drugs used in the treatment of congestive heart failure (CHF). The responses of older patients (at least 65 years of age) were evaluated as part of a large multicenter trial utilizing angiotensin-converting enzyme (ACE) inhibitors in the treatment of CHF. A prospectively planned subgroup analysis of older CHF patients' therapeutic response to the long-acting (approximately 24-hour) ACE inhibitor lisinopril was compared with their response to captopril, a short-acting (less than eight-hour) ACE inhibitor. Symptomatic improvement occurred in both the lisinopril and captopril groups. Exercise duration also improved for patients treated with both agents. However, there was a tendency for lisinopril to be more effective than captopril (p = 0.08). Thus, the low level of renin activity often found in the plasma of older patients did not decrease the ability of the ACE inhibitors to improve effort tolerance. Left ventricular ejection fraction increased in patients treated with lisinopril but not in those treated with captopril. The improvement in left ventricular ejection fraction with lisinopril may be indicative of a more favorable prognosis in patients with CHF, since another long-acting ACE inhibitor, enalapril, reduces the rate of mortality associated with CHF. ACE inhibitors were generally well-tolerated by the older patients in the study. Therefore, ACE inhibitors appear to offer a useful therapeutic approach to the management of CHF in the older age group.

Age Factors↗
PubMed1988

Role of calcium antagonists as initial pharmacologic monotherapy for systemic hypertension in patients over 60 years of age.

Hypertension is most prevalent in older patients and is associated with increasing morbidity and mortality with age. The ability of antihypertensive treatment to reduce these complications in the elderly is now well established. However, several aspects of the treatment of hypertension are being evaluated. In particular, there is a growing trend to avoid individualizing the choice of medication. This is of particular concern in older patients who may differ in the pathophysiology of their hypertension, in their accompanying medical conditions, and in how they may respond to antihypertensive drugs. In addition, elderly hypertensives are often taking a number of medications in addition to antihypertensive drugs. This, along with the fact that the elderly often metabolize drugs more slowly, makes this group particularly susceptible to drug-drug interactions and pharmacologically induced toxic side effects. Considering these points, it appears that the calcium channel blockers are attractive antihypertensive agents for the elderly population.

Aged↗
PubMed1988

The effect of area postrema lesions on hemodynamic responses to systemic methionine-enkephalin in conscious dogs.

In the intact conscious dog, intravenous methionine-enkephalin (ME) increases heart rate and mean arterial blood pressure (MAP). These hemodynamic responses are produced at lower dosages when ME is injected into the vertebral artery, but not the carotid artery, suggesting that ME receptors are localized in the vertebrobasilar artery circulation. The area postrema (AP), a circumventricular organ devoid of a functional blood-brain barrier, represents a likely site for these receptors. We have tested the effects of chronic AP ablation upon hemodynamic responses to ME in conscious dogs. In three dogs with subtotal AP destruction, ME responses were preserved. However, in another dog with complete ablation of both the AP and the area subpostrema, ME responses were eliminated. These results indicate that total destruction of the AP, and perhaps of deeper structures as well, is necessary to abolish hemodynamic responses to ME.

Animals↗
PubMed1988

Remission of mild to moderate hypertension after treatment with carteolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic activity.

Previous studies have indicated that some hypertensive patients, following a period of effective treatment with certain antihypertensive drugs, may experience prolonged normotension after drug withdrawal. We have studied the ability of carteolol, a nonselective beta-adrenoceptor antagonist with intrinsic sympathomimetic activity, to produce such remissions of hypertension. Thirty-four patients whose diastolic blood pressure was controlled at 90 mm Hg or less with carteolol monotherapy (2.5 to 5.0 mg/d for an average of 328 days) were randomized to a nine-month, double-blind, placebo-controlled drug-withdrawal trial. Those patients randomized to continue carteolol therapy had initially responded to carteolol treatment with reduction in blood pressure from 151 +/- 4/99 +/- 2 to 132 +/- 4/80 +/- 2 mm Hg. Those randomized to treatment with placebo had initially responded with blood pressure reductions from 154 +/- 4/97 +/- 2 to 137 +/- 4/81 +/- 2 mm Hg. Changes in mean systolic and diastolic blood pressure (mm Hg +/- SEM) from baseline during carteolol therapy to the final visit at nine months were not different for patients receiving placebo (13 +/- 5/6 +/- 4 mm Hg, recumbent; 11 +/- 6/4 mm Hg, standing) or carteolol (11 +/- 5/7 +/- 3 mm Hg, recumbent; 12 +/- 6/7 +/- 3 mm Hg, standing). The final mean recumbent diastolic blood pressure (86.9 mm Hg) was the same in both groups. Prolonged normotension may follow a period of carteolol treatment, again suggesting the potential importance of periodic withdrawal of antihypertensive medication.

Blood Pressure↗
PubMed1988

N-allylnormetazocine: hemodynamic actions and inhibition of leucine-enkephalin hemodynamic activity in conscious dogs.

The hemodynamic actions of dl-, d-, and l-N-allylnormetazocine (NANM) were examined. dl-NANM significantly increased heart rate and systemic arterial pressure in a dose-dependent manner. Naloxone (1 mg/kg) inhibited the hemodynamic actions of 0.5 mg/kg dl-NANM. At a dose of 0.25 mg/kg, l-NANM, but not d-NANM, significantly increased heart rate and mean arterial pressure. The effects of l-NANM were blocked by naloxone but not by naloxone-methylbromide, indicating that the opiate effects are mediated by receptors located in the central nervous system. At a higher dose (0.5 mg/kg), d-NANM consistently produced small increases in heart rate and blood pressure which were statistically significant. The hemodynamic actions of Leu-enkephalin were inhibited by pretreatment with dl-NANM and l-NANM but not d-NANM. These results indicate that NANM has opiate hemodynamic activity which resides with the levorotary isomer. Dextrorotary isomer activity is nonopiate or possibly nonspecific. Furthermore, there appears to be a inhibitory interaction between NANM-opiate and enkephalin hemodynamic actions. This suggests that NANM-opiate receptors may be involved in modulation of the hemodynamic response to circulating enkephalins.

Animals↗
PubMed1987

Comparison of nitrendipine and hydrochlorothiazide for systemic hypertension.

Left ventricular (LV) hypertrophy with associated LV systolic and diastolic dysfunction is frequently found in patients with systemic hypertension, and is multifactorial in origin. Although a reduction in blood pressure (BP) often results in regression of hypertrophy, the pharmacologic profiles of the antihypertensive agents used may determine the probability of such regression despite similar levels of BP reduction. Thiazide diuretic drugs may actually result in increased LV hypertrophy; calcium channel antagonists may cause regression or no change. The effects of treatment with nitrendipine (20 mg/day) or hydrochlorothiazide (50 mg/day) were compared in an 8-week, double-blind study of 18 hypertensive subjects aged 50 years or older. BP was significantly reduced (p less than 0.05) by both nitrendipine (from 161 +/- 29/102 +/- 4 to 145 +/- 24/92 +/- 7 mm Hg; mean +/- standard deviation) and hydrochlorothiazide (from 162 +/- 15/105 +/- 6 to 143 +/- 20/95 +/- 7 mm Hg). Plasma norepinephrine increased in the nitrendipine group, from 202 +/- 110 to 332 +/- 220 pg/ml at 8 weeks of therapy and in the hydrochlorothiazide group, from 147 +/- 130 to 313 +/- 277. Plasma renin activity changed from 3.2 +/- 2.4 to 3.5 +/- 2.1 during nitrendipine treatment, but from 2.1 +/- 2.1 to 10.5 +/- 10.8 ng angiotensin l/ml/90 min (p less than 0.05) during treatment with hydrochlorothiazide. Left ventricular mass index did not change significantly with either therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗
PubMed1987

A double-blind comparison of lisinopril with captopril in patients with symptomatic congestive heart failure.

Angiotensin-converting enzyme (ACE) inhibition with captopril is accepted therapy for the treatment of symptomatic congestive heart failure. In this trial, we compared the new ACE inhibitor, lisinopril, to captopril during a 12-week randomized double-blind study. One hundred twenty-nine patients with New York Heart Association class II, III, or IV congestive heart failure were randomized to receive either lisinopril 5 mg/day (n = 64) or captopril 37.5 mg/day (n = 65) in 15 centers. Drug doses could be titrated upwards every 4 weeks. The primary measure of drug efficacy was improvement in treadmill exercise time using a modified Naughton protocol. Secondary measures of efficacy and the development of adverse effects were also examined. Lisinopril improved exercise time (following 12 weeks of therapy) more than captopril [from 500 +/- 30 to 682 +/- 34 sec (mean +/- SEM) with lisinopril versus 480 +/- 26 to 600 +/- 35 sec with captopril; difference between groups, p less than 0.05]. Adverse drug effects were unusual and similar in frequency in the two groups, although an increase in blood urea nitrogen was more common with lisinopril than with captopril (p less than 0.05). These results indicate that using the doses and treatment regimens studied, lisinopril is more effective than captopril for the treatment of symptomatic congestive heart failure. Adverse experiences with lisinopril were infrequent and similar in incidence to those observed with captopril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Evidence for Des-Tyr1-D-Ala2-leucine5-enkephalinamide calcium agonist activity in vascular smooth muscle.

Intravenous administration of the enkephalin analog Des-Tyr1-D-Ala2-Leu5-enkephalinamide (DTALE) to conscious dogs produces a pressor response that is not inhibited by naloxone. In an attempt to explain this observed pressor activity in vivo, the effect of DTALE on vascular smooth muscle was investigated in vitro. DTALE was found to contract rat thoracic aorta strips in a dose-dependent and naloxone-insensitive manner. Pretreatment with reserpine (5 mg/kg) or prazosin was without significant effect. However, a significant inhibition was obtained with cyproheptadine (p less than 0.001, n = 5), a 5-hydroxytryptamine (5-HT) receptor antagonist that also has calcium channel blocking activity. Treatment with ketanserin (0.1 microM), a selective 5-HT2-receptor antagonist, had no effect. Reduction of the extracellular calcium concentration from 1.6 to 1.2 mM or 0.8 mM significantly diminished DTALE activity (1.2 mM, p less than 0.025; 0.8 mM, p less than 0.01; n = 3). Pretreatment with the calcium channel antagonists verapamil (0.1 microM) and nitrendipine (0.05 microM) significantly inhibited DTALE activity (p less than 0.001 for both treatments). DTALE also exhibited increased potency in partially depolarized smooth muscle preparations. These results suggest that DTALE may produce vasoconstriction by inducing or facilitating calcium influx. This activity upon arterial vascular strips may provide explanation for the observed pressor response in chronically instrumented conscious dogs.

Animals↗
PubMed1987

Acute and short-term effects of clonidine in heart failure.

The authors performed a randomized, double-blind, placebo-controlled trial to assess the tolerance and effects of chronic oral clonidine administration on the clinical status, exercise tolerance, and ventricular function of 10 male patients with chronic heart failure. Patients were given either oral clonidine (400 micrograms/day) or matching placebo for twelve weeks and then tapered off medication over a two-week period. Results are summarized as follows: Profiles over time between groups were significantly different for resting heart rate (p = 0.0005), were different for arterial pressure (p = 0.04), were different for left ventricular ejection fraction (p less than 0.006), and were different for mean accumulated workload (p = 0.076). Exercise double product at 25 watts changed little in three patients and showed a decrease in 2 patients following six weeks of oral clonidine; after twelve weeks, it decreased in three patients, increased in 1, and changed little in another. After washout, double product returned toward baseline values. In the placebo groups, double product showed little change. Resting of the heart by decreasing heart rate, systemic arterial blood pressure, and venous tone are thought by the authors to be major contributing factors to the observed beneficial effect of chronic oral clonidine in chronic heart failure.

Administration, Oral↗
PubMed1986

Non-opiate and peripheral-opiate cardiovascular effects of morphine in conscious dogs.

Morphine is generally regarded as having a centrally mediated depressant effect upon the cardiovascular system. We report here that in chronically instrumented conscious dogs, morphine produces a biphasic response; heart rate and mean arterial pressure initially increase followed by a reduction to below baseline levels. Differential inhibition by naloxone (NAL) and methylnaloxone (MRZ), a quaternary opiate antagonist which does not readily enter the CNS, suggests that the initial pressor response is mediated peripherally, while the latter occurring vasodepressor and bradycardic responses are mediated centrally. The initial tachycardia was not inhibited by NAL or MRZ, suggesting that this response is mediated by a non-opiate mechanism.

Animals↗