Reduction In Total Peripheral Resistance Research Articles

Effects of Renin Inhibitor A-72517 on Hemodynamics and Cardiac Function in Sodium-Depleted Dogs

A-72517 is a potent inhibitor of human renin (IC50 = 1.0 nmol/L, pH 7.4 in plasma) and, aside from displaying modest activity against canine plasma renin (IC50 = 110 nmol/L), has been shown to be orally active in the dog and other animals. Renin inhibitors, in general, are presumed to exert their hypotensive effect through a reduction in total peripheral resistance. To elucidate the hemodynamic mechanism of action of this new dipeptidic renin inhibitor, the cardiac and systemic hemodynamic effects of A-72517 were studied in sodium-depleted, pentobarbital-anesthetized dogs. Each dog received either vehicle (n = 8) or a single dose (n = 8/dose) of A-72517 administered intravenously as a priming bolus followed by a 30 min constant infusion; infusion doses were 0.01, 0.05, and 0.1 mg/kg/min. A-72517 elicited significant (P < .05) dose-related reductions in mean arterial pressure (MAP) and systemic vascular resistance (SVR) compared to baseline values and the vehicle-treated group, and the recoveries of MAP and SVR were also dose-related. Plasma renin activity, measured by radioimmunoassay, was nearly completely suppressed during drug infusion at all doses. The hypotensive responses did not alter cardiac output nor did they induce reflex tachycardia at any dose. Left ventricular dP/dtmax did not change during infusion of A-72517, but, when corrected for changes in afterload, showed dose-related increases with drug treatment. Moreover, left ventricular end-diastolic pressure and pulmonary arterial wedge pressure were significantly reduced at the high dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Regression of Left Ventricular Hypertrophy With Isradipine Antihypertensive Therapy

To assess left ventricular (LV) structural and functional changes, 45 hypertensive patients were studied by echocardiography after 2 weeks of placebo and 6 months of isradipine monotherapy. Although LV cavity size did not change, LV wall thickness decreased dramatically (P < .0001), producing a significant decrease in LV mass index (from 158 g/m2 to 136 g/m2; P < .0001). In addition, LV fractional shortening (FS) did not change (1.2%; P = NS) whereas the cardiac index increased (6.4%; P = .0007) due to a modest tachycardia accompanied by a reduction in total peripheral resistance (-22.1%; P < .0001). The magnitude of the reduction of LV mass was related to the degree of FS increase (r = -0.70; P < .0001), an indication of beneficial LV remodeling. It can be concluded that isradipine antihypertensive therapy leads to regression of LV hypertrophy without depression of LV pump function.

Cardiac Effects of ACE Inhibition

Hypertension frequently is associated with a number of changes in heart structure and function, such as left ventricular hypertrophy, disturbed diastolic function, and subnormal stroke volume during exercise. Most of these changes probably are related to myocardial fibrosis. Antihypertensive agents reverse the structural and functional changes to different degrees. The hemodynamic changes in central hemodynamics at rest and during exercise were studied before and after angiotensin-converting enzyme (ACE) inhibition in 68 patients with essential hypertension (ranging from severe to moderately severe). In patients with moderately severe hypertension who were administered perindoprilat intravenously, mean arterial pressure was reduced by approximately 17% due to reduction in total peripheral resistance and no changes in heart pump function. Chronic treatment with captopril, enalapril, or lisinopril for 6-12 months induced reduction in blood pressure associated with decreased peripheral resistance. In general, there were only minor changes in cardiac output, stroke volume, and heart rate. Studies from other laboratories have shown that ACE inhibitors reverse left ventricular hypertrophy and improve left ventricular diastolic function. Captopril also appears to improve coronary circulation. The effect of ACE inhibitors on heart structure and function appears promising with regard to cardioprotection during chronic use, but long-term studies are needed to prove that this will occur in clinical practice.

Antihypertensive Therapy in the Geriatric Patient: II. A Review of the Alpha1‐Adrenergic Blocking Agents

The prevalence of hypertension increases with age. Multiple physiologic factors are involved in the development of hypertension in the elderly. Alpha1-adrenergic blocking agents lower blood pressure through a reduction in total peripheral resistance. Prazosin, terazosin, and doxazosin have been shown to be equally effective in reducing blood pressure in older persons. The bioavailability, terminal elimination half-life, and volume of distribution of prazosin is increased in the elderly. Hybrid drugs, such as ketanserin, urapidil, and indoramin are also effective in lowering blood pressure. Ketanserin seems to have a greater effect on blood pressure reduction in persons older than 60 years of age. Alpha1-adrenergic blockers may be used safely in patients with diabetes, asthma, and hyperlipidemia.

Prostaglandin E2 in dogs with heart failure: hemodynamic, hormonal, and renal effects.

To test the efficacy of exogenous prostaglandins for vasodilator therapy in heart failure, we studied the hemodynamic, hormonal, and renal effects of prostaglandin E2 (1.5-150 ng/kg/min) in six conscious dogs before and after induction of heart failure by right ventricular pacing (250 beats/min, 10 days). In healthy dogs, PGE2 decreased the mean arterial pressure (MAP) by a reduction in total peripheral resistance (TPR), increased cardiac output (CO), stroke volume (SV), and heart rate with no effect on right atrial pressure (RAP). Plasma levels of renin (PRC) and norepinephrine (NE) were increased at the highest dosage. Renal plasma flow (RPF) and sodium excretion (UNaV) were augmented without a change in the glomerular filtration rate (GFR) and urine flow (UF). In dogs with heart failure, PGE2 lowered the MAP and TPR and elevated the CO and SV without an effect on the RAP, PRC, and NE. The RPF and GFR were not changed, but the increase in UNaV was preserved and UF significantly augmented. In experimental heart failure, PGE2 increases the CO due to arteriolar dilation and afterload reduction without inducing further neurohumoral activation and exerts potent natriuretic and diuretic action. Therefore, PGE2 may have beneficial effects in heart failure therapy.

Effects of carvedilol on atrial natriuretic peptide, catecholamines, and hemodynamics in hypertension at rest and during exercise.

Possible counterregulatory neurohumoral and hemodynamic responses to carvedilol (a new vasodilating nonselective beta-receptor blocker) were studied in 19 men with essential hypertension (age range, 34-59 years; mean age, 44 years). Intra-arterial pressure, cardiac output (Cardio-green), heart rate, and the vasoactive peptides norepinephrine, epinephrine, and atrial natriuretic peptide (ANP) were measured at rest supine and sitting and during 100-W bicycle exercise before and 2 h after administration of 25 mg carvedilol. The same protocol was followed after 9 months of chronic carvedilol treatment (mean dose, 52 mg/day). Carvedilol induced both acute and chronic reductions (at rest supine, 11%) in mean arterial pressure, due in part to reduction in cardiac output (5%) and in part to reduction in total peripheral resistance (5%). At rest supine, carvedilol induced a reduction in ANP (27%) that could be viewed as a counterregulatory response to decrease in cardiac output, preventing excessive blood pressure reduction. ANP decreased (18%) when the patient sat up from the supine position and increased (67%) during exercise, but no further change was seen after acute or chronic carvedilol treatment. With the patient in the sitting position, norepinephrine was 110% higher than at rest supine; during 100-W exercise, norepinephrine increased 368%. A further increase (38-86% in the three situations, respectively) was seen after the first dose of carvedilol. Epinephrine showed similar but less marked changes. Neither extracellular fluid volume nor plasma volume (isotope dilution techniques) changed significantly during the study, but the acute blood pressure response to carvedilol was directly related to changes in extracellular fluid volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and chronic effects of nitrendipine in patients with precapillary pulmonary hypertension due to pulmonary fibrosis

Eleven patients with histologically confirmed fibrosis of the lung were investigated for the effects of the dihydropyridine calcium antagonist nitrendipine on pulmonary hemodynamics. After 5 mg of acute sublingual nitrendipine, mean pulmonary artery pressure was significantly lowered (p less than or equal to 0.05) from 32 +/- 3 to 29 +/- 3 mmHg at rest, and significantly lowered (p less than or equal to 0.05) during exercise from 55 +/- 4 to 49 +/- 4 mmHg. Short-term oxygen application at rest significantly reduced this parameter to 28 +/- 3 mmHg (p less than or equal to 0.001). Nitrendipine lowered total pulmonary vascular resistance during both rest (from 412 +/- 50 to 351 +/- 49 dyn.s.cm-5; p less than or equal to 0.05), although it did not affect pulmonary arteriolar resistance. Also, oxygen treatment at rest influenced only total pulmonary vascular resistance (reduction from 412 +/- 50 to 373 +/- 48 dyn.s.cm-5; p less than or equal to 0.01), but not pulmonary arteriolar resistance. Pressure-flow curves, which were derived from cardiac output at rest and during exercise and from the corresponding gradient between mean pulmonary artery pressure and pulmonary capillary wedge pressure, remained unchanged by acute medication. Since a change in arterial oxygen partial pressure was not noticed after nitrendipine, arteriovenous shunting or a worsening of ventilation perfusion relationships can be excluded. Long-term (3 weeks) treatment (double-blind parallel design) with 10 mg of nitrendipine (4 patients) once daily showed no advantage in comparison to placebo (6 patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Nebivolol on Haemodynamics, Cardiac Dimensions and Function, Cardiovascular Reflexes and Biochemical Measures of Sympathetic Activity in Normal Human Subjects

Nebivolol is a β-adrenergic antagonist with novel pharmacodynamic properties. We examined its effects in 8 normal subjects in a randomised double-blind, placebo-controlled crossover study. Nebivolol lowered resting and ambulatory blood pressure (BP). The latter fall averaged 11/10mm Hg after 1 week of therapy (both p < 0.01). The fall in BP was due to a reduction in total peripheral resistance. Stroke volume increased. Nebivolol reduced resting heart rate and heart rate responses to head-up tilting, Valsalva’s manoeuvre and mental challenge. However, BP responses to these stimuli were unaltered. The drug had no effect on plasma noradrenaline (norepinephrine) or on norepinephrine spillover or clearance, either at rest, during mental challenge or tilting. Despite markedly reducing resting heart rate, nebivolol had only a slight effect on left ventricular (LV) dimensions determined echocardiographically. LV systolic function was unchanged but there was evidence of effects on diastolic filling as nebivolol decreased deceleration time (p < 0.003) and pressure half-time.

Neural and humoral controlling mechanisms of cardiovascular functions in man under weightlessness simulated by water immersion

To clarify how neural and humoral mechanisms operate to control cardiovascular unctions in man under weightlessness, the response of sympathetic nerve activity was observed in healthy human subjects by means of microneurographic technique with the changes of several hemodynamic parameters and hormonal responses during thermoneutral head-out water immersion. Muscle sympathetic nerve activity was markedly suppressed by head-out immersion, concomitantly with a reduction of the leg volume, an increase of the stroke volume and a reduction of total peripheral resistance. At the same time, plasma level of norepinephrine, vasopressive and antidiuretic hormones (ADH, aldosterone, renin activity, angiotensin I·II) were reduced, while vasodepressive and diuretic hormone (ANP) was markedly increased. The systemic blood pressure was maintained almost unchanged during head-out water immersion. The suppressive response of sympathetic nerve activity seemed to be age-dependent. This response was less prominent in the elderly than in young subjects. It is concluded that the suppressive response of muscle sympathetic activity plays an important role to maintain hemodynamic homeostasis under weightlessness to compensate for the cephalad fluid shift and the resultant increase of the stroke volume in cooperation with the hormonal responses.

Hemodynamics, fluid volume, and hormonal responses to chronic high-salt intake in dogs

The sequential hemodynamics, fluid and electrolyte balances, and the hormonal responses to a 7-day high-salt (NaCl) intake were investigated in sodium-depleted conscious dogs (n = 6). Studies were carried out in metabolic cages mounted on sensitive load cells, which enabled continuous 24 h/day monitoring of total body weight (TBW) as an index of changes in body water. Beat-by-beat hemodynamics were determined 24 h/day. Water (700 ml/day iv) intake was maintained constant. Daily fluid and electrolyte balances and hormonal analyses were performed. An increase of daily salt intake from 8 to 120 meq increased TBW 251 +/- 44 g (P less than 0.05), which was sustained thereafter. Average 24-h mean arterial pressure (MAP) and heart rate (HR) remained unchanged. Average cardiac output (CO) increased 11% (P less than 0.05) above control values by day 2, while total peripheral resistance (TPR) decreased proportionally. CO and TPR returned to control values only when low salt was resumed. Blood volume (BV) was unchanged on day 2 as indicated by direct measurement of BV (51Cr-labeled red blood cells) or by analysis of plasma protein concentration. A 92-meq (P less than 0.05) sodium retention was observed initially, and plasma sodium concentration increased slightly. Plasma renin activity, angiotensin II, and aldosterone levels decreased significantly, whereas vasopressin and atrial natriuretic peptide levels remained unchanged. In summary, chronic high-salt intake resulted in a net retention of water and sodium with no changes in MAP, HR, or BV. The rise in CO was offset by a reduction in TPR, which appeared at least in part related to angiotensin II suppression.

Effect of long-term diltiazem treatment on central haemodynamics and exercise endurance in essential hypertension

The effects of long-term treatment with diltiazem on blood pressure, central haemodynamics and exercise endurance were studied in 16 men (mean age 52 years) with essential hypertension. Intra-arterial pressure and heart rate (HR) were monitored continuously. Cardiac output (CO) was measured by Cardiogreen at rest (supine and sitting) and during 50 W, 100 W and 150 W bicycle exercise. Haemodynamic measurements were repeated after continuous bicycling at 150 W for 20 min or until exhaustion. After 1 year on diltiazem (mean daily dose 278 mg) intra-arterial pressure was reduced (P less than 0.001) in all situations (at rest sitting from 183/108 mmHg to 157/92 mmHg (14%] due to reduction in total peripheral resistance. HR was reduced at rest (7%) and during exercise (10%). Stroke volume tended to increase while CO was unchanged. Exercise time at constant workload increased by 25%. After a peak level, intra-arterial pressure fell by 3% to 5% (P less than 0.05) due to a decrease in total peripheral resistance both before and during diltiazem treatment. Stroke volume and CO remained unchanged during endurance exercise while HR showed a small increase. Thus, there was no reduction in the overall cardiac pump function after long-term diltiazem treatment, and blood flow during exercise was maintained.

Potential benefit of combination therapy with diuretics and beta blockers having intrinsic sympathomimetic activity

When combining a beta blocker with a diuretic in patients with hypertension, consideration should be given to the potential advantages of intrinsic sympathomimetic activity (ISA). During long-term administration of a beta blocker without ISA, total peripheral resistance stabilizes at or slightly above the pretreatment level. Since cardiac output is decreased, blood pressure falls. Thus, beta blockers without ISA may exacerbate the underlying haemodynamic abnormality of long-standing hypertension, increased systemic resistance. In contrast, the reduction in pressure which occurs with a beta blocker possessing a high degree of ISA, such as pindolol, is associated with a reduction in total peripheral resistance and little change in cardiac output. Thiazide diuretics and most beta blockers without ISA also have an adverse impact on the blood lipid profile, potentially increasing cardiovascular risk. With the exception of oxprenolol, monotherapy with beta blockers which possess ISA have generally had no adverse blood lipid changes. Indeed, pindolol has been shown to increase HDL-cholesterol and to reduce the ratio of total cholesterol to HDL-cholesterol. Pindolol administered in combination with several diuretics has not increased the adverse lipid effects of these agents and, in some studies, evidence suggests that pindolol may counteract some or all of these changes. The clinical significance of these differences between beta blockers with and without ISA remains uncertain. Nevertheless, the potential haemodynamic and metabolic benefit of agents with ISA mandate that they receive careful consideration when selecting a beta blocker to administer with a diuretic.

Angiographic response to a vasodilating drug, nicorandil, in patients with coronary artery disease.

To investigate the usefulness of nicorandil as an antianginal drug, we compared the coronary vasodilatory response in nonstenotic coronary artery segments and the hemodynamic response in 26 coronary artery disease patients. Both responses were studied prior to sublingual administration of 10 mg of this drug and 10, 30 and 60 min afterward. The plasma nicorandil concentration was determined up to 120 min after administration. The mean coronary dilating ratio of nicorandil was 117% 30 min after administration (p less than 0.01) and showed a good correlation to the plasma nicorandil concentration. The mean maximum dilating ratio of each patient was 125%. There was no difference between individual coronary arteries or between proximal and distal segments in terms of the coronary artery dilating ratio. The plasma nicorandil concentration required for 120% dilation of the coronary arteries was 26 ng/ml, 89 ng/ml and 142 ng/ml for those cases with variant angina, exertional angina and postinfarction angina, respectively. Hemodynamic changes due to administration of this drug included a decrease in blood pressure, and a reduction in total peripheral resistance, rate-pressure product, pulmonary capillary pressure and stroke-work index. These results indicate that the antianginal effects of nicorandil are derived from its coronary vasodilatory action and an inhibitory effect on myocardial oxygen consumption.

Acute and long-term hemodynamic effects of tiapamil at rest and during exercise in essential hypertension

The first dose and long-term hemodynamic responses to tiapamil--an aralkylamine calcium-channel blocker--were studied both at rest and during exercise in 18 male patients (mean age, 45 years) with essential hypertension (EH). Blood pressure (BP) was measured intra-arterially, cardiac output (CO) was measured by dye dilution and heart rate (HR) was measured by electrocardiogram. One hour after the first oral dose of 600 mg tiapamil, mean arterial pressure (MAP) fell 14%. Total peripheral resistance (TPR) fell 21%, while HR and CO increased 7% and 11%, respectively. Thereafter the effects leveled off. After 11 months of chronic tiapamil therapy (mean dose 980 mg per day), MAP was reduced 11% at rest sitting. The reduction in BP was associated with a modest reduction in TPR. Similar responses were seen at rest supine and during 100-W bicycle exercise. A small reduction was seen in HR while CO was preserved. In conclusion, tiapamil exerts a moderate antihypertensive effect, both at rest and during exercise, through reduction of TPR without a fall in heart pump function. The long-term hemodynamic changes are rather similar to those of verapamil.

Comparative acute blood pressure reduction from intravenous fenoldopam mesylate versus sodium nitroprusside in severe systemic hypertension

Fenoldopam mesylate (SK&F 82526J) (FNP) is a specific postsynaptic dopamine-1 receptor agonist, 1 with weak α 2-antagonistic properties. 2 The agent is devoid of dopamine-2, α-1 or β-adrenergic activity. 3 Fenoldopam functions as an arteriolar vasodilator with dilation in the renal, mesenteric, skeletal muscle and lumbar beds. 4,5 Although a primary effect is through renal vasodilation with consequent increases in renal blood flow, 1–2,4–6 reduction in total peripheral resistance appears to be the mechanism of blood pressure (BP) reduction. 7,8 Furthermore, fenoldopam improves renal blood flow, fractional sodium and free water clearance while lowering BP. 4,9,10 Fenoldopam has a rapid onset (4 minutes) and a short duration of action (<10 minutes) with intravenous administration, 11 and has been reported to be an effective parenteral agent in severely hypertensive patients. 9 The agent undergoes sulfate, methylate and glucuronide conjugation, and produces no accumulation of toxic metabolic or degradation products. 12 Sodium nitroprusside (sodium nitroferricyanide) (NTP) has potent venodilating and arteriolar-dilating properties 13 and in many respects is an ideal antihypertensive agent when rapid reduction of BP is required. NTP quickly and reliably reduces BP in most patients and its short half-life aids in rapid titration of the drug. One major drawback associated with the use of NTP is that the very potency that gives it utility has often led to restrictions on its use. Restrictions include invasive monitoring requirements or use in an intensive care setting, thus dramatically escalating the cost associated with NTP's use. 14 A second drawback is that the formation of thiocyanate degradation products resulting in toxicity has limited its utility. 14 While thiocyanate toxicity has been primarily associated with impaired renal or hepatic function, in which the typical 4-day half-life of thiocyanate is prolonged, reports of toxicity in patients with normal renal function have also occurred. 14 Herein, we compared and evaluated the effects of sodium nitroprusside and intravenous fenoldopam mesylate in an open-label, randomized, multicenter trial of patients with severe systemic hypertension.

A review of the preclinical cardiovascular pharmacology of cilazapril, a new angiotensin converting enzyme inhibitor.

1. Cilazapril is the monoethyl ester prodrug form of the di-acid cilazaprilat, a new angiotensin converting enzyme (ACE) inhibitor. Cilazaprilat has an IC50 of 1.9 nM as an inhibitor of rabbit lung ACE in vitro making it one of the most potent ACE inhibitors currently available. Studies on a wide range of other enzymes show that the inhibition is highly specific. 2. An oral dose of 0.1 mg kg-1 cilazapril evoked the same maximum degree of plasma ACE inhibition (approximately 76%) in the rat as 0.25 mg kg-1 enalapril. Cilazapril (0.25 mg kg-1 p.o.) inhibited plasma ACE by greater than 95%. The rate of recovery of ACE activity was slower with cilazapril (5-6% h-1) than with enalapril (10% h-1). 3. In anaesthetised rats cilazaprilat was equipotent with ramiprilat and slightly more potent (1.5x) than enalaprilat as an inhibitor of the angiotensin I pressor response. 4. Following oral administration to conscious rats and intravenous administration to anaesthetised dogs, cilazapril was 2-4.5x more potent than enalapril as an ACE inhibitor. 5. In cats cilazapril (0.1 and 0.3 mg kg-1 p.o.) dose dependently decreased plasma ACE activity and the angiotensin pressor response. Peak effects occurred at 2 h after dosing and plasma ACE inhibition was maintained at greater than or equal to 50% for up to 18 h. Mean arterial pressure was also decreased dose dependently with a peak effect at 3-4 h. 6. Daily oral dosing of cilazapril (30 mg kg-1 p.o.) to spontaneously hypertensive rats evoked a progressive and prolonged (24 h) antihypertensive response with a maximum decrease in systolic blood pressure of 110 mm Hg. 7. Cilazapril (10 mg kg-1 p.o. twice daily for 3.5 days) progressively decreased blood pressure in volume depleted renal hypertensive dogs. The maximum fall in systolic pressure was 39 +/- 6 mm Hg. 8. Haemodynamic studies in open chest anaesthetised dogs showed that the hypotensive response to intravenous cilazapril was accompanied by a reduction in total peripheral resistance. Small decreases in cardiac output and myocardial contractile force were seen at high doses. 9. Cilazapril had no adverse effect on cardiovascular reflexes. There was no impairment of the baroreflex in rats. Exercise-induced tachycardia and pressor responses in conscious cats were unchanged. 10. Cilazapril is exceptionally well absorbed by the oral route (98% in rats).

Systemic and regional hemodynamic effects of dietary calcium supplementation in mineralocorticoid hypertension.

This study was undertaken to determine the systemic and regional hemodynamic effects of long-term dietary calcium supplementation in mineralocorticoid (DOC)-salt hypertension. Systemic and regional hemodynamic measurements were determined by the radioactive microsphere technique in conscious and unrestrained rats (kidneys intact) with DOC-salt-induced hypertension that were pair-fed either a normal calcium (0.6% by weight, n = 12) or a calcium-supplemented (high-calcium) diet (2.5% by weight, n = 12). After 7 to 8 weeks, there were no differences in weight, heart rate, or cardiac output between the two groups. In contrast, the high-calcium rats had a significantly lower mean blood pressure (125 +/- 4 mm Hg, mean +/- SEM) than the normal calcium rats (143 +/- 5 mm Hg); this finding appeared to result predominantly from a reduction in total peripheral resistance. The high-calcium rats had a higher renal blood flow (7.8 +/- 0.5% vs. 6.2 +/- 0.4% cardiac output; p less than 0.05) and lower renal (14.3 +/- 1 vs. 19.3 +/- 2 mm Hg/min/ml/g tissue; p less than 0.05) and jejunal vascular resistance than did the normal calcium rats. Two additional identical groups of normal calcium-and high-calcium-DOC-salt rats (n = 12 each) were also studied. In these rats, serum-ionized calcium decreased significantly (p less than 0.05) from baseline in both groups. Urinary sodium increased in both groups but did not differ significantly. In conclusion, dietary calcium supplementation attenuates the rise in peripheral vascular resistance that accompanies DOC-salt hypertension. This attenuated resistance appears to be relatively selective and is noted particularly in the renal vasculature.

HAEMODYNAMIC AND HEART RATE REFLEX RESPONSES TO PROPOFOL IN THE RABBIT: Comparison with Althesin

Propofol was administered to eight rabbits by constant i.v. infusion at 0.2, 0.4 and 0.6 mg kg-1 min-1 to produce light sedation. The lowest dose was compared with an infusion of Althesin 0.1 mg kg-1 min-1. The rabbits had been previously implanted with aortic and vena caval perivascular balloon cuffs to examine the baroreceptor-heart rate reflex and an aortic thermistor catheter for cardiac output (CO) measurements. A silastic catheter was placed in the pericardial sac so that the cardiac nerves could be blocked with local anaesthetic. Mean arterial pressure (MAP) was well maintained with all anaesthetic infusions. At the lower doses of propofol, CO increased by 20% (P less than 0.01) with a corresponding decrease in total peripheral resistance (TPR). However, CO and TPR were not changed significantly by Althesin. Both anaesthetics induced a similar tachycardia. Cardiac nerve blockade did not abolish the different CO and TPR responses observed for the two agents. A dose-related reduction in the range and gain of the baroreceptor-heart rate reflex was observed with propofol (P less than 0.05). The pattern of alteration of the reflex curve, however, differed between the two anaesthetics and the vagal efferent component was more resistant to blockade with propofol. The relative preservation of baroreceptor reflex responses, and the reduction in TPR by a reduction of resting constrictor tone, suggest propofol may have significant clinical advantages when used as a sedative infusion.

Left ventricular hypertrophy: Its prime importance as a controllable risk factor

Left ventricular hypertrophy, which is defined as an abnormal increase in the mass of the left ventricle, has become recognized as an important independent risk factor for predicting several untoward cardiac events, including myocardial infarction, congestive heart failure, and sudden death. The presence of left ventricular hypertrophy is difficult to detect by electrocardiography but can be accurately assessed by echocardiography. Left ventricular hypertrophy can be detected in about 5% of all hypertensive patients by electrocardiography but is found in about 50% by echocardiography. Although it is possible to restore left ventricular mass to normal by controlling hypertension with pharmacotherapy, several commonly prescribed antihypertensive medications, including diuretics and vasodilators, have failed to demonstrate the ability to reverse left ventricular hypertropity. Other agents, including most β-blockers, have been found to reverse it. Reversal may take 18 to 24 months from the initiation of therapy. This reversal may be accompanied by an increase in cardiac index, reductions in total peripheral resistance, and improvements in the diastolic properties of the left ventricle. It has yet to be determined whether these improvements reduce the risk of myocardial infarction, heart failure, and sudden death. However, it is likely that some antihypertensive medications may be superior to others in reducing long-term cardiac risks.

New alpha 1-adrenergic receptor antagonists for the treatment of hypertension: Role of vascular alpha receptors in the control of peripheral resistance

The pharmacology, clinical efficacy and safety of new alpha-adrenergic receptor antagonists for the treatment of hypertension was reviewed (Table XIV). Although all these agents block alpha 1 receptors, some of them have additional effects on histamine, serotonin, dopamine, and alpha 2 receptors. These other actions account for the differences in the side effect profiles observed, i.e., increased incidence of central nervous system side effects found with indoramin, ketanserin, and urapidil, as well as for some additional beneficial effects of ketanserin (i.e., antiplatelet aggregation activity). The magnitude of BP reduction observed with antagonists of alpha 1-adrenergic receptors is modest. In most studies, the degree of BP reduction is comparable to that of prazosin, but less than that achieved with thiazide diuretics, beta-receptor antagonists, or methyldopa. Studies on the comparative efficacy and safety of new alpha 1 antagonists with converting enzyme inhibitors or calcium-channel blockers are not available. In general, alpha 1 antagonists produce greater reductions in standing than in supine BP, an effect due to the venodilatory action of these drugs. New alpha 1 antagonists appear to have equal efficacy in black and white hypertensive individuals. Their comparative efficacy and safety in young vs elderly hypertensive individuals requires further investigation. No information about the possible development of tolerance during treatment with new alpha 1 blockers was encountered. The effects of alpha 1 antagonists on HR are variable and depend on how long after the oral dose the measurements were obtained. In most studies, no significant HR changes are noticed for readings obtained 24 hours post dose; whereas tachycardia has been observed at the time of peak hypotension. Since alpha 1 antagonist-induced tachycardia is most likely of reflex nature, i.e., mediated to an increase in sympathetic activity, the increased HR may be associated with increases in myocardial contractility and in myocardial oxygen consumption. Consequently, a 24-hour HR monitoring during treatment with alpha 1 antagonists should be required for evaluation of new agents. The hemodynamic, humoral, and hormonal effects of the newer alpha 1-receptor antagonists are comparable to those of prazosin. The most consistent finding is a reduction in total peripheral resistance associated with either no change or with only small increases in cardiac index. These agents have been shown either not to change or to increase renal blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)