Hyperventilating the hypoventilator.

A 65-year-old man had chronic hypoventilation and was demonstrated to have primary neuromuscular disease with major involvement of the thoracic bellows. By use of accessory muscles, he was able to voluntarily hyperventilate and reduce his PCO2 to normal. Hyperventilation gases must be interpreted with care in neuromuscular disease; the ability to reduce PCO2 to normal range does not exclude neuromuscular disease as a cause of chronic respiratory failure.

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.

Time-dependent antihypertensive effect of carteolol--a beta-adrenoceptor antagonist with partial agonist activity.

The antihypertensive effect of carteolol (0.5 to 60 mg daily), a beta-adrenoceptor antagonist with partial agonist activity, was studied in a double-blind parallel protocol. A 3-wk placebo period was followed by an 8-wk treatment period during which patients received 0.5, 2.5, 20, and 60 mg in an increasing (group 1) or decreasing (group 2) manner for successive 2-wk intervals, followed by a 2- to 6-wk withdrawal period. Resting supine and standing blood pressures (BP) and heart rates (HR) were measured at each visit. Isometric handgrip exercise and treadmill exercise were used to evaluate beta-blockade. Plasma carteolol concentration was measured by radioimmunoassay. Recumbent BP fell from 154 +/- 10/100 +/- 2 to 143 +/- 10/84 +/- 11 mm Hg for group 1 and from 153 +/- 10/100 +/- 3 to 138 +/- 14/78 +/- 8 mm Hg for group 2 after 8 wk of treatment. HR was unchanged. The greater reduction in BP for each dose was observed with the later administrations, but was not related to serum concentration. beta-Blockade was evident at all doses of carteolol. Carteolol is an effective antihypertensive. Duration of carteolol therapy, independent of dosage, is important in its effectiveness.

Prolonged hemodynamic benefits from a high-dose bolus injection of human atrial natriuretic factor in congestive heart failure.

The physiologic and potential pharmacologic roles of atrial natriuretic factor in congestive heart failure have remained confusing. We have evaluated the hemodynamic responses to human atrial natriuretic factor [ANF (102-126)] given as bolus intravenous doses of 2.0 or 4.5 micrograms/kg to 12 patients with congestive heart failure. Responses were monitored with pulmonary and systemic arterial catheters in place. By 30 minutes after 4.5 micrograms/kg ANF (n = 6), heart rate decreased from 97 +/- 16 to 91 +/- 15 beats/min, right atrial pressure from 14 +/- 4 to 12 +/- 3 mm Hg, and pulmonary capillary wedge pressure from 33 +/- 3 to 23 +/- 2 mm Hg (all p less than 0.05); responses persisted for 120 minutes. Mean arterial pressure, cardiac index, stroke volume index, and pulmonic and systemic vascular resistances did not change significantly. The 2.0 micrograms/kg ANF dose produced similar responses, but only heart rate and right atrial pressure decreased significantly. No clinically important side effects were noted. High-dose ANF bolus doses can be administered simply and safely and improve hemodynamic parameters in chronic heart failure. Therefore ANF does have pharmacologic activity in heart failure and may have therapeutic potential.

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.

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)

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)

Interactions of leucine-enkephalin with alpha-adrenoceptors in the conscious dog.

Leucine-enkephalin (Leu-ENK) administered systemically to the conscious dog increases heart rate and blood pressure, a response prevented by naloxone and hence mediated by opiate receptors. Clonidine attenuates the heart rate increase without affecting the pressor response. Propranolol also reduces the magnitude of the heart rate increase but to a lesser degree than does clonidine. Clonidine appears to inhibit the Leu-ENK-induced heart rate increase by both a centrally mediated increase in vagal tone and a peripheral presynaptic alpha 2-agonist effect. The presence of a pressor response to Leu-ENK after prazosin pretreatment suggests that Leu-ENK may also increase blood pressure independently of the alpha 1-adrenoceptor. Thus, Leu-ENK appears to act via a naloxone-sensitive receptor (perhaps a vagal afferent chemoreceptor), the response involving both sympathetic and parasympathetic mechanisms. The pressor response may also involve a direct effect on peripheral vessels or a non-alpha 1-adrenergic efferent pathway.

The effect of intravenous clonidine hydrochloride on the isolated forearm venous segment in heart failure.

The effects of intravenous (IV) clonidine (150 micrograms) on the isolated forearm venous segment of ten patients with heart failure were studied. Clonidine reduced pressure in the isolated venous segment of all patients (12.8 +/- 2.1 to 10.6 +/- 1.4 mm Hg, p less than 0.005). In addition, IV clonidine decreased the pressor response to mental arithmetic (2.9 +/- 0.3 mm Hg to 1.8 +/- 0.3 mm Hg, p less than 0.05), while the pressor response to deep breath was slightly enhanced (4.5 +/- 0.8 mm Hg to 6.1 +/- 0.7 mm Hg, p less than 0.05).

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.

Preservation of left ventricular function and coronary flow by angiotensin I-converting enzyme inhibition in the hypertensive-diabetic Dahl rat.

The effect of the angiotensin I-converting enzyme (ACE) inhibitor benazepril (55 mg/kg orally) on the preservation of cardiac performance in diabetic-hypertensive Dahl S rats was investigated. Diabetes mellitus was produced by streptozotocin. Fasting (4-h) blood glucose levels were 279 +/- 50 mg/dL in diabetic Dahl salt-sensitive v 79 +/- 5 mg/dL in nondiabetic Dahl salt-sensitive rats. Cardiac performance was determined at the end of 8 weeks in an isolated perfused working heart apparatus. Peak left ventricular pressure (LVPmax), left ventricular peak negative dP/dt, and coronary flow were depressed in diabetic Dahl S rats (P < or = .05 v control). These deficits in cardiac function were not observed in diabetic Dahl S rats chronically treated with benazepril. The beneficial effects of benazepril apparently were independent of systolic blood pressure reduction. Although plasma ACE activity was increased in diabetic Dahl S rats, plasma renin activity was reduced. This suggests that the beneficial effects of ACE inhibition may be due to an effect upon the kinin system rather than the renin-angiotensin system. The benazepril-associated preservation of cardiac function in this study suggests that ACE inhibitors may be beneficial in the treatment of diabetic heart disease.

Comparative effects of nitrendipine and hydrochlorothiazide on calciotropic hormones and bone density in hypertensive patients.

The effects of the calcium antagonist nitrendipine and the diuretic hydrochlorothiazide on plasma calciotropic hormone concentrations and lumbar bone density were compared during the treatment of hypertension in a randomized, double-blind, 8 week parallel study, followed by a 52 week open label study. There were 32 subjects with stable essential hypertension (sitting diastolic blood pressure > or = 95 mm Hg and < or = 115 mm Hg without medication) without evidence of renal insufficiency or active heart disease. They were randomly assigned to receive either 10 mg nitrendipine twice daily or 50 mg hydrochlorothiazide daily. In order to reach and maintain target blood pressure (diastolic blood pressure < or = 95 mm Hg) during the open label period, the nitrendipine dose was titrated up to 30 mg twice daily, and additional antihypertensive drugs, of differing classes, were added as necessary. Blood samples were analyzed for concentrations of calcium, parathyroid hormone, and calcitonin, and lumbar bone density was determined by dual photon absorptiometry, at the baseline and at 24 and 52 weeks of antihypertensive drug therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of interleukin-2 to alter systolic blood pressure in Dahl salt-sensitive rats.

The effect of interleukin-2 (IL-2) on systolic blood pressure in Dahl salt-sensitive rats was investigated. The treatment group received human IL-2 injections (5000 units/kg). Control animals received subcutaneous saline injections. Both groups of animals were placed on a diet containing 1.5% sodium the day of the first injection and maintained on that diet for the duration of the study. Systolic blood pressure increased in both the IL-2 treated and the control groups (P = .0001) over 7 weeks. The increase in SBP was the same for both groups (P = .8823 for between group differences). At the end of 7 weeks, when SBP in both groups was elevated to a similar degree, the IL-2 group and the control group were each administered 5000 units/kg of IL-2. SBP in both groups remained elevated, showing no decrease over the next two weeks. These results indicate that perhaps unlike in SHR, IL-2 does not alter systolic blood pressure in Dahl salt-sensitive rats.

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.

Relationship between resting metabolic rate and the composition of the fat-free mass.

Although a low resting metabolic rate (RMR) has been shown to be a risk factor for future weight gain, little is known about the mechanisms determining its level. We tested the hypothesis that the composition of the fat-free mass (FFM) is a main determinant of RMR. If this hypothesis is true, a regression model including internal organ masses as independent variables should explain a larger fraction of the variance in RMR than is explained using only FFM as a predictor. We measured fat mass by hydrodensitometry, liver and kidney volumes by computed tomography (CT), heart mass by echocardiography, muscle mass by dual-energy x-ray absorptiometry (DEXA), and RMR by calorimetry in 40 subjects. FFM and fat mass explained 83% of the variability in RMR (standard error of the estimate [SEE], 420 kJ/d) in a multiple regression analysis. Combinations of organ and muscle masses performed as well as but not better than stepwise multiple regression models. The fact that the composition of the lean mass could not improve the prediction of RMR in comparison to the traditional FFM-fat mass model suggests that the weight of internal organs is not a main determinant of RMR. This may indicate that the variability in RMR is associated with variation in energy expenditure per kilogram of tissue of the individual organs.

Intravenous captopril in congestive heart failure.

Hemodynamic and neurohumoral effects of intravenous captopril were studied in ten patients with severe chronic congestive heart failure (NYHA Functional Class III and IV). Incremental bolus doses of captopril, titrated to a maximum cumulative dose of 15 mg, were given at 10-minute intervals. Systemic arterial pressure, mean pulmonary capillary wedge pressure, systemic vascular resistance, mean pulmonary artery pressure, and heart rate decreased (P less than .05). Cardiac index and stroke volume index increased (P less than .05). Maximum hemodynamic effects occurred after cumulative doses of 7 mg and were seen within 30 minutes after initiation of therapy; responses persisted for 30-90 minutes after the last dose. Plasma renin activity increased, and plasma atrial natriuretic factor concentration decreased. No adverse effects were observed with the use of intravenous captopril. Thus, intravenous captopril produces rapid and favorable hemodynamic improvement in advanced heart failure patients.

Efficacy of nicardipine in angina pectoris.

The dose-related efficacy and safety of nicardipine, a new calcium antagonist of the dihydropyridine class, was assessed by exercise tolerance testing in a randomized, double-blinded, placebo-controlled study in 19 patients with chronic, stable effort angina pectoris. Four patients were assigned to each of four treatment sequences receiving nicardipine three times daily in an extended Latin-Square study design. An increase in total exercise capacity, time to onset of angina and time to 1 mm ST segment depression was observed with nicardipine 90 mg/day compared to placebo (P less than .05). Gradual upward dose titration in 30 mg/day increments starting from 30 mg/day appeared to produce maximal increase in exercise capacity. Two patients developed adverse side effects attributable to the drug when administered nicardipine 90 mg/day directly from placebo.

Enkephalin analogs and dermorphin in the conscious dog: structure-activity relationships.

Those structural features of enkephalins (ENK) responsible for in vitro organ bath and receptor binding activity have been investigated in detail in the conscious, chronically instrumented dog. Amide analogs of Leu5-ENK display reduced activity, which is restored by D-Ala2 substitutions. N-terminal L-Tyr is required for full opiate activity. Although proven delta-receptor agonists do appear generally more active, distinctions made in vitro between mu and delta binding are not apparent in the complex hemodynamic responses which occur in the intact unanesthetized dog. The amphibian skin peptide dermorphin, which contains D-Ala2, elevates heart rate, systemic arterial pressure, and induces vomiting with near maximal activity at a dose of 1.0 microgram/kg; this activity is inhibited by naloxone. This activity, coupled with dermorphin's apparent presence in mammalian tissue, suggests that it may represent another peptide factor in cardiovascular regulation. In the conscious dog, ENK elevate heart rate and systemic arterial pressure; this activity does not appear to be fully explained by in vitro receptor models.

Mechanism of the cardiovascular response to systemic intravenous administration of leucine-enkephalin in the conscious dog.

Leucine-enkephalin (Leu5-ENK) (35 micrograms/kg) increased heart rate and mean systemic arterial blood pressure following intravenous injection into chronically-instrumented, conscious dogs. Repeated injections at five-minute intervals were not associated with a diminished response. Naloxone (1 mg/kg) pre-treatment inhibited both heart rate and blood pressure increases. Prazosin (1 mg/kg) attenuated the increase in blood pressure but did not influence the heart rate response. Propranolol (1 mg/kg) attenuated the heart rate response but not the pressor response. Clonidine (30 micrograms/kg) attenuated the positive chronotropic effect of Leu5-ENK. Atropine (1 mg/kg) plus propranolol (1 mg/kg) blocked the heart rate response but the pressor effect was still present. The attenuation of the heart rate response by propranolol and the pressor response by prazosin suggests an adrenergic component to the enkephalin response; the reduction in the heart rate response by clonidine and atropine-propranolol indicates a role for cholinergic mechanisms in the chronotropic response. Hexamethonium (10 mg/kg) blocked the heart rate response and markedly inhibited the pressor response. Vagal interruption attenuated both heart rate and blood pressure responses. It is concluded that intravenous Leu5-ENK stimulates afferent pathways located in fibers which are contained in the vagosympathetic trunk to reflexly increase heart rate and blood pressure.

The influence of the inter-dose time interval on the cardiovascular response to methionine-enkephalin in the conscious dog.

Intravenous injection of methionine-enkephalin (10 micrograms/kg) into the conscious dog increased both heart rate and mean systemic arterial pressure. Progressive shortening of the inter-dose time interval from 5 min to 1 min and then to 30 sec did not alter the response, as the maximal mean systemic arterial pressure elevation was maintained and the maximal heart rate response increased slightly. In contrast to the results after discrete bolus dosing, continuous infusion of methionine-enkephalin at a constant rate of 10 micrograms/kg/min produced an initial elevation in heart rate and mean arterial pressure, but these parameters then began to return toward pretreatment levels despite continuous infusion at the same rate, indicating receptor desensitization. This desensitization pattern is most compatible with receptors of the nicotinic-cholinergic type. These data indicate the importance of dosing techniques in assessing cardiovascular responses to systemically administered enkephalins.