The influence of dose of angiotensin I-converting enzyme inhibitor on systolic blood pressure variability in heart failure: a substudy of the Assessment of Treatment with Lisinopril and Survival in heart failure (ATLAS) trial.

UNLABELLED: Heart failure is associated with a decreased variability in circadian systolic blood pressure. ACE inhibitors have been shown to be beneficial in CHF. However, the effect of the magnitude of the dose of ACE inhibitor on blood pressure variability has not been reported. The objective of this sub-study of the ATLAS trial was to determine if there was a difference in effect on systolic blood pressure variability of two doses (35mg, 'high'; and, 5mg, 'low') of the ACE inhibitor, lisinopril, in patients with heart failure (class II-IV; NYHA). Criteria for inclusion were: symptomatic heart failure (class II-IV; NYHA), left ventricular ejection fraction < or = 30%, and 2 months of conventional therapy with diuretics with, or without, digoxin. Twenty-four hour ambulatory blood pressure was recorded prior to randomization and after peak titration (4 weeks) of the study drug for analysis of variability of systolic blood pressure variability. The high dose of lisinopril was associated with greater variability of 24 h systolic blood pressure as noted by inspection of the 24 h recordings or calculation of the blood pressure variability index (P < 0.05). The greater variability in SBP was not associated with a difference in mean 24 h arterial blood pressure. CONCLUSIONS: Variation in circadian systolic blood pressure is useful in reflecting the influence of the magnitude of dose of the ACE inhibitor lisinopril on the pharmacodynamics of patients with heart failure.

Coronary vasodilator responses to bradykinin in euglycemic and diabetic rats.

Diabetes mellitus is associated with endothelial dysfunction that is believed to result in impaired release of vasoconstrictor and vasodilator substances from the endothelium and thereby diminished reactivity of many vascular beds. This study was designed to characterize bradykinin (BK)-induced coronary vasodilation in normal and diabetic rats. Bradykinin-stimulated vasodilation of the rat coronary vasculature is mediated by a cytochrome P450-1A (CYP-1A)- inhibitable metabolite that activates KCa, but not KATP, channels on the coronary vascular smooth muscle. Although BK stimulates the release of nitric oxide from the vascular endothelium, the released nitric oxide and its ability to stimulate guanylate cyclase only modulates the duration of, rather than the magnitude of, BK-induced coronary vasodilation. Twelve weeks of streptozotocin-induced diabetes did not affect the coronary vascular responses to BK or the components that mediate BK-induced vasodilation (ie, K-channel activation, nitric oxide-guanylate cyclase). The data support the conclusions that the coronary vasodilator response of the rat to BK is CYP-1A and KCa-channel mediated, that coreleased nitric oxide only modulates the duration of BK-induced vasodilation, and that these mechanisms are unaffected by moderate diabetes.

Echocardiographic texture analysis using the wavelet transform: differentiation of early heart muscle disease.

Echocardiographic quantitation of myocardial texture for diagnosis of early cardiomyopathy (CMP) remains problematic. Conventional statistical methods are limited, contributed by a small image region-of-interest (ROI) and difficulty in discrimination from noise. This study was performed to evaluate the 2-D Haar wavelet decomposition method as a tool to identify textural changes in a rat model of early CMP, focusing on changes that occur before development of M-mode structural abnormalities. Early diabetic CMP, ethanol CMP and diabetic-ethanol CMP rat models were evaluated. Echocardiography was performed on two groups of rats. Group I (5 week cohort, n = 4 per subgroup) included controls, rats on 12% ethanol, a diabetic subgroup, and diabetic rats on 4% ethanol. Group II (10 week cohort, n = 5 per subgroup) included the same categories as group I with an additional subgroup taking 4% ethanol was also studied. M-mode left ventricular measurements were comparable in all subgroups of group I. However, diabetic rats in group II had an increased left ventricular dimension (LVD) compared to all others and an increased septal dimension (IVSD) and posterior wall dimension (PWD) were noted in the 4% and 12% ethanol groups. End-diastolic digital images of all rats in the parasternal short axis view, at the papillary muscle level, were downloaded to a computer. A 16 x 16 (ROI) was selected from the anterior interventricular septum. Although standard statistical methods could not differentiate any of the groups, calculation of textural energy and normalized textural energy with the 2-D Haar wavelet decomposition method found at 5 weeks increased normalized texture energy in diabetics compared to all others. At 10 weeks increased texture energy was noted in diabetics. Diabetic-ethanol rats at both 5 and 10 weeks revealed a blunted textural energy compared to diabetic rats. In a rat model of diabetic cardiomyopathy, the 2-D wavelet decomposition method identified textural energy changes before development of echocardiographic structural changes. Ethanol-associated blunting of textural changes in diabetic rats was also noted. This method for quantitation of ventricular texture may be relevant for diagnosis of early cardiomyopathy.

Protein kinase C isozymes in skeletal muscles during the early stage of genetic and streptozocin diabetes.

This study examined the changes in PKC isozyme activity, content, and cellular distribution in rat gastrocnemius and soleus muscles prior to any evidence of neural degeneration or impaired skeletal muscle function, during the onset of streptozocin-induced (STZ) and genetic diabetes mellitus (DM). PKC activity was increased more in the particulate than in the soluble fractions of the soleus and gastrocnemius muscles obtained from rats treated with STZ and the gastrocnemius muscle obtained from BB-Wor diabetic rats (D rats). The predominant constitutive PKC isozymes in the skeletal muscles obtained from the STZ-treated and D rats were PKCalpha >> PKCepsilon > PKCdelta as determined by Western immunoblot assay. The content of each PKC isozyme did not differ between the soleus and gastrocnemius muscles of the control Sprague-Dawley rats for the STZ-treated rats and the BB Wor diabetic resistant (DR) rats. Moreover, the PKC isozyme content did not differ in the soluble fraction of D or STZ rats when compared to their corresponding control animals. PKCdelta increased more than PKCalpha or PKCepsilon in the particulate fraction of gastrocnemius and soleus muscles when obtained from either D or STZ rats. Since similar changes in skeletal muscle PKC isozyme profiles occurred independent of the duration of the diabetes and thereby the degree of nerve degeneration, insulin resistance, and the model of DM tested, we conclude that changes in skeletal muscle PKC precede the skeletal muscle myopathy of DM.

Changes in protein kinase C in early cardiomyopathy and in gracilis muscle in the BB/Wor diabetic rat.

Hyperglycemia can upregulate protein kinase C (PKC), which may be an important mediator of the progression from normal heart and muscle function to diabetic myopathy in the myocardium and skeletal muscle in type 1 insulin-dependent diabetes mellitus (IDM). We evaluated this possibility during the early stage of IDM in BB/Wor diabetic (D) rats and age-matched BB/Wor diabetes-resistant (DR) rats. Interventricular septal thickness, E wave peak velocity of tricuspid inflow (both minimum and maximum), and left ventricular (LV) weight index were increased, and the rate of change in LV pressure (LV dP/dt) decreased in D rats subjected to M-mode and two-dimensional echocardiography and hemodynamic recording of heart rate, LV pressure (LVP), + LV dP/dt, -LV dP/dt, and LV end-diastolic pressure (LVEDP) in vivo and in vitro 41 days after the onset of hyperglycemia. Whole ventricle basal PKC activity was increased by 44.4 and 18.4% in the particulate and soluble fractions, respectively, from D rats compared with that from DR rats using r-32P phosphorylation of appropriate peptide substrates. When measured by Western blot gel densitometry, particulate PKC-alpha and PKC-delta content increased by 89 and 24%, respectively, but soluble PKC-beta and soluble and particulate PKC-epsilon were unchanged compared with that of DR rats. Similarly, gracilis muscle PKC activity and PKC-alpha and PKC-delta were elevated in the gracilis muscle, whereas that of the circulating neutrophil did not differ between the D and DR rats. Thus, in vivo, the early diabetic cardiomyopathy of the D rat is characterized by a restrictive LV with increased septal thickness and is associated with elevated PKC activity and increased amounts of myocardial particulate PKC-alpha and PKC-delta, which are also seen in the skeletal muscle. We conclude that increased PKC isozymes may play a pivotal role during IDM in the development of diabetic cardiomyopathy and skeletal muscle myopathy.

Detection of right to left shunts in decompression sickness in divers.

The diagnostic accuracy of bubble contrast transthoracic and transesophageal echocardiography and transcranial Doppler sonography in the detection of patent foramen ovale in divers with decompression sickness was assessed. Transcranial Doppler has a better positive and negative predictive value than the other modalities.

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.

Acute hypotension alters hemodynamic response to methionine-enkephalin in conscious dogs.

In the conscious dog, intravenous administration of methionine-enkephalin produces simultaneous increases in both heart rate (HR) and mean arterial blood pressure (MAP). This report describes both depressor and cardioaccelerator responses to methionine-enkephalin (10 micrograms/kg IV) in conscious dogs following acute hypotension induced by either bolus injection of isoproterenol (0.1-5.0 micrograms/kg IV) or infusion of sodium nitroprusside (SNP, 3-8 micrograms/kg/min). Cardiovascular responses to methionine-enkephalin were blocked by naloxone. Pretreatment of the dogs with the beta-adrenergic receptor antagonist propranolol failed to prevent the hypotensive response to methionine-enkephalin following SNP infusion. The results indicate that the hemodynamic responses to methionine-enkephalin can be altered by acute manipulation of blood pressure. These results may have implications relative to the role of endogenous opiates in regulation of blood pressure, especially in acute hypotensive states.

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.

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.

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)

Hemodynamic actions of endothelin in conscious and anesthetized dogs.

The newly described endogenous peptide, endothelin, was administered to five chronically instrumented conditioned dogs. Endothelin produced significant and simultaneous increases in both heart rate (HR) and mean arterial pressure (MAP) in conscious dogs. Endothelin also produced significant increases in MAP in anesthetized animals. Ganglionic suppression induced by hexamethonium (10 mg/kg) and atropine (0.1 mg/kg) blocked HR responses and markedly inhibited the pressor responses to endothelin in conscious animals. These results suggest that endothelin in part acts to elevate blood pressure and heart rate through modification of autonomic nervous system tone. When endothelin and angiotensin II were administered in mole equivalent doses, angiotensin II produced a pressor response of greater magnitude than did endothelin in conscious animals.

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.

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.

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.

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)

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.

Effects of acetaldehyde condensation products on human platelet aggregation.

Condensation products (CP) of the ethanol metabolite, acetaldehyde, and endogenous amines, such as dopamine and serotonin, have been proposed to be effectors of some symptoms of chronic ethanol use. Since hemostatic defects are known to occur in chronic ethanol use, the effects of CP on in vitro human platelet aggregation responses induced by several agents were determined. Both isoquinoline and beta carboline type CP significantly inhibited aggregation responses induced by epinephrine, with the concentrations to produce 50% inhibition ranging from 8-347 uM. The beta-carbolines significantly inhibited ADP-induced aggregation and also inhibited aggregation induced by collagen or arachidonic acid, but at high concentrations. Effects on epinephrine aggregation and ADP aggregation were reversible. Potential mechanisms of the inhibitory effects were briefly examined. Concomitant use of the phosphodiesterase inhibitor theophylline potentiated the effect of some but not other CP, possibly indicating an involvement of cyclic AMP. Concomitant use of the non-specific beta-adrenergic inhibitor propranolol had no effect on CP inhibition, indicating that CP probably do not stimulate platelet adenylyl cyclase-coupled beta 2-adrenoceptors. Thus, general inhibition by CP of platelet responses in the circulation is unlikely, except, possibly, for epinephrine-induced aggregation, because of the high concentrations of CP required. However, local regulation of platelet responses by release of stored CP during aggregation is possible since CP are stored in platelet dense granules.

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.