John D. Parker

Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin.

BackgroundVasodilator therapy may be associated with reflex counter-regulatory responses, and these responses may play a role in the development of tolerance to nitroglycerin (GTN). Methods and ResultsStanding systolic blood pressure, body weight, urinary sodium, and hormonal responses to continuous (n = 10) and intermittent (n = 10) transdermal GTN administration were studied in normal volunteers. There was rapid attenuation of the hypotensive response to transdermal GTN therapy in the continuous but not in the intermittent therapy group. Significant weight gain and sodium retention occurred during continuous but not during intermittent GTN therapy. This was accompanied by a greater decrease in hematocrit in the continuous group, a finding that suggests that plasma volume expansion occurred during continuous GTN therapy. Continuous GTN therapy was associated with increases in plasma norepinephrine, atrial natriuretic peptide, arginine, vasopressin, and plasma renin activity. A different pattern of neurohormonal response was seen during intermittent therapy, with values tending to return to baseline levels after the nitrate-free interval. ConclusionsContinuous transdermal GTN therapy leads to counter-regulatory responses associated with sodium retention and probable plasma volume expansion. By contrast, intermittent transdermal GTN therapy is associated with a different pattern of hormonal response, the lack of sodium retention and no evidence of plasma volume expansion. It is likely that these counter-regulatory responses play an important role in the attenuation of nitrate effects.

Morning increase in ambulatory ischemia in patients with stable coronary artery disease. Importance of physical activity and increased cardiac demand.

BackgroundThe morning increase in asymptomatic ambulatory ischemia may be due to heightened coronary tone, increased physical activity, or both. If ambulatory ischemia is primarily due to physical activity, then alterations in the schedule of physical activity should be reflected in a corresponding alteration in the occurrence of ischemia. This study was designed to examine the relation between activity patterns and the frequency of ambulatory ischemic episodes and the effect of nadolol on these relations. Methods and ResultsA double-blind, randomized, placebocontrolled, crossover trial of nadolol versus placebo was performed in 20 patients with stable coronary artery disease. At the end of each 2-week treatment phase, patients were hospitalized for 48 hours. In the hospital, there was a regular activity day (awaken and assume normal activities at 8:00 AM) and a delayed activity day (awaken at 8:00 AM, arise at 10:00 AM, and begin normal activity at noon). Ambulatory ECG monitoring was performed throughout the hospitalization. On the regular activity day, there was a morning increase in heart rate and in the number of ischemic episodes during therapy with placebo that began at 8:00 AM. In contrast, on the delayed activity day, there was a 4-hour phase shift of the increases in heart rate and the increase in ischemic episodes (ie, at noon) corresponding to the onset of physical activities. Therapy with nadolol caused a 50% reduction in the total number of ischemic episodes (129 versus 65, placebo versus nadolol; P < .02). During nadolol therapy, there was no discernible circadian peak in the number of ischemic episodes on either activity day. During placebo treatment, 87% of ischemic episodes were preceded by an increase in heart rate ≤5 beats per minute. Although nadolol caused a significant reduction in the total number of episodes preceded by a heart rate increase compared with placebo (99 versus 38 episodes, P ≤ .04), this therapy was associated with a significant increase in the number of episodes not associated with a heart rate increase (15 versus 21 episodes, P ≤ .002). ConclusionsThe morning increase in ambulatory ischemic episodes is due to physical activity patterns. The majority of ischemic episodes are preceded by a heart rate increase, and it is these episodes that are primarily responsible for the morning increase in ischemia. Therapy with nadolol caused a reduction in the total number of ischemic episodes solely by reducing those episodes preceded by a heart rate increase. In contrast, nadolol caused a significant increase in the number of ischemic episodes not associated with a heart rate increase, perhaps in part because it potentiated coronary vasoconstriction.

Effects of myocardial alpha 1-adrenergic receptor stimulation and blockade on contractility in humans.

BackgroundAlthough α-adrenergic receptors are present in both normal and failing human left ventricular myocardium and mediate a positive inotropic effect in several other species, it is not known whether stimulation of myocardial ca-adrenergic receptors exerts a positive inotropic effect or contributes to basal contractile state in vivo in humans. Methods and ResultsWe studied 15 patients with angiographically normal coronary arteries (seven with normal left ventricular function and eight with left ventricular failure). To avoid the confounding effects of changes in ventricular loading conditions and systemic reflex mechanisms, the α-adrenergic receptor-selective antagonist phentolamine and agonist phenylephrine were infused directly into the left main coronary artery, and the change in contractile state was assessed by measuring left ventricular peak (+)dP/dt. Phentolamine alone had no effect on left ventricular contractility. Phenylephrine exerted a concentration-related positive inotropic effect in patients with normal as well as those with failing ventricles. The a,adrenergic effect of phenylephrine, defined as the component blocked by phentolamine, was significantly less in patients with ventricular failure (108 ± 28 mm Hg/sec) than in normal subjects (248 ± 54 mm Hg/sec; p < 0.03). ConclusionsMyocardial α-adrenergic receptors do not contribute to the maintenance of basal left ventricular contractile state in humans. However, stimulation of myocardial α-adrenergic receptors exerts a positive inotropic effect, the magnitude of which may be attenuated in patients with heart failure.

Effect of therapy with an angiotensin-converting enzyme inhibitor on hemodynamic and counterregulatory responses during continuous therapy with nitroglycerin

OBJECTIVESnWe sought to characterize the reflex counterregulatory responses throughout a 6-day period of continuous nitroglycerin therapy and to examine the effect of concurrent administration of a non-thiol angiotensin-converting enzyme inhibitor (benazepril) on the nature of those responses.nnnBACKGROUNDnTherapy with nitroglycerin has been shown to be associated with reflex counterregulatory responses.nnnMETHODSnStanding systolic blood pressure, hormonal responses, urinary sodium and hematocrit levels were monitored during 6 days of continuous transdermal nitroglycerin therapy in normal volunteers. Using a double-blind randomized parallel design, 11 subjects received placebo and 9 received benazepril. Hemodynamic responses to sublingual nitroglycerin administration were evaluated before and after sustained therapy with transdermal nitroglycerin.nnnRESULTSnAttenuation of the hypotensive response to transdermal nitroglycerin was rapid in the group receiving placebo and the group receiving benazepril. There were no significant hormonal responses to transdermal nitroglycerin in either group, and sodium retention was modest and transient. Hematocrit levels decreased after transdermal nitroglycerin therapy and remained depressed for the duration of nitroglycerin therapy, a finding that suggests plasma volume expansion. Blood pressure responses to sublingual nitroglycerin in both groups were similar before and after continuous transdermal nitroglycerin therapy.nnnCONCLUSIONSnThese data suggest that plasma volume expansion plays a more important role than neurohormonal responses in the loss of nitrate effects during sustained therapy. That therapy with an angiotensin-converting enzyme inhibitor did not modify the hemodynamic responses to continuous nitroglycerin therapy supports this conclusion. Further investigation will be necessary to confirm whether therapy with an angiotensin-converting enzyme inhibitor has any role in the prevention of nitrate tolerance.

Effects of intracoronary acetylcholine and atropine on basal and dobutamine-stimulated left ventricular contractility.

BACKGROUNDnThe role of cholinergic pathways in modulating left ventricular contractile function in humans is not known. This study evaluated the effect of a cholinergic agonist (acetylcholine) and antagonist (atropine) on basal and beta-adrenergically stimulated left ventricular contractile function in normal subjects and subjects with denervated hearts after cardiac transplantation.nnnMETHODS AND RESULTSnSix subjects with normal left ventricular function and seven subjects who were 1 to 3 years after cardiac transplantation were studied. Acetylcholine, atropine, and the beta-adrenergic agonist dobutamine were infused via the left main coronary artery, and changes in left ventricular contractile function were assessed by measurement of peak +dP/dt. Intracoronary dobutamine increased +dP/dt by 70 +/- 15% and 66 +/- 20% in the normal subjects and transplant recipients, respectively. Intracoronary acetylcholine and atropine alone each had no effect on left ventricular +dP/dt in either normal subjects or transplant recipients. The concurrent infusion of acetylcholine with dobutamine reduced the response to dobutamine by 66 +/- 10% and 79 +/- 9% in normal subjects and transplant recipients, respectively. The concurrent infusion of atropine with dobutamine potentiated the response to dobutamine by 25 +/- 7% in normal subjects but had no effect in transplant recipients.nnnCONCLUSIONSnStimulation and inhibition of cholinergic receptors in the human heart can modulate the positive inotropic response to beta-adrenergic stimulation.

Effects of diuretic therapy on the development of tolerance during continuous therapy with nitroglycerin

OBJECTIVESnThis study examined the effects of concurrent diuretic therapy on the hemodynamic responses to short-term and sustained therapy with transdermal nitroglycerin.nnnBACKGROUNDnSodium retention and plasma volume expansion occur during therapy with nitroglycerin and may play a role in the loss of nitroglycerin effects during sustained therapy.nnnMETHODSnTwenty-two normal male volunteers were treated for 1 week with either hydrochlorothiazide and amiloride (50 + 5 mg) (n = 11) or placebo (n = 11) in a randomized, double-blind fashion. All 22 subjects then received continuous transdermal nitroglycerin (19 +/- 1 mg/24 h) for 5 to 7 days.nnnRESULTSnOn the first and last day of transdermal nitroglycerin therapy, standing heart rate, systolic blood pressure and hematocrit values were assessed at 8, 9 and 10 AM and 12 noon. Heart rate and blood pressure responses to sublingual nitroglycerin (0.6 mg) were also evaluated before and after sustained transdermal nitroglycerin therapy. A significant loss of the hemodynamic effects of transdermal and sublingual nitroglycerin occurred during sustained therapy in both the diuretic and placebo therapy groups. In both groups, transdermal nitroglycerin therapy was associated with a significant decrease in hematocrit that persisted for the entire treatment period.nnnCONCLUSIONSnThese results suggest that diuretic therapy does not prevent plasma volume expansion or the loss of hemodynamic effects during sustained transdermal nitroglycerin therapy. The persistent decrease in hematocrit suggests that plasma volume expansion plays a role in the attenuation of nitrate effects. It also provides evidence of continued vascular activity of nitroglycerin despite loss of systemic hemodynamic effects.

Neurohormonal activation during nitrate therapy: A possible mechanism for tolerance

The hemodynamic and antianginal effects of the organic nitrates are greatly reduced during therapy designed to provide 24-hour protection throughout each day. Although the mechanisms of tolerance are not clearly understood, it is likely that tolerance is related to a combination of reduced sulfhydryl groups in vascular smooth muscle and neurohormonal activation. These changes would reduce nitrate-induced vasodilation and induce sodium and water retention with an increase in plasma volume. These reflex neurohormonal changes would reduce the hemodynamic effect of any given degree of nitrate-induced vasodilation. Although preliminary studies suggest that diuretic therapy or the use of converting enzyme inhibitors may reduce or abolish tolerance, further clinical studies are required to confirm these findings.

Serial assessment of left ventricular function and mass after orthotopic heart transplantation: A 4-year longitudinal study

Long-term changes in left ventricular performance and geometry in the transplanted human heart have been incompletely described. Therefore, two-dimensional echocardiograms were performed on 22 recipients of an orthotopic heart transplant at 1 month (32 +/- 20 days), 1 year (11 +/- 3 months) and 4 years (54 +/- 9 months) after transplantation. All studies were performed at a time when the patient had no pathologic evidence of rejection. Ten healthy men served as a normal control group. Over 4 years of follow-up, mean systolic blood pressure in the study patients increased from 121 +/- 12 (p = NS vs. values in the control group) to 139 +/- 11 mm Hg (p less than 0.05 vs. both control values and values at 1 month); mean diastolic blood pressure increased from 72 +/- 7 (p = NS vs. normal values in the control group) to 93 +/- 8 mm Hg (p less than 0.05 vs. both control values and values at 1 month). Left ventricular end-systolic volume increased from 42 +/- 10 (p = NS vs. control values) to 51 +/- 14 ml (p less than 0.05 vs. both control values and values at 1 month) and end-diastolic volume increased from 103 +/- 28 (p = NS vs. control values) to 112 +/- 27 ml (p less than 0.05 vs. control values) over 4 years. Left ventricular mass and ejection fraction did not change significantly within the patient cohort and remained similar to that found in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimation of mitral valve area from regression analysis of the pressure gradient in mitral stenosis

Estimation of mitral valve area (MVA) in the cardiac catheterization laboratory is prone to pitfalls because of the time required for calculations and inaccuracies in the measurement of cardiac output. Because the rate of decrease in the mitral gradient directly correlates with the severity of mitral stenosis, an on-line estimate of MVA at the time of catheterization may be possible with regression analysis of digitized pressure recordings. A total of 61 comparisons of mitral gradient measurements and MVA were obtained in 37 patients at diagnostic catheterization and in 24 patients after balloon mitral valvotomy. Linear and nonlinear regression parameters yielded pressure half-time values and empiric constants similar to those used in Doppler echocardiography for estimation of MVA. The correlations derived from linear analysis were as good as those obtained from nonlinear analysis: from linear analysis, MVAregression = 0.79.MVAGorlin -0.03; r2 = 0.64, p = 0.0001; and from double exponential analysis, MVAregression = 0.86.MVAGorlin -0.07; r2 = 0.74; p = 0.0001. The correlations were not significantly affected by the presence of mild to moderate mitral regurgitation or whether they were obtained after balloon valvotomy. In summary, linear regression analysis yields accurate estimates of MVA despite the theoretical superiority of nonlinear methods. On-line digital analysis of mitral gradient tracings may thus be useful at the time of diagnostic cardiac catheterization or balloon mitral valvotomy to assess the severity of mitral stenosis and the response to interventions.

958-93 Prevention of Mental Stress-induced Wall Motion Abnormalities by Nifedipine GITS and Atenolol Therapy

Previous investigators have demonstrated that mental stress can induce myocardial ischemia in selected patients with coronary disease manifested by new wall motion abnormalities on radionuclide ventriculography. It is unknown whether such ischemia is due to coronary vasoconstriction or to increased myocardial O2demand. We studied the effect of nifedipine GITS and atenolol as single-agent therapy on mental stress-induced ischemia in a double-blind. placebo-controlled, three-way crossover trial in 16 patients with stable angina. Each patient received maximally tolerated doses of nifedipine (mean daily dose: 88xa0mg). atenolol (mean daily dose: 91xa0mg) or placebo during each of 3 4-week treatment phases. At the end of each phase, patients underwent a mental stress procedure (Stroop color word test, mental arithmetic, and stress interview) with skin conductance monitored to gauge physiologic arousal. Left ventricular wall motion was graded in each of 5 regions using a scale from 3 (normal) to -1 (dyskinesis), and by regional ejection fraction. The segment with the largest deterioration in wall motion during placebo therapy was determined, and the effects of nifedipine and atenolol on this segment were compared. Results Mental stress caused a significant increase in skin conductance levels, with peak values similar on each therapy. Therapy with either nifedipine or atenolol prevented a deterioration in wall motion score (-0.6 for placebo; 0.0 for nifedipine. 0.0 for atenolol, each pxa0lxa00.01 vs. placebo). while only nifedipine prevented a significant decrease in regional ejection fraction (-13.0% on placebo; -5.6% for atenolol, pxa0=xa00.08 vs. placebo; -1.9% on nifedipine, pxa0=xa00.01 vs placebo, pxa0=xa00.4 vs. atenolol). The rate pressure product (heart rate x systolic blood pressure. RPP) at peak mental stress (i.e., peak myocardial O2demand)was 15.792 on placebo, and was reduced only by atenolol (12,287, pxa0=xa00.001). but not by nifedipine (15,185, pxa0=xa0NS). Conclusion Both nifedipine GITS and atenolol are effective at preventing mental stress-induced ischemic wall motion abnormalities. although the mechanisms may be different. Nifedipine improved reg’lonal wall motion without reducing RPP. and thus may have prevented mental stress-induced coronary vasoconstriction. Atenolol improved regional wall motion and reduced RPP. and thus may have been effective by reducing myocardial O2demand.