Lack of cross-tolerance to short-term linsidomine in forearm resistance vessels and dorsal hand veins in subjects with nitroglycerin tolerance.

BACKGROUND: Therapy with nitroglycerin is widely used in the treatment of angina pectoris, but development of tolerance is a major problem. Nitrovasodilators other than nitroglycerin may be less prone to induce vascular tolerance. This investigation was designed to test whether the alternative nitric oxide donor linsidomine maintains its vasodilator effects in the presence of nitroglycerin tolerance. METHODS: We tested the vascular effects of nitroglycerin and linsidomine (SIN-1) in forearm resistance arteries (venous occlusion plethysmography) and hand veins (venous compliance technique) using a randomized, double-blind placebo-controlled regimen in 33 healthy subjects (age range, 22 to 38 years; mean age, 26 years) before and after 7 days of assignment to either 1 week of nitroglycerin administration (0.83 mg/hr) for induction of tolerance or placebo administration. RESULTS: Vascular responses of both vascular beds to nitroglycerin (in veins: mean difference, 42.3%; confidence interval [CI], 3% to 81.7%; p < 0.05; in arteries: mean difference, 65.0%; CI, 38.9% to 91.1%; p < 0.01) but not to linsidomine (in veins: mean difference, -13.8%; CI, -53.5 to 25.8%; not significant; in arteries: -19.7%; CI, -33.7% to -5.6%; not significant) were attenuated in the nitroglycerin patch group, whereas the placebo group showed no differences to either nitroglycerin (in arteries: mean difference, -7.5%; CI, -44.6% to 29.6%; in veins: -10.6%; CI, -58.2% to 36.9%) or linsidomine (in arteries: 4.5%; CI, -12.8% to 21.7%; in veins: -13.1%; CI, -4.5% to 29.8%). CONCLUSION: These results suggest that short-term administration of sydnonimines can overcome the loss of vascular relaxation associated with long-term nitroglycerin therapy.

Isradipine improves endothelium-dependent vasodilation in normotensive coronary artery disease patients with hypercholesterolemia.

OBJECTIVE: The dihydropyridine calcium antagonist isradipine has anti-atherosclerotic effects in animals and improves endothelium-mediated nitric oxide (NO)-dependent vasodilation in vitro. As improved endothelial function may be beneficial we investigated its effects in patients with a high likelihood of endothelial dysfunction. DESIGN: Thirty patients (two female, age 55.4 +/- 10.5 years) with known coronary artery disease and elevated (> 6 mmol/l) total cholesterol (cholesterol: mean 6.7 +/- 0.78 mmol/l) or a cholesterol/high density lipoproteins (HDL) ratio of > 5 not on lipid lowering therapy, participated in the study. Endothelial vasodilator function was assessed before and after double-blind, randomized administration of isradipine 5 mg/day or placebo for 3 months. METHODS: Endothelial function was assessed as forearm blood flow (FBF, venous occlusion plethysmography) responses to graded brachial artery infusions of acetylcholine (Ach), to the NO-synthase blocker NG-monomethyl-L-arginine (L-NMMA) and to the endothelium-independent vasodilator sodium nitroprusside (SNP). Blood pressure was measured either directly from the brachial arterial or by sphygmomanometer during clinic visits. RESULTS: Blood pressure was unchanged in both groups after 3 months (isradipine: 88.8 versus 92.1 mmHg; placebo: 81.0 versus 82.5 mmHg; NS) but cholesterol levels decreased similarly in both groups (isradipine: 6.7 versus 6.1 mmol/l, NS; placebo: 6.6 versus 5.9 mmol/l, P< 0.05). The vasodilator response to SNP and the decrease in FBF in response to blockade of NO synthesis by L-NMMA were unchanged in both groups. However, isradipine, but not placebo, enhanced the NO-dependent vasodilator response to Ach (P < 0.05). CONCLUSION: Isradipine improves acetylcholine-mediated vasodilation in hypercholesterolemic patients independent of changes in lipids or blood pressure.

Cyclosporine A and control of vascular tone in the human forearm: influence of post-transplant hypertension.

OBJECTIVE: The use of cyclosporine A after organ transplantation is associated with a high incidence of hypertension, but the underlying mechanisms for this process are not clear. We investigated the effects of blockade of basal release of endothelial nitric oxide and the effects of endothelium-independent and -dependent vasodilators and vasoconstrictors in patients treated with cyclosporine A after heart transplantation. DESIGN: We measured blood pressure and forearm blood flow responses to brachial artery infusions of NG-monomethyl-L-arginine (L-NMMA), sodium nitroprusside, acetylcholine, norepinephrine and vasodilating and vasoconstricting doses of endothelin-1 in eight patients early (< 3 months) and in 11 patients late (> 18 months) after transplantation. RESULTS: Diastolic blood pressure was higher late after transplantation, but calculated forearm vascular resistance was lower (P < 0.01). Thus, increased forearm vascular resistance does not contribute to the increase in blood pressure. The vasoconstrictor response to L-NMMA was similar in both groups but a reduced endothelium-dependent vasodilator response to acetylcholine was seen late after transplantation. However, impaired smooth muscle responsiveness to nitric oxide may have contributed to this finding, since the response to sodium nitroprusside tended to be reduced. Vasoconstrictor responses to norepinephrine and endothelin-1 were comparable but no vasodilation was seen with low doses of endothelin-1 late compared with early after transplantation (P < 0.05). CONCLUSIONS: The findings in the forearm circulation question the concept of generalized increases in vasoconstrictor responses or a disturbance of tonic, basal release nitric oxide in the pathogenesis of cyclosporine-A-induced hypertension. Although the forearm vasodilator responses to the stimulation of endothelial nitric oxide production and release by acetylcholine, and to low doses of endothelin-1, were impaired, these findings could be explained by the increase in blood pressure rather than cyclosporine A itself.

Atrioventricular block after administration of atropine in patients following cardiac transplantation.

BACKGROUND: Atropine is widely used as a parasympatholytic agent during diagnostic and therapeutic procedures. We observed an unexpected paradoxical response to atropine after cardiac transplantation. METHODS: In a study investigating the occurrence of autonomic reinnervation after cardiac transplantation, atropine, at 0.015 mg/kg body weight, was given intravenously to 23 patients (mean age, 56+/-8 years) 98 days to 6.4 years after transplantation. RESULTS: Two patients experienced a witnessed syncope 40 and 150 min after administration of atropine. Second-degree atrioventricular (AV) block was documented in the first patient immediately afterward, and third-degree AV block was seen on 24-hr electrocardiogram monitoring in the second patient. A third patient developed documented AV block 15 min after atropine but experienced no sequelae because of a previously implanted pacemaker. CONCLUSIONS: Although the underlying mechanism is not clear, these findings suggest that atropine may paradoxically cause high-degree AV block in patients after transplantation. Accordingly, it should be used with caution and appropriate monitoring in these patients.

Circadian variations of blood pressure and heart rate early and late after heart transplantation.

Cardiac reinnervation late after heart transplantation has been reported in individual patients. As a measure for reinnervation, circadian changes in arterial blood pressure and heart rate have been used but not yet systemically evaluated in cardiac transplant recipients. Ambulatory blood pressure and heart rate monitoring was performed in 62 patients for 24 hr early (<6 months, mean 26 days, range 5-90 days, n=30) and late (> or = 6 months, mean 12 months, range 7-78 months, n=32) after heart transplantation. A loss of physiological nocturnal decline in blood pressure and heart rate was noted early after transplantation, whereas late after operation an improvement in circadian changes of blood pressure and heart rate was observed. The patients late after heart transplantation had a significant higher diastolic blood pressure. A pathological circadian blood pressure and heart rate pattern was observed in patients early after heart transplantation, which was improved late after operation. This could be explained by partial reinnervation of the heart. Diastolic hypertension late after transplantation may be due to cyclosporine treatment and/or neuroendocrine hyperactivity.

Relative frequency of functional sympathetic and parasympathetic reinnervation after heart transplantation.

Although there is evidence of partial sympathetic reinnervation late after transplantation, little is known about the relative frequency of sympathetic and, in particular, parasympathetic reinnervation. We examined the heart rate response to various maneuvers (standing up, handgrip exercise, phase 2 of Valsalva maneuver for sympathetic function, carotid sinus massage, phase 4 of Valsalva maneuver, and atropine for parasympathetic function) in 65 patients 3 to 110 months after transplantation and in 16 healthy volunteers and defined reinnervation as either one normal (>50% of control group) and at least one partial (>33% of control group) heart rate response or partial responses in all three tests of the respective part of the autonomic nervous system. Thirty-five (54%) patients had sympathetic reinnervation, but only 16 (25%) had parasympathetic reinnervation (p < 0.001); earliest reinnervation was found 11 months after transplantation, and all but one patient with parasympathetic reinnervation also had sympathetic reinnervation. Signs of sympathetic but not parasympathetic reinnervation were common late (>5 years) after transplantation (74% vs 30%).

Transcutaneous measurement of oxygen and carbon dioxide tension (TcPO2 and TcPCO2) during treadmill exercise in patients with arterial occlusive disease (AOD)--stages I and II.

Transcutaneous oxygen and carbon dioxide tensions were measured during treadmill exercise in 30 patients with stages I and II arterial occlusive disease and 28 normal controls. Measuring sites were the dorsum of the foot and the frontal thorax. The calculated oxygen index at maximum exercise/rest (foot/thorax) differentiated with 100% sensitivity and specifity between the two groups. The oxygen index was the only parameter with a significant positive correlation with the pain-free walking distance, whereas, eg, oscillography and Doppler analysis did not correlate. Carbon dioxide tensions showed significant differences only in the recovery time between patients and normal controls.

[Transcutaneous oxygen pressure in the foot in treadmill stress before and after percutaneous atherectomy]. / Transkutaner Sauerstoffdruck am Fuss unter Laufbandbelastung vor und nach perkutaner Atherektomie.

Transcutaneous oxygen pressure (tcPO2) on the dorsum of the foot and Doppler ankle/arm pressure ratio (AAR) were measured in nine patients with peripheral arterial occlusive disease (PAOD)-stage IIb-III during treadmill exercise before and after (two days and one month) atherectomy. These parameters were compared with nine normal controls and nine PAOD I-IIa patients without atherectomy. All patients with atherectomy showed an increase in their pain free walking distance, and, both two days and one month after the intervention, a significant (p less than 0.05) increase in their exercise/rest tcPO2 ratio (pre-atherectomy: 25% (12-81), two days after: 78% (49-92), one month after: 85% (81-92). AAR displays a significant increase only between pre- and two days after atherectomy, without further significant improvement after one month. We conclude that tcPO2 measurement is an adequate measurement for follow-up studies in patients with PAOD after invasive therapeutic interventions. Furthermore, these data suggest that, while the maximum improvement for the macrocirculation (AAR) occurs shortly after atherectomy, improvement of the microcirculation (tcPO2) is delayed for a prolonged period after revascularization of major arteries, possibly due to reperfusion injury.

[A plea for the foundation of a counseling center for people using artificial respiration and their relatives]. / Ein Plädoyer für die Einrichtung einer Beratungsstelle für Menschen mit Beatmung und deren Angehörige.

BACKGROUND AND AIMS: Since the 1980s the group of people surviving with the aid of artificial respiration has expanded. So far, however, no information centre for such persons exists in Germany. Likewise, peer counselling is not a widely accepted method of allocating responsibility to afflicted persons. The task of an information centre would be to provide peer counselors who would advise people on artificial respiration. PATIENTS AND METHODS: Interviews with subjects and their relatives regarding the various aspects of artificial respiration. CONCLUSION: The foundation of such a counselling centre is recommended on account of the present need for a national information exchange and contact centre.

Circadian pattern of blood pressure and heart rate in the longer term after heart transplantation.

A loss of the circadian rhythm pattern of the blood pressure (BP) and heart rate (HR) as well as the development of hypertension has been found after heart transplantation (Htx). To determine whether a reappearance of this rhythm occurs in the long term after Htx, we used 24-h ambulatory monitoring to study 27 patients 1.7+/-1.6 years (range of 10 days to 4.3 years) after Htx. Patients were divided into two groups: group I (short term), Htx less than 6 months (n = 7); and group 2 (long term), Htx more than 6 months previously (n = 20). Group 2 had significantly higher diastolic BP as well as a greater fall in systolic BP during the night (-0.4+/-8.0 vs. 9.0+/-7.2 mm Hg, p < 0.01). There was also a higher day HR found in group 2 (73.2+/-14.5 vs. 96.8+/-12.5 beats/min, p < 0.001) as well as a larger fall in night HR in group 2 (4.2+/-5.5 vs. 11.9+/-4.9 beats/min, p < 0.005). The return of the circadian rhythm pattern in the longer term after Htx may result from partial reinervation of the heart, although other neurohumoral factors or concomitant medication (lower steroid dosages) may play a role.

[Return of circadian blood pressure and heart rate changes in patients with heart transplants]. / Rückkehr des zirkadianen Blutdruck- und Herzfrequenzverhaltens bei Herztransplantierten.

A loss of the circadian rhythm pattern of blood pressure (BP) and heart rate, as well as the development of hypertension have been found after heart transplantation (Htx). To study whether a return of this rhythm occurs in the long-term after Htx, we used 24-h ambulatory monitoring to study 62 patients 5 days to 6.5 years after Htx. Patients were divided into two groups (Group 1: less than 6 months after Htx (n = 30), Group 2: 6 months or more after Htx (n = 32)). Group 2 had a higher BP and heart rate, as well as a significantly higher difference between systolic day and systolic night BP than group 1. There was also a significantly higher difference in heart rate between day and night values in group 2. The return of the circadian rhythm pattern in the longer term after heart transplantation may result from partial reinnervation of the heart, although other neurohumoral factors or concomitant medication may play a role.