Jay D. Coffman

Total and Capillary Fingertip Blood Flow in Raynaud's Phenomenon

Abstract Total (plethysmography) and capillary (radioisotope disappearance rate) fingertip flows were measured in 24 patients with Raynauds phenomenon and compared to 10 normal subjects in a warm room and during reflex sympathetic nerve stimulation by body cooling. Arteriovenous shunt flow was estimated by subtraction of capillary from total flow. Patients with Raynauds phenomenon had a significantly smaller capillary flow in both warm (6.4 vs. 10 ml per 100 g per minute) and cool (4.0 vs. 7.0 ml) rooms than normal subjects. With body cooling, total and arteriovenous shunt flow, but not capillary flow, decreased significantly in normal controls, whereas all three decreased in Raynauds phenomenon. During oral reserpine treatment, 11 patients with Raynauds phenomenon showed a significantly larger capillary flow during warming (8.7 vs. 5.7 ml) and cooling (6.2 vs. 2.8 ml). Patients with Raynauds phenomenon have a smaller finger nutritional (capillary) flow than normal subjects, and this flow decreases s...

Pharmacological concentrations of ascorbic acid are required for the beneficial effect on endothelial vasomotor function in hypertension.

Increased production of superoxide anion may contribute to impaired bioactivity of endothelium-derived nitric oxide in hypertension. Ascorbic acid is capable of scavenging superoxide anion; however, experimental studies have shown that high physiological concentrations (>1 mmol/L) of ascorbic acid are required to prevent superoxide-mediated vascular dysfunction. To seek kinetic evidence that superoxide anion contributes to endothelial vasomotor dysfunction in human hypertension, we examined the effects of 2.4 or 24 mg/min ascorbic acid intra-arterial infusions on forearm blood flow responses to methacholine or sodium nitroprusside in 30 patients with hypertension and 22 age-matched controls. Endothelium-dependent vasodilation to methacholine was significantly impaired in the hypertensive patients, with a response to the highest dose of methacholine (10 microg/min) of 12.3+/-6.7 compared with 16.1+/-5.8 mL. min(-1). dL tissue(-1) in the controls (P<0.001). The response to sodium nitroprusside was equivalent in the 2 groups. Ascorbic acid at 24 mg/min significantly improved the forearm blood flow response to methacholine in hypertensive patients with a peak response of 16.1+/-7.1 mL. min(-1). dL tissue(-1) (P=0.001). This dose produced a cephalic vein ascorbic acid concentration of 3.2+/-1. 4 mmol/L. In contrast, ascorbic acid at 2.4 mg/min had no effect on the methacholine response. Ascorbic acid at both doses had no effect on the vasodilator response to sodium nitroprusside in hypertensive patients or the methacholine response in the controls. These results agree with the predicted kinetics for superoxide anion-mediated impairment of endothelium-derived nitric oxide action. Thus, superoxide anion may contribute to impaired endothelium-dependent vasodilation in patients with hypertension.

Intermittent Claudication — Be Conservative

Severe peripheral vascular disease is a common disorder that frequently creates substantial morbidity in our aging population. A nonsurgical approach to the treatment of intermittent claudication, ...

Beta-adrenergic vasodilator mechanism in the finger.

The digital vasospastic phenomena, which are induced by beta-adrenergic-blocking agents, suggest a beta-adrenergic finger vasodilator mechanism. We measured fingertip total blood flow with venous occlusion plethysmography and studied nutritional blood flow with Na131I clearance. During fingertip vasoconstriction caused by branchial artery infusion of norepinephrine or angiotensin, intra-arterial isoproterenol caused a sustained increase in fingertip total blood flow. Furthermore, propranolol significantly potentiated the vasoconstriction caused by intra-arterial norepinephrine and attenuated the vasodilator action of isoproterenol. No change in branchial artery blood pressure occurred to explain the changes in fingertip blood flow. Isoproterenol did not change nutritional flow, implying beta-adrenergic vasodilation solely of the fingertip arteriovenous shunts. When fingertip vasoconstriction was induced by reflex sympathetic nerve action during environmental cooling and mental stress, or by norepinephrine release from sympathetic nerves caused by intra-arterial tyramine infusion, isoproterenol and propranolol had no effect on fingertip total blood flow. This effect is probably specific for the beta-receptor agonist, since intra-arterial histamine caused a large increase in finger blood flow during environmental cooling. We conclude that there is a beta-adrenergic vasodilator mechanism in human digital arteriovenous shunts that may be humorally activated, but which has no apparent functional role in modulating sympathetic vasoconstriction. Our results suggest a spatial dissociation of the effector sites for vasoactive humoral agents and sympathetic vasoconstrictor nerves.

Role of alpha-adrenoceptor subtypes mediating sympathetic vasoconstriction in human digits

Abstract. The effects of intra‐arterial administration of alpha‐1 and alpha‐2 adrenoceptor agonists and antagonists on human digital blood flow were studied before and during reflex sympathetic vasoconstriction in normal subjects. Total finger flow was measured by venous occlusion air plethysmography and capillary flow by the disappearance rate of a radioisotope from a local injection in a fingerpad. Intra‐arterial phenylephrine (0·2–1·3 μg min‐1) and clonidine (0·12–0·48 μg min‐1) produced dose‐related decreases in finger blood flow and increases in vascular resistance. Clonidine was the more potent vasoconstrictor. Prazosin (0·48 μg min‐1) effectively blocked the vasoconstrictor effect of phenylephrine but not clonidine, while yohimbine (30–70 μg min‐1) blocked the effect of clonidine but not phenylephrine. In a 20°C room, prazosin (0·4–13·2 μg min‐1) caused no significant changes in finger blood flow (7·7 ± 2·1 to 11·7 ± 3·3 ml min‐1) 100 ml‐1) or vascular resistance (30·9 ± 8·8 to 28·1 ± 8·7 mmHg ml‐1 min‐1 100 ml‐1). In the 20°C room, yohimbine (30–70 μg min‐1) produced a significant increase in finger blood flow (7·8 ± 2·8 to 23·4 ± 6·8 ml, P>0·01) and decrease in vascular resistance (20·5 ± 5·7 to 6·0 ± 2·2 units, P>0·01). No significant changes occurred in finger capillary flow with prazosin or yohimbine infusions. It is concluded that alpha‐1 and alpha‐2 adrenoceptors are present in human digital vasculature and that alpha‐2 adrenoceptors are more important than alpha‐1 adrenoceptors in sympathetic neural vasoconstriction. Since capillary blood flow was unaffected by yohimbine infusions during reflex sympathetic vasoconstriction, the alpha‐2 adrenoceptors predominantly influence arteriovenous shunts in the finger.

Central and peripheral hemodynamic effects of angiotensin inhibition in patients with refractory congestive heart failure.

The central and peripheral hemodynamic responses to the angiotensin-converting enzyme inhibitor teprotide (SQ20881) were simultaneously determined in 10 patients with severe, refractory congestive heart failure using Swan-Ganz catheterization and venous-occlusion calf plethysmography. Significant declines in mean arterial pressure (82.5 ± 4.9 to 67.1 4 5.0 mm Hg [SEM], p < 0.001), systemic vascular resistance (1787 ± 130 to 1272 i 115 dyn-sec-cm-5, p < 0.001) and mean pulmonary capillary wedge pressure (26.8 ± 2.5 to 17.1 ± 2.5 mm Hg, p < 0.001) accompanied improvement in cardiac index (2.04 4 0.17 to 2.47 i 0.20 I/min/m2, p < 0.001). Reduction in mean right atrial pressure (9.8 4 2.0 to 5.2 : 1.8 mm Hg, p < 0.005) was not a result of limb venodilation, as calf venous capacitance did not change. The decrease in limb vascular resistance (76.6 ± 11.0 to 62.9 + 10.7 units, p < 0.05) did not parallel the fall in systemic vascular resistance in either magnitude or duration (p < 0.05). Pulmonary arteriolar resistance was not appreciably changed.Teprotide therefore reduces ventricular afterload and significantly improves cardiac function in patients with congestive heart failure. The greater change in systemic than in limb vascular resistance implies preferential redistribution of flow to other regions. These findings shed light upon the role of the renin-angiotensin system in the regulation of regional vasoconstriction in congestive heart failure and suggest that teprotide may act as a unique “vasoreleaser” of pathophysiologic arteriolar constriction.

Raynaud's phenomenon. An update.

The pathogenesis of primary Raynauds phenomenon remains an enigma. Most evidence favors a local abnormality in the digital arteries as opposed to an increased activity of the sympathetic nervous system. The local fault may involve the alpha 2-adrenergic receptors, which are most important in reflex sympathetic vasoconstriction. Cooling blood vessels increase the sensitivity of alpha 2-adrenergic receptors, increased levels of alpha 2-adrenergic receptors are present in primary Raynauds disease, and patients show an increased sensitivity to alpha 2-adrenergic receptor agonists on finger blood flow. Serotonin has also been implicated, but the evidence is not compelling. In secondary Raynauds phenomenon, vasospastic attacks can often be explained by a low arterial distending pressure, a thickened vessel wall, or absence of beta-adrenergic receptor activity. Diagnosis of primary Raynauds disease relies on a typical history and normal physical examination, laboratory studies, and nailfold capillaroscopy. Finger systolic blood pressures during local cooling with ischemia may be helpful to document vasospastic attacks but does not distinguish primary from secondary Raynauds phenomenon. The treatment of Raynauds phenomenon is usually conservative. Pavlovian conditioning or biofeedback may be beneficial. When drug therapy is necessary, the calcium channel entry blocker nifedipine or sympatholytic agents have been shown to decrease the frequency and duration of vasospastic attacks in about two thirds of patients, although subjective improvement does not usually correlate with objective testing. Direct-acting vasodilators have not been shown to be of definite benefit. New therapies include prostaglandins, captopril, and the serotonergic antagonist ketanserin. Surgical sympathectomy has not been beneficial.

The effect of aspirin on pain and hand blood flow responses to intra-arterial injection of bradykinin in man.

A new method of evoking pain by the intra‐arterial injection of bradykinin (into the brachial artery) was used in the evaluation of the analgesic activity of sodium and calcium acetylsalicylate. At the same time, hand blood flows were measured by venous occlusion plethysmography, and the plasma was analyzed for acetyl, free, and protein‐bound salicylate. The analgesic effect of aspirin appears during the second half of the first hour and continues beyond the second hour after drug administration. Bradykinin increases the hand blood flow and there is an apparent increase in flow after aspirin. No correlation could be found between the plasma salicylate level and the state of analgesia.

International study of ketanserin in Raynaud's phenomenon

PURPOSE The effects of ketanserin on primary or secondary Raynauds phenomenon due to connective tissue disease were studied in a large, international group of patients. PATIENTS AND METHODS The study population consisted of 222 patients from 10 countries. After a run-in period of one month of placebo therapy, patients were randomly assigned in a double-blind manner to receive ketanserin 40 mg three times daily (n = 113) or placebo (n = 109) for three months. Total finger blood flow was measured in 41 patients in a warm and cool room before and during treatment. Vasospastic episodes were assessed by diaries and global evaluations. RESULTS A significant reduction of 34% in frequency of episodes occurred with ketanserin, compared to 18% with placebo (p = 0.011). There was a 1% reduction in duration of episodes with ketanserin therapy, compared to a 2% increase with placebo therapy, but this finding was not statistically significant (p = 0.29). No difference was observed in severity of attacks. Global evaluations by investigators (p = 0.03) and patients (p less than 0.01) showed an overall benefit with ketanserin compared to that seen with placebo. Patients with primary or secondary Raynauds phenomenon responded similarly to treatment. No changes in total finger blood flow were found. CONCLUSION Ketanserin significantly improves the subjective symptoms of patients with primary or secondary Raynauds phenomenon and is an appropriate agent to use in this disease when conservative measures fail.

Failure of Vasodilator Drugs in Arteriosclerosis Obliterans

Abstract Vasodilator drugs were evaluated at rest (nylidrin, isoxsuprine, and tolazoline) and during exercise (nylidrin, isoxsuprine, and nicotinyl alcohol) in patients with intermittent claudicati...