Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia.

AIMS: To assess the efficacy and safety of alogliptin added to insulin in patients with type 2 diabetes inadequately controlled with insulin alone or combined with metformin. METHODS: In this 26-week, double-blind, placebo-controlled study, 390 patients were randomized to receive alogliptin 12.5 mg (n = 131), alogliptin 25 mg (n = 129) or placebo (n = 130) once daily, as add-on to stable insulin therapy with or without metformin. The primary endpoint was change in haemoglobin A(1C) (HbA(1C)) at week 26. RESULTS: At week 26, mean HbA(1C) changes from the mean baseline value of 9.3% were significantly greater for alogliptin 12.5 mg (-0.63 +/- 0.08%) and alogliptin 25 mg (-0.71 +/- 0.08%) than placebo (-0.13 +/- 0.08%; p < 0.001). Significantly greater proportions of patients receiving alogliptin 12.5 or 25 mg than placebo had HbA(1C) decreases of > or =0.5, > or =1.0 and > or =1.5%. Insulin doses remained unchanged, and there were no differences in the proportions of patients experiencing hypoglycaemia among placebo (24%), alogliptin 12.5 mg (27%) and alogliptin 25 mg (27%). Mean weight increases from baseline at week 26 were similar for placebo (0.6 +/- 0.2 kg), alogliptin 12.5 mg (0.7 +/- 0.2 kg) and alogliptin 25 mg (0.6 +/- 0.2 kg). Incidences of overall adverse events, and of gastrointestinal, dermatological and infection-related events, were similar among groups. CONCLUSIONS: Adding alogliptin to previous insulin therapy (with or without metformin) significantly improved glycaemic control in patients with type 2 diabetes inadequately controlled on insulin, without causing weight gain or increasing the incidence of hypoglycaemia. Further studies are warranted to explore the role of alogliptin added to optimized basal insulin regimens.

Post pressure hyperemia in the rat.

In prior studies in man, we have demonstrated that pressure-induced hyperemia lasts for prolonged periods as compared to the short-term hyperemia created by proximal arterial occlusion. We have analyzed this phenomenon in our well-studied rat model of skin blood flow. Skin blood flow was measured using laser Doppler techniques in Wistar Kyoto rats at the back, a nutritively perfused site, and at the plantar surface of the paw, where arteriovenous anastomotic perfusion dominates. A customized pressure feedback control device was used to vary applied pressures. At the back, pressures in excess of 80 mmHg resulted in occlusion, whereas at the paw 150 mmHg was required. The peak hyperemic flow after release of pressure was comparable to that elicited by proximal arterial occlusion with a blood pressure cuff. However, the post pressure hyperemia peak descended to a plateau value, which was 50-100% greater than baseline and continued for up to 20 min while the peak following proximal arterial occlusion returned to baseline within 4 min. At the back, post pressure hyperemia reached a maximum after application of 100 mmHg pressure. The application of higher pressures than required for occlusion produced no greater hyperemic response. At the paw, maximum post pressure hyperemia occurred at 100 mmHg, although this pressure level was not totally occlusive. Higher pressures resulted in no greater hyperemia. At the back, 10 min of occlusion produced a maximal peak value whereas 1 min was sufficient at the paw. The application of pressure to a heated probe with subsequent release, produced a hyperemic response. Normalized to baseline blood flow, there was no difference between the hyperemic responses at basal skin temperature and at 44 degrees C. There is a prolonged hyperemic response following local pressure occlusion compared to a much shorter period following proximal ischemic occlusion. One can presume two different mechanisms, one related to ischemia and the other a separate pressure related phenomenon. The thermal vasodilatory response is additive, not synergistic with the post pressure hyperemia we have demonstrated. This finding suggests that different mechanisms are involved in thermal vasodilation and post pressure hyperemia.

Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study.

PURPOSE: To evaluate the efficacy and tolerability of pioglitazone in combination with a sulfonylurea in the treatment of type 2 diabetes mellitus. SUBJECTS AND METHODS: This 16-week, double-blind study included patients on a stable regimen of a sulfonylurea for > or = 30 days and with a glycosylated hemoglobin (HbA1C) level > or = 8.0%. Patients were randomly assigned to receive once daily pioglitazone 15 mg (n = 184), pioglitazone 30 mg (n = 189), or placebo plus sulfonylurea (n = 187). RESULTS: Patients receiving pioglitazone + sulfonylurea had significant (P < 0.05) decreases from baseline in HbA1C and fasting plasma glucose levels compared with patients treated with placebo + sulfonylurea. As compared with placebo, HbA1C decreased by 0.9% (95% confidence interval [CI]: 0.06% to 1.2%) with pioglitazone 15 mg and 1.3% (CI: 1% to 1.6%) with 30 mg pioglitazone; fasting plasma glucose levels decreased by 39 mg/dL (95% CI: 27 to 52 mg/dL) with pioglitazone 15 mg and by 58 mg/dL (95% CI: 46-70 mg/dL) with 30 mg pioglitazone. Both pioglitazone + sulfonylurea groups had significant (P < 0.05) mean percent decreases in triglyceride levels (17%, 95% CI: 6% to 27% for 15 mg; 26%, 95% CI: 16% to 36% for 30 mg) and increases in high-density lipoprotein cholesterol levels (6%, 95% CI: 1% to 11% for 15 mg; 13%, CI: 8% to 18% for 30 mg) compared with placebo + sulfonylurea. There were small but statistically significant mean percent increases in low-density lipoprotein cholesterol levels in all groups. Pioglitazone was well tolerated, and the rates of adverse events were similar in all groups. CONCLUSION: In patients with type 2 diabetes, pioglitazone plus sulfonylurea significantly improves HbA1C and fasting plasma glucose levels with beneficial effects on serum triglyceride and HDL-cholesterol levels.

Pharmacotherapy of type 2 diabetes mellitus.

OBJECTIVE: To review the drug treatments and some of the popular, nontraditional remedies now available for type 2 diabetes mellitus, as well as selected investigational agents; to describe each medication's place in the overall approach to treatment. DATA SOURCES: English-language journals, abstracts, review articles, and newspaper accounts. DATA SYNTHESIS: In the past five years, there has been tremendous progress in the pharmacotherapy of diabetes, particularly type 2 diabetes. Several new agents have entered the clinical arena, and many more are in the late stages of investigation leading to approval. Sulfonylureas stimulate the production and release of insulin; these drugs must be used in patients with an intact pancreas. The meglitinides are nonsulfonylurea agents that are also insulin secretagogues. Unlike the sulfonylureas, repaglinide appears to require the presence of glucose to close the adenosine triphosphate-sensitive potassium channels and induce calcium influx. Metformin reduces hepatic glucose production in some patients and increases peripheral glucose utilization, but its use is hampered by a high percentage of adverse reactions. Disaccharidase inhibitors effectively compensate for the defective early-phase insulin release by slowing the production of sugars from carbohydrates. Thiazolidinediones appear to activate peroxisome proliferator-activated receptor gamma, which is involved in the metabolism of lipids. Short-acting insulin and the role of weight-loss agents are also discussed. CONCLUSIONS: The availability of new options for diabetes therapy provides a chance for successful therapy in a larger number of patients. However, it is important to consider how much true benefit these new forms of treatment will have on the diabetic community. The best choice for a patient remains controversial.

A comparison of the microvascular response in the healing wound in the spontaneously hypertensive and non-hypertensive rat.

BACKGROUND: In the Spontaneously Hypertensive Rat (SHR), there is a significantly greater blood flow at the paw but not at the back than in the non-hypertensive Wistar Kyoto (WKY) rat. We wanted to assess the effect of this higher blood flow on wound healing at the paw. MATERIALS AND METHODS: We characterized the microvascular composition of wounds at the back and paw of 9 SHR rats and 10 WKY rats using a quantitative imaging program. Blood flow was compared using laser Doppler technology. RESULTS: The blood flow response to wounding at the back was identical in the SHR and WKY rats. There was an immediate sharp increase in flow at the center of the wound. Blood flow reached a peak at 3 days and then decreased somewhat by day 7, but still remained five-fold higher than the prewound baseline values. There was also a two-fold increase at the back wound perimeter. There were no differences in microvascular composition at the back between the SHR and WKY rats. In contrast, there was an immediate enormous increase in blood flow at paw wound center in the SHR rats. Flow increased to 75 ml/min/100 gm by 24 h then fell back sharply. Blood flow at the paw in the WKY rats changed very little over the 7 days post wounding. At 3 days, the flow was about twice as high in the SHR than in the WKY wound, but, by day 7, flow was similar in the two rat strains. At the SHR wound perimeter, there was a small increase in flow which was sustained through day 7. Although the microvascular composition at the paw wound center was similar in the SHR and WKY rats, there was a notable difference at the paw perimeter. At baseline, there was a slightly greater capillary density in the SHR paw (32 +/- 1 per mm3) than the WKY paw (25 +/- 8 per mm3). At 7 days after wounding, there was a substantial increase in capillary number in the SHR rats (48 +/- 8 per mm3) as compared to baseline (p = 0.05). In contrast, there was no significant difference in capillary number in the WKY paw wound perimeter (20 +/- 3 per mm3) as compared to baseline. CONCLUSIONS: There is a substantial difference in wound blood flow response between the hypertensive and the non-hypertensive rat. At the back, the blood flow effects of wounding are similar, but, at the paw, the SHR rat shows a dramatic transient increase in flow in the early phases of wound healing. There is apparently no capability to upmodulate microvascular resistance in response to increased pressure at this early stage of wound healing. However, within several days, the granulation tissue microvasculature becomes capable of controlling the effects of raised pressure in the SHR rat. In the SHR paw wound perimeter, there are significantly more capillaries than in the WKY rat. It is possible that greater capillary proliferation in the SHR rat results from higher blood flow in the early phase of wounding. The contrast between the WKY rat and the SHR rat serves to further illustrate the complexity of blood flow regulation which occurs during wound healing.

A comparison of the cutaneous microvascular properties of the spontaneously hypertensive rat and the Wistar-Kyoto rat.

The Spontaneously Hypertensive rat (SHR) and its non-hypertensive companion strain, the Wistar-Kyoto (WKY) rat, provide an excellent comparative model to permit study of the differential properties of cutaneous microvascular beds. We explored the possibility that chronically elevated vascular pressures in the SHR rat might affect the microvascular constitution of the skin. We measured skin blood flow at the back and at the paw of a group of 20-week-old WKY rats and a contrast group of SHR rats. We then performed skin biopsies at these two locations and used the NIH Image program to count and measure the size of capillaries, arterioles, and venules. We also determined microvascular density as percentage of total tissue area. At basal temperature, skin blood flow was similar in the two rat strains at both the back and paw. Heat induced vasodilatation resulted in a 50% increase in blood flow at the back, reaching the same level in the two rat groups. However, at the paw site, thermal stimulation resulted in significantly greater flow (39.3 +/- 3.1 ml/100 gm tissue per min) in the SHR rats than the WKY rats (28.6 +/- 1.9 ml/100 gm tissue per min, P < 0.05). The ratio of systemic arterial pressure to skin blood flow was computed as an index of vascular resistance to flow. At basal temperature, this index was 50% greater for the SHR rats at both skin sites. At 44 degrees C, the resistance index decreased at both sites in both rat groups but was still approximately 50% higher at the back of the SHR than the WKY rats. In contrast, the resistance index at 44 degrees C at the paw site fell to the same level in both the SHR and WKY rats. There were twice as many capillaries at the back of the WKY rats than at the back of the SHR rats (9.2 +/- 2.0 per mm2 vs. 4.7 +/- 1.2 per mm2, P < 0.05). Expressed as a percentage of total tissue area, the capillary density at the back in the WKY rats was 0.064 +/- 0.010% as compared to 0.034 +/- 0.008% in the SHR rats (P < 0.05). There were five times more arterioles at the paw compared to the back in both rat groups with no significant difference between the groups. We measured the diameter of the lumen and the thickness of the wall of each arteriole and computed their ratio as an index of possible media hypertrophy. There were minimal differences seen in these parameters between the two rat groups at the back and paw sites. The venular density was significantly higher at the paw than at the back in both rat groups with no significant difference between them. Reduced capillary density at the back of the SHR rats may be a developmental adaptation to high blood pressure. Such a reduction in the pathways of blood flow may help account for increased flow resistance at that site, independent of arteriolar vasoconstriction.

Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. Sildenafil Diabetes Study Group.

CONTEXT: Erectile dysfunction is common in men with diabetes. OBJECTIVE: To assess the efficacy and safety of oral sildenafil citrate in the treatment of erectile dysfunction in men with diabetes. DESIGN: A multicenter, randomized, double-blind, placebo-controlled, flexible dose-escalation study conducted May through November 1996. SETTING: Patients' homes and 19 clinical practice centers in the United States. PATIENTS: A total of 268 men (mean age, 57 years) with erectile dysfunction (mean duration, 5.6 years) and diabetes (mean duration, 12 years). INTERVENTIONS: Patients were randomized to receive sildenafil (n = 136) or placebo (n = 132) as needed, but not more than once daily, for 12 weeks. Patients took the study drug or placebo 1 hour before anticipated sexual activity. The starting dose of sildenafil citrate was 50 mg, with the option to adjust the dose to 100 mg or 25 mg based on efficacy and tolerability, to be taken as needed. MAIN OUTCOME MEASURES: Self-reported ability to achieve and maintain an erection for sexual intercourse according to the International Index of Erectile Function and adverse events. RESULTS: Two hundred fifty-two patients (94%) completed the study (131/136 in the sildenafil group, 121/132 in the placebo group). By intention-to-treat analysis, at 12 weeks, 74 (56%) of 131 patients in the sildenafil group reported improved erections compared with 13 (10%) of 127 patients in the placebo group (P<.001). The proportion of men with at least 1 successful attempt at sexual intercourse was 61 % (71/ 117) for the sildenafil group vs 22% (25/114) for the placebo group (P<.001). Adverse events related to treatment were reported for 22 (16%) of 136 patients taking sildenafil and 1 (1%) of 132 patients receiving placebo. The most common adverse events were headache (11% sildenafil, 2% placebo), dyspepsia (9% sildenafil, 0% placebo), and respiratory tract disorder (6% sildenafil, 2% placebo), predominantly sinus congestion or drainage. The incidence of cardiovascular adverse events was comparable for both groups (3% sildenafil, 5% placebo). CONCLUSION: Oral sildenafil is an effective and well-tolerated treatment for erectile dysfunction in men with diabetes.

Ischemic and pressure-induced hyperemia: a comparison.

OBJECTIVE: There is reason to question whether hyperemia after pressure occlusion is caused solely by local ischemia. This study quantitatively compared the response to the two forms of occlusion on the finger. DESIGN: Blood flow was measured by laser Doppler continuously before, during, and for 40 minutes after a 2-minute occlusion of flow at the finger dorsum and at the plantar surface of the finger tip (finger pulp), which has a much higher arteriolar density than the dorsum. Occlusion to the same low level was carried out either with a cuff at the base of the finger or by direct pressure of the laser Doppler probe head. Comparison experiments were performed with the probe head heated to 44 degrees C to elicit maximal local vasodilation. SETTING: Outpatient clinic. PARTICIPANTS: Eleven healthy volunteers. MAIN OUTCOME MEASURES: Magnitude and duration of skin blood flow after occlusion. RESULTS: Cuff occlusion at the base of the finger produced a typical, short-lived hyperemic response at both finger dorsum and finger pulp. The peak level at finger dorsum was 17.6 +/- 1.4mL/min/100g, approximately a twofold increase over the baseline flow level. The duration of the hyperemic response was 3.6 +/- 0.8 minutes. The baseline flow at the finger pulp was three times greater than at the finger dorsum, and peak flow after occlusion was also three times higher (44.3 +/- 2.6 mL/min/100g). The duration of hyperemia at finger pulp was 4.2 +/- 0.9 minutes. After pressure occlusion at the finger dorsum the hyperemic peak was higher (26.7 +/- 4.2 mL/min/100g; p < .05) and the duration of hyperemia was four times longer (16.9 +/- 2.3 minutes; p < .01) than after cuff occlusion. At the finger pulp, the pressure-induced hyperemic peak was also greater than the peak after cuff occlusion (56.3 +/- 1.7mL/min/100g; p < .05), with a longer duration than after cuff occlusion (11.1 +/- 1.1min; p < .01). Thermal stimulation significantly reduced the differences between cuff- and pressure-induced occlusion. There was a slow increase in flow over the 40-minute monitoring period. The maximal flow reached was approximately 100mL/min/100g at both finger dorsum and finger pulp. At both sites, however, the maximal flow level was attained more rapidly than the control condition without prior occlusion. CONCLUSIONS: These results confirmed that the pressure-induced hyperemic response is greater and of longer duration than that produced by flow ischemia alone. Thermal stimulation essentially abolishes the differences, suggesting that there is a common mechanism of vasodilatation. The mechanistic differences between pressure-induced and ischemic hyperemia remain to be determined.

A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes.

OBJECTIVE: The objective of the study was to assess the efficacy and safety of repaglinide compared with placebo in the treatment of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a phase II multicenter, double-blind, placebo-controlled, randomized, dose-adjustment and maintenance trial. After screening and a 2-week washout period, 99 patients were randomized to receive either repaglinide (n = 66) or placebo (n = 33). Patients underwent 6 weeks of dose adjustment followed by 12 weeks of dose maintenance. Fasting and stimulated glycosylated hemoglobin (HbA1c), plasma glucose, insulin, and C-peptide were measured at predetermined intervals. Adverse events and hypoglycemic episodes were recorded. RESULTS: From baseline to last visit, mean HbA1c decreased from 8.5 to 7.8% in patients treated with repaglinide and increased from 8.1 to 9.3% in patients receiving placebo, with a statistically significant difference of - 1.7% (P < 0.0001) between treatment groups at the last visit. Mean fasting plasma glucose and postprandial glucose increased in patients receiving placebo and decreased in patients treated with repaglinide, with statistically significant (P < 0.01) differences between groups at the last visit. Concentrations of fasting and postprandial insulin and C-peptide were lower at the last visit compared with baseline for patients treated with placebo and higher for patients treated with repaglinide, and the differences between groups were statistically significant (P < 0.05). Overall, repaglinide was well tolerated. CONCLUSIONS: This study demonstrated that repaglinide was safe and efficacious in lowering blood glucose concentrations. In addition to overall improvement in glycemic control noted with repaglinide in both sulfonylurea-treated patients and oral hypoglycemic agent-naive patients, repaglinide had a potent glucose-lowering effect in the postprandial period.

The relationship of laser-Doppler skin blood flow measurements to the cutaneous microvascular anatomy.

The hairless plantar paw surface of the rat shows high skin blood flow with a substantial response to thermal stimulation. This contrasts with hair-covered areas such as the back, where there is much lower basal flow and thermal response. These properties are similar to the differences seen in humans between skin sites which have a high density of arterioles and venules (AV areas) and sites with predominantly nutritive (NUTR) capillary perfusion. However, there has been no previous study of the microvascular anatomy of rodent skin. We used NIH Image, a quantitative imaging program, to count the capillaries, arterioles, and venules in the skin of the plantar paw surface and the back of 14 Wistar-Kyoto rats. We also used laser-Doppler techniques to determine skin blood flow at these sites. We found significantly more vessels per unit area at the paw. There were twice as many capillaries in the paw (19.6 +/- 2.4 per mm2) compared to the back (9 +/- 1.5 per mm2) (P < 0.001). Similarly, there were three times as many venules (11.8 +/- 1.2 per mm2 vs 3. 48 +/- 0.45 per mm2; P < 0.001). The largest difference was in the number of arterioles (7.76 +/- 0.74 per mm2 vs 0.79 +/- 0.13 per mm2 at the back; P < 0.001). The greater microvascular density at the paw was reflected in a threefold higher basal blood flow (6.6 +/- 0. 44 ml/min/100 g) compared to that in the back (1.99 +/- 0.07 ml/min/100 g) (P < 0.001). Microvascular volume at the back was 0.14 +/- 0.01 x 10(6) RBC/ml in the basal state compared to 0.31 +/- 0.01 x 10(6) RBC/ml at the paw. Thus, the increased number of vessels at the paw resulted in a twofold increase in microvascular volume. The plantar paw surface has considerably more vessels than the back. As might be expected, there is a higher proportion of arterioles and venules compared to capillaries at the paw than at the back. Thus, the plantar paw surface is an AV site compared to the back, which is a NUTR site. Although our prior studies have largely assumed that we could use the paw and back as contrast sites comparable to AV and NUTR sites in humans, we have now for the first time conclusively established this fact. The increased microvascular density at the paw results in higher skin blood flow at this site.

The microvascular composition of the healing wound compared at skin sites with nutritive versus arteriovenous perfusion.

Background. In the rat, there is a significantly greater blood flow response to wounding at the back, a site perfused mainly by small capillaries, than at the paw, which has a much higher density of arterioles and venules. Materials and methods. We characterized the microvascular composition of wounds at the two skin sites in 11 Wistar Kyoto rats using a quantitative imaging program. Blood flow was compared using laser Doppler technology. Results. Prior to wounding, skin blood flow was much greater at the paw (7.1 +/- 0.5 ml 100 g tissue-1 min-1) than at the back (2.1 +/- 0.1 ml 100 g tissue-1 min-1, P < 0.01) at baseline. Seven days after wounding, blood flow both at the center (8.3 +/- 1.4 ml 100 g tissue-1 min-1) and at the perimeter of the back wound (4.1 +/- 0.5 ml 100 g tissue-1 min-1) had increased substantially. In contrast, skin blood flow at the perimeter of the paw wound had increased moderately (12. 7 +/- 2.0 ml 100 g tissue-1 min-1), but there was no change at the center of the wound (6.9 +/- 0.9 ml 100 g tissue-1 min-1). There were three times more microvessels per mm2 at the paw site (39.3 +/- 3.6) than at the back (13.1 +/- 1.5) prior to wounding. The wound granulation tissue was very vascular; the numerical density of vessels was identical at back (166 +/- 9) and at paw (154 +/- 6). Despite the marked increase in blood flow at the perimeter of the back wound, there was no difference in the microvascular density (15. 2 +/- 1.4) compared to baseline, nor was there a difference at the paw perimeter (39.4 +/- 3.6) compared to baseline. Conclusions. This study demonstrates that the microvascular constitutions of granulation tissues at the paw and back are identical. Thus, the rise in flow at the back wound and reduction in flow at the paw wound are entirely consistent with similar microvascular compositions of these two sites. Yet, there is increased flow at the back wound perimeter where there is no significant change in microvascular constitution compared to unwounded skin. Therefore, a microvascular structure no different from that prior to wounding functions very differently after wounding. Clearly vasoregulatory factors impact on the wound to modify flow through the microvascular network.

Post-exercise cutaneous hyperaemia resulting from local exercise of an extremity.

Large changes in skin blood flow occur after exercise. Most studies have concentrated on the systemic effects of vigorous exercise on skin blood flow. We were interested in the post-exercise response in the neighbourhood of focal exercise. We used a painless neuromuscular electronic stimulator to exercise the muscles of the forearm, producing flexion of the fingers. There was no change in blood pressure and only a small increase in heart rate during this exercise. We measured blood flow during a 5-min pre-exercise period and a 5-min post-exercise period at the forearm, at the dorsum of the index finger and on the pad of the index finger. We also measured values on the contralateral non-exercised extremity during exercise as well as during matched time periods in control experiments with no exercise. Exercise did elicit an increased blood flow in the post-exercise period at all three sites compared with the control experiments with no exercise and on the contralateral extremity. For example, the increase in blood flow at the finger dorsum was 2.1 +/- 0.1 ml (min 100 g)-1 after exercise compared with -0.08 +/- 0.09 ml min-1 100 g-1 during the control experiment and 0.1 +/- 0.1 ml (min 100 g)-1 on the contralateral arm (all P < 0.01). The local application of heat at the site of blood flow monitoring produced a substantial increase in the post-exercise response at the two finger locations [27.4 +/- 0.4 ml (min 100 g)-1 at the finger dorsum], but not at the arm. This is the first demonstration that highly focal exercise, unaccompanied by a systemic haemodynamic response, can elicit a post-exercise cutaneous hyperaemia. Local heating produced a large synergistic increase in the post-exercise hyperaemia at sites with arteriovenous microvascular perfusion but not at sites with primarily nutritive perfusion. These findings show that local vasoregulatory changes occur in response to exercise, even in the absence of whole-body haemodynamic and thermal change.

The skin blood flow response in wound healing.

Although vasodilation is conventionally held to be the predominant microvascular response to a wound, there has been no previous attempt to actually quantitate skin blood flow within and in the neighborhood of wounds. In particular, there has been no differentiation between sites with primarily nutritive (NUTR) blood flow and those with considerable arteriovenous (AV) perfusion. We used our previously described model of cutaneous blood flow in the rat to study the blood flow response to wounding. We measured skin blood flow at the centers and at the undisturbed perimeters of wounds placed at the back, a NUTR site, and at the paw, an AV site, in 11 Wistar Kyoto rats. Measurements were performed at baseline, and then at 3 hr, 24 hr, 72 hr, and 7 days postwounding. At 3 hr, flow at the center of the back wound had increased to 11.3 +/- 1.4 ml/min/100 g from a baseline of 2.1 +/- 0.1 ml/min/100 g and remained elevated at 7 days (8.3 ml/min/100 g). Flow at the perimeter of the back wound rose as well, but not as high as at wound center, to twice the baseline level (4.1 ml/min/ 100 g at Day 7). Flow values at control sites on the back did not increase from baseline. Flow at the center of the paw wound rose from 7.2 +/- 0.5 ml/min/100 g at baseline to 15.6 +/- 4.3 ml/min/100 g at Day 3 but then fell back to 6.9 +/- 0.9 ml/min/100 g at Day 7. There was only a very small increase in the basal temperature wound response at the paw perimeter. Blood flow at all wound sites showed a response to heat. At the back, heating to 44 degrees stimulated an 80% increase in blood flow at baseline. This degree of increase was maintained at both the center and the perimeter of the back wound. In contrast, although there was also a thermal response at the paw wound center, it was of much lower magnitude than the nonwounded baseline response. As a result, the heat-stimulated flow value actually fell over the 7 days to approximately half of the baseline level. At the paw wound periphery, there was an initial fall in the heat stimulated response, but it then recovered to the baseline level and remained stable over the 7 days. Thus, the skin blood flow response seen at the paw wound challenges the conventional concept of vasodilation as the expected wound blood flow response. The mechanisms of blood flow response in the healing wound may be more complex than the simple inflammatory vasodilation conventionally postulated.

Effect of calcium channel blockade on skin blood flow in diabetic hypertension: a comparison of isradipine and atenolol.

In previous studies, using laser Doppler techniques, the authors have demonstrated a duration-dependent reduction in skin blood flow reserve at sites of nutritive (NUTR) perfusion that occurs in diabetes and correlates with the presence of diabetic retinopathy and proteinuria. They speculated that it might be possible to reverse this decrease in blood flow by using agents with peripheral vasodilating properties. They chose the calcium channel blocking agent isradipine as a prototype. As a contrast agent, they chose atenolol, which has an equivalent antihypertensive effect but minimal peripheral vasodilating properties. They studied 24 diabetic hypertensive patients in a randomized, two-way crossover design. They assigned patients randomly to one or the other active drug and titrated to a maximum tolerated maintenance dose. Skin blood flow was measured at the end of the titration and maintenance phases. Patients then entered a four-week washout period, followed by crossover to the alternative drug, and measurements were repeated. At baseline, the twenty-four-hour mean ambulatory systolic blood pressure was 150 +/- 2 mm Hg with a twenty-four-hour mean diastolic blood pressure of 93 +/- 1 mm Hg. Thermally stimulated skin blood flow reserve was about 50% lower in these patients as compared with an age-, sex-, and weight-matched group of 28 nondiabetic, nonhypertensive patients. There was no difference in skin blood flow between the two groups at basal skin temperature or at a controlled temperature of 35 degrees C. Both atenolol and isradipine successfully lowered blood pressure in the study patients. There was a slightly greater decrease in systolic blood pressure with isradipine and a greater decrease in heart rate with atenolol. Neither isradipine nor atenolol treatment affected skin blood flow values at the maximal 44 degrees C temperature. However, at basal skin temperature and at 35 degrees C, isradipine-treated patients had substantial increases in skin blood flow at NUTR sites. For example, skin blood flow at the knee at 35 degrees C with isradipine treatment was 3.1 +/- 0.4 mL/min/100 g compared with 1.1 +/- 0.2 with atenolol, 1.3 +/- 0.1 with placebo, and 0.9 +/- 0.1 for the nondiabetic controls (all P < 0.01). The authors found a twofold to threefold increase in basal skin blood flow at NUTR sites with isradipine treatment. This degree of increase is substantially greater than that previously demonstrated by their group using pentoxifylline. Locally reduced skin blood flow is a factor in promoting skin breakdown and delayed healing. Further study is needed to explore the possibility that isradipine treatment may enhance healing of diabetic skin ulcers.

The effect of chronic hypertension on skin blood flow.

OBJECTIVE: To determine whether the cutaneous microvasculature of the spontaneously hypertensive rat (SHR) is affected by chronic hypertension. DESIGN: We used laser Doppler techniques to measure skin blood flow in 22 SHR and in 22 non-hypertensive Wistar-Kyoto (WKY) rats over a 1-year time span, beginning at age 3 months. Sites of measurement included the back, leg, and root of the tail, areas with a predominantly nutritive perfusion, and the plantar surface of the paw, which has a large contribution from large arterioles and venules. Flow was measured at basal skin temperature and at the maximally heat-stimulated condition of 44 degrees C. Systolic tail arterial blood pressures were measured concurrently. RESULTS: At baseline, systolic blood pressures were considerably higher in the SHR (190 +/- 4 mmHg) than they were in the WKY rats (138 +/- 2 mmHg). Skin blood flow values at the three nutritive sites were similar in the two species. However, at 44 degrees C, flow was significantly higher at the paw in the SHR (46.8 +/- 3.5 versus 34.3 +/- 2.2 ml/min per 100 g). We attribute this difference to the effect of high perfusion pressure on large arterioles. During the 1-year measurement period, there was no appreciable change in blood flow in the WKY rats. In contrast, the SHR showed a steady progressive decline in skin blood flow at all sites. The largest decline was at the paw with a rate of fall of about 2.4%/month. After 1 year, there was no difference between paw blood flow in the SHR (27.5 +/- 1.8 ml/min per 100 g) and in the WKY rats (27.6 +/- 1.9 ml/min per 100 g). CONCLUSIONS: Skin blood flow reserve falls in response to chronic hypertension. The rate of fall is greater at sites with significant arteriovenous perfusion that at nutritive sites.

Decreased skin blood flow early in the course of streptozotocin-induced diabetes mellitus in the rat.

We have previously used laser Doppler technology to demonstrate that skin blood flow is reduced in Type 1 (insulin-dependent) diabetic patients. The possibility of using the skin as an extremely accessible indicator of diabetic microvascular disease is attractive. The streptozotocin diabetic rat is an appealing potential animal model. We performed measurements of skin blood flow in two rat species, nine Sprague Dawley (SD) rats and nine Wistar Kyoto (WKY) rats, observing early changes following the inception of diabetes. Four of the SD rats and five of the WKY rats were made diabetic, the rest serving as controls. There were no significant differences in skin blood flow between the two rat strains. As in man, there appear to be rat skin sites with primarily nutritive capillary supply and those with arteriovenous anastomotic predominance. The back and base of tail, both hair-covered areas, demonstrated low flow characteristics, consistent with nutritive perfusion. In contrast, the plantar surface of the paw behaved similarly to the finger or toe pulps in man, sites of arteriovenous perfusion, with high basal flow and a marked increment with thermal stimulation. In diabetic rats of both species, there was significantly lower flow at the back and base of tail than in non-diabetic animals. The differences were of the order of 30-40%. As a function of time, the decrease in blood flow at the base of tail parallelled the increase in glycohaemoglobin levels in the diabetic rats. In contrast, blood flow at the plantar surface of the paw was unchanged throughout the 3-month post-streptozotocin observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

Skin blood flow in the Wistar-Kyoto rat and the spontaneously hypertensive rat.

1. Using laser Doppler techniques in man, we have previously demonstrated differences in skin blood flow properties at sites with primarily nutritive (NUTR) perfusion, such as the elbow or knee, as compared to sites such as the finger pulp, with predominantly arteriovenous anastomotic (AVA) perfusion. 2. Basal and heat stimulated flow is greater at AVA sites. In man, blood pressure changes are reflected primarily by changes at AVA rather than NUTR sites. 3. These blood pressure induced changes affect the red blood cell velocity (VEL) component at AVA sites more than microvascular volume (VOL). 4. Given these findings in man, we decided to compare skin blood flow properties in a suitable animal model. 5. We chose the Wistar-Kyoto (WKY) and Spontaneously Hypertensive Rat (SHR) strains, in view of the marked difference in systemic blood pressure in these two related strains. 6. Skin blood flow varied considerably at different skin sites in the rats. Skin sites with hair covering, on the back and at the base of the tail, showed low basal and heat stimulated blood flow. 7. In contrast, the plantar surface of the paw behaved similarly to the finger or toe pulps in man, with 3-4-fold higher basal flow than the hair covered areas and a 7-8-fold rise with local heating to 44 degrees C. 8. Furthermore, there was a 25% greater blood flow at the plantar paw surface in the SHR rats as compared to the WKY rats, corresponding to the 25% higher systemic blood pressure in these animals. 9. The heat induced increase in flow at the plantar surface of the paw was primarily a result of a marked increase in VEL rather than VOL. 10. The higher flow at this site in SHR as compared to WKY rats was likewise ascribable to an increase in VEL, VOL being equivalent in the two strains.

The effect of increasing temperature on skin blood flow and red cell deformability.

Using laser Doppler techniques in nine healthy volunteers, we contrasted the effect of increasing local skin temperature at the elbow, a skin site with nutritive microvasculature, and the finger pulp, with predominantly arteriovenous anastomic (AVA) perfusion). We also assessed flow at the finger dorsum, with contributions of both types of microvasculature. In parallel with the laser Doppler studies, we determined the effect of increasing temperature on the red cell deformability of our subjects, using the new technique of Cell Transit Time Analysis (CTTA). Thermal stimulation produced very large increases in skin blood flow at all three sites tested. However, the magnitude and the pattern of increase were different at the three sites. At the finger pulp, there was a linear approximately threefold increase in flow as temperature increased from the basal level to 44 degrees C. At the elbow, basal flow was considerably lower than at the finger pulp and increased very slowly until skin temperature reached 38 degrees C. From that point, flow increased sharply, reaching tenfold the basal level at 44 degrees C. The thermally induced increase at the finger dorsum was intermediate between the other two sites, with a pattern resembling the elbow more than the finger pulp. These differences among the sites were attributable to substantially different patterns of change in the two components of flow, microvascular volume and velocity. At the finger pulp, there was very little increase in microvascular volume with increasing temperature. The curve was practically flat from basal temperature to 44 degrees C. In contrast, there was a linear increase in red blood cell velocity of about 300%. At the elbow, both microvascular volume and red blood cell velocity exhibited a parallel curvilinear pattern of equivalent increase, on the order of 300% for each. There was only a small increase in both parameters until the temperature reached 38 degrees, at which point there was a sharp increase in both. At the finger dorsum, the situation was intermediate, again resembling the elbow more than the finger pulp. Cell Transit Time Analysis revealed a progressive decrease in red cell transit time (TT), from 3.28 ms at 28 degrees C to 2.48 m at 44 degrees C, an overall change of 24%. The decrease in TT was accompanied by an increase in transit frequency, measured as counts s-1 (C s-1), from 3.1 to 5.3, an overall change of 71%. The changes in both TT and C/S were essentially linear.(ABSTRACT TRUNCATED AT 400 WORDS)

Current perception thresholds in ageing.

We studied 40 healthy elderly and 31 healthy young volunteers and 25 elderly diabetic and 37 young diabetic patients. All subjects received detailed neurological examinations focusing particularly on sensory symptom and physical evaluations. Standardized assessment of symptoms and physical testing of light touch, pain, vibratory and thermal sensation were performed at the hand, wrist, elbow, foot, ankle and knee. The total symptom score (SS) and the total physical score (PS) were defined by summing test scores at each site. Current perception threshold (CPT) testing using constant current sine wave alternating current was completed at the same anatomical sites. CPT findings did not differ significantly between young and old healthy subjects. Older diabetic patients had higher CPTs than younger diabetic patients, but the severity of clinical diabetic neuropathy was greater in the older group. CPTs correlated with the degree of clinical diabetic neuropathy (r = 0.47 with SS and r = 0.60 with PS) rather than with age (r = 0.12). We conclude that current perception does not decline with age. Nor does ageing by itself worsen CPT values in patients with neuropathy. CPT testing is easily performed, clinically applicable and the first objective sensory measure not affected by the process of ageing.

The laser Doppler analysis of posturally induced changes in skin blood flow at elevated temperatures.

Recently, it has become possible to use laser Doppler techniques to separately quantitate the two components of blood flow, microvascular volume and red blood cell velocity. We used these techniques in 21 normal volunteers to quantitate the effect of postural changes in skin blood flow and its components at 35 degrees C and at 44 degrees C. Postural skin blood flow changes have ben studied extensively at basal skin temperature, but not at elevated temperatures. We contrasted changes at sites with arteriovenous anastomotic (AVA) blood flow (toe and finger pulps) with changes at sites with primarily nutritive flow (elbow and knee). Skin blood flow increased markedly with increasing temperature. The increases at the elbow and knee were the products of equivalent increases in both microvascular volume and velocity. In contrast, the increases on the finger and toe pulps were mainly due to increases in velocity. Elevation of both upper and lower extremities brought about a decrease in skin blood flow. Dependency increased blood flow. The magnitudes of observed changes were greater on the lower extremity than on the upper extremity and greater at 44 degrees C than at 35 degrees C. Once again, with postural change, the nutritive areas exhibited similar changes in volume and velocity while the AVA areas primarily showed velocity alterations. The correlation of systolic pulse pressures with blood flow was greater at the AVA areas than at nutritive areas and greater at 44 degrees C than at 35 degrees C. This correlation was with the velocity rather than with the volume component.(ABSTRACT TRUNCATED AT 250 WORDS)