Reversal by heparin of norepinephrine-induced constriction of normal hand veins was studied. Venous size was measured using a linear variable differential transformer (LVDT) during infusions of saline, norepinephrine, insulin and norepinephrine, and graded doses of heparin with norepinephrine. Heparin reduced the venoconstrictive effects of norepinephrine (p, 0.01), with the effects beginning at 18.5 nmol/min (0.05 U/min) and reaching a maximum between 185 nmol/min and 1.85 mmol/min (0.5 and 5 U/min). Maximal heparin-induced venorelaxation correlated with the maximal insulin effect within individuals (r = 0.8, p, 0.01) and was unchanged by the addition of insulin. Methylene blue, a non-specific inhibitor of the nitric oxide cGMP cascade, reduced heparin-induced venorelaxation. In conclusion, heparin in either physiologic or pharmacologic concentrations attenuated norepinephrine-induced venoconstriction. A common mechanism of venorelaxation by heparin and insulin is not excluded given the correlation and lack of additivity of maximum effects and their inhibition by methylene blue.
Yokokawa K, Mandal AK, Kohno Met al.Heparin suppresses endothelin-1 action and production in spontaneously hypertensive rats. Am J Physiol1992; 263(32): R1035-R41.
2.
Susic D, Mandal AK, Jovovic D, Stojanov M, Djordjevic-Denic G, Kentera D.Antihypertensive action of heparin: role of the renin-angiotensin aldosterone system and prostaglandins. J Clin Pharmacol1993; 33: 342-347.
Susic D, Mandal AK, Kentera D.Heparin lowers the blood pressure in hypertensive rats. Hypertension1982; 4: 681-685.
5.
Kongsgaard UE, Smith-Erichsen N, Hysing Eet al.Hemodynamic effects of heparin during coronary bypass surgery. Acta Anaesthesiol Scand1997; 35(8): 758-761.
6.
Urban P, Scheidegger D, Buchmann B, Skarvan K.The hemodynamic effects of heparin and their relation to ionized calcium levels. J Thoracic Cardiovasc Surg1986; 91(2): 303-306.
7.
Seltzer JL, Gerson JI.Decrease in arterial pressure following heparin injection prior to cardiopulmonary bypass. Acta Anaesthesiol Scand1979; 23(6): 575-578.
8.
Pacaud P, Loirand G, Baron A, Mironneau C, Mironneau J.Ca2+ channel activation and membrane depolarization mediated by Cl-channels in response to noradrenaline in vascular myocytes. Br J Pharmacol1991; 104(4): 1000-1006.
9.
Pacaud P, Loirand G, Grégoire G, Mironneau C, Mironneau J.Noradrenaline-activated heparin-sensitive Ca2+ entry after depletion of intra-cellular Ca2+ store in portal vein smooth muscle cells. J Biol Chem1997; 268(6): 3866-3872.
10.
Yokokawa K, Kohne M, Mandal AK, Tahara H, Yanagisawa M, Takeda T.Heparin suppresses endothelin-1 peptide and mRNA expression in cultured endothelial cells of spontaneously hypertensive rats. J Am Soc Nephrol1994; 4: 1683-1689.
11.
Yokokawa K, Tahara H, Kohno M, Mandal AK, Yanagisawa M, Takeda T.Heparin regulates endothelin production through endothelium-derived nitric oxide in human endothelial cells. J Clin Invest1993; 92: 2080-2085.
12.
Lewandowski K, Kulinska A, Zozulinska M, Zawilska K.Age-related changes in plasma endogenous heparin-like activity in healthy male volunteers. Thromb Res1991; 62: 109-114.
13.
Vannucchi S, Pasquali F, Chiarugi V, Ruggiero M.Internalization and metabolism of endogenous heparin by cultured endothelial cells. Biochem Biophys Res Commun1986; 140(1): 294-301.
14.
Cavari S, Stramaccia L, Vannucchi S.Endogenous heparinase-sensitive anticoagulant activity in human plasma. Thromb Res1992; 67: 157-165.
15.
McKee RF, Hodson S, Dawes J, Garden OJ, Carter DC.Plasma concentrations of endogenous heparinoids in portal hypertension. Gut1992; 33: 1549-1552.
16.
Luscher TF.Endothelium in the control of vascular tone and growth: role of local mediators and mechanical forces. Blood Pres1994; (Suppl 1): 18-22.
17.
Grover A, Padginton C, Wilson MF, Sung BH, Izzo JL Jr, Dandona P.Insulin attenuates norepinephrine-induced venoconstriction. An ultrasonographic study. Hypertension1995; 25: 779-784.
18.
Tack CJJ, Lutterman JA, Vervoort G, Thien T, Smits P.Activation of the sodium-potassium pump contributes to insulin-induced vaso-dilation in humans. Hypertension1996; 28: 426-432.
19.
Feldman RD, Bierbrier GS.Insulin mediated vasodilation. Impairment with increased blood pressure and body mass. Lancet1993; 342: 707-709.
20.
Trovati M, Massucco P, Mattiello Let al.Insulin increases cyclic nucleotide content in human vascular smooth muscle cells: a mechanism potentially involved in insulin-induced modulation of vascular tone. Diabetologia1995; 38: 936-941.
21.
Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P.Nitric oxide release accounts for insulin’s vascular effects in humans. J Clin Invest1994; 94: 2511-2515.
22.
Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD.Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest1994; 94(3): 1172-1179.
23.
Alradi AO, Carruthers SG.Evaluation and application of the linear variable differential transformer technique for the assessment of human dorsal hand vein alpha-receptor activity. Clin Pharmacol Ther1985; 38: 495-502.
24.
Aellig WH.Clinical pharmacology, physiology and pathophysiology of superficial veins. Br J Clin Pharmacol1994; 38: 181-196.
25.
Cavari S, Vannucchi S.Detection of heparin-like glycosaminoglycans in normal human plasma by polyacrylamide-gel electrophoresis. Clin Chim Acta1996; 252: 159-170.
Hirsh J, Raschke R, Warkentin TE, Dalen JE, Deykin D, Poller L.Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest1995; 108(4): 258S-275S.
28.
Mayer B, Brunner F, Schmidt K.Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol1998; 45(2): 367-374.
29.
Kontos HA, Wei EP.Hydroxyl radical-dependent inactivation of guanylate cyclase in cerebral arterioles by methylene blue and by LY83583. Stroke1993; 24(3): 427-434.
30.
Pfaffendorf M, Brunung TA, Batnik HD, van Zwieten PA.The interaction between methylene blue and the cholinergic system. Br J Pharmacol1998; 122(1): 95-98.
31.
Sloand EM, Kessler CM, McIntosh CL, Klein HG.Methylene blue for neutralization of heparin. Thromb Res1998; 54(6): 677-686.
32.
Upchurch GR, Welch GN, Freedman JE.High-dose heparin decreases nitric oxide production by cultured bovine endothelial cells. Circulation1997; 95: 2115-2121.
33.
Luscher TF, Diederich D, Siebenmann Ret al.Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts. N Engl J Med1988; 319(8): 462-467.
34.
Sung BH, Ching M, Izzo JL Jr, et al.Hypercholesterolemia impairs insulin-mediated but not nitroprusside-induced venodilation. Circulation1995; 92 (suppl 1): I-154.
35.
Treasure CB, Klein JL, Weintraub WSet al.Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease [see comments]. N Engl J Med1995; 332: 481-487.
36.
Creager MA, Cooke JP, Mendelsohn MEet al.Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest1990; 86(1): 228-234.
