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Background: Protamine administration may lead to systemic hypotension, perhaps because of vasodilatation produced by endothelial nitric oxide. This study compared release of vasoactive substances from canine coronary microvessels with that from paired conductance arteries., Methods: Microvessels were mounted in a videoscopic no-flow system, and circumflex arteries were studied in organ chambers; both were induced to contract by endothelin-1., Results: Protamine (10 to 160 micrograms/mL) produced concentration-dependent relaxation in both microvessel and conductance arteries (46% +/- 14% maximal relaxations in microvessel and 82% +/- 15% in conductance arteries, n = 10 each). Removal of the endothelium abolished this relaxation (P < .05, n = 6). Indomethacin (10(-5) mol/L) did not alter the relaxation in either group (51% +/- 10% in microvessel and 103% +/- 7% in conductance arteries, n = 6 each). NG-monomethyl-L-arginine (L-NMMA, 10(-4) mol/L) attenuated relaxation in conductance arteries (38% +/- 12%, P = .04, n = 6) but had no effect on microvessel arteries (58% +/- 10%, n = 6). Tetraethylammonium chloride (10(-3) mol/L), an inhibitor of voltage-dependent potassium channels, had no effect on conductance arteries (103% +/- 9%, n = 6) but abolished relaxation in microvessels (-25% +/- 11%, P = .03, n = 6)., Conclusions: Protamine sulfate causes endothelium-dependent relaxation in microvessel and conductance arteries in the heart by different mechanisms--that is, by nitric oxide release in conductance arteries and by endothelium-derived hyperpolarizing factor (EDHF) release in microvessels. This is the first description of the release of EDHF in response to protamine administration.

The internal mammary artery (IMA) is the preferred conduit for coronary artery bypass graft because of superior late patency. However, IMA vasospasm may contribute to myocardial ischemia and early postoperative morbidity. To investigate mechanisms of vasospasm, we compared the reactivity of human and canine IMA segments in vitro to agonists known to release endothelium-derived contracting factor and endothelium-derived relaxing factor. Rings (4 mm in length) of human and canine IMA were studied in organ chambers. Human and canine vascular smooth muscle exhibited comparable contraction to norepinephrine (maximum = 7.55 +/- 0.63 gm and 6.4 +/- 0.90 gm, respectively) and relaxation to sodium nitroprusside. Human and canine IMAs exhibited comparable endothelium-derived relaxing factor-mediated relaxations to acetylcholine (human) and methacholine (canine). Human and canine IMA also exhibited comparable endothelium-dependent contraction to hypoxia (to 173.3% +/- 8.1% and 178.9% +/- 16.0% of initial prehypoxic tension; means +/- SEM; n = 12). Endothelium-dependent contraction to hypoxia in human and canine IMA could be attenuated by NG-monomethyl-L-arginine (10(-6) mol/L), a competitive inhibitor of L-arginine metabolism (n = 9 and n = 10 for human and canine; p less than 0.05). These studies establish that the canine is an appropriate model for study of human IMA vascular reactivity and that hypoxia can induce the release of an L-arginine-dependent, endothelium-derived contracting factor in the human and canine IMA. In vivo, the release of endothelium-derived contracting factor in response to hypoxemia may be cause of IMA vasospasm.

Complement activation by the alternate pathway has been implicated in the pathophysiology of cardiopulmonary bypass (CPB), and laboratory studies suggest that the complement cascade may be activated by the protamine-heparin complex. To determine if the administration of protamine to patients receiving heparin activates complement, we studied 100 patients undergoing CPB by assaying levels of C3a and C4a (classic pathway) at regular intervals before and after protamine administration. In group I (90 patients), protamine was given at the usual interval (median 5 minutes) after CPB. In group II (10 patients), protamine was withheld until skin closure (median 45 minutes) after CPB. Results demonstrated that C4a was not activated during CPB in either group. After CPB, the C4a level in group I was 459 ng/dl and increased to 1047 ng/dl 10 minutes after protamine administration (p less than 0.001). In group II, the C4a level was 484 ng/dl at the end of CPB and 354 ng/dl 15 minutes later, which corresponds to the value immediately after protamine administration in group I. The delayed administration of protamine in group II caused a significant increase in C4a at the time of skin closure (1090 ng/dl; p less than 0.001). Corresponding results from C3a analysis before and after protamine administration confirmed the activation of complement cascade. Our study provides the first clinical evidence that the protamine-heparin complex activates complement via the classic (C4a) pathway. The hemodynamic effects of protamine after CPB may be related to complement activation.

Intramyocardial gas tension monitoring with mass spectrometry allows for the continuous assessment of myocardial metabolic activity during prolonged global ischemia. With aortic cross-clamping there is a rapid decrease in intramyocardial oxygen tension (PmO2) and a steady increase in carbon dioxide tension (PmCO2). In laboratory studies the extent to which myocardial metabolic activity is reduced has correlated with the degree of myocardial protection being afforded. In the present study the metabolic consequences of single-dose versus multiple-dose infusions of a hyperkalemic cardioplegic solution were compared in 23 patients undergoing aortic valve replacement (AVR) for severe aortic stenosis. Group I (n = 13) had single-dose cardioplegia during AVR, while group II (n = 10) had multiple-dose cardioplegia. The preoperative status and the surgical procedures were identical except for two multiple-dose patients who also underwent single coronary bypass grafting. In group I the PmCO2 rose steadily and at cross-clamp release was 182 +/- 20 mm Hg, while in group II the PmCO2 rose only to 77 +/- 8 mm Hg (P less than 0.01). During reperfusion the peak PmCO2 in group I was 219 +/- 22 mm Hg versus 111 +/- 5 mm Hg in group II (P less than 0.01). After operation six patients in group I required pharmacologic support, and two other patients died of low cardiac output. In contrast, only one patient in group II required inotropic support, and there were no deaths. The significantly lower PmCO2 values with multiple-dose cardioplegia suggest both reduced metabolic activity and washout of metabolic end products, with resultant improved myocardial protection, evidenced by less postoperative left ventricular dysfunction.

A five year experience with 20 patients who had penetrating vascular injuries of the thoracic outlet was reviewed. A median sternotomy with extension into the right neck was used to explore six patients with right subclavian vascular injuries. With injuries to the origin of the left common carotid artery, repair was accomplished through a median sternotomy combined with a left anterior thoracotomy in one patient and through a left posterolateral thoracotomy in the other. Injury to the left subclavian vessels occurred in five patients and was exposed through a left anterolateral thoracotomy combined with a supraclavicular incision in four patients and through a supraclavicular incision with clavicular resection in one patient. Axillary vessel trauma generally was managed with an extrathoracic incision only. The two deaths in this series were due to postoperative respiratory complications (mortality rate of 10%). Twenty arteries were repaired and all were patent on follow-up examination. Associated neural and venous injury caused significant morbidity in 28% and 10% of patients, respectively. As a result of this experience we continue to recommend an extended median sternotomy for repair of right-sided cervicothoracic vascular injury. Anterior or posterolateral thoracotomy combined with a supraclavicular incision is advocated for trauma to left-sided vessels of the thoracic outlet. When possible, injured veins should be repaired rather than ligated.