Juan Martínez-León

Relaxation by urocortin of human saphenous veins

Urocortin, an endogenous peptide structurally related to corticotropin‐releasing factor (CRF), has potent cardiovascular effects, suggesting that it may be of significance in cardiovascular regulation. The objective of this study was to analyse the effects of urocortin and its action mechanisms on human blood vessels. To this, 3 mm long segments from human saphenous veins were prepared for isometric tension recording in an organ bath. In the segments at basal resting tone, urocortin did not produce any effect, but in the segments precontracted with endothelin‐1 (1 – 10 nM), urocortin (1 pM – 10 nM) produced concentration‐dependent relaxation. This relaxation was not modified by the inhibitor of nitric oxide synthase NG‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μM), but it was potentiated by the cyclo‐oxygenase inhibitor meclofenamate (10 μM) and it was reduced by the inhibitors of high‐conductance Ca2+‐dependent potassium channels tetraethylammonium (TEA, 10 mM) and charybdotoxin (100 nM). These results indicate that human saphenous veins are very sensitive to urocortin, which produces vascular relaxation by a mechanism independent of nitric oxide and dependent of high‐conductance Ca2+‐dependent potassium channels, and that it may be opposed by the release of vasoconstrictor prostanoids. Therefore, urocortin may be of significance for regulation of the venous circulation in humans.

Effects of sildenafil on human penile blood vessels.

OBJECTIVES To investigate the effects of sildenafil on human penile blood vessels and evaluate the interaction of sildenafil with neurogenic-mediated responses. Sildenafil is currently used in the treatment of erectile dysfunction. METHODS Penile dorsal arteries and deep dorsal veins were obtained from 14 multiorgan donors. Vascular rings were suspended in organ bath chambers, and the isometric tension was recorded. We then studied the effects of sildenafil on precontracted vessels and the neurogenic (noradrenergic and nitrergic) responses. RESULTS Sildenafil (10(-9) to 3 x 10(-6) M) caused concentration-dependent relaxation and amplified the relaxation induced by sodium nitroprusside. Relaxation was unaffected by the inhibitor of nitric oxide synthase N(G)-monomethyl-L-arginine (10(-4) M). Compared with zaprinast, sildenafil was 8 to 10 times more potent in terms of the median effective concentration (EC(50)) values. Electrical field stimulation of the vessels under resting tension caused frequency-dependent contractions that were attenuated in the presence of sildenafil. When penile vessels were contracted after blockade of norepinephrine release with guanethidine (10(-6) M), electrical stimulation induced frequency-dependent, nitric oxide-dependent relaxations that were enhanced by sildenafil. CONCLUSIONS These results indicate that the relaxation of human penile arteries and veins induced by sildenafil involves inhibition of noradrenergic contraction, enhancement of neurogenic nitric oxide-mediated relaxation, and inhibition of smooth muscle contraction.

Arginine Vasopressin Enhances Sympathetic Constriction Through the V1 Vasopressin Receptor in Human Saphenous Vein

BACKGROUND Arginine vasopressin (AVP) not only acts directly on blood vessels through V1 receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vivo and in vitro. The aim of the present study was to investigate whether AVP can contribute to an abnormal adrenergic constrictor response of human saphenous veins. METHODS AND RESULTS Saphenous vein rings were obtained from 32 patients undergoing coronary artery bypass surgery. The vein rings were suspended in organ bath chambers for isometric recording of tension. AVP (3x10[-9] mol/L) enhanced the contractions elicited by electrical field stimulation at 1, 2, and 4 Hz (by 80%, 70%, and 60%, respectively) and produced a leftward shift of the concentration-response curve to norepinephrine (half-maximal effective concentration decreased from 6.87x10[-7] to 1.04x10[-7] mol/L; P<.05). The V1 vasopressin receptor antagonist d(CH2)5Tyr(Me)AVP (10[-6] mol/L) prevented the potentiation evoked by AVP. The selective V1 receptor agonist [Phe,2 Orn8]-vasotocin (3x[-10]-9 mol/L) induced potentiation of electrical stimulation-evoked responses, which was also inhibited in the presence of the V1 receptor antagonist (10[-6] mol/L). In contrast, the V2 receptor agonist desmopressin (10[-9] to 10[-7] mol/L) did not modify neurogenic responses, and the V2 receptor antagonist [d(CH2)5, D-Ile,2 Ile,4 Arg8]-vasopressin (10[-8] to 10[-6] mol/L) did not prevent the potentiation induced by AVP. The dihydropyridine calcium antagonist nifedipine (10[-6] mol/L) did not affect the potentiating effect of AVP. CONCLUSIONS The results suggest that low concentrations of AVP facilitate sympathetic neurotransmission and potentiate constrictor effects of norepinephrine in human saphenous veins. These effects appear to be mediated by V1 receptor stimulation and are independent of calcium entry through dihydropyridine calcium channels. Thus, AVP may contribute to vascular mechanisms involved in acute ischemic syndromes associated with venous grafts, particularly if the sympathetic nervous system is activated.

Relaxation induced by cGMP phosphodiesterase inhibitors sildenafil and zaprinast in human vessels.

BACKGROUND Sildenafil is currently used in the treatment of erectile dysfunction. However, assessment of direct effects of sildenafil on coronary arteries and on arteries used as coronary grafts is unknown. This study was designed to investigate the effects of sildenafil on contracted human coronary, internal mammary, and radial arteries obtained from multiorgan donors. The observations were extended to forearm veins. Zaprinast was included in this study for comparison. METHODS Segments of left coronary, internal mammary, and radial arteries, and forearm veins were obtained from 16 multiorgan donors. Vascular rings were suspended in organ bath chambers and isometric tension was recorded. Then the effects of sildenafil, zaprinast, and sodium nitroprusside on precontracted vessels were studied. RESULTS Sildenafil (10(-8) - 3 x 10(-5) mol/L) caused concentration-dependent relaxation in the internal mammary arteries, radial arteries, and forearm veins. In the coronary arteries, sildenafil had a modest relaxant effect. In addition, sildenafil amplified the relaxation induced by sodium nitroprusside in all four vessels. Relaxation was unaffected by the inhibitor of nitric oxide synthase NG-monomethyl-L-arginine (10(-4) mol/L). Compared with zaprinast, sildenafil was eight to ten times more potent in terms of EC50 values. CONCLUSIONS The direct relaxant effects of sildenafil together with its synergistic interaction with nitric oxide donors should be considered in patients undergoing coronary bypass surgery, patients with low blood pressure, and patients receiving antihypertensive regimes.

Endothelium-dependent relaxation of human saphenous veins in response to vasopressin and desmopressin

PURPOSE The goal of this study was to determine the effects of vasopressin and the selective V2-receptor agonist desmopressin on human saphenous veins, with special emphasis on endothelium-mediated responses. METHODS Human saphenous vein segments were obtained from 35 patients undergoing coronary bypass surgery. Paired segments, one normal and the other deendothelized by gentle rubbing, were mounted for isometric recording of tension in organ baths. Concentration-response curves to vasopressin and desmopressin were determined in the presence and in the absence of either the V1-receptor antagonist d(CH2)5Tyr (Me)AVP (10(-6) mol/L), the V1-V2-receptor antagonist desGly-d(CH2)5D-Tyr(Et)ValAVP (10(-6) mol/L), indomethacin (10(-6) mol/L), or NG-nitro-L-arginine methyl ester hydrochloride (L-NAME, 10(-4) mol/L). RESULTS In vein rings under resting tension, vasopressin produced concentration-dependent, endothelium-independent contractions with a concentration of vasopressin producing half-maximal contractions (EC50) of 3.44 x 10(-8) mol/L. The vasopressin V1-receptor antagonist (10(-6) mol/L) displaced the control curve to vasopressin 9.86-fold to the right in a parallel manner. In precontracted vein rings previously treated with the V1-antagonist (10(-6) mol/L) vasopressin caused endothelium-dependent relaxations. This relaxation was reduced significantly by indomethacin (10(-6) mol/L) and unaffected by the V1-V2-receptor antagonist (10(-6) mol/L) or by L-NAME (10(-4) mol/L). Desmopressin caused endothelium-dependent relaxations in precontracted vein rings that were inhibited by the mixed V1-V2-receptor antagonist and by indomethacin, but not by the V1-antagonist or by pretreatment with L-NAME. CONCLUSIONS These observations indicate that vasopressin exerts contractile effects on human saphenous vein by V1-receptor stimulation. Vasopressin causes dilatation of human saphenous vein only if V1-receptor blockade is present. This relaxation appears to be mediated by the release of relaxant prostaglandins, probably derived from endothelial cells, and is independent of V2-receptor stimulation or release of nitric oxide. Desmopressin elicits relaxation that is largely dependent on V2-receptor stimulation, which may bring about the release of dilating prostaglandins from the endothelial cells.

Factors for development of late significant tricuspid regurgitation after mitral valve replacement: the impact of subvalvular preservation

OBJECTIVE Development of late significant tricuspid regurgitation (TR) after successful mitral valve replacement (MVR) is not infrequent. The impact of different aetiologies or diverse surgical procedures has not been adequately investigated. We studied the influence of subvalvular preservation techniques during MVR on the incidence of late TR. METHODS A total of 801 patients with grade ≤ 2+/4+ preoperative TR underwent MVR without associated tricuspid procedures from January 1994 to August 2008. In 595 patients, only posterior mitral leaflet preservation was performed (group A). In the remaining 206 patients, both anterior and posterior leaflets were retained (group B). Postoperative development of significant TR was defined as a TR increase by more than one grade from preoperative or final TR grade ≥ 3+/4+ at follow-up. RESULTS The global incidence of postoperative significant TR was 8.6%, with higher incidence in females (9.4% vs 6.7%, p=0.12), rheumatic disease (9.7% vs 6.5%, p=0.07), patients with previous AF (11.8% vs 3.8%, p<0.001) and, especially, in group A (10.8% vs 2.4%, p<0.001). The Maze procedure was protective in patients with AF (the incidence with and without associated Maze was 6.7% vs 13.2%, p=0.04). Preoperative left-atrial diameters were higher in patients with postoperative development of TR (56 ± 9 mm vs 51 ± 12 mm, p=0.01). Group A (p=0.04) and preoperative atrial fibrillation (p=0.001) were significant predictors of late postoperative TR. Late functional TR decreased free survival from chronic heart failure. CONCLUSIONS Several clinical and operative factors are associated with the development of significant TR after MVR. Although early surgical intervention for TR may be recommended in selected patients, complete subvalvular preservation of the mitral valve and routine surgical ablation of atrial fibrillation can significantly reduce its incidence.

Mitral Valve Replacement in Rheumatic Patients: Effects of Chordal Preservation

BACKGROUND Subvalvular preservation is beneficial in patients undergoing mitral valve replacement, especially in degenerative mitral regurgitation. Its feasibility and benefit is less evident in rheumatic disease. Our aim was to study the impact of preservation techniques in rheumatic patients and determine risk factors for mortality. METHODS Five hundred sixty-six rheumatic patients undergoing mitral valve replacement between 1996 and 2006 have been included. One hundred fifty-six patients had complete excision of the subvalvular apparatus (group 1), 248 had preservation of the posterior leaflet (group 2), and 162 had total chordal preservation (group 3). Echocardiography was performed preoperatively, at discharge, at 1 year, and at late follow-up. RESULTS Reduction of ventricular volume was greater in groups 2 and 3, especially if previous mitral regurgitation or mixed disease were present. In mitral stenosis, valve resection caused postoperative increase of volume. Ventricular ejection and pulmonary hypertension had better outcome with valve preservation. Valve resection was associated with late mortality (hazard ratio, 2.64; p < 0.05), and complete chordal preservation was protective (hazard ratio, 0.31; p = 0.13). Actuarial survival (130 months) was better in group 3: 77.18% +/- 0.04%, 85.38% +/- 0.03%, and 93.22% +/- 0.02%, respectively (p < 0.01 group 1 versus group 3). Group 1 exhibited more low cardiac output syndrome (p < 0.01) and more patients in New York Heart Association functional class III and IV at last follow-up: 17.8% versus 3.9% and 2.0% (p < 0.001). CONCLUSIONS Complete chordal preservation is possible in a large percentage of rheumatic patients. Greater decrease of ventricular volume is obtained for mitral regurgitation. In mitral stenosis, subvalvular preservation may avoid postoperative ventricular dilatation. Consequently, ventricular ejection, pulmonary hypertension, and clinical outcomes may improve with time.

U-46619-induced potentiation of noradrenergic constriction in the human saphenous vein: antagonism by thromboxane receptor blockade

OBJECTIVE We investigated the potentiating effect of U-46619, a synthetic analogue of thromboxane A(2) (TXA(2)), on the adrenergic responses in human saphenous vein. METHODS Saphenous vein rings were obtained from 35 patients undergoing coronary artery bypass surgery. The rings were suspended in organ bath chambers for isometric recording of tension. RESULTS U-46619 (10(-10)-3 x 10(-7) mol/l) produced concentration-dependent and endothelium-independent contractile responses. U-46619 (10(-10) mol/l) potentiated the contractions elicited by electrical stimulation and potassium chloride, and produced leftward shifts of the concentration-response curve for noradrenaline. The TXA(2) receptor antagonist SQ-30741 (10(-8) mol/l) prevented the potentiation evoked by U-46619. The dihydropyridine calcium antagonist nifedipine (10(-6) mol/l) did not affect the potentiation of electrical stimulation and noradrenaline induced by U-46619, but abolished the potentiation of U-46619 on KCl-induced contractions. CONCLUSIONS U-46619 facilitates sympathetic neurotransmission and potentiates constrictor effects of noradrenaline in human saphenous veins through stimulation of TXA(2) receptors. These effects are independent of calcium entry through dihydropyridine calcium channels.

A combined approach for ischemic mitral valve regurgitation: Scar plication and the role of magnetic resonance imaging

T he incidence and severity of ischemic mitral regurgitation (MR) are higher with posteroinferior infarctions. More localized remodeling without important left ventricular (LV) dilation can result in greater geometric changes with displacement of the posterior papillary muscle (PPM). A variety of techniques have been advocated to correct these changes. Cardiac magnetic resonance (CMR) has emerged as a new technique that provides detailed information about LV and mitral valve morphology and function with precise myocardial scar assessment. We report a combined diagnostic-surgical approach for the management of patients with ischemic MR secondary to posteroinferior infarction. It is based on cardiac catheterization, CMR, and perioperative transesophageal echocardiography followed by a 3-staged surgical procedure: selective scar plication, restrictive annuloplasty, and coronary artery bypass grafting.

Is off-pump technique a safer procedure for coronary revascularization? A propensity score analysis of 20 years of experience

OBJECTIVES We aim to describe our experience in coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass by comparing intraoperative and postoperative outcomes. METHODS From January 1993 to June 2013, 3097 patients underwent consecutive emergency and scheduled CABG surgery. A total of 1770 patients underwent on-pump CABG (ONCABG) and 1327 off-pump CABG (OPCABG). A propensity score matching was performed to identify appropriate matched-pair patients; univariable and multivariable logistic regression analyses were performed to assess significant predictors of hospital and 30-day morbidity and mortality composite end-points. Morbidity composite end-point was defined as any renal, pulmonary, cardiovascular and neurological complication that occurred during hospital stay. We collected all-cause mortality data during the study period. RESULTS We identified 1004 patients in each group. There were no significant differences in thirty day mortality, 2.8 vs 3.8%, in OPCABG and ONCABG, respectively (P = 0.21). Cardiovascular, neurological, respiratory and renal complications were more frequent in the ONCABG group: 13.9 vs 8.7% (P < 0.001), 3.9 vs 2.2% (P = 0.03), 13.5 vs 7.5% (P < 0.001), 7.1 vs 5.3% (P = 0.095), respectively. The long-term all-cause mortality rate was 12.3 vs 12.9% in the OPCABG versus ONCABG group (P = 0.42), respectively. In both uni- and multivariable analysis preoperative renal failure, chronic obstructive pulmonary disease and ONCABG were independent predictors of mortality and morbidity composite end-points. CONCLUSIONS OPCABG is associated with less postoperative morbimortality and shorter hospital and intensive care unit length of stay. ONCABG resulted as an independent predictor of morbidity and mortality composite end-point. No statistically significant differences were observed in long-term all-cause mortality between groups.