No description available.

BACKGROUND: Endothelial dysfunction is a principal player in the development of allograft vasculopathy and allograft failure. The hallmark of endothelial dysfunction is impaired nitric oxide bioavailability. Recent evidence implicates endothelin-1 as an integral component of endothelial dysfunction. Immunosuppressive drugs have also been associated with the development of graft vasculopathy. We speculated that endothelin-1 results in endothelial dysfunction by impairing nitric oxide homeostasis and is a player in hypoxia and reperfusion induced vasomotor injury. In addition, we hypothesized that endothelin-1 antagonism with bosentan will limit hypoxia and reperfusion injury and prevent immunosuppressive drug injury. METHODS: We utilized human saphenous vein endothelial cells to evaluate the effects of endothelin-1, hypoxia and reperfusion on endothelial function, protein kinase modulation and cell survival. We also employed a rodent model of chronic drug therapy to assess the effect of cyclosporine and rapamycin treatment on vasomotor function. We investigated the role of nitric oxide augmentation and bosentan in preventing hypoxia and reperfusion injury and in limiting immunosuppressive drug induced vasomotor dysfunction. RESULTS: Elevated endothelin-1 levels resulted in impaired nitric oxide release and endothelial function. The effects of endothelin-1 as well as hypoxia and reperfusion were mediated by altered protein kinase B and protein kinase C activity resulting in endothelial dysfunction. We revealed that endothelin-1 is a key player in hypoxia and reperfusion induced endothelial injury. The immunosuppressive drug cyclosporine induced vasomotor dysfunction while rapamycin preserved vessel homeostasis. Vasomotor dysfunction was characterized by impaired nitric oxide and endothelin-1 homeostasis. Bosentan limited the deleterious effects of endothelin-1, hypoxic injury, reperfusion injury and cyclosporine induced vasomotor impairment. CONCLUSIONS: Our study revealed that endothelin-1 exposure as well as hypoxia and reperfusion results in endothelial dysfunction by altering specific protein kinase C isoform activities and inhibiting protein kinase B. Cyclosporine induced vasomotor dysfunction was mediated by altered nitric oxide and endothelin-1 homeostasis while rapamycin was endothelial protective. Bosentan proved to be an effective therapy at preventing endothelin-1, hypoxia and reperfusion and cyclosporine induced endothelial dysfunction. Protein kinase C modulation as well as bosentan may prove to be NOVEL therapies to prevent endothelial injury during cardiac transplantation.

BACKGROUND: Endothelial dysfunction is a principal player in the development of allograft vasculopathy and allograft failure. The hallmark of endothelial dysfunction is impaired nitric oxide bioavailability. Recent evidence implicates endothelin-1 as an integral component of endothelial dysfunction. Immunosuppressive drugs have also been associated with the development of graft vasculopathy. We speculated that endothelin-1 results in endothelial dysfunction by impairing nitric oxide homeostasis and is a player in hypoxia and reperfusion induced vasomotor injury. In addition, we hypothesized that endothelin-1 antagonism with bosentan will limit hypoxia and reperfusion injury and prevent immunosuppressive drug injury. METHODS: We utilized human saphenous vein endothelial cells to evaluate the effects of endothelin-1, hypoxia and reperfusion on endothelial function, protein kinase modulation and cell survival. We also employed a rodent model of chronic drug therapy to assess the effect of cyclosporine and rapamycin treatment on vasomotor function. We investigated the role of nitric oxide augmentation and bosentan in preventing hypoxia and reperfusion injury and in limiting immunosuppressive drug induced vasomotor dysfunction. RESULTS: Elevated endothelin-1 levels resulted in impaired nitric oxide release and endothelial function. The effects of endothelin-1 as well as hypoxia and reperfusion were mediated by altered protein kinase B and protein kinase C activity resulting in endothelial dysfunction. We revealed that endothelin-1 is a key player in hypoxia and reperfusion induced endothelial injury. The immunosuppressive drug cyclosporine induced vasomotor dysfunction while rapamycin preserved vessel homeostasis. Vasomotor dysfunction was characterized by impaired nitric oxide and endothelin-1 homeostasis. Bosentan limited the deleterious effects of endothelin-1, hypoxic injury, reperfusion injury and cyclosporine induced vasomotor impairment. CONCLUSIONS: Our study revealed that endothelin-1 exposure as well as hypoxia and reperfusion results in endothelial dysfunction by altering specific protein kinase C isoform activities and inhibiting protein kinase B. Cyclosporine induced vasomotor dysfunction was mediated by altered nitric oxide and endothelin-1 homeostasis while rapamycin was endothelial protective. Bosentan proved to be an effective therapy at preventing endothelin-1, hypoxia and reperfusion and cyclosporine induced endothelial dysfunction. Protein kinase C modulation as well as bosentan may prove to be NOVEL therapies to prevent endothelial injury during cardiac transplantation.

Master of Science / Department of Food, Nutrition, Dietetics and Health / Mark Haub / The coronary microcirculation is the principle site of blood flow control and myocardium oxygen delivery within the coronary artery tree. Coronary arteriole tone is determined by three major endothelium derived vasoactive substances: endothelin, nitric oxide (NO), and reactive oxygen species (ROS). The effects of these substances change with aging and differ between sexes. Endothelin-1 (ET-1), the primary endothelin isoform in the coronary circulation, acts on smooth muscle receptors endothelin-A (ET[subscript A]) and endothelin-B (ET[subscript B]) to induce vascular smooth muscle (VSM) contraction and vasoconstriction. Whereas ET-1 activation of the ET[subscript B] receptor on the endothelium initiates a cascade of events leading to NO production via endothelium derived NO synthase (eNOS) enzyme activation and VSM relaxation. Aged males maintain ET[subscript A] receptor expression and higher levels of vasoconstriction than do age-matched females. High levels of ET[subscript A] receptor activity are associated with hypertension, myocardial infarction, coronary artery spasm, atherosclerosis, and finally heart failure (HF). Additionally, NO can displace ET-1 from the VSM ET[subscript A] and ET[subscript B] receptors. Thus, with reduced eNOS activity and decreased NO production, there is a simultaneous loss of vasodilatory capacity and increase in vasoconstrictive capacity. In both rodent and human models aged males and females ROS production increases with age. ROS, such as superoxide, scavenge NO, decreasing its bioavailability and producing peroxynitrite. Peroxynitrite is a potent reactive nitrogen species that leads to endothelial cell apoptosis and eNOS enzyme dissociation, potentiating superoxide production and NO reduction. It has been shown that the reduction in NO bioavailability may be a primary mechanism of coronary artery disease. However, the ROS hydrogen peroxide, also increased with aging, produces a potent vasodilatory effect in the coronary microcirculation and seems to be one mechanism that buffers the loss of NO-induced vasodilation. In postmenopausal women diminished estrogen levels further reduce eNOS production of NO. Males, however, tend to experience decrements in arteriole function a decade before women and estrogen may be one mechanism preserving vascular health into middle age that separates the chronology of coronary artery disease between sexes. Determining the mechanisms of disease onset that accompany the aging process will provide insight into potential therapies to preserve endothelium dependent dilation with aging such as exercise, dietary NO supplementation, and increased dietary anti-oxidant consumption.

No description available.

Endothelin-1 (ET-1) binds to endothelin A (ETA) and B (ETB) receptors on vascular smooth muscle cells, resulting in profound vasoconstriction and cellular proliferation. In contrast, activation of endothelial cell (EC) ETB receptors releases nitric oxide (NO) and prostacyclin (PGI2), which are anti-mitotic and mediate vasodilatation. ETB receptors are also responsible for the clearance of ET-1 from the circulation and renal ETB receptors contribute to sodium and water balance. Pharmacological blockade and genetic models featuring total ETB ablation, demonstrate salt sensitive hypertension. However, these do not allow the role of the EC ETB in cardiovascular homeostasis to be determined. Mice featuring loxP sites flanking exons 3 and 4 of the ETB gene (floxed ETB mice: FF/--) were crossed with Tie2-Cre mice (WW/Tie2-Cre), in which the expression of a Cre recombinase cDNA transgene is limited to EC, to generate EC-specific ETB down-regulated mice (FF/Tie2-Cre). Having demonstrated EC-specific down-regulation of ETB receptors using autoradiography, the role and relative contribution of the EC ETB to the regulation of systemic BP, to the clearance of ET-1 from the plasma, as well as to the development of pulmonary arterial hypertension were investigated. Autoradiography revealed significant down-regulation of ETB in EC-rich tissues such as lung of FF/Tie2-Cre animals (8 ± 3 amol.mm-2) compared to controls (80 ± 21 amol.mm-2) (n=4; p<0.05). Levels of ETA expression were preserved despite higher concentrations of plasma ET-1 in the FF/Tie2-Cre samples (12.4 ± 3.0 pg.ml-1) compared to controls (3.0 ± 0.8 pg.ml-1) (n=6; p<0.001). Using radiotelemetry, mean arterial blood pressure of FF/Tie2 mice was not significantly different to that of FF/- controls on low salt (FF/Tie2-Cre: 122.7 ± 1.52 mmHg, n=10; FF/--: 125.7 ± 0.58 mmHg, n=12), normal salt (FF/Tie2-Cre: 133.8 ± 4.0 mmHg, n=10; FF/--: 131.5 ± 3.33 mmHg, n=12) or high salt diet (FF/Tie2-Cre: 149.2 ± 2.71 mmHg, n=10; FF/--: 143.9 ± 2.97 mmHg, n=12). Similarly no differences in SBP, DBP or HR were seen between genotypes. The clearance of an intravenous bolus of radiolabelled ET-1 was significantly impaired in FF/Tie2-Cre mice (0.054 ± 0.006 ml.sec-1) compared to control mice (0.175 ± 0.032 ml.sec-1) (n=5; p<0.01). ETB blockade of control mice reduced ET-1 clearance to that of untreated FF/Tie2-Cre animals (n=4). Two weeks of hypobaric hypoxia induced an exaggerated increase in systolic right ventricular pressure in FF/Tie2-Cre mice (34.4 ± 1.2 mmHg, n=10) compared with FF/-- mice (24.6 ± 1.4mmHg, n=10; p<0.05), associated with an increased right ventricular/ left ventricular + septum ratio in FF/Tie2-Cre mice (normoxia: 0.224 ± 0.009; hypoxia: 0.285 ± 0.017; p<0.01), but not in FF/-- mice. Hypoxia increased the percentage of remodeled vessels in FF/-- mice (normoxia: 5.6 ± 0.6%; hypoxia: 11.4 ± 0.6%; n=6; p<0.001), and this was augmented in FF/Tie2-Cre mice (normoxia: 7.1 ± 0.5%; hypoxia: 18.5 ± 1.2%; n=6; p<0.001). The EC ETB receptor does not play a significant role in the BP response to salt, suggesting that ETB signalling on other cell types is responsible for ETB mediated natriuresis. However, the EC ETB receptor is crucial to the elimination of ET-1 from the circulation and is protective against the development of pulmonary arterial hypertension, most likely by preventing remodeling of small pulmonary arteries.

Η κιρσοκήλη είναι η κιρσοειδής ανεύρεση του οσχεϊκού τμήματος των φλεβών του σπερματικού τόνου (ελικοειδούς πλέγματος). Η κιρσοκήλη έχει αναγνωρισθεί ως μια από τις πιο κοινές αιτίες της ανδρικής υπογονιμότητας. Η συχνότητα στο γενικό πληθυσμό είναι περίπου 15%. Περίπου το 30% - 50% των ανδρών που πάσχει από πρωτοπαθή υπογονιμότητα εμφανίζει κιρσοκήλη. Η κιρσοκήλη είναι περισσότερο συνηθισμένη στην αριστερή πλευρά. Επίσης είναι δυνατόν να εμφανιστεί νωρίς στην ήβη, καθώς και περιστασιακά στα αγόρια που βρίσκονται σε προεφηβική ηλικία. Στα παιδιά η συχνότητα εμφάνισής της θεωρούνταν μικρή, αλλά σε πρόσφατες μελέτες διαπιστώθηκε η ύπαρξή της στο 6% των παιδιών ηλικίας 10 ετών, ενώ σε εφήβους το ποσοστό αυτό ανήλθε στο 16%. Πολύ σπάνια εμφανίζεται πριν από την ηλικία των 7-8 ετών. Παρόλο όμως που η κιρσοκήλη αποτελεί μία τόσο συχνή «πάθηση» στους υπογόνιμους άνδρες και μία συχνή «ανατομική ιδιομορφία» στον γενικό πληθυσμό, η αιτιολογία της παραμένει ασαφής. Παλαιότερες θεωρίες σε σχέση με το μήκος των φλεβών, φαινόμενα «συμπίεσης» κ.α. δεν επαρκούν να εξηγήσουν την τόσο συχνή δημιουργία των κιρσοειδών φλεβών, ούτε την ετερογενή επίδραση που έχουν στη λειτουργία του σπερματικού επιθηλίου. Ένα εξάλλου σημαντικό ερώτημα παραμένει πως είναι δυνατόν η ετερόπλευρη κιρσοκήλη να επηρεάζει τη λειτουργία και των δύο όρχεων! Έτσι τα τελευταία χρόνια διαφαίνεται η ανάγκη ανάπτυξης και επιβεβαίωσης κάποιου βιολογικού μηχανισμού που πιθανώς βρίσκεται πίσω από την ανάπτυξη κιρσοκήλης σε ένα μεγάλο κομμάτι του ανδρικού πληθυσμού. Πρόσφατες μελέτες υποστηρίζουν πως η ανάπτυξη κιρσοειδών φλεβών έχει έναν κληρονομικό χαρακτήρα, ειδικά στους πρώτους βαθμούς συγγένειας. Έρευνες σε περιπτώσεις χρόνιας φλεβικής ανεπάρκειας σε κιρσούς κάτω άκρων, υποδηλώνουν ως πιθανή αιτία την κληρονομική αδυναμία-λέπτυνση του αγγειακού τοιχώματος και δυσλειτουργία του ενδοθηλίου, καθώς καταδεικνύονται από μία παρεκκλίνουσα έκφραση της Ενδοθηλίνης-1 (ΕΤ-1, Endothelin-1) και των υποδοχέων της ΕΤΑ και ΕΤΒ (Endothelin Receptors A, B). Η ενδοθηλιακή δυσλειτουργία και η απρόσφορη παραγωγή της ΕΤ-1 ή των υποδοχέων μπορεί να εμπλέκονται στη δημιουργία νέο-ενδοθηλίου και στη διαστολή των φλεβών οδηγώντας στην ανάπτυξη κιρσοειδών φλεβών. Σε μελέτες κιρσών κάτω άκρων έχει αναδειχθεί ως σημαντικό αίτιο η ελαττωμένη έκφραση των υποδοχέων ΕΤΒ στο τοίχωμα των κιρσοειδών φλεβών, το οποίο οδηγεί σε μειωμένη συσταλτική επίδραση της Ενδοθηλίνης-1. Μία αντίστοιχη δυσλειτουργία θα ήταν αναμενόμενη και στην κιρσοκήλη, στα πλαίσια της γενικότερης βιολογικής συμπεριφοράς των φλεβών που υπόκεινται σε κιρσοειδή διάταση. Ωστόσο τα υπάρχοντα δεδομένα στην σύγχρονη βιβλιογραφία όσον αφορά στους κιρσούς σπερματικών φλεβών είναι υπερβολικά πτωχά. Μέχρι και την έναρξη αυτής της μελέτης μία μόνο μελέτη αναφερόταν σε πιθανή δυσλειτουργία του ενδοθηλίου των σπερματικών φλεβών. Ως εκ τούτο, αναπτύξαμε ως βάση αυτής της μελέτης την υπόθεση εργασίας ότι: η ανάπτυξη κιρσοειδών σπερματικών φλεβών οφείλεται όχι σε «εξωτερικά» αίτια όπως συμπίεση κλπ. αλλά σε ενδογενή βλάβη στην λειτουργία του ενδοθηλίου και συγκεκριμένα σε ενδογενή ελάττωση της έκφρασης της ενδοθηλίνης ή/και των υποδοχέων των σπερματικών φλεβών. Για να ελεγχθεί λοιπόν πειραματικά η υπόθεση εργασίας, οργανώθηκε η παρούσα προοπτική μελέτη ανοσοϊστοχημικού προσδιορισμού της ενδοθηλίνης και των υποδοχέων της σε δείγμα κιρσοειδών σπερματικών φλεβών από ασθενείς που υπεβλήθησαν σε χειρουργική αποκατάσταση κιρσοκήλης λόγω υπογονιμότητας. Η σύγκριση με φυσιολογικές φλέβες έγινε με χρήση φυσιολογικού υλικού από τον αντίστοιχο ασθενή ώστε κάθε ασθενής να είναι ταυτόχρονα και μάρτυρας. Επιπλέον μελετήθηκαν οι μορφολογικές αλλοιώσεις των κιρσοειδών καθώς και ένα σημαντικό μέλος του σηματοδοτικού μονοπατιού της ενδοθηλίνης, η ERK1/2 MAP Κινάση, η οποία σχετίζεται με την συστολή των λείων μυϊκών κυττάρων των αγγείων αλλά και με τη ρυθμιστική δράση στον πολλαπλασιασμό, διαφοροποίηση, μετανάστευση των λείων μυϊκών κυττάρων, κοινά ευρήματα στην ανάπτυξη κιρσοειδών φλεβών. Τέλος, σε μία προσπάθεια διερεύνησης της επίδρασης της παραμέτρου του χρόνου στην επίδραση της ενδοθηλιακής δυσλειτουργίας, χρησιμοποιήθηκε υλικό από παιδιά που είχαν υποβληθεί σε επέμβαση κιρσοκήλης. / Varicocele is the pathological finding of varicose veins at the scrotal portion of the spermatic cord (pampiniform plexus) and occurs more selectively on the left side. Varicocele has been recognized as one of the most common causes of male infertility. The frequency in the general population is approximately 15%. Almost 30% to 50% of men who suffer from primary infertility display varicocele. It is also possible to be discovered in early puberty and occasionally in prepubertal boys. In children the frequency of varicocele is considered to be rare but recent studies have shown its presence in 6% of children aged 10 years, while in adolescents this figure rises up to 16%. Before the age of 7-8 years it occurs very rarely. Although varicocele is such a common “disease” in subfertile men and a common “anatomic entity” in the general population, its etiology remains unclear. Previous theories concerning the length of the veins, “compression” phenomena etc. are insufficient to explain the frequency of varicose veins and the heterogeneous effect they may have on the seminiferous epithelium dysfunction. An even more difficult question is how the unilateral varicocele can affect the function of both testicles! Therefore, confirmation of a biological mechanism that probably lies behind the development of varicocele in a large part of the male population seems necessary nowadays. Recent studies suggest that the development of varicoce veins has a hereditary character, especially in first degree relatives. Research in cases of chronic venous insufficiency in lower limbs varicose veins implies the hereditary failure - thinning of the vessel wall and endothelial dysfunction as a cause for varicosity. This is often attributed to aberrant expression of endothelin-1 (ΕΤ-1) and its receptors ETA and ETB (endothelin receptors A, B). The endothelial dysfunction and the inappropriate production of ET-1 or its receptors may be involved in vein wall remodeling and the dilation of veins, leading to the development of varicose veins. In studies concerning varicose veins of the lower limbs decreased expression of ETB receptors in the varicose vein wall and a reduced contractile effect of endothelin-1, have emerged as an important mechanism of varicose veins. A similar dysfunction would be expected in the varicocele setting, as part of the broader biological behavior of veins which are subjected to varicose dilatation. However, the data available in contemporary bibliography regarding the varicose spermatic veins are extremely poor. Until the beginning of this study only one study referring to a possible dysfunction of the endothelium of the spermatic veins was available. Therefore, we developed a working hypothesis that the development of the varicose spermatic veins is not due to ‘’external’’ causes such as compression, etc. but due to endogenous damage to the endothelial function and specifically in reduction of endogenous endothelin and/or its receptors at the spermatic vein wall level. In order to test this hypothesis in an experimental setting we organized this prospective study of the immunohistochemical detection of endothelin-1 and its receptors in varicose veins specimens from infertile patients undergoing surgical correction of varicocele. Normal subcutaneous veins were harvested from each patient at the time of surgery and used as control specimens, so that each patient should serve as its own control. Furthermore, we studied the morphological alterations of varicose veins as well as a substantial part of the endothelin - ERK1/2 MAP kinase signaling pathway, which is related to the contraction as well as with the regulation of proliferation, differentiation and migration of smooth muscle cells at the vein wall. Finally, we also included surgical specimens from children who had undergone surgery for varicocele correction at an early age in an effort to investigate the effect of time parameters on endothelial dysfunction.

Aging is associated with increases in regional and systemic vascular resistance and arterial blood pressure. One possible mechanism through which these age-associated alterations occur is enhanced vasoconstrictor responsiveness, or alterations in the structural properties of the resistance vasculature. We hypothesized that stiffness and vasoconstriction would be greater in skeletal muscle arterioles from old rats, and that endurance exercise training would ameliorate the associated with aging alterations. METHODS: Young sedentary (YS; 4 months), old sedentary (OS; 24 months), young trained (YT) and old trained (OT) male Fischer 344 rats were used. Training modality was treadmill exercise at 15 m/min up a 15o incline, 5 days/wk for 12wks. Skeletal muscle first-order arterioles were isolated for in vitro experimentation. Intraluminal diameter was measured in response to the cumulative addition of endothelin-1, norepinephrine, KCl, and isoproterenol. Stiffness was measure by examining the arterioles' stress and strain relation to increased luminal pressure in Ca++ free solution. RESULTS: Skeletal muscle arterioles had augmented vasoconstriction to endothelin-1 and norepinephrine. Adrenergic vasodilation was diminished in aged rat arterioles. Stiffness increased with age. Exercise training ameliorated the age-associated changes in stiffness and norepinephrine vasoconstriction. Exercise training did not alter endothelin-1 vasoconstriction or adrenergic vasodilation. CONCLUSIONS: These findings suggest that enhanced vascular sensitivity to vasoconstrictors and increased arteriole stiffness may play a role in the increase in skeletal muscle and systemic vascular resistance and, thus, contribute to the elevated blood pressure which occurs in aging humans. These results also demonstrate some of the cardioprotective effects of exercise training.

The work reported in this thesis is an investigation of certain aspects of both the blood pressure (BP) elevating properties and BP lowering properties of arginine vasopressin (AVP). The hypothesis that endothelin (ET) contributes to the exaggerated pressor responsiveness of the spontaneously hypertensive rat (SHR) to AVP was tested by comparing the changes of BP, cardiac output (CO), and total peripheral conductance (TPC) to AVP in SHR to those in Wistar-Kyoto rats (WKY) both in the presence and absence of bosentan, a non-selective ET antagonist. Bosentan antagonized the BP responses to exogenous ET-1 in a competitive fashion. The pressor effects of AVP and Ang II were exaggerated in the SHR compared to WKY. Except for the highest dose of AVP, pre-treatment with bosentan blunted the increases in BP and the decreases in total peripheral conductance (TPC) evoked by AVP in the SHR, but not in the WKY. In contrast to AVP, bosentan blunted the increases in BP evoked by lower doses of Ang II in both strains, although the effect was more pronounced in the SHR. These results suggest that ET contributes to the hemodynamic effects of AVP in the SHR and to the effects of Ang II in both strains. The findings support the hypothesis that ET contributes to the exaggerated pressor responsiveness of SHR to AVP. Cessation of a 3 hour infusion of AVP (20 ng/kg/min) results in a dramatic and prolonged decrease in BP below pre-infusion basal levels in hypertensive rats, but not in normotensive control rats. This phenomenon has been termed the "withdrawal-induced antihypertensive phenomenon" (WAP). In order to determine the time course of the WAP, and the role of CO and TPC in the WAP, BP was recorded by radiotelemetry and CO was recorded from aonic flowprobes in conscious unrestrained rats before, during, and after a 3 hr i.v. infusion of 20 ng/kg/min of AVP. Baseline mean arterial BP values were lower, and the magnitude of the WAP was less in SHR when BP was recorded with radiotelemetric implants than in another group in which BP was recorded with conventional externalized femoral arterial catheters. Strikingly, absolute BP values recorded both during and after the AVP infusion were similar in the two groups. BP remained decreased for several days in SHR infused with AVP with complete recovery requiring 6-7 days. In rats instrumented with aortic flow probes, the fall in pressure following cessation of the AVP infusion was associated with a large decrease in CO below control levels in the SHR. The time-course of the CO responses approximated the time-course of the pressure responses. These results lead to the following conclusions: firstly, telemetry is a superior method for recording BP in hypertensive animals, and the lower magnitude of the WAP was probably related to the lower basal BPs recorded by this method; secondly, the mechanism accounting for the WAP must be of a long duration; thirdly, the WAP is mediated by a fall in CO and not by an increase in TPC. In conclusion, the results of the thesis support the hypothesis that ET contributes to the BP elevating properties of AVP and, consequently, the exaggerated pressor responsiveness of SHR to the peptide, and that the BP lowering properties of AVP are mediated by a fall in CO.

Aging is associated with increases in regional and systemic vascular resistance and arterial blood pressure. One possible mechanism through which these age-associated alterations occur is enhanced vasoconstrictor responsiveness, or alterations in the structural properties of the resistance vasculature. We hypothesized that stiffness and vasoconstriction would be greater in skeletal muscle arterioles from old rats, and that endurance exercise training would ameliorate the associated with aging alterations. METHODS: Young sedentary (YS; 4 months), old sedentary (OS; 24 months), young trained (YT) and old trained (OT) male Fischer 344 rats were used. Training modality was treadmill exercise at 15 m/min up a 15o incline, 5 days/wk for 12wks. Skeletal muscle first-order arterioles were isolated for in vitro experimentation. Intraluminal diameter was measured in response to the cumulative addition of endothelin-1, norepinephrine, KCl, and isoproterenol. Stiffness was measure by examining the arterioles' stress and strain relation to increased luminal pressure in Ca++ free solution. RESULTS: Skeletal muscle arterioles had augmented vasoconstriction to endothelin-1 and norepinephrine. Adrenergic vasodilation was diminished in aged rat arterioles. Stiffness increased with age. Exercise training ameliorated the age-associated changes in stiffness and norepinephrine vasoconstriction. Exercise training did not alter endothelin-1 vasoconstriction or adrenergic vasodilation. CONCLUSIONS: These findings suggest that enhanced vascular sensitivity to vasoconstrictors and increased arteriole stiffness may play a role in the increase in skeletal muscle and systemic vascular resistance and, thus, contribute to the elevated blood pressure which occurs in aging humans. These results also demonstrate some of the cardioprotective effects of exercise training.