Rad54 is required for the normal development of male and female germ cells and contributes to the maintainance of their genome integrity after genotoxic stress.

Rad54 is an important factor in the homologous recombination pathway of DNA double-strand break repair. However, Rad54 knockout (KO) mice do not exhibit overt phenotypes at adulthood, even when exposed to radiation. In this study, we show that in Rad54 KO mouse the germline is actually altered. Compared with the wild-type (WT) animals, these mice have less premeiotic germ cells. This germ cell loss is found as early as in E11.5 embryos, suggesting an early failure during mutant primordial germ cells development. Both testicular and ovarian KO germ cells exhibited high radiation sensitivity leading to a long-term gametogenesis defect at adulthood. The KO female germline was particularly affected displaying decreased litter size or sterility. Spermatogenesis recovery after irradiation was slower and incomplete in Rad54 KO mice compared with that of WT mice, suggesting that loss of germ stem cell precursors is not fully compensated along the successive rounds of spermatogenesis. Finally, spermatogenesis recovery after postnatal irradiation is in part regulated by glial-cell-line-derived neurotrophic factor (GDNF) in KO but not in irradiated WT mice, suggesting that Sertoli cell GDNF production is stimulated upon substantial germ cell loss only. Our findings suggest that Rad54 has a key function in maintaining genomic integrity of the developing germ cells.

Cloning and sequencing of SOB3, a human gene coding for a sperm protein homologous to an antimicrobial protein and potentially involved in zona pellucida binding.

We have previously characterized an 18-19 kDa cationic protein, SOB3, that was detected in the epididymis and localized within the acrosome and on the neck region of human spermatozoa. We suggested that it is involved in secondary sperm binding to the zona pellucida. The present study describes its purification to homogeneity by preparative electrophoresis and non-equilibrium pH gradient electrophoresis. Degenerate primers deduced from microsequencing were used to amplify a specific fragment from human epididymal RNA by reverse transcription-polymerase chain reaction (RT-PCR). This 164 bp fragment was extended by 5' and 3'-RACE to obtain the 548 bp full length cDNA. The open reading frame encodes a 170 amino acid protein. SOB3 is a single copy gene. It is 98% identical to prepro-FALL39 and 100% identical to CAP18, two human genes which were initially identified by screening a human bone marrow (lambda)gt11 library, and which encode an antimicrobial protein. Northern blots of human tissues revealed a 1 kb transcript in corpus and cauda epididymis only, while RT-PCR showed presence of the mRNA in the three epididymal regions and also in round spermatids. The above results suggest that SOB3 has two roles in sperm protection and fertilization, depending on its dual origin and final sperm localization.

Genetic abnormalities detected by comparative genomic hybridization in a human endometriosis-derived cell line.

Comparative genomic hybridization (CGH) was used in parallel with fluorescence in-situ hybridization (FISH) and conventional karyotyping to perform a genome-wide survey of DNA gains and losses in the endometriosis-derived permanent cell line, FbEM-1. The cytogenetic analysis showed a complex karyotype with numerical changes and multiple chromosome aberrations, including the der(1) complement marker exhibiting a large homogenous staining region (HSR). The chromosomal rearrangement interpreted as der(5) t(5;6)(q34;p11) was found in the majority of the metaphases indicating a clonal abnormality. Repeated CGH experiments demonstrated over-representation of chromosomes 1, 2, 3, 5, 6p, 7, 16, 17q, 20, 21q and 22q, while chromosomes 6q, 9, 11p, 12, 13q, 18 and X were under-represented. Using DNA from the original endometriotic tissues, including a peritoneal implant and ovarian endometrioma, CGH analysis revealed loss of DNA copy number on 1p, 22q and chromosome X, while gain was found on chromosomal arms 6p and 17q. FISH analysis confirmed that the gain at 17q includes amplification of the proto-oncogene HER-2/neu in 16% of the FbEM-1 nuclei and in 12% of cells from the primary ovarian endometrioma tissue. These findings demonstrate that FbEM-1 cells share certain molecular cytogenetic features with the original tissue and suggest that chromosomal instability is important in the development of endometriosis.

Cellular and genetic constitution of human endometriosis tissues.

For many years, endometriosis has been an enigmatic and confusing disorder, but there have been recent contributions to the subject, provided by modern techniques in cellular and molecular biology, regarding the cell lineage involved, the stage of differentiation, and genomic features. This review deals mainly with the cellular, cytochemical, cytogenetic, and molecular cytogenetic features of primary endometriotic lesions and cultured endometriotic cells. The FbEM-1 cell line, taken as an in vitro model, showed cell proliferation and differentiation features suggesting an immature endometriosis-related cell lineage. Chromosomal analysis of these cells demonstrate a complex karyotype including a rearrangement interpreted as der(5) t(5q34;6p11) indicating a clonal cell proliferation. Data of recurrent DNA sequence copy number alterations detected by the comparative genomic hybridization in a series of primary endometriotic lesions also are described. Predominant recurrent anomalies were found on chromosome 1p and 22q in 50% of the studied samples. Additional losses were seen on chromosomes 5p(33%), 6q(27%), 7p(22%), 9q(22%), and 1q(22%), as well as on 17q segments in one case. Gain of DNA sequences was seen on chromosomes 6q, 7q, and 17q. The potential role of the genetic changes identified are discussed in relation to the putative oncogenes and/or tumor suppressor genes possibly involved in development of endometriosis.

Detection of DNA copy number changes in human endometriosis by comparative genomic hybridization.

Endometriosis is characterized by infertility and pelvic pain in 10-15% of women of reproductive age. The genetic events involved in endometriotic cell expansion remain in large part unknown. To identify genomic changes involved in development of this disease, we examined a panel of 18 selected endometriotic tissues by comparative genomic hybridization (CGH), a molecular cytogenetic method that allows screening of the entire genome for chromosomal gains and/or losses. The study was performed on native, nonamplified DNA extracted from manually dissected endometriotic lesions. Recurrent copy number losses on several chromosomes were detected in 15 of 18 cases. Loss of chromosome 1p and 22q were detected in 50% of the cases. Additional common losses occurred on chromosomes 5p (33%), 6q (27%), 7p(22%), 9q (22%), 16 (22%) as well as on 17q in one case. Gain of DNA sequences were seen at 6q, 7q and 17q in three cases. To validate the CGH data, selective dual-color FISH was performed using probes for the deleted regions on chromosomes 1, 7 and 22 in parallel with the corresponding centromeric probes. Cases showing deletion by CGH all had two signals at 1p36, 7p22.1 and 22q12 in less than 30% of the nuclei in comparison to the double centromeric labels found in more than 85% of the cells. These findings indicate that genes localized to previously undescribed chromosomal regions play a role in development and progression of endometriosis.

Human endometriosis-derived permanent cell line (FbEM-1): establishment and characterization.

A human epithelial-like cell line derived from peritoneal implants from a patient with gonadotrophin-releasing hormone (GnRH) agonist-resistant endometriosis graded as stage IVd according to the American Fertility Society classification was established in vitro. This cell line, designated FbEM-1, exhibited an epithelial-like morphology, grew in suspension and was immunoreactive for cytokeratins 8, 18, 19, vimentin and human leukocyte class I antigens. The cultured cells were negative for various haematopoietic cell markers, including the lymphoid cell antigens CD3, CD20 and CD45, von Willebrandt factor, carcinoembryonic antigen and the carcinoma antigen-125 (CA-125). In addition, the FbEM-1 cells were found to be moderately positive for periodic acid Schiff's (PAS) solution but were negative for alpha-naphthyl acetate esterase, peroxidase and chloroacetate esterase activities. Using specific antibodies against the progesterone, androgen and oestrogen receptors, approximately 40% and 5-10% of the cells immunostained for progesterone and androgen receptors respectively, while oestrogen receptors were not detected. On cytogenetic analysis using R-banding, these cells showed numerous chromosomal aberrations, including loss of one chromosome X, 4q+, 5q+, trisomy 7,8 and 10 and tetrasomy of chromosomes 17, 18, 19 and 20. These data show that the continuously growing FbEM-1 cell line established from endometriotic implants may be useful in achieving better understanding of the histogenesis of endometriosis.

Carrier detection and prenatal diagnosis of X-linked agammaglobulinemia.

We investigated the pregnant mother of a boy with X-linked agammaglobulinemia (XLA) but with no family history of immune disease. The X-inactivation pattern was found, using a methylation-sensitive probe, to be skewed in the maternal B cells but random in the polymorphonuclear cells, indicating carrier status and a 50% risk of inheritance for her male fetus. Using probes assigned to regions on either side of the XLA locus and defining RFL polymorphism, we excluded for the first time a diagnosis of XLA on a chorionic villus sample, with a risk of error less than 0.003. Immunological studies performed at the 19th week of gestation and 3 days after birth confirmed normality. Carrier detection based on the X-chromosome inactivation pattern, together with prenatal studies using probes close to the disease locus, thus permits prenatal diagnosis in families with isolated cases of XLA.

Wiskott-Aldrich syndrome carrier detection with the hypervariable marker M27 beta.

Whole-blood cells of obligate carriers of the X-linked Wiskott-Aldrich syndrome (WAS) exhibit nonrandom inactivation of the X-chromosomes. However, because of the limited polymorphism of the probes available, the X-methylation pattern can only be determined in a restricted proportion of females. We thus analysed a large set of normal females and members of WAS families, using the recently described marker M27 beta, which detects the hyperpolymorphic locus DXS255. The probe was used to detect differences in methylation between the active and inactive X-chromosome, and the findings were compared with the pattern obtained using the well-documented probes from the 5' end of the PGK and HPRT genes. All the normal females were found to use either X-chromosome randomly, and there was complete correlation between the three probes in the populations studied. Segregation analysis performed with M27 beta and other related markers in the WAS families was fully in accordance with the X-inactivation data. The use of M27 beta, for both X-inactivation and segregation analysis of WAS kindreds, provides a basis for genetic counselling in the majority of families, including those with no surviving males.

Hyper-IgM immunodeficiency syndrome: influence of lymphokines on in vitro maturation of peripheral B cells.

Peripheral B cells from six patients affected with the hyper-IgM immunodeficiency syndrome, characterized by an absence of IgG and IgA in serum with a concomitant elevated level of IgM, were analyzed for phenotypic and functional characteristics. We report that although the membrane antigenic pattern expression was characteristic of mature B cells, B cells from most patients exhibited an impairment in their in vitro response to several lymphokines, such as recombinant interleukin 2 (rIL-2) and low molecular weight B-cell growth factor (BCGF), that induce proliferation of anti-mu-activated B cells. This impairment was also found in response to a lymphokine mixture from a CD2-activated T-cell clone. The decrease in lymphokine-induced B-cell proliferation was accompanied by a low B-cell differentiation, whether patients' B cells were stimulated by the T-cell clone supernatant or rIL-2 and rIL6, lymphokines able to support differentiation of Staphylococcus aureus Cowan I (SAC)-activated B cells. In addition, none of the lymphokines tested were able to induce patients' B cells to switch from IgM-secreting cells to IgG- and IgA-secreting cells. We conclude that this syndrome is associated with a defect in lymphokine-dependent maturation of B lymphocytes, although the T- or the B-cell origin of the defect still cannot be determined.

Systemic and regional haemodynamic interactions between K+ channel openers and the sympathetic nervous system in the pithed SHR.

1. The interactions between two K+ channel openers, cromakalim and SR 44866 (infused i.v. at equihypotensive doses), and the sympathetic nervous system at the systemic and regional (mesentery, kidney, hindlimb) vascular levels were investigated in the pithed spontaneously hypertensive rat (SHR) by use of the pulsed Doppler technique. 2. The two K+ channel openers did not affect postsynaptic alpha 1- but slightly reduced postsynaptic alpha 2-adrenoceptor mediated systemic pressor and regional vasoconstrictor responses. 3. Both drugs significantly decreased the systemic pressor and regional vasoconstrictor responses elicited by spinal cord stimulation. These sympathoinhibitory effects were not homogeneously distributed among the different vascular beds, the decreasing rank order being: mesentery greater than kidney greater than hindlimb. Simultaneously, the spinal cord stimulation-induced tachycardia remained unaffected. 4. After treatment with K+ channel openers, restoration of initial blood pressure and vascular tone values by infusion of prostaglandin F2 alpha (PGF2 alpha) and vasopressin respectively did not affect and abolished the sympathoinhibitory effects of cromakalim and SR 44866. 5. We conclude that in SHRs the two K+ channel openers that we investigated exert similar sympathohibitory effects which affect some vascular beds more than others. These effects are not dependent upon the arterial blood pressure level and are most likely prejunctionally located.

Differential systemic and regional hemodynamic profiles of four angiotensin-I converting-enzyme inhibitors in the rat.

Angiotensin-converting enzyme (ACE) inhibitors decrease blood pressure by reducing systemic vascular resistance. That the peripheral vasodilating properties of ACE inhibitors might not be homogeneously distributed in all vascular beds and might differ from one drug to another has been investigated in the normotensive rat by the pulsed Doppler technique using the active components of four different ACE inhibitors: captopril, enalapril, perindopril, and ramipril. Systemic (cardiac output and blood pressure) and regional (kidney, mesentery, hindquarter) hemodynamic responses to saline or to cumulative bolus injections (0.01-1 mg/kg) of captopril, enalaprilat, perindoprilat, or ramiprilat were continuously monitored. The effects of successive bolus injections (0.3-300 ng/kg) of angiotensinII were also investigated. The four ACE inhibitors produced an almost complete blockade of plasma angiotensin-II converting-enzyme activity (83%, 100%, 100%, and 100%, respectively), induced dose-dependent decreases in mean blood pressure, did not significantly affect cardiac output, and reduced total peripheral and mesenteric vascular resistances to the same extent. Hindlimb vascular resistance was identically decreased, but to a lower extent than total peripheral resistance by enalaprilat, perindoprilat, and ramiprilat, whereas it was increased by captopril at low doses only. Renal resistance was markedly decreased by the four drugs, and especially by captopril. The decreasing rank order for ACE-inhibitor-induced vasodilation is exactly the same (renal greater than total peripheral = mesenteric greater than hindlimb vascular resistances) as that of angiotensin-H-induced regional vasoconstriction, indicating that the vasodilator properties of ACE inhibitors are mainly due to angiotensin-II vasomotor tone suppression. None of the investigated compounds significantly affected mesenteric and hindlimb blood flows, except captopril, which lowered the latter significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

[Potassium agonists: regional vasodilator profile in rats]. / Agonistes potassiques: profil vasodilatateur régional chez le rat.

The systemic and regional (kidney, mesentery, hindlimb) hemodynamic effects of (a) two potassium agonists: cromakalim (1 to 8 micrograms.kg-1.min-1/15 min) and SR 44866 (0.125 to 2 micrograms.kg-1.min-1/15 min) and (b) a calcium antagonist, nicardipine (0.5 to 2 micrograms.kg-1.min-1/15 min) have been investigated by the pulsed doppler technique, and compared in the anesthetized normotensive rat. The two potassium agonists and nicardipine lowered blood pressure (BP) and total peripheral resistance (TPR) dose-dependently and slightly increased heart rate. Cardiac output (QC) remained unchanged. SR 44866 was as potent as nicardipine in reducing BP and about three to four times more potent than cromakalim (the DE20s, doses producing a 20 p. 100 decrease in BP, being: SR 44866: 0.7 micrograms.kg-1.min-1, cromakalim: 2.8 micrograms.kg-1, nicardipine: 0.8 micrograms.kg-1.min-1). At these equihypotensive doses, the three drugs (a) similarly decreased TPR (SR 44866: -16 p. 100, cromakalim: -17 p. 100, nicardipine: -19 p. 100, (b) reduced mesenteric vascular resistance (MVR) (SR 44866: -18 p. 100, cromakalin: -20 p. 100, nicardipine: -21 p. 100) and renal vascular resistance (RVR) (SR 44866: -16 p. 100, cromakalim: -21 p. 100, nicardipine: -13 p. 100 to the same extent as TPR, but (c) SR 44866 and nicardipine reduced hindlimb vascular resistance (HVR) to a larger extent than TPR (SR 44866: -25 p. 100, nicardipine: -25 p. 100.(ABSTRACT TRUNCATED AT 250 WORDS)

Ketanserin: systemic and regional hemodynamics in spontaneously hypertensive rats. Role of alpha 1-adrenoceptor blockade.

The systemic and regional hemodynamic effects of ketanserin were investigated in spontaneously hypertensive rats (SHRs) using either the pulsed Doppler or the microsphere technique. In addition, the contribution of ketanserin alpha 1-adrenoceptor blocking properties to these hemodynamic effects was assessed. Ketanserin, directly after infusion or secondarily after bolus injection, induced dose-dependent decreases in blood pressure and regional vascular resistances. Peripheral vasodilatation was not homogeneous, affecting in a decreasing rank order: muscle = spleen greater than brain = kidney = total peripheral resistance = liver greater than mesentery = skin. Cardiac output and hindlimb blood flow increased, renal blood flow was maintained whereas mesenteric blood flow was decreased. Prazosin pretreatment, followed by PGF 2 alpha infusion in order to restore initial vascular tone, reduced the ketanserin-induced decrease in blood pressure (by about 70%) and abolished the drug-induced reductions in regional vascular resistances, indicating that these effects in SHRs were mostly due to the alpha 1-adrenoceptor blocking properties of the drug.

[Atrial natriuretic factor. Systemic and regional hemodynamic profile and interaction with the alpha-adrenergic system in pithed SHR rats]. / Facteur natriurétique atrial. Profil hémodynamique systémique et régional et interaction avec le système alpha-adrénergique chez le SHR amyélé.

The hemodynamic effects of ANF (1 and 5 micrograms/kg/min) and its potential interactions with the sympathetic system were investigated at the systemic and regional (pulsed Doppler) levels in the pithed SHR. ANF dose-dependently decreased cardiac output CO, renal (RBF), mesenteric (MBF) and hindquarter (HQBF) blood flows and increased the corresponding vascular resistances: total peripheral (TPR), renal (RR), mesenteric (MR) and hindquarter (HQR), all these effects being significant at 5 micrograms/kg/min. Mean blood pressure (MBP) and heart rate were also significantly decreased at 5 micrograms/kg/min. ANF significantly reduced the responses to cirazoline of MBP, TPR and RR (1 microgram/kg/min) and of MR (5 micrograms/kg/min) but did not affect those of HQR ANF also significantly reduced the responses to UK-14,304 of MBP, TPR and MR (5 micrograms/kg/min) but did not affect those of RR and HQR. These data indicate that (a) ANF, in the absence of reflex phenomenons, exerts intrinsic regional vasoconstrictor effects, (b) ANF exhibits a postsynaptic sympatho-inhibitory effect. The latter is more marked vs the alpha 1-(especially renal) than vs the alpha 2-adrenoceptor-mediated responses but does not affect the hindquarter vascular bed, which suggest that its contribution to the overall antihypertensive action of ANF is of limited importance.

Systemic and regional hemodynamic profile of five angiotensin I converting enzyme inhibitors in the spontaneously hypertensive rat.

The effects of 5 angiotensin I converting enzyme (ACE) inhibitors--captopril, enalapril, perindopril, trandolapril and ramipril--on general and regional hemodynamics were investigated (using radioactive microspheres) and compared in anesthetized adult spontaneously hypertensive rats. The 5 treatments were administered daily by gavage for 8 days in doses inducing identical decreases in arterial blood pressure. This effect was entirely due to a decrease in total peripheral resistance inasmuch as cardiac index was not affected by the 5 ACE inhibitors. In addition, despite their different chemical structures, all exhibited the same regional vasodilator pattern, which thus appears to be related only to ACE inhibition. The vascular beds resistances were decreased in the following order: renal greater than splenic = liver greater than skin greater than total peripheral greater than muscle = brain. Simultaneously, and despite the decrease in perfusion pressure, most regional blood flows and especially renal blood flow were increased. Finally, renal vasodilator effects of ACE inhibitors were observed even after doses that lacked any effect on total peripheral resistance.

Systemic and regional pre- and post-junctional sympathoinhibitory effect of perindopril in spontaneously hypertensive rats.

The interaction between converting enzyme inhibition and sympathetic system activity at systemic and regional (renal, mesenteric, hindlimb) levels was investigated in adult pithed spontaneously hypertensive rats (SHR) using perindopril (5 mg/kg orally every day for 8 days) and the pulsed Doppler technique. Perindopril induced a decrease in systolic blood pressure and in regional vascular resistance which was abolished by binephrectomy. In addition, the drug had a sympathoinhibitory effect on the systemic vasopressor and the regional vasoconstrictor responses to cirazoline, especially UK 14304, an effect which was kidney-dependent (abolished by binephrectomy) and postjunctional, and spinal cord stimulation, an effect which was kidney-independent and most likely prejunctional in its mechanism.

Perindopril, a new converting enzyme inhibitor: systemic and regional hemodynamics and sympathoinhibitory effects in spontaneously hypertensive rats.

The effects of a new converting enzyme inhibitor, perindopril (5 mg/kg p.o. q.d. for 8 days), on systemic and regional hemodynamics, as well as its interferences with the sympathetic nervous system at the cardiovascular level, were investigated in nonbinephrectomized and in binephrectomized spontaneously hypertensive rats (SHRs). Perindopril abolished plasma converting enzyme activity and lowered arterial blood pressure (BP) without affecting heart rate. Cardiac index (microspheres) was not drug affected; thus, the reduction in BP was due to a decrease in total peripheral resistance which was shown to be homogenous, since all investigated vascular resistances were reduced to the same extent. In nonbinephrectomized, pithed SHRs, perindopril decreased BP and renal and hindlimb vascular resistances (pulsed Doppler). In addition, perindopril exerted a sympathoinhibitory effect as evidenced by (a) a reduction in the systemic vasopressor and regional vasoconstrictor responses to the alpha 1-adrenoceptor agonist, cirazoline, and especially to the alpha 2-adrenoceptor agonist UK 14.304; and (b) a decrease in the systemic pressor and in the hindlimb vasoconstrictor responses to spinal cord stimulation. In binephrectomized, pithed SHRs, perindopril no longer decreased BP; however, whereas its sympathoinhibitory effect versus alpha-adrenoceptor agonists was abolished, that versus spinal cord stimulation persisted. These results indicate that (a) perindopril lowers BP in SHRs by a renal-dependent mechanism; (b) perindopril exerts in SHRs a sympathoinhibitory effect versus alpha-adrenoceptor agonists and spinal cord stimulation; (c) the sympathoinhibitory effect of perindopril versus alpha-adrenoceptor agonists is postjunctional and kidney dependent; and (d) the sympathoinhibitory effect of perindopril versus spinal cord stimulation is possibly prejunctional in its mechanism and does not require the presence of the kidneys.

Influence of captopril and enalapril on regional vascular alpha-adrenergic receptor reactivity in SHR.

The effects of short-term oral treatment with captopril and enalapril (two angiotensin-I-converting-enzyme inhibitors [ACEIs] that were administered in equipotent antihypertensive doses) on the systemic vasopressor response and on the renal, mesenteric, and hindlimb vascular responses to cirazoline and UK-14,304 (alpha 1- and alpha 2-adrenergic receptor-specific agonists, respectively) were investigated in adult pithed spontaneously hypertensive rats (SHR) of the Okamoto-Aoki strain. In the nonbinephrectomized animal, captopril and enalapril reduced to the same extent the systemic blood pressure and renal and hindlimb vascular resistances. They also decreased to the same extent systemic pressor and regional vasoconstrictor responses to cirazoline and UK-14,304, especially in the renal and mesenteric vascular beds. Simultaneously, the effects of angiotensin I and angiotensin II on the pressor response were abolished and almost not modified. In the binephrectomized animals, captopril and enalapril no longer reduced the systemic blood pressure and regional vascular resistances, but whereas the sympathoinhibitory effect of captopril vs the systemic pressor and regional vasoconstrictor responses to cirazoline and UK-14,304 persisted, those of enalapril disappeared.(ABSTRACT TRUNCATED AT 250 WORDS)

Postsynaptic alpha adrenoceptors and attenuation of vascular sympathetic responses in SHRs by captopril and enalapril.

The effects of a short-term oral treatment with captopril or enalapril, two converting enzyme inhibitors (CEIs) administered in equipotent antihypertensive doses, on the systemic vasopressor and on the renal, mesenteric and hind-limb vascular responses to cirazoline and UK 14304, respectively alpha1- and alpha2- adrenoceptor specific agonists, were investigated in the adult pithed SHR. Cirazoline and UK 14304 induced vasoconstrictor responses in the three investigated territories, demonstrating the location and a functional role at these levels of the two sub-types of alpha-adrenoceptors. Both captopril and enalapril reduced, to the same extent, the systemic pressor and the regional vasoconstrictor responses, especially in the renal and mesenteric territories, elicited by cirazoline and UK 14304, demonstrating that both subtypes of alpha-adrenoceptors are involved in the CEIs-induced attentuation of sympathetic responses.

Effects of captopril and enalapril on regional vascular resistance and reactivity in spontaneously hypertensive rats.

The present study compares the effects of short-term treatments with captopril and enalapril, administered in equipotent antihypertensive doses, on the regional vascular resistances and on the regional vascular responsiveness to vasopressor agents of adult spontaneously hypertensive rats (SHRs). Three groups of animals were treated by gavage with captopril (100 mg/kg), enalapril (25 mg/kg), or distilled water for 8 days. Arterial blood pressure (BP), heart rate (HR), plasma renin concentration (PRC), and plasma converting-enzyme activity (CEA) were measured. Cardiac index (CI), total peripheral resistance (PR), and organ flow distribution were determined using microspheres. Renal and mesenteric vascular responsiveness to vasopressor agents was evaluated by continuous measurement of renal and mesenteric blood flows with miniaturized pulsed Doppler flow probes. Data showed that in the anesthetized SHR the two drugs induced similar reductions in BP, PR, and HR, without affecting CI. They simultaneously produced a strong converting-enzyme inhibition as evidenced by the suppression of angiotensin I effects accompanied by a potentiation of angiotensin II responses, a reduction in CEA, and an increase in PRC. Organ flows were similarly and homogeneously increased, especially in the kidneys, in both treated groups. Norepinephrine (NE) vasoconstrictor responses were abolished in the mesenteric vascular bed by both drugs, but in the renal, NE responses although completely abolished by captopril were only partially reduced by enalapril. It thus appears that diminished vascular responsiveness to NE, especially in the case of captopril, is probably involved along with converting-enzyme inhibition in the antihypertensive action of converting enzyme inhibitors (CEI), the mechanism of the difference between captopril and enalapril remaining still speculative.