Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

All four components of the kallikrein-kinin system--kininogens, tissue kallikreins, kinins, and kininases--have been found in human male genital secretions. Kinins are continuously released from seminal plasma kininogens through limited proteolysis by kininogenases like tissue kallikrein from prostate and sperm acrosin. Kinins are the terminal effectors of the kallikrein-kinin system and increase sperm motility and sperm metabolism at nanomolar concentrations. Recent investigations indicate that these effects are possibly mediated by a specific sperm membrane integrated bradykinin receptor, subtype B2. The two major kininase that are present in seminal plasma are kininase II and neutral metallo-endopeptidase. Kininase II, which is identical with angiotensin-converting enzyme, is also involved in the renin-angiotensin system as it converts angiotensin I into angiotensin II and thus is the connecting enzyme of both systems. Apart from the observed effects of kinins on sperm motility, the kallikrein-kinin system is thought to be involved in the regulation of spermatogenic functions of the testis: in the rat, kallikrein activates Sertoli cell function, increases the relative number of spermatocytes and the [3H] thymidine incorporation of testicular tissue, enhances glucose-intake, and increases testicular blood flow. Clinical trials showed that systemic administration of kallikrein may be particularly useful for treatment of infertile men suffering from asthenozoospermia and/or oligozoospermia. During kallikrein therapy, the number of spermatozoa and both quantitative and qualitative sperm motility increased, and a significant improvement of the conception rate was achieved. An increased sperm number was also observed after application of the specific kininase II inhibitor captopril.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Possible effects of the kallikrein-kinin system on male reproductive functions. 131 46

Inhibitors of the angiotensin-converting enzyme (ACE = kininase II) by definition have a dual action: prevention of angiotensin II generation and inhibition of kinin degradation. Although the first mechanism is generally accepted, it may not by itself be sufficient to explain the acute blood pressure-lowering action of these compounds. Studies in experimental and clinical hypertension, including the use of selective angiotensin II and bradykinin receptor antagonists, suggest additional vasodilator, non-renin-dependent mechanisms in their action on blood flow and blood pressure. Inhibition of kinin degradation by ACE inhibitors will amplify kinin-mediated reactions on local vessel tone, in particular, if kinin generation is stimulated or this situation is experimentally mimicked by addition of exogenous bradykinin. The acute blood pressure-lowering action of ACE inhibitors is inhibited by indomethacin-type cyclooxygenase inhibitors, suggesting a contribution of bradykinin-induced release of vasodilator prostaglandins to their action. Bradykinin stimulates the phospholipase-dependent release of arachidonic acid from membrane phospholipids, allowing for subsequent generation of its metabolites, the eicosanoids. This stimulation is receptor-mediated and involves one or more types of B2 receptors, coupled via G-proteins to intracellular messenger systems that control cytosolic calcium levels. Bradykinin-induced changes in vessel tone are transient, caused by a rapidly developing tachyphylaxis at the receptor level. The potent vasodilator action of systemic bradykinin administration is not consistently reflected in studies performed on isolated blood vessels. This is probably due to the indirect nature of kinin-mediated vasomotor responses, i.e., the release of vasoactive mediators, most notably the eicosanoids and endothelium-derived relaxing factor (EDRF).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Converting enzyme inhibitors and the interaction between kinins and eicosanoids. 169 63

This study was conducted to examine the role of bradykinin in the persistence of the renal vasodilator effect of captopril during angiotensin II receptor blockade. Blood pressure and renal blood flow were monitored in eight groups of pentobarbital-anesthetized rabbits. In group 4, captopril alone was administered, and it decreased blood pressure by 14 +/- 4 mm Hg and increased renal blood flow by 21 +/- 4 ml/min. After a bolus injection and a constant intravenous infusion of the imidazole derivative angiotensin II receptor antagonist DuP 753 (group 5), captopril decreased blood pressure by 9 +/- 2 mm Hg and increased renal blood flow by 8 +/- 1 ml/min (12 +/- 1% change in renal blood flow, p less than 0.05 versus group 4). In the presence of a constant intravenous infusion of saralasin (group 6), captopril decreased blood pressure by 13 +/- 5 mm Hg and increased renal blood flow by 7 +/- 2 ml/min (17 +/- 5% change in renal blood flow, p less than 0.05 versus group 4). These results did not differ from those in group 5. During a constant intrarenal arterial infusion of a B2 bradykinin receptor antagonist, DArg0, [Hyp3-Thi5,8-DPhe7]-bradykinin (BkA) (group 7), captopril decreased blood pressure by 14 +/- 4 mm Hg and increased renal blood flow by 10 +/- 4 ml/min. Combined administration of DuP 753 intravenously and BkA intra-arterially (group 8) eliminated the effect of captopril. In group 8, captopril caused insignificant changes in blood pressure and renal blood flow. The results indicate that DuP 753 and saralasin antagonize the renin-angiotensin system to a comparable extent in vivo. Although blockade of the latter system accounted for a significant part of the increase in renal blood flow caused by captopril, the remaining component was contributed by endogenous bradykinin.
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PMID:Kinin contribution to renal vasodilator effect of captopril in rabbit. 184 1

Mean arterial pressure (BP) was measured in conscious, spontaneously hypertensive rats (SHR). Oral administration of the angiotensin I-converting enzyme inhibitor (ACEI) CGS 16617 significantly lowered BP. In contrast, the thromboxane synthetase inhibitor (TxSI) CGS 12970 lacked an antihypertensive action in SHR. When administered concurrently, the TxSI significantly potentiated the antihypertensive actions of the ACEI. Inhibition of thromboxane synthetase did not potentiate the antihypertensive actions of metoprolol or verapamil, indicating that a specific interaction exists between a TxSI and an ACEI. The antihypertensive actions of CGS 16617 also were potentiated by the cyclooxygenase inhibitor indomethacin, a result suggesting that CGS 12970 may enhance the action of CGS 16617 by inhibiting the action of vasoconstrictor prostaglandins produced after administration of an ACEI. The potentiation of the antihypertensive actions of CGS 16617 by CGS 12970 remained unaffected by either the kallikrein inhibitor aprotinin or a bradykinin receptor antagonist. Thus, although the interaction between an ACEI and a TxSI is a prostaglandin-dependent mechanism, it is not mediated by endogenous kinins. Inhibition of thromboxane synthetase significantly stimulated renin release and significantly attenuated the pressor response to exogenously administered angiotensin II. An increase in the dependency of BP upon the renin-angiotensin system and attenuation of the vascular actions of angiotensin II may serve to explain the potentiation of the antihypertensive action of ACEI after inhibition of thromboxane synthetase. The interaction between ACEI and TxSI was not restricted to SHR, because a TxSI potentiated the actions of an ACEI in both normotensive and deoxycorticosterone acetate/Na hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of thromboxane synthetase potentiates the antihypertensive action of an angiotensin-converting enzyme inhibitor by a prostaglandin-dependent but kinin-independent mechanism. 192 Jan 18

Inhibition of angiotensin-converting enzyme (ACE) inhibits formation of angiotensin II and, by inhibition of kinin metabolism, may also increase vascular bradykinin. The present experiments were done in sodium-depleted, conscious, unrestrained marmosets (n = 5-11) to examine the contribution of bradykinin to ACE inhibitor-induced hypotension. Aortic blood pressure and heart rate (HR) were monitored via telemetry. After sodium depletion (low-sodium diet and furosemide), captopril (1 mg/kg po) caused a significant (P < 0.05) decrease in mean arterial blood pressure (MABP) (-34 +/- 3 mmHg, maximally, from 79 +/- 2 mmHg) but no change in HR compared with vehicle treatment. The bradykinin receptor antagonist HOE-140 (1 mg/kg sc) significantly inhibited the hypotensive response to captopril and caused marked tachycardia (+133 +/- 14 beats/min from 214 +/- 8 beats/min). HOE-140 (1 mg/kg sc) followed by vehicle administration had no effect on MABP but increased HR similarly. The hypotensive response to captopril was inhibited by HOE-140 regardless of the order of administration or the route of captopril administration (by mouth vs. subcutaneously). The hypotensive response to a renin inhibitor, A-72517 (3 mg/kg sc), was not inhibited by prior HOE-140 administration despite a similar HOE-140-induced tachycardia. These data suggest that the hypotensive effect of captopril in sodium-depleted, conscious marmosets is dependent on functional bradykinin B2 receptors. Also, blockade of B2 receptors uncovers marked tachycardia in this model, suggesting a tonic effect of bradykinin on control of HR in marmosets.
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PMID:Captopril-induced hypotension is inhibited by the bradykinin blocker HOE-140 in Na(+)-depleted marmosets. 748 52

On the basis of evidence suggesting the activation of the kallikrein-kinin system in steroid-induced hypertension, we considered the possibility that the angiotensin-converting enzyme inhibitor captopril would lower the arterial blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive rats through kininase II inhibition. In conscious DOCA-salt hypertensive rats with intact kidneys (n = 6) or uninephrectomized rats (n = 5), the short-term administration of captopril (8 mg/kg IV) decreased mean blood pressure from 141 +/- 3 to 118 +/- 3 mm Hg (P < .05) and from 176 +/- 12 to 158 +/- 15 mm Hg (P < .05), respectively. The maximal effect of captopril was manifested between 40 and 50 minutes after its administration, and blood pressure remained depressed for at least 2 hours. The bradykinin B2 receptor antagonist Hoe 140 (500 micrograms/kg IV) abolished the antihypertensive effect of captopril in the DOCA-salt hypertensive rats, indicating kinin involvement. Losartan, an angiotensin type 1 receptor antagonist, had no effect on blood pressure in another group of DOCA-salt hypertensive rats (n = 9) and did not significantly change the response to captopril. No effect of the angiotensin-converting enzyme inhibitor was seen in normotensive control rats (n = 5), indicating the absence of a nonspecific hypotensive action of the drug. Plasma renin activity was lower in the DOCA-salt hypertensive rats (0.7 +/- 0.2 ng angiotensin I/mL per hour, n = 4) than in normotensive control rats (8.8 +/- 1.7, n = 4). The involvement of kinins in the antihypertensive effect of captopril in DOCA-salt hypertension supports the contention that the kallikrein-kinin system contributes to blood pressure regulation in this hypertension model.
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PMID:Kinin-mediated antihypertensive effect of captopril in deoxycorticosterone acetate-salt hypertension. 859 94

To determine the role of the renin-angiotensin system and the bradykinin pathway in the mechanism of action of angiotensin-converting enzyme inhibitors in heart failure, the acute effects of enalaprilat (1 mg/kg) were compared with those of a renin inhibitor (ciprokiren, 1 mg/kg i.v.) in 10 chronically instrumented conscious dogs with heart failure induced by right ventricular pacing (3 wk, 240 beats/min). The effects of enalaprilat and ciprokiren on bradykinin infusion (3, 10, and 30 micrograms/min) and the effects of enalaprilat in the presence of the bradykinin B2 receptor antagonist Hoe-140 (10 micrograms/kg i.v.) were also examined. Both inhibitors significantly decreased mean aortic pressure and increased cardiac output. However, enalaprilat induced significantly greater hemodynamic effects than ciprokiren (mean aortic pressure, -13 +/- 3 vs. -6 +/- 1 mmHg; cardiac output, 0.4 +/- 0.1 vs. 0.15 +/- 0.1 l/min). Bradykinin infusion led to dose-dependent decreases in mean aortic pressure and increases in cardiac output that were not modified by pretreatment with ciprokiren but were potentiated 10-fold by enalaprilat. Hoe-140 significantly reduced the hemodynamic effects of enalaprilat. Thus endogenous bradykinin is involved in the acute hemodynamic effects of enalaprilat in experimental heart failure.
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PMID:Bradykinin pathway is involved in acute hemodynamic effects of enalaprilat in dogs with heart failure. 876 48

Spectral analysis was recently chosen to characterize the fast oscillations, depending on the autonomic nervous system, in heart rate and blood pressure variabilities. Humoral stimuli could impinge on the low-frequency domain of blood pressure variability since the time lag to humoral system activation is greater. This study was designed to analyse low-frequency components of short-term variability of blood pressure of conscious rats in conditions where humoral systems were activated. We studied rats with two-kidney, one-clip Goldblatt hypertension in which the blood pressure level was dependent upon the renin-angiotensin and kallikrein-kinin systems. Spectral powers of the systolic and diastolic blood pressure and heart rate were computed in the high (respiratory)-, mid (0.2-0.6 Hz)- and low (0.02-0.2 Hz)-frequency bands, as detected by the fast Fourier transform technique in consecutive 102-s stationary periods. Hypertensive rats exhibited a marked low-frequency component of systolic (+261%) and diastolic (+169%) blood pressure variabilities when compared to sham-operated animals. First, losartan, a selective non-peptide angiotensin AT1 receptor antagonist, reduced this low-frequency component (-44% and -25% for systolic and diastolic blood pressure). In a second series of hypertensive rats, HOE 140, D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin, a bradykinin B2 receptor antagonist, decreased the low-frequency component of systolic (-28%) and diastolic (-40%) blood pressure. Losartan, added after HOE 140, induced a supplementary decrease of the low-frequency component (-60% and -42% for systolic and diastolic blood pressure). After the combined blockade, the low-frequency components of systolic and diastolic blood pressure variabilities of the hypertensive rats were equivalent to those of the control rats. Two-kidney, one-clip hypertension was also associated with an elevation of the mid-frequency component of the systolic blood pressure (+55%). The administration of HOE 140 did not change this component while losartan, alone or added after HOE 140, led to an increase (around +100%) in mid-frequency oscillations of systolic blood pressure. The high-frequency oscillations of systolic blood pressure were increased by losartan in the two series of hypertensive rats. Losartan increased the mid-frequency component of heart rate variability in sham-operated rats while the heart rate variability was not modified during any of the treatment periods in two-kidney, one-clip rats. In conclusion, an increase in the low-frequency component of blood pressure variability was observed in a model of hypertension where the blood pressure is dependent upon humoral activities. The reduction of the slow fluctuations following the combined blockade of the kallikrein-kinin and the renin-angiotensin systems suggested the contribution of these humoral systems to this low-frequency component of blood pressure variability.
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PMID:Contribution of the renin-angiotensin and kallikrein-kinin systems to short-term variability of blood pressure in two-kidney, one-clip hypertensive rats. 885 Nov 67

The role of the renin-angiotensin system in the haemodynamic changes induced by acute administration of N omega-nitro-L-arginine methyl ester in anaesthetised dogs was investigated. The left femoral artery and vein were cannulated for blood pressure measurement and drug administration, respectively. A Swan-Ganz catheter was introduced through the right femoral vein and advanced to the pulmonary artery. Pulmonary arterial pressure, right atrial pressure and cardiac output were also determined. N omega-Nitro-L-arginine methyl ester (0.01-10.0 mg/kg) was administered alone (control animals, n = 18) or in the presence of the angiotensin-converting enzyme inhibitors, captopril (2 mg/kg, n = 9) or enalapril (2 mg/kg, n = 7) or of the bradykinin B2 receptor antagonist D-[Arg-Hyp3, Thi5, D-Tic7, Oic8]bradykinin (Hoe 140, 0.1 mg/kg, n = 6). Cerebellum nitric oxide synthase and serum angiotensin-converting enzyme activities were also measured. N omega-Nitro-L-arginine methyl ester induced dose-dependent increases in blood pressure and systemic vascular resistance and decreases in heart rate and cardiac output. Nitric oxide synthase activity was inhibited 58% by N omega-nitro-L-arginine methyl ester (from 3.37 +/- 0.30 to 1.40 +/- 0.24 pmol/min per mg protein, P < 0.05, n = 5). Both enalapril and captopril potentiated the cardiovascular changes induced by bradykinin (300 ng/kg, bolus). Moreover, enalapril inhibited angiotensin-converting enzyme activity from 12.8 +/- 1.2 to 1.1 +/- 0.2 nmol/ml per min (P < 0.05, n = 6). Under these conditions, N omega-nitro-L-arginine methyl ester administration elicited the same haemodynamic changes as those observed in non-treated animals, except for preventing the decrease in systolic index. Hoe 140 had no effect on the cardiovascular responses to N omega-nitro-L-arginine methyl ester. These results indicate that the renin-angiotensin system does not modulate these haemodynamic changes.
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PMID:In vivo inhibition of nitric oxide synthesis does not depend on renin-angiotensin system activation. 899 12

A local renin-angiotensin system (RAS) is present in the vasculature and might have an important role in the control of vascular resistance. In order to assess its functional role in the control of vasomotor tone, we investigated the effect of the RAS of a donor vessel (rat carotid artery) on the diameter of a recipient rat mesenteric resistance artery. Arteries were perfused in series in an arteriograph at a rate of 100 microL/min, under a pressure of 100 mm Hg. The two vessels were superfused in separate organ chambers to which drugs were added. Recipient artery internal diameter was measured continuously. Phenylephrine (0.1 mumol/L) was present in the organ baths throughout the experiments, ensuring a preconstriction of the recipient artery (236 +/- 4 to 174 +/- 3 microns, n = 65 arterial segments from 34 rats). The angiotensin I-converting enzyme inhibitors (ACEIs) cilazapril (1 mumol/L) and captopril (10 mumol/L) inhibited phenylephrine-induced constriction by 30 +/- 12% (n = 7, P < .001) and 20 +/- 8% (n = 5, P < .01), respectively. Addition of cilazapril (1 mumol/L) or captopril (10 mumol/L) to the donor vessel chamber further inhibited the constriction by 8 +/- 3% (n = 7, P < .01) and 31 +/- 10% (n = 5, P < .05), respectively. The angiotensin II receptor (AT1) antagonist losartan (10 mumol/L) prevented, in part, the relaxation due to the ACEI. The association of losartan (10 mumol/L) with the bradykinin B2 receptor antagonist HOE 140 (1 mumol/L) totally prevented the relaxation due to the ACEI. Finally, angiotensin II was measured in the perfusate of the carotid artery and was found to be released at a rate of 11.9 +/- 2.2 pg in 60 minutes (n = 8), which was significantly decreased to 1.4 +/- 0.4 pg in 60 minutes (n = 4) by cilazapril (1 mumol/L). This study provides functional evidence that tissue-generated angiotensin II and bradykinin, produced locally and in upstream arteries, control the diameter of a resistance mesenteric artery.
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PMID:In vitro modulation of a resistance artery diameter by the tissue renin-angiotensin system of a large donor artery. 901 41


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