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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertension is a multigene and multifactorial disorder affecting approximately 25% of the population. To demonstrate potential therapeutic effects of human tissue kallikrein in hypertension, spontaneously hypertensive rats were subjected to somatic gene therapy. Two human tissue kallikrein DNA constructs, one under the promoter control of the metallothionein metal response element and the other under the control of the Rous sarcoma virus 3'-LTR, were generated. We delivered naked DNA constructs into spontaneously hypertensive rats via intravenous injection. The expression of human tissue kallikrein in rats was identified in the heart, lung, and kidney by reverse transcription polymerase chain reaction followed by Southern blot analysis and an ELISA specific for human tissue kallikrein. A single injection of both human kallikrein plasmid DNA constructs caused a sustained reduction of blood pressure which began 1 wk after injection and continued for 6 wk. A maximal effect of blood pressure reduction of 46 mmHg in rats was observed 2-3 wk after injection with kallikrein DNA as compared to rats with vector DNA (n = 6, P < 0.05). The hypotensive effect caused by somatic gene delivery of human tissue kallikrein in hypertensive rats is reversed by subcutaneous injection of aprotinin, a potent tissue kallikrein inhibitor. No antibodies to either human tissue kallikrein or kallikrein DNA were detected in rat sera after injection of the human kallikrein gene. These results show that direct gene delivery of human tissue kallikrein causes a sustained reduction in systolic blood pressure in genetically hypertensive rats and indicate that the feasibility of kallikrein gene therapy for treating human hypertension should be studied.
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PMID:Direct gene delivery of human tissue kallikrein reduces blood pressure in spontaneously hypertensive rats. 770 44

We recently found that transgenic mice expressing human tissue kallikrein develop sustained hypotension. The result suggests that a continuous supply of human tissue kallikrein could have a prolonged effect on blood pressure reduction. In the present study, we investigated the potential of using human tissue kallikrein for gene therapy by injecting a kallikrein gene construct into the skeletal muscle of spontaneously hypertensive rats. Expression of the human tissue kallikrein messenger RNA in spontaneously hypertensive rats was identified by reverse transcription-polymerase chain reaction with Southern blot. Human tissue kallikrein was detected in the injected animals by an enzyme-linked immunosorbent assay. Injection of the human kallikrein gene into spontaneously hypertensive rats caused a significant reduction of systemic blood pressure, ranging from 15 to 26 mm Hg, compared with the control group. The differences were significant 1 week after the injection and continued for more than 2 months. Blood pressure reduction could be reversed after the administration of the bradykinin antagonist Hoe 140. The results indicate that somatic delivery of the human tissue kallikrein gene induces a sustained reduction of systemic blood pressure in spontaneously hypertensive rats. The present study raises the possibility of applying kallikrein gene therapy to the treatment of human hypertensive diseases.
Hypertension 1995 Apr
PMID:Muscle delivery of human kallikrein gene reduces blood pressure in hypertensive rats. 772 21

During the past year, a number of significant publications have provided data that clearly establish the basis for the important role of the tissue kallikrein-kinin system in cardiovascular control and renal function. These publications include a report of advances in techniques for system component measurement, reports of the localization of central bradykinin receptors and an alteration in the sensitivity of the central bradykinin system in hypertension, and a description of the effects of new kinin receptor antagonists on our understanding of endogenous and exogenous kinin-induced vasorelaxation and its possible alteration in hypertension. Several significant reports describe the potentiation of endogenous kinin action by kininase inhibitors and establish the important interaction between kininase activity and kinin control of blood pressure.
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PMID:Kinins as vasoactive peptides. 792 88

We investigated whether long-term infusion of kallikrein would attenuate renal injury in salt-induced hypertension in Dahl salt-sensitive rats. A subdepressor dose of purified rat urinary kallikrein (700 ng/d IV) was infused by osmotic minipump for 4 weeks in male Dahl salt-sensitive rats fed a high salt (2% NaCl) diet. This dose did not affect the time-dependent elevation of blood pressure; however, urinary protein excretion was significantly decreased, and glomerular filtration rate was increased. These beneficial effects were reflected morphologically by an attenuation of glomerulosclerotic lesions and tubular injury seen in the hypertensive Dahl salt-sensitive rats. Kallikrein infusion increased urinary excretion of bradykinin and stimulated excretion of cyclic GMP, suggesting that the kallikrein-kinin-prostaglandin and nitric oxide axes were enhanced by rat urinary kallikrein infusion. The alterations induced by kallikrein infusion were potentiated by the concomitant administration of the angiotensin-converting enzyme inhibitor alacepril. These studies indicated that long-term replacement with rat tissue kallikrein attenuates renal injury in hypertensive Dahl salt-sensitive rats.
Hypertension 1994 Dec
PMID:Long-term infusion of kallikrein attenuates renal injury in Dahl salt-sensitive rats. 799 36

Angiotensin-converting enzyme or kininase II (ACE-KII) plays a central role in the control of circulating and tissue levels of angiotensin II and kinins. Both peptides have been implicated in the regulation of renal function and growth during normal development. We tested the hypothesis that the developing rat kidney expresses ACE-KII mRNA transcripts and the active enzyme and evaluated whether the developmental expression of the ACE-KII gene is related to changes in circulating angiotensin II and tissue kallikrein. ACE-KII mRNA and enzymatic activity were low in the newborn kidney; peak expression occurred on days 15 and 20 of postnatal life (16-fold versus day 1). In extrarenal tissues, ACE-KII activity and mRNA levels were also low during the newborn period in the following order of abundance: lung > kidney > aorta > heart. The lung showed a higher age-related increase in active ACE-KII and mRNA abundance (15-fold) than heart and aorta (activity, 3- to 4-fold; mRNA, 6- to 10-fold). The developmental profile of ACE-KII correlated temporally with changes in circulating angiotensin II and tissue kallikrein. Plasma angiotensin II levels were 2.5-fold higher in newborn than adult rats, whereas renal and extrarenal kallikrein-like activity increased twofold to fivefold from birth to adulthood. These results demonstrate that the ACE-KII gene is developmentally regulated in a tissue-specific manner. Tissue kinin generation and degradation, reflected by kallikrein and ACE-KII activities, are coordinately regulated during development, whereas circulating angiotensin II and tissue ACE-KII change in a reciprocal manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Mar
PMID:Ontogeny of somatic angiotensin-converting enzyme. 812 65

It has been reported that kinins mediate part of the beneficial cardiac effects induced by treatment with angiotensin-converting enzyme inhibitors in situations such as ischemia-reperfusion injury, myocardial infarction, and cardiac hypertrophy. However, it is not known whether the heart contains an independent kallikrein-kinin system. We measured kallikrein in tissue and in the incubation medium of heart slices. Heart slices released active and total (trypsin-activatable) kallikrein into the medium (46 +/- 5 and 380 +/- 18 pg bradykinin/mg, respectively, after 1 hour and 78 +/- 6 and 654 +/- 14 pg bradykinin/mg after 2 hours, n = 7). Release was not due to tissue damage because lactate dehydrogenase, a cytosolic marker, decreased from 8.9 +/- 2.9 to 2.9 +/- 1.0 U/mg per hour. Although kallikrein was released, total tissue kallikrein in the slices did not change (423 +/- 25 pg bradykinin/mg in nonincubated slices and 370 +/- 42 pg bradykinin/mg after 2 hours, P = NS), suggesting pool replenishment. Cardiac kallikrein activity was inhibited by incubation with anti-glandular kallikrein antibodies. Pretreatment with the protein synthesis inhibitor puromycin (10 mg IP) lowered release of active kallikrein from 78 +/- 6 to 22 +/- 4 pg bradykinin/mg and total kallikrein from 654 +/- 14 to 113 +/- 9 pg bradykinin/mg (P < .001). By using reverse transcription polymerase chain reaction with kallikrein family oligonucleotide primers and a specific kallikrein probe, we found that mRNA for tissue kallikrein is present in both atrial and ventricular RNA. Kallikrein activity was also detected in primary cultures of neonatal rat atrial and ventricular cardiocytes and their incubation medium.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Jun
PMID:A local kallikrein-kinin system is present in rat hearts. 820 28

An imbalance in the activity of the vasopressor renin-angiotensin and vasodepressor kallikrein-kinin systems may play an important role in the pathogenesis of hypertension after unilateral renal artery constriction. To test this hypothesis, we examined the expression of the renin, angiotensinogen (Ao), and tissue kallikrein genes 7 and 25 days after placement of a 0.25-mm clip on the left renal artery of rats. One week after clipping, renin mRNA levels were 4.6-fold higher in the clipped and 50% lower in the nonclipped kidneys compared with kidneys from sham-operated rats. At 25 days, renin mRNA levels in the clipped kidneys were not different from sham kidneys, but were suppressed to almost undetectable levels in the nonclipped kidneys. Steady-state Ao mRNA levels in the clipped kidneys were not different from those of nonclipped or sham kidneys at either 7 or 25 days. However, at 25 days, Ao mRNA levels were lower in the liver (70%), left ventricle (55%), and aorta (45%) of clipped than sham-operated rats. The expression of the renal kallikrein gene was unchanged at 7 days and was suppressed by 50% at 25 days. These results are consistent with the notion that activation of the intrarenal renin-angiotensin system occurs during the initial phase of the two-kidney, one-clip hypertension model. The renal kallikrein gene, in marked contrast to renin, becomes downregulated in the chronic phase. The differential regulation of renin-angiotensin and kallikrein genes may be an important pathogenetic factor in renovascular hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renin, angiotensinogen, and kallikrein gene expression in two-kidney Goldblatt hypertensive rats. 830 64

The purpose of this study was to delineate the effects of prolonged (1 and 5 wk) unilateral ureteral obstruction (UUO) on the intrarenal renin-angiotensin and kallikrein-kinin systems in the rat. Systolic blood pressure (SBP) and plasma angiotensin (ANG) II levels were significantly higher at 1 and 5 wk of obstruction than in sham-operated groups. Also, plasma renin activity and ANG I levels were elevated at 1 wk (P < 0.05), and plasma angiotensin-converting enzyme (ACE)-kininase II activity was elevated at 5 wk (P < 0.05). Blockade of ANG II receptors with losartan (Dup 753) prevented the rise in SBP after UUO and normalized SBP in chronically hypertensive UUO rats. Renin mRNA levels and ANG II content were elevated in the obstructed kidneys at 1 and 5 wk compared with sham-operated kidneys (P < 0.05). ACE-kininase II activity was elevated in both the obstructed and contralateral kidneys at 5 wk compared with sham-operated kidneys (P < 0.05). In marked contrast to renin, total immunoreactive kallikrein contents and tissue kallikrein mRNA levels in the obstructed kidneys were reduced to 25% of sham-operated kidneys both at 1 and 5 wk (P < 0.001). The results indicate that urinary obstruction activates renin and suppresses kallikrein gene expression. Activation of ACE-kininase II by UUO also serves to enhance intrarenal ANG II generation and kinin degradation. The results implicate ANG II overproduction and kinin deficiency in the pathogenesis of UUO-induced hypertension and intrarenal vasoconstriction.
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PMID:Upregulation of renin-angiotensin system and downregulation of kallikrein in obstructive nephropathy. 849 41

Clinical studies show that an inverse correlation exists between blood pressure and urinary kallikrein levels. It has been postulated that the tissue kallikrein-kinin system contributes to the maintenance of normal blood pressure. To test this hypothesis, we have established transgenic mice that overexpress human tissue kallikrein under the promoter control of the mouse metallothionein gene and a liver-targeted albumin gene. These animals secrete human tissue kallikrein in plasma at levels 10- to 40-fold higher than that found in normal human serum, and they are chronically hypotensive. This hypotensive effect can be reversed by the injection of aprotinin, a potent tissue kallikrein inhibitor, or Hoe 140, a specific bradykinin receptor antagonist. Transgenic mice overexpressing human tissue kallikrein show a sustained reduction in blood pressure throughout their life spans, indicating the lack of sufficient compensatory mechanisms to reverse the hypotensive effect of kallikrein. Somatic gene delivery of rat kallikrein-binding protein by muscle injection increases the blood pressure of the hypotensive transgenic mice to levels comparable with those in normotensive control mice. These results indicate that a direct link exists between kallikrein gene expression and alterations in blood pressure. In addition, we have developed normotensive transgenic mice that harbor the human tissue kallikrein gene containing 801 bp of its native promoter. The tissue distribution pattern of human kallikrein in these transgenic mice is similar to that in human tissues, with the highest level in the pancreas and much lower levels in the kidney and salivary gland. These transgenic mice provide new animal models for investigating the tissue-specific regulation of tissue kallikrein and its role in altering blood pressure.
Hypertension 1996 Mar
PMID:Functional analysis of human tissue kallikrein in transgenic mouse models. 861 91

There is an inverse correlation between systemic blood pressure and urinary kallikrein levels in humans and hypertensive animal models, suggesting that the tissue kallikrein-kinin system plays an important role in blood pressure regulation. In this study, we explored the potential of human kallikrein gene delivery on blood pressure reduction in spontaneously hypertensive rats (SHR). The human tissue kallikrein gene or cDNA was placed under the control of following promoters: the metallothionein gene metal response-element (MRE-pHK), albumin gene (ALB-pHK), Rous sarcoma virus 3' long terminal repeat (LTR) (RSV-cHK), and cytomegalovirus (CMV-cHK). A single injection of these kallikrein DNAs results in a significant reduction of blood pressure in SHR, which lasts for 5-6 weeks. Systemic delivery of CMV-cHK, RSV-cHK, and MRE-pHK has a greater effect on blood pressure reduction than ALB-pHK, whereas intraportal vein gene delivery of ALB-pHK is more effective than the other kallikrein DNA constructs. The degree of blood pressure reduction depends on the amount of administered DNA and the age of the animals. Reduction of blood pressure was observed in adult, but not young, SHR. The expression of human tissue kallikrein in rats was identified by an ELISA that is specific for human tissue kallikrein. No antibodies to either human tissue kallikrein or its DNA were detected in rat sera after somatic gene delivery. These results show that somatic gene delivery of human tissue kallikrein causes a lowering effect of systolic blood pressure in genetically hypertensive rats and provide valuable information for kallikrein gene therapy in the treatment of hypertension.
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PMID:Systemic and portal vein delivery of human kallikrein gene reduces blood pressure in hypertensive rats. 872 4


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