PubMed Health⌕ Search

Biomedical subjects

K Higashimori

Publications and source records attributed to K Higashimori.

At least 37 records · Page 2Linked to original sources
PubMed1991

Exaggerated response to electrical nerve stimulation of angiotensin II release in isolated perfused hind legs of spontaneously hypertensive rats.

Previously we reported that a large amount of immunoreactive angiotensin II (Ang II) was released from isolated perfused rat hind legs at steady rates for several hours. In view of a recent intriguing hypothesis that the vascular renin-angiotensin system plays an important role in the maintenance of high blood pressure in certain forms of experimental hypertensive models, the release of immunoreactive Ang II from isolated hind legs of spontaneously hypertensive rats (SHR) was examined in comparison with normotensive rats of Wistar-Kyoto strain (WKY) by using a Sep-Pak C18 cartridge directly connected to the perfusion system. We also examined effect of electrically-induced nerve stimulation on the release of immunoreactive Ang II in the two strains. High performance liquid chromatography demonstrated the presence of Ang II in the perfusate. The spontaneous release of immunoreactive Ang II was as high as about 300 to 500 pg/30 min, tended to be higher in SHR rats (435.0 +/- 68.2 pg/30 min) than in WKY rats (342.1 +/- 65.1 pg/30 min), and stable up to 3 hours of perfusion for both strains. Periarterial nerve stimulation elicited a significant increment in the release of immunoreactive Ang II in either SHR (p less than 0.02) or WKY rats (p less than 0.05); however, the amount of released immunoreactive Ang II evoked by nerve stimulation was significantly greater in SHR than in WKY rats (781.3 +/- 89.6 vs 498.8 +/- 54.6 pg/30 min, p less than 0.05). These results further provide evidence for local generation and release of Ang II in peripheral vascular tissues, and are consistent with the hypothesis that the vascular renin-angiotensin system is one of important factors responsible for the maintenance of blood pressure.

Angiotensin II↗
PubMed1991

Juxtaglomerular cells as a source of intrarenal angiotensin II production.

While the contribution of angiotensin (Ang) II to the regulation of various renal functions is recognized, evidence exists that the kidney also is a major site for the production of Ang II. Since circulating renin in plasma accounts for only a small portion of intrarenally produced Ang II, we investigated juxtaglomerular (JG) cells as a source of Ang I and II. Light and electronmicroscopic immunohistochemical methods revealed highly concentrated Ang I and II in JG cells. This finding was supported by the demonstration of colocalization of renin, Ang I, and Ang II in cultured JG cells and in dense granular fractions of rat kidney separated by gradient centrifugation of rat kidney homogenate. Perfusion of rat kidney with Krebs-Ringer buffer containing bovine serum albumin showed that Ang I and Ang II are released in the perfusate in quantities which may account for a greater part of the intrarenal generation of Ang II observed in vivo. These results support the hypothesis that Ang II is intrarenally synthesized inside the JG cells, thereby contributing to the regulation of certain renal functions.

Angiotensin I↗
PubMed1990

Evidence for endothelin-1 release from resistance vessels of rats in response to hypoxia.

To elucidate further the contribution of endothelin into endothelium-dependent vasoconstriction evoked by hypoxia, we observed endothelin release during hypoxia. Endothelin was detectable in perfusate from mesenteric artery. Immunoreactive endothelin was confirmed as endothelin-1 by a reverse phase-HPLC. Endothelin release increased 4.1 +/- 1.3 to 12.4 +/- 2.0 pg/30 min without changing perfusion pressure. Thirty minutes of hypoxia stimulated endothelin release by 71 +/- 11% (P less than 0.05) and was associated with an elevation of perfusion pressure. These results suggest that endothelin contributes to endothelium-dependent vasoconstriction by hypoxia in mesenteric artery and may play an important role in the local peripheral vascular tone.

Animals↗
PubMed1990

Effects of endothelin on neuroeffector junction in mesenteric arteries of hypertensive rats.

The effect of endothelin, a novel vasoconstrictor peptide, on the adrenergic neuroeffector junction was investigated in isolated perfused mesenteric arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. The vasoconstrictor responses to periarterial sympathetic nerve stimulation and exogenous norepinephrine were determined. Infusion of endothelin-1 increased the baseline perfusion pressure dose dependently to similar extents in the two strains. A subpressor dose of endothelin-1 (10(-10) M) enhanced the pressor response to norepinephrine; its effect was greater in WKY rats than in SHR. Endothelin-1 (10(-12) to 10(-10) M) attenuated the pressor response to sympathetic nerve stimulation, and the degree of inhibition tended to be less in SHR than in WKY rats. Higher doses (3 x 10(-10) and 10(-9) M) of endothelin-1 enhanced the pressor response to nerve stimulation in both WKY rats and SHR. Endothelin-1 inhibited norepinephrine release from rat mesenteric arteries; the inhibition was significantly less in SHR than in WKY rats. These results suggest that endothelin enhances the responsiveness of alpha-adrenergic receptors to catecholamines, whereas it inhibits presynaptic adrenergic neurotransmission. Thus, endothelin can interact with the neuroeffector junction in addition to having a vasoconstricting effect in peripheral vessels. The difference in the mode of modulation by endothelin at the vascular neuroeffector junction in SHR from that in WKY rats might explain the maintenance of hypertension.

Animals↗
PubMed1990

Re-evaluation of the plasma renin-angiotensin system in anephric patients.

In view of recent observations that a number of extrarenal tissues have the potential to produce angiotensin II and release it in a regulated fashion, we made measurements of immunoreactive angiotensin I (irAng I) and angiotensin II (irAng II), along with active and inactive renin, and angiotensinogen in plasma of seven anephric patients and of 16 normal healthy volunteers to gain insight into possible sources of plasma Ang II. High performance liquid chromatography clearly demonstrated that the predominant component of irAng II in anephric plasma is the biologically active octapeptide Ang II. Plasma renin activity (PRA), and active and inactive renin all were detected in all of the anephrics but their levels were decreased to 33% for PRA, 12% for active renin, and 18% for inactive renin when compared with those in healthy subjects. While plasma angiotensinogen was significantly but only slightly increased in anephric patients (+28% over the mean value for normal subjects), irAng I and irAng II both were present in quantities almost comparable with those in normals. These results suggest that local angiotensin production contributes, in part at least, to the circulating plasma Ang II. Vascular tissue seems to be the best candidate responsible for such a mechanism, on the basis of recent demonstrations of unequivocal, regulated release of Ang II from diverse vascular beds.

Adult↗
PubMed1990

Endothelin activates the vascular renin-angiotensin system in rat mesenteric arteries.

The effects of endothelin on the vascular renin-angiotensin system were examined in isolated perfused rat mesenteric arteries by measuring vascular renin activity and angiotensin II released into the perfusate. Infusion of endothelin (10(-9)M and 10(-11)M) increased the vascular renin activity and angiotensin II release. Pretreatment with nicardipine (10(-6)M), a calcium channel blocker, significantly suppressed these effects of endothelin. These results suggest that endothelin activates the vascular renin-angiotensin system via intracellular calcium metabolism. Vascular angiotensin II produced by endothelin may modulate the local effect of endothelin on the resistance vessels.

Angiotensin II↗
PubMed1989

Pure human inactive renin. Evidence that native inactive renin is prorenin.

To clarify contradicting observations on the identity of inactive renin and prorenin, inactive renin was completely purified from native human chorion laeve and the culture medium of human chorion cells. A 720,000-fold purification with 14% recovery was achieved from chorion laeve in 6 steps, including immunoaffinity chromatography on a monoclonal antibody to human renin coupled to Protein A-Sepharose CL-4B. A 3,100-fold purification with 40% recovery was achieved from chorion culture medium in 4 steps, including immunoaffinity chromatography. Inactive renin purified from the two different sources migrated as a single protein band with the same molecular weight of 47,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and consisted of multiple components that could be resolved by isoelectric focusing. Both had the same pI values which shifted downward upon activation by trypsin; however, relative peak heights were different between the two preparations. The purified inactive renin from chorion laeve was completely inactive and did not bind to pepstatin-aminohexyl-Sepharose; however, that from chorion culture medium was partially active and completely bound to the pepstatin gel, indicating that each molecule is partially activated. Trypsin-activated inactive renins from both sources were identical with human renal renin in terms of pH optimum and Km. Specific activities of trypsin-activated inactive renin from chorion laeve and chorion culture medium were 529 Goldblatt units/mg of protein and 449 Goldblatt units/mg of protein, respectively. Amino acid sequence analysis of both of the purified inactive renin preparations demonstrated a leucine residue at the amino terminus. The sequence of 11 additional amino acids was identical in both and agreed with that predicted from the base sequence of the renin gene. These findings indicate that preprorenin is converted to prorenin following removal of a 23-amino acid signal peptide and that the native inactive renin, whose amino acid sequence commences with Leu-Pro-Thr..., is prorenin.

Amino Acid Sequence↗
PubMed1988

The renin-angiotensin system: an overview of its intracellular function.

The enzyme renin has been purified and characterized by structural analysis. Pure renin protein was used to produce a specific antibody to renin, which was useful in demonstrating the presence of a specific renin in many tissues other than kidney. Further, in these cells angiotensins I and II and converting enzyme all were found to coexist with renin by immunohistochemical studies, indicating the local production of renin, angiotensinogen and angiotensins in these cells. Angiotensin II produced in the cultured cells was secreted to the outside of the cells. Secretion of angiotensin II from the angiotensin-producing cells was demonstrated with perfused mesenteric artery. The secretion of angiotensin II from the vascular beds was inhibited by converting enzyme inhibitors, and was stimulated by the adrenergic beta-agonist isoproterenol. These studies demonstrate local production and controlled secretion of angiotensin II and define its physiologic role.

Angiotensin II↗
PubMed1988

Conceptual evolution of renin research.

Research on renin in the last 90 years has undergone numerous conceptual evolution since its discovery by Tigerstedt and Bergman in 1898. This paper briefly reviews the evolutionary steps leading up to the recently discovered intracellular function of renin and generation of angiotensin II in renin containing cells and molecular biological studies approaching the regulation of renin expression in various tissues.

Animals↗
PubMed1988

Direct evidence for the local generation of vascular angiotensin II and its prostaglandin-mediated release from isolated hind legs in the rat.

We examined the effect of prostaglandin synthesis inhibitors (indomethacin and meclofenamate) on the release of immunoreactive angiotensins I (irAng I) and II (irAng II) from isolated perfused rat hind-leg vasculature in order to delineate the possible relevance of prostaglandins to the vascular renin-angiotensin system in vitro. Isolated rat hind-legs were perfused with Krebs-Ringer solution and release of irAng I and irAng II into the perfusate was directly measured by using a Sep-Pak C18 cartridge connected to the perfusion system. The spontaneous release of irAng I and irAng II was as high as 600-700 pg per 30 min and was stable for at least 3 h. Addition of indomethacin and meclofenamate (10(-8) to 2 X 10(-6) mol/l) to the perfusion medium suppressed the release of both irAng I and irAng II to a similar extent in a dose-dependent fashion (P less than 0.001); the maximal percentage inhibition of irAng II release that was evoked by these inhibitors (2 X 10(-6) mol) was 60 +/- 6% (P less than 0.001) for indomethacin and 50 +/- 4% (P less than 0.001) for meclofenamate. There was a highly significant positive correlation between the amount of irAng I released and the amount of irAng II that was altered by indomethacin (r = 0.91) or meclofenamate (r = 0.94). These results provide direct proof of the local generation and subsequent release of Ang II by peripheral vascular tissue and suggest that prostaglandin plays an important role in the regulation of vascular Ang II release.

Angiotensin I↗
PubMed1988

Local generation and release of angiotensin II in peripheral vascular tissue.

Isolated rat hindlegs were perfused with Krebs-Ringer solution, and immunoreactive angiotensin II (irAng II) released into the perfusate was directly determined using a Sep-Pak C18 cartridge connected to the perfusion system. High performance liquid chromatography clearly demonstrated the presence of angiotensin I (Ang I), angiotensin II (Ang II), and a small amount of angiotensin III. The spontaneous release of irAng II was as high as about 600 pg/30 min, which was stable up to 3 hours. Captopril added to the perfusion medium (10(-9) to 10(-6) M) suppressed irAng II release in a dose-dependent manner (p less than 0.001), and it (10(-6)M) caused a reciprocal increase of irAng I release (p less than 0.05). Oral pretreatment of captopril (50 mg/kg/day) for 1 week suppressed the irAng II release by 31% (p less than 0.02). The same treatment with SA 446, a highly lipophilic angiotensin converting enzyme inhibitor, inhibited the irAng II release by 63% (p less than 0.001). On the other hand, the two inhibitors suppressed the plasma irAng II to very similar extents. Pretreatment with SA 446 plus nephrectomy did not cause any further change in irAng II release as compared with that with SA 446 alone. These results provide direct proof for local generation and subsequent secretion of Ang II by peripheral vascular tissue.

3-Mercaptopropionic Acid↗
PubMed1988

Suppression of angiotensin II release by prostaglandin synthesis inhibitors in hind legs.

Previously we reported that immunoreactive angiotensin II (Ang II) release from isolated perfused rat mesenteric arteries was mediated by beta-adrenergic receptor activation. However, the precise mechanism of regulation of vascular renin-angiotensin is not completely understood. In this study, we examined the effect of indomethacin and meclofenamate on immunoreactive angiotensin I (Ang I) and immunoreactive Ang II release from perfused rat hind leg vasculature to delineate the possible relevance of prostaglandins to the vascular renin-angiotensin system in vitro. We also examined the effects of isoproterenol and propranolol on the immunoreactive Ang I and II release. Isolated rat hind legs were perfused with Krebs-Ringer solution, and immunoreactive Ang I and II released into the perfusate were measured directly by using a Sep-Pak C18 cartridge connected to the perfusion system. Indomethacin and meclofenamate (10(-8) to 2 X 10(-6) M) added to the perfusion medium suppressed immunoreactive Ang I and II release to similar extents in a dose-dependent manner (p less than 0.001); the maximal percent inhibition of immunoreactive Ang II release evoked by these inhibitors (2 X 10(-6) M) was 60 +/- 6% (p less than 0.001) for indomethacin and 50 +/- 4% (p less than 0.001) for meclofenamate. Isoproterenol (10(-6) M) failed to cause a change in the release of both peptides, but propranolol (10(-6) M) slightly decreased the release of immunoreactive Ang I and II by 28 +/- 4% (p less than 0.001) and 32 +/- 4% (p less than 0.001), respectively. There was a highly significant positive correlation between the released amount of immunoreactive Ang I and that of immunoreactive Ang II altered by indomethacin (r = 0.91), meclofenamate (r = 0.94), or propranolol administration (r = 0.90). These results suggest that the renin-angiotensin in the hind legs is modulated by prostaglandins and that a difference exists in the beta-adrenergic receptor-mediated release of Ang II among diverse vascular beds.

Angiotensin I↗
PubMed1987

Direct release of angiotensins I and II from isolated rat kidney perfused with angiotensinogen-free medium.

A direct measurement of both angiotensins I and II immunoreactive substances was made in the perfusate from isolated rat kidney perfused with Krebs-Ringer solution which was free of any component of the renin-angiotensin system. The identity of the immunoreactive peptides was confirmed as angiotensin I and angiotensin II by high-pressure liquid chromatography in reference to standard compounds. The rate of release of angiotensins was as high as 1313.5 +/- 184.5 and 772.4 +/- 82.5 pg for angiotensins I and II, respectively, during the first perfusion period of 20 min, and it remained stable at least for 2 hours. There was a good relationship between the angiotensin I secretion rate and renin secretion rate simultaneously determined in the perfusate, and also between the angiotensin I secretion rate and angiotensin II secretion rate. These results taken together with the previous observations of the coexistence of renin and angiotensins I and II in juxtaglomerular cells of the kidney provide evidence for intrarenal formation and release of angiotensin II. It does not agree with the notion that these peptides are internalized from circulation. Angiotensin II secreted from the kidney may play diverse functions in intrarenal regulation.

Angiotensin I↗
PubMed1987

Lysophosphatidylcholines containing polyunsaturated fatty acids were found as Na+, K+-ATPase inhibitors in acutely volume-expanded hog.

Na+, K+-ATPase inhibitors possessing inhibitory activities against the specific binding of ouabain to Na+, K+-ATPase and 86Rb uptake into hog erythrocytes have been purified from the plasma of acutely saline-infused hog. The purifications were performed by a combination of Amberlite XAD-2 adsorption chromatography and four steps of high-performance liquid chromatography with four different types of columns. Fast atom bombardment (FAB) mass and proton NMR spectrometric studies identified the purified substances as gamma-arachidoyl- [LPCA(gamma), 34%], beta-arachidoyl- [LPCA(beta), 4%], gamma-linoleoyl- (LPCL, 33%), and gamma-oleoyl- (LPCO, 25%) lysophosphatidylcholine, expressed in molar ratio in the plasma. Small amounts of gamma-docosapentaenoyl-, gamma-eicosatrienoyl-, and gamma-palmitoyllysophosphatidylcholine were also detected by both FAB mass and 1H NMR spectrometric studies. Only gamma-acyl-LPC's showed inhibitory activities on Na+,K+-ATPase and ouabain-binding activities. These LPC's were effective at 100 microM levels in attaining 50% inhibition of the enzyme activity. The inhibition of Na+,K+-ATPase activity due to these compounds was always more sensitive than that of both ouabain-binding and 86Rb uptake activities. The ouabain-displacing activity in plasma due to these compounds increased with time during saline infusion. The maximal plasma level was approximately 10 times higher than that in the preinfusion plasma sample. Although these results suggest the gamma-acyl-LPC's with long-chain polyunsaturated fatty acids are not simple competitive inhibitors to Na+, K+ -ATPase, these compounds could be implicated in the pathogenesis of the circulation abnormality through the modulation of membrane enzyme.

Animals↗
PubMed1986

Circulating factor with ouabain-like immunoreactivity in patients with primary aldosteronism.

Circulating factor with ouabain-like immunoreactivity was studied in patients with primary aldosteronism. Anti-ouabain antibody was prepared from specific pathogen-free rabbits. In the plasma of patients with primary aldosteronism, the level of a factor with ouabain-like immunoreactivity was 2.59 +/- 1.39 pmol ouabain equivalent/ml plasma. This value was significantly (p less than 0.05) higher than that of age-matched normotensive subjects, 1.06 +/- 0.86 pmol ouabain equivalent/ml plasma. The plasma level of ouabain-like immunoreactivity correlated significantly (p less than 0.05) with blood pressure. These results indicate that the factor with ouabain-like immunoreactivity may play a pathophysiological role in the maintenance of the high blood pressure observed in patients with primary aldosteronism.

Antibody Affinity↗
PubMed1985

Identification of plasma inactive renin as prorenin with a site-directed antibody.

A sequence-specific antibody that recognizes a portion of the prosegment of human renin precursor was raised and used to provide direct evidence that plasma inactive renin contains the prosequence of renal renin and is therefore probably prorenin rather than an inactivated form of previously active renin. The information may help not only to resolve a major controversy concerning the nature of inactive renin in human plasma but also to elucidate its exact physiological role.

Antibody Formation↗
PubMedDate not supplied

Pilot study of a new angiotensin II receptor antagonist, TCV-116: effects of a single oral dose on blood pressure in patients with essential hypertension.

After a 1-week placebo control period, six hypertensive patients (mean age, 67 years) each received single doses of 1, 2.5, and 5 mg of TCV-116 at 2- to 3- day intervals. Systolic and diastolic blood pressures were significantly lower after the final dose (5 mg) of TCV-116 than on the last day of the placebo period. Blood pressures were decreased after each dose of TCV-116 in a dose-dependent fashion from 2 hours after administration and reached a nadir at 4 to 6 hours. After 2.5 and 5 mg of TCV-116, the hypotensive effect was sustained for 24 hours. Pulse rate did not change significantly. Plasma renin activity and angiotensin I levels increased in a dose-dependent fashion after TCV-116, but the changes were not significant. No changes were noted in plasma aldosterone or angiotensin II levels. One patient reported mild light-headedness after 5 mg of TCV-116. No other side effects or abnormal laboratory tests results were noted. It appears that TCV-116 is a safe and effective antihypertensive agent.

Aged↗