[A case of idiopathic orthostatic hypotension manifesting sick sinus syndrome due to sympathetic nervous dysfunction].

A 67-year-old woman with idiopathic orthostatic hypotension was presented. The patient started to experience faintness on standing since 1993. During a physical examination, her systolic blood pressure fell from 148 to 50 mmHg on standing. Blood pressure responses to the mental arithmetic test and hyperventilation stress were normal. However, cold pressor test failed to increase blood pressure. These observations, with the finding that phase IV response on Valsalva's maneuver was absent, indicate afferent sympathetic nervous dysfunction. Peripheral neuropathy including diabetes mellitus and involvement of central nervous system such as multiple system atrophy were excluded. Holter ECG examination revealed a 3.9 second sinus arrest and bradycardia (total beats 88901/day). the blunted responses of the heart rate to atropine as well as isoproterenol further suggested the presence of sick sinus syndrome. Amezinium administration significantly improved her orthostatic hypotension and eliminated sinus arrest. These findings indicate that sympathetic nervous dysfunction could account for at least a part of the sick sinus syndrome in this patient.

Gene expression of the type-1 angiotensin II receptor in rat adrenal gland.

To evaluate the biosynthesis of the type-1 angiotensin II (AT1) receptor and the regulation of AT1 receptor subtypes in the rat adrenal gland, we performed non-radioisotope in situ hybridisation histochemistry with an AT1 receptor complementary RNA (cRNA) probe and a messenger RNA (mRNA) probe. The levels of AT1A and AT1B receptor mRNAs were measured by the reverse transcriptase-polymerase chain reaction method after 4-week treatment with a selective AT1 receptor antagonist, TCV-116, and an angiotensin-converting enzyme inhibitor, delapril. Specific hybridisation signals were observed with the cRNA probe in both the cortex and medulla of the rat adrenal gland. An especially strong signal was observed in the zona glomerulosa. TCV-116 did not affect the levels of expression of AT1A and AT1B receptor mRNAs in the adrenal gland. Delapril, on the other hand, significantly reduced the levels of expression of AT1A and AT1B receptor mRNAs. These results indicate that the sites of biosynthesis of the AT1 receptor are mainly distributed in the adrenal zona glomerulosa. The observed differences in levels of expression of AT1 receptor mRNAs following treatment with TCV-116 and delapril suggest the involvement of the AT2 receptor in the regulation of AT1 receptor subtypes.

Differential gene expression and regulation of type-1 angiotensin II receptor subtypes in the rat.

A simplified and sensitive method for measuring expression levels of type-1 angiotensin II (AT1) receptor subtypes, AT1A and AT1B, was established. The two receptor cDNAs were co-amplified and measured by polymerase chain reaction using primers based on the corresponding receptor subtype genes. Both AT1A and AT1B mRNAs were widely expressed in the rat tissues including adrenal gland, kidney, heart, aorta, lung, liver, testis, pituitary gland, cerebrum and cerebellum. AT1A mRNA was predominantly expressed in the rat tissues examined except adrenal gland and pituitary gland where AT1B mRNA was predominantly expressed. Sodium depletion did not change mRNA levels of AT1A and AT1B in the all tissues. However, both AT1A and AT1B mRNA levels in the heart and aorta were down-regulated by treatment with AT1 specific antagonist, TCV 116. In contrast, AT1B mRNA in the adrenal gland was mainly reduced by the treatment. These results suggest that the expression level of AT1B mRNA in the adrenal gland depends on the activity of the renin-angiotensin-aldosterone system (RAAS) and both receptor subtypes mediate contraction and hypertrophy of the smooth and cardiac muscles via the RAAS.

Regulation of the gene expression of type-1 angiotensin II receptor in spontaneously hypertensive rats.

Regulation of the gene expression of type-1 angiotensin II receptor (AT1) by treatment with manidipine, a calcium channel blocker, or delapril, an angiotensin converting enzyme inhibitor, for one week was assessed in the adrenal gland, heart, kidney, and brain from spontaneously hypertensive rats (SHR). Tissue AT1 receptor messenger RNA (mRNA) content was measured by reverse transcriptase-polymerase chain reaction. Treatment with manidipine (3 mg/kg/day) or delapril (30 mg/kg/day) lowered systolic blood pressure (SBP) significantly (p < 0.01) (delta SBP; -73 mmHg or -67 mmHg, respectively). Although delapril markedly increased plasma renin activity (PRA), manidipine did not alter PRA. AT1 receptor mRNA content in the adrenal gland was significantly (p < 0.01) decreased by treatment with manidipine or delapril. In contrast, cardiac AT1 receptor mRNA content was significantly (p < 0.01) increased by treatment with either agent. There was no significant change in renal and brain AT1 receptor mRNA contents. These findings suggest that although the expression of AT1 receptor gene depends on the circulating renin-angiotensin system (RAS), it is regulated independently in a tissue-specific manner via the local RAS in each tissue of SHR.

Renal and extra-renal renin gene expression in spontaneously hypertensive rats.

To study the effect of antihypertensive therapy on the regulation of renin gene expression, the levels of tissue renin messenger RNA (mRNA) were measured after treatment with a calcium channel blocker (manidipine hydrochloride 3 mg/kg/day) or an angiotensin-converting enzyme inhibitor (delapril hydrochloride 30 mg/kg/day), administered orally for 1 week, in spontaneously hypertensive rats (SHR). Male SHR, aged 15 weeks old, were used in this study (n = 5 per group). Control rats were administered the vehicle alone. Tissue total RNA was isolated from kidney, adrenal gland, heart, and brain tissue, and tissue RNA was reverse-transcribed to complementary DNA (cDNA), which was specifically amplified by polymerase chain reaction with labeled-primers for the rat renin gene. The radioactivity of the cDNA products was measured directly. Although delapril increased plasma renin activity (PRA) about 5-fold compared with the control group, manidipine did not change PRA. The kidney renin mRNA content was increased about 6-fold by treatment with delapril. Manidipine and delapril significantly decreased the renin mRNA content in the heart (p < 0.01 and p < 0.05, respectively). The level of renin mRNA in the adrenal gland and brain tissues was not significantly changed by treatment with either drug. These results suggest that tissue renin gene expression in SHR is regulated by a tissue-specific process independent of the circulating renin-angiotensin system.

Renin gene restriction fragment length polymorphisms in a Japanese family with a high incidence of essential hypertension.

1. Human renin gene restriction fragment length polymorphisms (RFLP) were compared in a Japanese family which has a high incidence of essential hypertension. 2. RFLP of human renin gene were observed in three restriction enzymes, Mbo I, Bgl I and Hind III; 1.4 kb and 1.0 kb [Mbo I], 5.0 kb and 9.0 kb [Bgl I] and 9.0 and 6.2 kb [Hind III]. 3. Plasma renin activity was not associated with blood pressure. 4. Renin gene RFLP were not cosegregated with essential hypertension in this Japanese family.

[Beneficial effect of diltiazem on pulmonary hypertension in a patient with Hughes-Stovin's syndrome].

A 54 year-old female who had a history of hemoptysis was admitted to our hospital because of dyspnea on effort. Pulmonary arterial pressure was elevated and pulmonary arteriography showed multiple pulmonary arterial aneurysms and occlusion of the left upper lobe pulmonary artery. Systolic pulmonary arterial pressure was 110 mmHg when measured by continuous wave Doppler echocardiography. From the clinical and angiographical findings, we diagnosed this patient as having Hughes-Stovin's syndrome (forme fruste). 30 mg of diltiazem per day was initially used, and 80 mg was used thereafter. After 2 months follow up of the medication with diltiazem, systolic pulmonary arterial pressure decreased from 110 mmHg to 61 mmHg and clinical symptoms improved dramatically.

Infusion of red blood cell-loaded asparaginase in monkey. Immunologic, metabolic, and toxicologic consequences.

In order to evaluate enzyme loading of RBCs as a drug delivery system, the antitumor agent asparaginase was loaded into the erythrocytes of nine monkeys at three different doses and autologously injected back into these animals. Nine control monkeys were also once injected intravenously at the same doses of enzyme, but the enzyme was free in solution rather than entrapped in RBCs. The RBCs and asparaginase were labeled with 51Cr and 125I, respectively. The circulating half-life of the enzyme-loaded, resealed RBCs was 7 days, as compared to 9 days in the control RBCs. Beginning at 5 days, circulating enzyme activity was several orders of magnitude higher in the monkeys injected with RBC-loaded asparaginase than in controls. Targeting of drug-loaded RBCs into the spleen and liver was apparent. Suppression of the serum substrate level of asparaginase in the monkeys treated with the single intravenous injection of RBCs loaded with asparaginase was 20 days, which was twice as long as the suppression in the control monkeys. Production of anti-asparaginase antibody was shown to reach a higher level and persist longer in the monkeys with RBC-entrapped asparaginase. Evidence was also obtained showing that entrapping asparaginase in RBCs protects against anaphylaxis in the guinea pig. Thus this drug delivery system is also proposed as a strategy to avoid life-threatening allergic reactions. Advantages and limitations of RBC loading as a drug delivery system are discussed.

Asparaginase entrapped in red blood cells: action and survival.

As a strategy to avoid serious allergic reactions to the antitumor agent asparaginase, this enzyme was entrapped in autologous red blood cells before intravenous injection into monkeys. Additional advantages of this approach are prolonged enzyme half-life and targeting of this agent into the reticuloendothelial system.