The cause of pulmonary hypertension in chronic obstructive pulmonary disease (COPD) is considered to be hypoxic pulmonary vasoconstriction, which may be mediated in part by angiotensin II. We administered captopril (25 mg, orally) to seven patients with COPD and complicating cor pulmonale in stable state. Hemodynamic responses were recorded before and one hour after the administration of the drug. Captopril increased cardiac output by 23% (p < 0.025) and reduced mean systemic pressure by 12% (p < 0.03). There was an increase in pulmonary arterial pressure. Pulmonary and systemic vascular resistance fell, respectively, by 14% (p < 0.025) and 31% (p < 0.03). There was an increase in pulmonary /systemic vascular resistance ratio (p < 0.007). Heart rate, mean right atrial, pulmonary capillary wedge pressure, arterial oxygen tension and dioxide tension, and alveolar-arterial oxygen tension difference remained unchanged. These results suggest that captopril is successful in reducing pulmonary vascular resistance without affecting arterial blood gases, but does not change mean pulmonary arterial pressure probably because of the concurrent increase in pulmonary blood flow. In addition, results indicate that captopril has more effects on the systemic vasculature than on the pulmonary circulation.

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Noninvasive determination of right ventricular systolic pressure was attempted in 27 patients with ventricular septal defect based on the peak velocity of left-to-right shunt flow as measured in the right ventricle by a continuous wave Doppler technique. The systolic pressure gradient between the ventricles (Δp : mmHg) was calculated according to the simplified Bernoulli's formula, Δp =4 V², where V (m/sec) is the peak velocity of the left-to-right shunt flow. Right ventricular systolic pressure was determined by subtracting Δp from the systolic blood pressure measured in the upper arm, which was regarded as the left ventricular systolic pressure. The peak velocity of left-to-right shunt flow could be measured in all patients except one with muscular ventricular septal defect, and values ranged from 0.6 to 4.8 m/sec. The peak velocity of left-to-right shunt flow decreased inversely with the increase in right ventricular systolic pressure. The values of right ventricular systolic pressure determined by the continuous wave Doppler technique correlated highly (r=0.820) with those determined by cardiac catheterization. The peak velocity of left-to-right shunt flow also showed high negative correlations with the pulmonary to systemic pressure ratio (r=-0.876) and pulmonary to systemic resistance ratio (r = -0.855). These results indicate that the continuous wave Doppler technique is clinically useful for determination of right ventricular systolic pressure as well as the pulmonary to systemic pressure ratio and pulmonary to systemic resistance ratio.

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To clarify the mode of action of a selective thromboxane A₂ (TXA₂) blockade in platelet reactivity, we examined the effect of (E)-3-[4-(1-imidazolylmethyl) phenyl]-2-propenoic acid hydrochloride (OKY-046), a potent TXA₂ synthetase inhibitor, on human platelet aggregation induced by arachidonic acid (1mM) in the absence and presence of aspirin-treated aortic microsomes containing prostacyclin (PGI₂) synthetase activity ex vivo. The production of TXA₂ and PGI₂ in platelet rich plasma was determined by the amounts of their stable catabolites, TXB₂ and 6-keto-PGF_1α respectively, measured by radioimmunoassay. In the absence of aortic microsomes, OKY-046 (>10^-5 M) produced more than 90% inhibition of TXA₂ production, whereas platelet aggregation was less inhibited, about 40% inhibition, over control, by OKY-046 in that concentration. In the presence of aortic microsomes, the inhibitory effect of OKY-046 on platelet aggregation was markedly augmented in a dose-dependent manner in proportion to the increment of PGI₂ production, which paralleled the OKY-046-induced inhibition of TXA₂. These results suggest that a selective TXA₂ blockade produces effects on platelet aggregation mainly in dual fashion in the presence of PGI₂ synthetase : one is due to mere inhibition of TXA₂ synthetase and the other is due to the enhancement of PGI₂ production probably involving "prostaglandin H₂ (PGH₂) steal" mechanism, in which PGH₂ accumulated in platelets is partly converted to a substrate of PGI₂ synthetase in aortic microsomes to produce PGI₂.

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Exercise tests with sublingual nitroglycerin were performed on 7 patients with true positive and 8 patients with false positive exercise test results. Four of 7 patients with true positive changes and 8 patients with false positive changes underwent exercise cardiac scintigraphy. Scintigrams showed perfusion defects in 4 patients with true positive outcomes, and no perfusion defect in 8 patients with false positive outcomes. Exercise test with sublingual nitroglycerin were performed with the same load as that without nitroglycerin. In ally 7 patients with true positive exercise test results, ST segment depression observed in the control exercise test was not observed in the nitroglycerin exercise test. In the false positive patients, ST segment depression observed in the control exercise test remained unchanged in 7 of 8 patients receiving nitroglycerin. Exercise tests with sublingual nitroglycerin as well as exercise cardiac scintigraphy are valuable tods in differentiating false positive from true positive patients. Furthermore, these data suggest that ST segment depression in the false positive patients may not be related to myocardial ischemia.

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To investigate non-invasively the diagnostic significance of diastolic properties in coronary artery disease (CAD), the following early diastolic time intervals (EDTIs) : IIA-O time (from the aortic component of the second heart sound to the O-point on the apexcardiogram), IIA-MVO time (from IIA to the mitral valve opening) and MVO-O time (from MVO to the O-point), were estimated in 18 patients with angina pectoris (AP) and 29 with old myocardial infarction (OMI) who were subdivided into two groups according to ejection fraction (EF) : group I (OMI-I) : more than 50% and group II (OMI-II) : less than 50%. Seventeen patients without evidence of CAD were used as controls (N). Left ventricular pressure (LVP) and pulmonary capillary wedge pressure (PCWP) were measured simultaneously to clarify the relationship between EDTIs and early diastolic hemodynamics. IIA-O time and IIA-MVO time in AP, OMI-I and OMI-II were significantly longer than in N. This prolongation accorded with the reduction of left ventricular function. MVO-O time in AP and OMI-I also was significantly longer compared with that in N. In OMI-II, however, it was significantly shorter than in N. The prolongation of IIA-MVO time reflected impaired LV relaxation accompanied by LV dysfunction. The maintenance of low minimal LVP was the main contributor to the lengthening of MVO-O time in AP and OMI-I. Conversely, elevated minimal LVP and impaired LV relaxation resulted in the shortening of MVO-O time in OMI-II. These results indicate that EDTIs are useful and reliable non-invasive parameters for the evaluation of LV function and the prediction of early diastolic hemodynamic properties in patients with CAD.

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The effects of organic nitrates on tone and tissue cyclic nucleotide levels were studied, using canine coronary, mesenteric and renal arteries, and femoral veins. Glyceryl trinitrate (GTN) relaxed all vascular tissues examined and increased tissue cyclic GMP (cGMP) levels in a concentration-dependent manner, but GTN induced no significant changes in cyclic AMP (cAMP) levels. An increase in cGMP levels induced by 10 μM of GTN in coronary arteries was observed before the onset of relaxation. Methylene blue, an inhibitor of guanylate cyclase, inhibited the relaxant effect of GTN and decreased cGMP levels. In contrast, M B 22, 948, an inhibitor of cGMP phosphodiesterase, not only enhanced relaxation by GTN, but also increased cGMP levels. Other organic nitrates, pentaerythritol tetranitrate (PETN), nicorandil (NIC), and isosorbide dinitrate (ISDN), also relaxed coronary arteries and increased cGMP levels in a concentration-dependent manner. A significant correlation was observed between percentage increases in cGMP levels and percentage relaxation by 10 μM of GTN, PETN, NIC, and ISDN (r=0.952, p < 0.001). Plasma concentrations of 4 organic nitrates inversely correlated with percentage increases in cGMP levels by 10 μM of these agents in coronary arteries (r=-0.845, p < 0.001). These results suggest that an increase in cGMP is responsible for relaxation in vascular smooth muscles by organic nitrates, and that therapeutic plasma concentrations may be estimated by the degree of increase in cGMP levels induced by their administration.

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We examined the effects of preload alteration on global and regional (i.e., non-ischemic and ischemic areas) function in the presence of regional myocardial ischemia and on the degree of ischemia using 18 isolated, metabolically supported canine left ventricles. For this purpose, cardiac output (CO), systolic segment length change (SL), myocardial CO₂ tension (PmCO₂) and ST level of epicardial ECG were measured at 3 levels of left ventricular end-diastolic pressure (LVEDP), i.e., approximately 7 (low LVEDP), 11 (middle LVEDP), and 16 mmHg (high LVEDP) without and with left circumflex artery (LCx) stenosis under a constant mean aortic pressure (90 mmHg), mean coronary perfusion pressure (90 mmHg) and heart rate. In the Pre-ischemic stage, CO and SL increased significantly when LVEDP was elevated in a stepwise fashion by changing the height of the reservoir connected to the left atrium. There were no significant changes in PmCO₂ or ST level. On the other hand, with LCx stenosis, CO did not show a subsequent SL response in the LCx area following alterations of LVEDP, although there was considerable lengthening of end-diastolic length. Both increased PmCO₂ and ST level of the LCx area, following LCx stenosis, further increased significantly with elevation of LVEDP. These results suggest the possibility that considerable elevation of LVEDP worsens the degree of ischemia and does not significantly augment ischemic regional myocardial function or global function, while mild elevation of preload improves or tends to improve simultaneously regional ischemic and global functions without aggravating the ischemic injury significantly. Therefore, we conclude that the preload level is quite important in managing ischemia induced myocardial dysfunction.

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To determine the changes in myocardial water during acute cardiac rejection and the effects of Ciclosporin (CYA) on the myocardial water, 90 heterotopic cardiac transplants were performed in rats which were divided into 3 groups, namely those receiving 1) Lewis × Lewis isografts, 2) Lewis × Brown Norway allografts and 3) CYA treated allografts (15 mg/kg/day). The water content was measured in both recipient and donor hearts at 2, 4, 6, and 8 days after transplant. Pathological specimens were examined by light and electron microscopy, and scored on a 0 to 4+ scale of increasing evidence of rejection. The water content of the isografts showed no significant change throughout the post operative period. In contrast, the allografts had significant increase of water content as early as 2 days after transplant, compared to the isografts and recipients hearts. A significant difference in cellular infiltration was noted between isograft and allograft 4 days after transplant. CYA suppressed significantly the increase of myocardial water and cellular infiltration in the allografts. These data suggest that myocardial edema may precede cellular infiltration during the rejection process and it may be suppressed with CYA treatment. The measurement of myocardial water may be useful in early detection of acute cardiac allograft rejection and for examining the therapeutic effects of CYA.

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The aim of the study was to investigate whether or not the development of hypertension is influenced by chronic treatment with bromocriptine and/or domperidone. Rats treated with DOCA-salt were divided into 4 groups : control with vehicle, bromocriptine, bromocriptine with domperidone, and domperidone. Increased blood pressure by DOCA-salt treatment was significantly suppressed by treatment with bromocriptine and this bromocriptine suppression was significantly blocked by treatment with domperidone. Increased urinary excretion of norepinephrine by DOCA-salt treatment was significantly suppressed by bromocriptine and the inhibiting effect of bromocriptine disappeared with domperidone. In the four groups of rats, there were significant correlations between systolic blood pressure and urinary excretion of norpinephrine, systolic blood pressure and urinary excretion of epinephrine, and urinary excretion of dopamine and sodium. These results suggest that the chronic effect of bromocriptine is to suppress development of DOCA-salt hypertension, mainly through peripheral mechanisms which are involved in the decreased release of norepinephrine.

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A case of right adrenal pheochromocytoma masquerading as a dilated cardiomyopathy is described. This patient was normotensive throughout 8 years of observation. Hyperglycemia and an abnormal glucose tolerance test were a clue to the diagnosis which was confirmed by the findings of increased plasma and urinary epinephrine and norepinephrine values. In patients with dilated cardiomyopathy the possibility of a pheochromocytoma should be considered.

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To determine the central effects of 4-Amino-n-butyric acid (GABA), pressor and sympathetic nerve responses to electrical stimulation of the ventromedial hypothalamus were recorded following the intracerebroventricular (ICV) injection of GABA. In normotensive Wistar rats, anesthetized with urethane, ICV injections of GABA (50-200 μg) reduced sympathetic nerve activity, arterial blood pressure, and heart rate in a dose-dependent manner. Graded electrical stimulation of the ventromedial hypothalamus (50, 100, 150 μA) increased not only mean blood pressure but also the rate of sympathetic nerve firing, and both responses were attenuated by GABA pretreatment (100, 200 μg, ICV). In spontaneously hypertensive rats (SHR), ICV-injected GABA also reduced sympathetic and cardiovascular activity, but the magnitude of depressor responses was significantly larger in SHR than in normotensive Wister Kyoto controls (WKY). Pressor and sympathetic nerve responses elicited by ventromedial hypothalamic stimulation were initially larger in SHR than in WKY, but upon subsequent ICV injection of GABA, hypothalamic responsiveness in SHR was inhibited more prominently and became comparable to that in WKY. These results suggest that by depressing hypothalamic function, centrally injected GABA decreases sympathetic nerve activity to thereby lower blood pressure and heart rate, and in SHR, ICV-injected GABA reversed hypothalamo-sympathetic hyperactivity and thus attenuated hypertension.

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To determine the role of endogenous vasopressin (AVP) in cardiovascular response to central α-adrenoceptor stimulation, α₁-agonist methoxamine or α ₂-agonist clonidine was administered intracerebroventricularly (ICV) to conscious Long-Evans (LE) rats as well as Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI). In LE rats, ICV methoxamine increased blood pressure (BP) and decreased heart rate (HR), while ICV clonidine caused initial hypertension associated with bradycardia followed by prolonged hyportension with tachycardia. In DI rats, however, ICV methoxamine had no detectable effect on BP and HR, whereas CV clonidine produced greater hypotension than in LE rats together with less initial bradycardia. Plasma levels of AVP increased 5-15 fold by methoxamine but did not change by clonidine. The intravenous (IV) but not ICV pretreatment with AVP vascular receptor antagonist d (CH₂)₅ Tyr (Me) AVP significantly attenuated the cardiovascular effects of methoxamine in LE rat, while neither IV nor ICV pretreatment with AVP antagonist modulated the cardiovascular effects of clonidine. These results provide the evidence for the implication of endogenous AVP in the cardiovascular response to central stimulation of α-adrenoceptors.

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Studies were conducted to evaluate the role of water-sodium metabolism on the hypertensive mechanisms in obese patients with essential hypertension (EHT). The obesity index correlated positively with the mean arterial pressure, plasma volume, extracellular fluid volume or total exchangeable sodium, and negatively with plasma noradrenaline concentration or plasma renin activity in EHT. Hypotensive effects of sodium restriction (Na 35 mEq, K 75 mEq) or the natriuretic response to infused dopamine (3 μg/kg/min) was remarkable in obese EHT. Fractional excretion of sodium (FE_Na), which reflects the renal tubular reabsorption of sodium, was significantly lower in obese EHT than that in non-obese or midly obese EHT. Urinary excretion of free dopamine (UDA) had a positive relationship with simultaneously measured urinary excretion of sodium or FE_Na. In addition, UDA correlated positively with the obesity index in patients whose weight was under 115% of the ideal weight. On the contrary, the relation between the two parameters was significantly negative in patients whose weight was over 115% of the ideal weight. These findings suggest that the expansion of body fluid volume and sodium, which might result from the blunted natriuretic ability, at least in part, due to an attenuation of the renal dopaminergic activity, play an important role of the hypertensive mechanisms in obese EHT.

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To investigate the Ca-sensitivity of the erythrocyte membrane in hypertension, the changes of the osmotic fragility of erythrocytes by Ca-loading and the effects of Ca-channel blockers or calmodulin-antagonist were observed in patients with essential hypertension. Erythrocytes were obtained from untreated patients with essential hypertension and age-matched normotensive subjects. Treatment of erythrocytes with Ca-ionophore A23187 and Ca in bathing medium caused the reduction of the osmotic fragility of erythrocytes dose-dependently on Ca-concentration. The degree in alteration of the osmotic fragility of erythrocytes was greater in essential hypertension than that in normotensive controls. In addition, Ca-induced changes of erythrocyte osmotic fragility was inversely correlated with the plasma renin activity in essential hypertension. In the presence of Ca-antagonists (verapamil, diltiazem) or calmodulin-antagonist (trifluoperazine), the reduction of the osmotic fragility of erythrocytes by Ca-loading was inhibited, and the differences of the osmotic fragility of erythrocytes between the hypertensives and the normotensive controls were abolished by these drugs. These results suggest that the greater changes of the osmotic fragility of the erythrocytes by Ca-loading in essential hypertension might be due to the abnormality of Ca-handling of the cell membranes causing an increase in the intracellular Ca concentration, contributing at least partially to the pathogenesis of hypertension.

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Mature renin granules were isolated by the combination of discontinuous and continuous Percoll density gradient centrifugation. Stored renin in the renin granules was found to consist of isoelectrically seven different forms. The seven different isoelectric points (pIs) were 5.6, 5.35, 5.2, 5.0, 4.8, 4.6 and 4.4. Approximately 70% of the stored renin as the total enzymatic activities from all isoelectric peaks was found in a peak which pI corresponded to be 5.35. Renin secreted from isolated glomeruli was also focused into seven peaks possessing identical values. However, the distribution pattern of renin peaks was quite different from that of stored renin. In the secreted renin, peaks of 5.35 (pI) and 5.2 (pI) showed high renin activity and each had approximately 30% of released renin as the total recovered. These results indicate multiple forms of renin are stored and secreted by rat kidney. As the distribution pattern of enzymatic activities n renin peaks between stored renin and secreted renin are different, it is probable that renin may not secreted through mature renin granules by exocytotic mechanism.

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We investigated the effect of dietary salt restriction in spontaneously hypertensive rat (SHR) breeders to determine if the development of hypertension of offspring would be blunted. Weaning SHRs (F-0) were divided into 3 groups and were given a diets containing sodium of 0.4% (G1), 0.05% (G2), or 0.4% plus mefruside 0.001% (G3) with distilled water. Potassium content was 0.75% and the other ingredients except chloride were identical in all the diets. Offsprings (F-1) were derived from selective inbreeding within each group. Systolic blood pressure rose over 160 mmHg by 8 weeks of age in all the male rats of all the groups in both F-0 and F-1. There was no difference in blood pressure between G 1 and G 2 at any age, while in G 3 blood pressure was significantly lower than in G 1 at 12 and 20 weeks of age in F-1. The findings in pressure were ascertained by heart-body weight ratio determined at autopsy, which was similar between G 1 and G 2, and was smaller in G 3 than the others at 20 weeks of age. Aldostrone excretion rate was markedly higher in G 2 than G 1 and G 3 at all study points, whereas plasma renin content was similar between G 1 and G 2, and higher in G 3. Plasma concentrations of noradrenaline and adrenaline did not differ among the 3 groups at any age in both F-0 and F-1. There was also no difference in cardiovascular responsiveness to intravenous noradenaline or hexamethonium among the groups at any age in both F-0 and F-1. It is concluded that life-long sodium restriction does not blunt the development of hypertension in SHR, which might be attributed to failure of suppression in sympathetic nervous function.

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The effect of ketanserin (KET), a specific 5-hydroxytryptamine₂ (5-HT₂) receptor blockade, on pressor response to vasoactive substances was examined in rats with one-kidney, one clip renal artery stenosis of 2 days' duration (2-day clipped rat) and in rabbits with renal artery stenosis of 3 days' duration (3-day clipped rabbits). The 2-day clipped rats showed hyperresponsiveness to norepinephrine (NE), arginine vasopressin (AVP) and 5-HT. All hyperresponsiveness were attenuated by a subdepressor dose of KET. The infusion of KET, 10 μg/kg/min for 30 minutes, decreased mean arterial pressure of the 3-day clipped rabbits ; the dose did not alter blood pressure of the normal controls. Exaggerated pressor response to NE was observed in the 3-day clipped rabbits and was abolished by a subdepressor dose of KET, 2.5 μg/kg/min. These results suggest that 5-HT may be involved in the enhanced pressor response to vasoconstrictor substances in the 2-day clipped rats and 3-day clipped rabbits, and that it may also play an important role in maintaining blood pressure in the 3-day clipped rabbits.

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To assess the pathophysiological role of atrial natriuretic factors in the regulation of blood pressure, we studied the effect of chronic infusion of a synthetic atrial natriuretic factor of 25 amino-acid residues on blood pressure and sodium-water excretion. Experimental subjects were rats with hypertension made by chronic infusion of vasopressin on regular intakes of sodium or on sodium loading with 1% NaCl as drinking water. When a subdepressor dose (150 μg/kg/day) of synthetic atrial natriuretic factor was delivered via an osmotic minipump into the jugular vein simultaneously with 7.2 U/kg/day of vasopressin infused intraperitoneally by another osmotic minipump, the expected elevation of systolic blood pressure was completely inhibited. This was not accompanied by any changes in urine volume and urinary sodium excretion. The antihypertensive effect was sustained throughout the experimental period lasting 3 days in rats on regular sodium intake (p < 0.01) or on sodium loading with 1% NaCl as drinking water (p < 0.01). These results indicate that a subdepressor dose of synthetic atrial natriuretic factor can modulate the vasopressor effect of vasopressin. Therefore it is suggested that an atrial natriuretic factor may be involved in the regulation of blood pressure via its antagonizing effect to vasopressin.

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