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The relationship between blood pressure (BP) and cardiovascular morbidity has been appreciated for many years. Casual BP may not be representative of the pressure at other times. It is recognized that BP during exercise may be a more accurate predictor than casual BP. There is, however, little information about the effects of antihypertensive drugs on the BP during exercise. This study was designed to investigate the effects of various antihypertensive agents on BP during exercise. Sixty-four patients (age, 49+/-10 years) with untreated essential hypertension (WHO I, II) were studied during a supine ergometric exercise regimen. A graded exercise test was started at a workload of 50 W, and the load was increased by 25 W every 3 min. The hemodynamic responses to exercise were evaluated by changes in systolic and diastolic BP (SBP, DBP) and heart rate (HR). Plasma norepinephrine (NE) levels were measured at rest and during submaximal exercise, and before and after 4 weeks of treatment with metoprolol (METO), doxazosin (DOXA), trichlormethiazide (TCTZ), nifedipine (NIFE), amlodipine (AMLO) and temocapril (TEMO) between left ventricular mass index (LVMI) and BP values at rest, during exercise, and during the recovery period after exercise were assessed by multiple regression analysis. The stepwise selection (forward conditional) method showed that LVMI was significantly associated with SBP during submaximal exercise and during the recovery period. All antihypertensive treatments decreased SBP and DBP (p<0.01) at rest. METO, AMLO and TEMO significantly lowered SBP (p<0.05) during exercise, whereas DOXA, TCTZ and NIFE induced no change in SBP. The exercise-induced increase of plasma NE was further enhanced by METO and NIFE but not by AMLO, DOXA, or TCTZ, and it was significantly suppressed by TEMO (p<0.01). These results suggest that BP during exercise is more highly associated with the progression of left ventricular hypertrophy (LVH) than is casual BP. Because antihypertensive agents differ in their effects on exercise hemodynamics, we recommend that hemodynamic factors during exercise be considered when selecting the optimal antihypertensive medication for highly active patients.

To evaluate the mechanism of neurally mediated syncope (NMS), we investigated basal autonomic nerve function using a conventional pharmacological method and [123I]-metaiodobenzyl-guanidine (MIBG) single photon emission computed tomography (SPECT). Nine patients with NMS, whose syncope was induced by head-up tilt test with or without isoproterenol, underwent [123I]-MIBG SPECT. Eight of nine NMS patients showed reduced myocardial uptake (two patients, diffuse; four patients, anteroseptal and inferior; one patient, anteroseptal; one patient, inferior). In the study of pharmacological autonomic nervous function test, atropine sulfate (atr.) (0.04 mg/kg), isoproterenol (isp.) (5 x 10(-3) microg/kg/min), propranolol (prop.) (0.2 mg/kg), phenylephrine (phenyl.) (0.4 microg/kg/min), and phentolamine (phent.) (0.2 mg/kg) were successively administered to patients with NMS (n = 5) and control subjects (n = 5). The heart rate (HR) after atr. and prop., and systolic blood pressure (SBP) after phent. were defined as intrinsic HR (IHR) and intrinsic SBP (ISBP). Parasympathetic activity (increase in HR by atr.), beta-sympathetic tone (HR after atr. minus IHR), beta-sensitivity (change in HR by 1 microg isp./kg/min), beta-secretion (beta-tone/beta-sensitivity), alpha-sympathetic tone (SBP before phenyl. minus ISBP), alpha-sensitivity (change in SBP by 1 microg phenyl./kg/min) and alpha-secretion (alpha-tone/alpha-sensitivity) were also calculated. The beta-secretion was decreased (0.0027+/-0.0008 versus 0.0060+/-0.0004 microg/kg/min/isp.; p < 0.05), while the beta-sensitivity was increased (5850+/-947 versus 3150+/-292 beats/microg/kg/min isp.; p < 0.05) in NMS compared with control subjects. In the other indexes, there were no significant differences between two groups. The results of the present study suggest that increased beta-sensitivity may contribute hypercontraction of left ventricles, which might partially explain the mechanism of NMS.

Although the angiotensin II subtype 2 receptor (AT2-R) is expressed abundantly in the adrenal medulla, its physiological significance has not yet been determined. To obtain fundamental knowledge of the regulation of AT2-R expression in the adrenal medulla, we investigated the effects of modulating several ion channels on AT2-R expression in PC12W cells. Experiments were performed after 24 hours of serum depletion under subconfluent conditions. After 48 hours of treatment with various agonists or antagonists, the receptor density and mRNA level of AT2-Rs were quantified by 125I-[Sar1, Ile8]angiotensin II binding and Northern blot analysis. Ouabain (10 to 100 nmol/L) and insulin (10 to 100 nmol/L) dose-dependently increased receptor density and mRNA level. Analysis of the binding characteristics revealed that the ouabain-dependent increase in AT2-R levels was due to an increase in binding capacity without a change in the Kd value. These increases were blocked by lowering the Na+ concentration in the medium. A low concentration of the sodium ionophore monensin (10 nmol/L), the K+-channel blocker quinidine (10 micromol/L), and the ATP-sensitive K+-channel blockers tolbutamide (100 micromol/L) and glybenclamide (10 micromol/L) also significantly increased receptor density, but the ATP-sensitive K+-channel agonist cromakalim (100 micromol/L) decreased receptor density significantly (P<0.01). Nifedipine (10 micromol/L) decreased basal receptor density and completely blocked the increase in receptor density caused by these agents. The increase in receptor density caused by an increase in intracellular Na+ was accompanied by an increase in mRNA level, whereas the ATP-sensitive K+-channel blockers did not change mRNA level. Nifedipine slightly decreased mRNA level. These results suggest that AT2-R expression is sensitively regulated by intracellular cation levels. The change in intracellular Na+ level transcriptionally regulates AT2-R expression, whereas the K+-channel blocker-dependent upregulation appears to be at least in part posttranslational.

To investigate mechanisms underlying the agonist-induced desensitization of the type 1A angiotensin II receptor (AT1A-R), we have stably expressed in Chinese hamster ovary (CHO) cells the wild-type receptor and truncated mutants lacking varying lengths of the cytoplasmic tail. Assay of inositol 1,4,5-trisphosphate (IP3) formation in response to agonist demonstrated that the truncated mutants T318, T328, and T348 lacking the last 42, 32, or 12 amino acid residues, respectively, couple with Gq protein with an efficiency similar to that of full-length receptors, whereas coupling of Gq protein was abolished in the T310 truncated mutant devoid of the carboxyl-terminal 50 amino acids. Exposure of CHO/AT1A-R cells expressing the wild-type AT1A-R to angiotensin II resulted in rapid and dose-dependent homologous desensitization of receptor-mediated IP3 formation, which was independent of the receptor internalization. Mastoparan, an activator of G protein-coupled receptor kinase (GRK), induced desensitization of the AT1A-R. The agonist-induced desensitization of the receptor was largely prevented by heparin, a potent inhibitor of GRK, whereas it was only partially attenuated by a protein kinase C (PKC)-specific inhibitor. The homologous or heterologous desensitization of the receptor was greatly impaired in the truncated mutants T318 and T328, lacking the Ser/Thr-rich (13 or 12 Ser/Thr residues) cytoplasmic tail of the AT1A-R. Deletion of the last two Ser residues, including one PKC consensus site in the receptor tail, prevented only phorbol 12-myristate 13-acetate-induced desensitization by 30%. Moreover, we found an agonist-induced translocation of a heparin-sensitive kinase activity. The angiotensin II-stimulated heparin-sensitive kinase could phosphorylate a thioredoxin fusion protein containing the entire AT1A-R cytoplasmic tail (N295 to E359), which lacks consensus phosphorylation sites for GRK1, GRK2, and GRK3. The heparin-sensitive kinase may not be GRK2, GRK3, or GRK6 expressed in CHO/AT1A-R cells, since angiotensin II did not induce translocation of these receptor kinases. Potential Ser/Thr phosphorylation sites located between S328 and S347 in the cytoplasmic tail of AT1A-R seem to play a critical role in the heterologous and homologous desensitization of the receptor. A heparin-sensitive kinase other than GRK2, GRK3, or GRK6 may be involved in the agonist-induced homologous desensitization of the AT1A-R.