It is generally acknowledged that heart failure is characterized by several disorders in cardiac autonomic properties, including sympathetic, parasympathetic and baroreceptor responses. Part of the mechanism of altered cardiovascular control and reduced catecholamine responsiveness in heart failure involves changes in end-organ responses mediated via beta adrenergic receptors. We have now determined the changes that occur in these components during the inception of heart failure induced by cardiac pacing. First, we quantitiated the stoichiometry and function of each of the components of the beta-adrenergic signaling pathway, including the receptor itself, Gs and the adenylylcyclase catalyst. Two key abnormalities occur: (1) the receptor uncouples from Gs, as indicated by loss of high affinity agonist binding sites without a change in receptor density; (2) there is an associated loss adenylylcyclase catalytic activity without any change in the concentration or function of the stimulatory GTP-binding protein Gs. To understand, therefore, what factors underlie the loss in adenylylcyclase catalytic activity; i.e., whether these are the results of a reduced concentration of the catalyst or due to its post-translational modification, we first cloned the cardiac isoforms of adenylylcyclase. Two novel adenylylcyclase cDNAs, types V and VI, were identified that share the motif of tandem six-transmembrane spans separated by a large hydrophilic cytoplasmic loop. Our data suggest that a decrease in the content of the adenylylcyclase catalyst itself contributes to impaired cyclic AMP production in heart failure and may represent a fundamental defect contributing to a progressive decline in LV function. (Hypertens Res 1993; 16: 79-83)

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For the first 98.5% of mankind's existence, prehistoric people all ate low-sodium, high-potassium, low-fat diets. With evolutionary forces working all this while, humans became very well adapted to the low-sodium, high-potassium, low-fat diet. In modern times, man has deserted his ancient cuisine and now favours a high-sodium, low-potassium, high-fat diet, which has produced several ‘diseases of civilization, ’ including hypertension. Many studies indicate that a high-potassium diet can prevent many of these arterial and renal lesions, even though the blood pressure may remain equally hypertensive. The high-potassium diet also tends to significantly retard the development of hypertension. The use of the high potassium diet is a prime example of protecting arteries in a hypertensive setting. This is the new dimension in hypertension therapy, protecting the arteries in addition to normalizing the blood pressure. (Hypertens Res 1993; 16: 85-90)

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To clarify the mechanisms of the cardiovascular responses to Intracerebroventricular administration (i.c.v.) of somatostatin=14 (SS-14), the effects of pretreatment by i.c.v. α-antagonists or intravenous administration (i.v.) of vasopressin antagonist were investigated in conscious male Wistar rats. Plasma arginine vasopressin (AVP) concentration was also measured. The i.c.v. SS-14 (1.0nmol/kg) caused an increase in mean arterial pressure (MAP) of 16±2mmHg and a decrease in heart rate (HR) of -20 ±3 beats/min, and an increase in plasma AVP concentration from 3.2±0.7 to 21.7±2.9pg/ml (p< 0.05). Pretreatment with either i.c.v. phentolamine (200μg/kg) or i.c.v. bunazosin (50μg/kg) significantly attenuated the pressor response (16±2 to 7±2mmHg, p<0.05, or 16±2 to 7±1mmHg, p<0.05, respectively) and the plasma AVP response (21.7±2.9 to 4.8±1.8pg/ml, p<0.05, or 21.7 ±2.9 to 5.2±2.0pg/ml, p<0.05, respectively) to i.c.v. SS-14. Pretreatment with i.c.v. yohimbine (20 μg/kg) did not affect the cardiovascular responses to i.c.v. SS-14. Pretreatment with i.v. AVP antagonist significantly attenuated the pressor response to i.c.v. SS-14 (16±2 to 6±1mmHg, p<0.05). These results suggest that the pressor response to i.c.v. SS-14 is mediated through activation of central α₁-adrenergic mechanisms which cause elevation of plasma AVP concentration.(Hypertens Res 1993; 16: 91-96)

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The purpose of this study was to evaluate the effects of the calcium channel blocker verapamil on CNS modulation of blood pressure and to determine whether its effects were mediated through central cholinergic muscarinic receptors. Unanesthetized and unrestrained Wistar rats with catheters previously inserted into the lateral cerebral ventricle and femoral artery received verapamil 50μg/kg, either into the lateral cerebral ventricle (ICV) or intravenously (i.v.). The role of central cholinergic muscarinic receptors was assessed by administration of atropine sulphate, 20μg/kg, ICV prior to verapamil. Verapamil ICV but not i.v. produced a significant (p<0.05) decrease in blood pressure and heart rate. Atropine sulphate, ICV, significantly (p<0.05) increased heart rate but did not alter blood pressure. This dose of atropine antagonized the effect of acetylcholine as it significantly (p<0.05) altered the effects of the cholinesterase inhibitor physostigmine on blood pressure and heart rate. Atropine sulfate did not significantly alter the blood pressure response to verapamil. Verapamil-induced reduction in heart rate completely overcame the increase in heart rate produced by atropine and the heart rate was decreased to the same extent after verapamil regardless of atropine pretreatment. These data suggest that the brain is a site of action of the blood pressure reduction produced by the calcium channel antagonist verapamil. The action on blood pressure and heart rate can be independent of mechanisms operating through central cholinergic muscarinic receptors.(Hypertens Res 1993; 16: 97-103)

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In this study, the subcellular mechanism of impaired prostacyclin (PGI₂) synthesis in the vascular system of Dahl salt-sensitive (Dahl S) rats was investigated. Arachidonate liberation in response to PDGF or bradykinin was decreased in cultured aortic smooth muscle cell (VSMC) from Dahl S rats, compared with Dahl salt-resistant (Dahl R) rats. Phospholipase C (PIP₂-PLC) activity was lowered and the inositol 1, 4, 5-triphosphate content was also decreased in the VSMC from Dahl S rats. In fact, cytosolic calcium levels in basal and angiotensin-II stimulated conditions were significantly decreased in VSMC from Dahl S rats, compared with those in Dahl rats. There was no difference, however, in phospholipase A₂ (PLA₂) activity in the two strains. Moreover, the PLA₂ enzyme properties, e.g., its Ca²⁺ requirement, pH profile, K_m value and V_max, were equal in Dahl S and Dahl R rats. The level of functional PLA₂ messenger RNA was found to be greater in the VSMC from Dahl S rats. Similarly, PGI₂ synthesis was reduced in Dahl S rats and this was associated with an unaltered PLA₂ concentration and decreased PIP₂-PLC activity in the arterial wall. Thus, these data indicate that dysfunction of receptor-mediated PLA₂ activation is responsible for altered PGI₂ synthesis in Dahl S rats. This finding is likely mediated by a decrease in phosphoinositides metabolism. (Hypertens Res 1993; 16: 105-111)

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The present study examined polymorphisms of genes that might be involved in the onset of essential hypertension (HT). These included the (i) growth hormone gene (GH1), whose locus has recently been linked to elevated blood pressure (BP) in the stroke-prone SHR, although recent sib-pair analysis of a polymorphism near the human chorionic somatomammotropin gene (a member of the GH cluster) was unable to show linkage with HT; (ii) renal kallikrein gene (KLK1); and (iii) atrial natriuretic factor gene (ANF), where a primary defect in production or activity of kallikrein or ANF could cause NaCl retention and vasoconstriction. Association analyses were conducted to compare restriction fragment length polymorphisms (RFLPs) of each gene in 85 HT and 95 normotensive (NT) Caucasian subjects whose parents had a similar BP status at age ≥50 years. The frequency of the minor allele of (i) a RsaI RFLP in the promoter of GH1, amplified from leukocyte DNA by the polymerase chain reaction, was 0.15 in the HT group and 0.14 in the NT group (X²=0.34, P=0.55); (ii) a TagI RFLP for KLK1 was 0.035 in the HT group and 0.015 in the NT group (X²=1.5, P=0.21); and (iii) a XhoI RFLP for ANF was 0.50 in HTs and 0.46 in NTs (X²=0.20, P=0.65). Studies of HT pedigrees found one family in which the ANF locus and HT were not linked, owing to an obligate recombinant. The present data thus provide no evidence for involvement of the growth hormone, renal kallikrein, nor ANF gene in the causation of essential hypertension. (Hypertens Res 1993; 16: 113-120)

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A monoclonal antibody against human renin was shown to recognize, by immunoblot, a 39kDa protein (possibly renin) in crude homogenates of several marmoset brain regions, and used to investigate the distribution of renin-like molecules in the brain by using light and electron microscopic immunohistochemistry. Cells with renin-like immunoreactivity were detected not only in hypothalamic nuclei and the parabrachial nuclei relevant to the control of blood pressure and water-electrolyte balance but also in other brain regions including the basal ganglia, basal magnocellular nucleus of Meynert, hippocampus, thalamus, midbrain, certain cranial nerve nuclei, raphe nuclei and the cerebellum. Preembedding electron microscopy demonstrated that renin-like Immunoreactivity was mainly present in neuronal perikarya and proximal dendrites and rarely in axon terminals and neuroglial components. The widespread and uneven localization of renin in marmoset brain may provide a morphological basis for certain central effects of renin and angiotensins injected into the cerebral ventricles. It is unlikely that brain renin is actively conveyed from neuronal soma to nerve endings. (Hypertens Res 1993; 16: 121-130)

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The cellular mechanism by which bradykinin induces nitric oxide (NO) formation was studied in cultured bovine endothelial cells. The basal release of nitrate/nitrite (NOx) from endothelial cells increased linearly during one-min incubation and reached plateau levels thereafter. Bradykinin dose-dependently and similarly stimulated NOx release and cyclic GMP production, both of which were abolished by N^G-monomethyl L-arginine. D-Arg-[Hyp³, Thio^5′8, D-Phe⁷]-bradykinin (B₂-antagonist), but not Leu⁸-des Arg⁹-bradykinin (B₁-antagonist), inhibited bradykinin-induced production of both NOx and cyclic GMP. Removal of extracellular Ca²⁺ by EGTA failed to affect bradykinin-induced NOx and cyclic GMP production, whereas intracellular Ca²⁺ release inhibitor (TMB-8) completely abolished NOx and cyclic GMP production stimulated by bradykinin. A relatively selective calmodulin inhibitor (W-7) blocked bradykinin-induced production of NOx and cyclic GMP. Our data suggest that bradykinin stimulates B₂ receptor-mediated NO formation via activation of Ca²⁺/calmodulin-dependent constitutive NO synthase, and that NO may function as an autocrine/paracrine factor in endothelial cells. (Hypertens Res 1993; 16: 131-137)

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The present guidelines were prepared by the Guidelines Sub-Committee* of the WHO/ISH Mild Hypertension Liaison Committee. They represent the third revision of the WHO/ISH guidelines and were finalized after presentation and discussion at the 6th WHO/ISH Meeting on Mild Hypertension held in Chantilly, France on 28-31 March 1993. The previous WHO/ISH guidelines were published in Bull WHO 1989; 67: 493-498, and J Hypertens 1989; 7: 689-693. (Hypertens Res 1993; 16: 149-161)

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