Long-term blood pressure control: is there a set-point in the brain?

Abstract

Mean arterial pressure fluctuates depending on physical or psychological activity, but should be stable at rest at around 100 mmHg throughout an entire life in human. The causes of hypertension and the blood pressure regulation mechanisms have been discussed for a long time, and many aspects have recently become more clear. Circulatory shock or short-term hypotension can be treated based on what is now known, but chronic hypertension is still difficult to treat thoroughly. The exact mechanisms for long-term blood pressure regulation have yet not been elucidated. Neuro–humoral interaction has been suggested as one of the mechanisms. Then, from the 1990s, paracrine hormones like nitric oxide or endothelins have been extensively researched in order to develop endothelial local control mechanisms for blood pressure, which have some relationships to long-term control. Although these new ideas and mechanisms are newly developed, no clear explanation for long-term control has yet been discussed, except for renal abnormality. Recently, a central set-point theory has begun to be discussed. This review will discuss the mechanisms for long-term blood pressure control, based on putative biological missions of circulatory function for life support.

Fig. 1

Analog recordings from a Sprague–Dawley rat (350 g body weight), showing responses of arterial pressure (AP), mean arterial pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA) and mean RSNA to an intravenous injection of hexamethonium (40 mg kg⁻¹)

Fig. 2

A conceptual scheme for the blood pressure regulation system by the neuron-humoral interaction. Baro baroreceptors, CNS central nervous system, N neural control, H humoral control, H the heart, TPR total peripheral resistance, VOL circulating blood volume, AP arterial pressure

Fig. 3

Effects of intravenous infusion of arginine vasopressin (AVP) on the baroreflex curve and the reflex gain curve of renal sympathetic nerve activity (RSNA) in a rabbit, modified from Ref. [21]. MAP mean arterial pressure

Fig. 4

Responses of the baroreflex curve of RSNA to the AVP infusions in intact rabbits, 1CSN + 1AoN rabbits, and 1CSN rabbits, modified from Ref. [32]. 1CSN + 1AoN rabbits the rabbits with one carotid sinus nerve intact and one aortic nerve intact but the others severed, 1CSN rabbits the rabbits with just one carotid sinus nerve intact but the other carotid sinus nerve and two aortic nerves severed, RSNA renal sympathetic nerve activity, AVP arginine vasopressin, MAP mean arterial pressure

Fig. 5

A hypothetical mechanism of vasopressin effects on the central nervous system to suppress renal sympathetic nerve activity. AVP arginine vasopressin, AP area postrema, NTS nucleus tractus solitarius, RVLM rostral ventrolateral medulla, CVLM caudal ventrolateral medulla, ImL intermediate lateral column, RSNA renal sympathetic nerve activity

Fig. 6

Typical responses of the baroreflex curve of heart rate to intra-arterial angiotensin II in a rabbit, and average data of the parameters of the sigmoid curves (n = 7), modified from Ref. [34]. va vertebral arterial infusion, A II: angiotensin II, with infusion rate of 5, 10, 20 ng kg⁻¹ min⁻¹ for less than 5 min. HR heart rate, MAP mean arterial pressure

Fig. 7

Responses of RSNA and HR baroreflex curves to intra-vertebral angiotensin II in a rabbit, modified from Ref. [34]. RSNA renal sympathetic nerve activity, HR heart rate, va vertebral arterial infusion, A II angiotensin II infused at a rate of 20 ng kg⁻¹ min⁻¹

Fig. 8

A hypothetical mechanism of angiotensin II effects on the central nervous system to enhance heart rate and to suppress renal sympathetic nerve activity. AP area postrema, AN ambiguus nucleus, DMN dorsal motor nucleus of the vagus nerve, NTS nucleus tractus solitarius, RVLM rostral ventrolateral medulla, CVLM caudal ventrolateral medulla, ImL intermediate lateral column, HR heart rate, RSNA renal sympathetic nerve activity

Fig. 9

Putative concept for long-term control of sympathetic activity by a neuro–humoral interaction mechanism via the area postrema

Fig. 10

Effects of the 5-day infusion of vasopressin on arterial pressure and heart rate in intact and area postrema-lesioned rabbits, modified from Ref. [37]. INT intact rabbits, APX rabbits with the area postrema lesioned, MAP mean arterial pressure, HR heart rate, AVP arginine vasopressin. *p < 0.05 compared with control, ^† p < 0.05 between INT and APX

Fig. 11

Conceptual scheme for the critical mission of the circulation system for organisms to be alive. MAP mean arterial pressure

Fig. 12

Putative concepts for two missions and each method for regulation of arterial pressure

Fig. 13

Histograms of 24-h MAP in an intact rabbit and in a SAD rabbit, modified from Ref. [44]. MAP mean arterial pressure, SAD sinoaortic denervated, All all MAP data (8,474 points for intact, 8,398 points for SAD) during 24 h, Rest MAP data (4,059 points for intact, 4,258 points for SAD) during rabbits sitting without movement, Move MAP data (2,507 points for intact, 2,140 points for SAD) during rabbits standing or moving, Other the other data (1,908 points for intact, 2,000 points for SAD) which are recorded during neutral phases

Fig. 14

Histograms of 24-h heart rate (HR), aortic blood flow (AoBF) and total peripheral resistance (TPR) in an intact rabbit and a SAD rabbit, modified from Ref. [44]. AoBF equals (cardiac output − coronary flow). TPR is calculated from [(arterial pressure − central venous pressure)/AoBF]. Abbreviations and sampling points are as in Fig. 13

Fig. 15

Conceptual scheme for main regulation axes for arterial pressure. Black lines feedback regulation axes, purple lines central drive axes, red lines local control, green words examples

Fig. 16

Contractions evoked by norepinephrine (NE, 10⁻⁸ to 10⁻⁶ M) in aortic rings of rats in the 4 groups, modified from Ref. [65]. DS-8% rats Dahl salt-sensitive rats fed 8% NaCl diet (n = 10); DS-0.4% rats Dahl salt-sensitive rats fed 0.4% NaCl diet (n = 12); DR-8%, 0.4% rats Dahl salt-resistant rats fed 8 or 0.4% NaCl diet (n = 12, 10, respectively); ED50 half maximal responses, Emax maximum responses. *p < 0.05 between high-salt and normal-salt Dahl salt-sensitive rats

Fig. 17

Analog recordings showing responses of arterial pressure (AP), mean arterial pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA), and mean RSNA to a ramp decrease in MAP by caval occlusion (Oc) before and after intraperitoneal administration of 7-nitroindazole (nNOS inhibitor, 307 μmol/kg) in a hypertensive Dahl salt-sensitive rat. PE phenylephrine (15 μg/kg) intravenously, modified from Ref. [73]

Fig. 18

Analog recordings showing responses of arterial pressure (AP), mean arterial pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA), and mean RSNA to a ramp decrease in MAP by caval occlusion (Oc) after the intracerebroventricular (icv) infusion of artificial cerebrospinal fluid (aCSF), and then of s-methyl-l-thiocitrulline (SMTC, 50 nmol), and l-arginine (l -Arg, 1,000 nmol), modified from Ref. [76]. Each arrow indicates a peak response of mean RSNA to a ramp decrease in MAP by caval occlusion, modified from Ref. [76]

Fig. 19

Distribution of neurons containing neuronal nitric oxide synthase (nNOS neurons) in the rat brain, modified from Ref. [77]. Red bars nNOS neuronal area where its number was increased in salt-sensitive hypertensive rats compared with salt-sensitive normotensive rats. Red characters of the name show the part of sympathetic center. Numbers are the plate number in the book by George Paxinos, The Rat Brain in Stereotaxic Coordinates, London: Academic, 1988). PVN paraventricular nucleus, SON supraoptic nuecleus, DMH dorsomedial hypothalamus, PAG periaqueductal grey matter, PB parabrachial nucleus, NTS nucleus tractus solitarius, RM raphe magnus, RVLM rostral ventrolateral medulla, CVLM caudal ventrolateral medulla, CPA caudal pressor area, IML intermediolateral column

Fig. 20

Putative characteristics of the target organs and the control system in Dahl salt-sensitive hypertension

Fig. 21

Conceptual scheme for the meaning and method of blood pressure control. The blood pressure control system has separate functions for two biological missions. One is homeodynamic regulation by feed-forward control for the ‘all for one’ theory. The other is homeostatic regulation by feedback control and local control for the support of life

Fig. 22

Author’s reflections: the peripheral vascular resistance has two missions, a seeming dilemma for maintaining circulation function normally