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We hypothesized that sympathetic hyperactivity and parasympathetic insuficiency in spontaneously hypertensive rats (SHR) underlie their exaggerated cardiovascular response to acute stress and impaired adaptation to repeated restraint stress exposure compared to Wistar-Kyoto rats (WKY). Cardiovascular responses to single (120 min) or repeated (daily 120 min for 1 week) restraint were measured by radiotelemetry and autonomic balance was evaluated by power spectral analysis of systolic blood pressure variability (SBPV) and heart rate variability (HRV). Baroreflex sensitivity (BRS) was measured by the pharmacological Oxford technique. Stress-induced pressor response and vascular sympathetic activity (low-frequency component of SBPV) were enhanced in SHR subjected to single restraint compared to WKY, whereas stress-induced tachycardia was similar in both strains. SHR exhibited attenuated cardiac parasympathetic activity (high-frequency component of HRV) and blunted BRS compared to WKY. Repeated restraint did not affect the stress-induced increase in blood pressure. However, cardiovascular response during the post-stress recovery period of the 7th restraint was reduced in both strains. The repeatedly restrained SHR showed lower basal heart rate during the dark (active) phase and slightly decreased basal blood pressure during the light phase compared to stress-naive SHR. SHR subjected to repeated restraint also exhibited attenuated stress-induced tachycardia, augmented cardiac parasympathetic activity, attenuated vascular sympathetic activity and improved BRS during the last seventh restraint compared to single-stressed SHR. Thus, SHR exhibited enhanced cardiovascular and sympathetic responsiveness to novel stressor exposure (single restraint) compared to WKY. Unexpectedly, the adaptation of cardiovascular and autonomic responses to repeated restraint was more effective in SHR., (© 2024. The Author(s).)

Chronic treatment with acetylcholinesterase inhibitors may be a promising therapeutic strategy for treatment of cardiovascular diseases. The aim of our study was to analyze the changes in blood pressure (BP) and heart rate (HR) during 14 days of treatment with two different acetylcholinesterase inhibitors - pyridostigmine (PYR) having only peripheral effects or donepezil (DON) with both peripheral and central effects. In addition, we studied their effects on the cardiovascular response to restraint stress and on sympathovagal control of HR in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). SHR were characterized by elevated BP and increased low-frequency component of systolic BP variability (LF-SBPV), but their cardiac vagal tone and HR variability (HRV) were reduced compared with WKY. Chronic treatment with either acetylcholinesterase inhibitor decreased HR and increased HRV in both strains. PYR treatment slightly decreased BP and LF-SBPV in the dark phase of the day. Neither drug significantly altered BP response to stress, but PYR attenuated HR increase during restraint stress. Regarding sympathovagal balance, acute methylatropine administration caused a greater increase of HR in WKY than in SHR. Chronic PYR or DON treatment enhanced HRV and HR response to methylatropine (vagal tone) in WKY, whereas PYR but not DON treatment potentiated HRV and vagal tone in SHR. In conclusion, vagal tone was lower in SHR compared with WKY, but was enhanced by chronic PYR treatment in both strains. Thus, chronic peripheral, but not central, acetylcholinesterase inhibition has major effects on HR and its variability in both normotensive and hypertensive rats., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Increased level of C-reactive protein (CRP) is a risk factor for cardiovascular diseases, including myocardial infarction and hypertension. Here, we analyzed the effects of CRP overexpression on cardiac susceptibility to ischemia/reperfusion (I/R) injury in adult spontaneously hypertensive rats (SHR) expressing human CRP transgene (SHR-CRP). Using an in vivo model of coronary artery occlusion, we found that transgenic expression of CRP predisposed SHR-CRP to repeated and prolonged ventricular tachyarrhythmias. Excessive ischemic arrhythmias in SHR-CRP led to a significant reduction in infarct size (IS) compared with SHR. The proarrhythmic phenotype in SHR-CRP was associated with altered heart and plasma eicosanoids, myocardial composition of fatty acids (FAs) in phospholipids, and autonomic nervous system imbalance before ischemia. To explain unexpected IS-limiting effect in SHR-CRP, we performed metabolomic analysis of plasma before and after ischemia. We also determined cardiac ischemic tolerance in hearts subjected to remote ischemic perconditioning (RIPer) and in hearts ex vivo. Acute ischemia in SHR-CRP markedly increased plasma levels of multiple potent cardioprotective molecules that could reduce IS at reperfusion. RIPer provided IS-limiting effect in SHR that was comparable with myocardial infarction observed in naïve SHR-CRP. In hearts ex vivo, IS did not differ between the strains, suggesting that extra-cardiac factors play a crucial role in protection. Our study shows that transgenic expression of human CRP predisposes SHR-CRP to excess ischemic ventricular tachyarrhythmias associated with a drop of pump function that triggers myocardial salvage against lethal I/R injury likely mediated by protective substances released to blood from hypoxic organs and tissue at reperfusion., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

The effect of chemical sympathectomy on cardiovascular parameters and the compensatory role of adrenal hormones, the renin-angiotensin system, and cardiovascular sensitivity to vasoconstrictors were studied in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Sympathectomy was induced in 20-week-old rats by daily intraperitoneal guanethidine administration (30 mg/kg b.w.) for 2 weeks. Basal blood pressure (BP), heart rate (HR), and restraint stress-induced cardiovascular changes were measured by radiotelemetry. The BP response to catecholamines was determined in rats with implanted catheters. Sympathectomy decreased BP only transiently, and after 14-day guanethidine treatment, BP returned to basal values in both strains. Sympathectomy permanently lowered HR, improved baroreflex sensitivity, and decreased the low-frequency domain of systolic blood pressure variability (a marker of vascular sympathetic activity). Guanethidine also attenuated the BP and HR responses to restraint stress. On the other hand, the BP response to catecholamines was augmented in sympathectomized rats, and this was not due to the de novo synthesis of vascular adrenergic receptors. Sympathectomy caused adrenal enlargement, enhanced the expression of adrenal catecholamine biosynthetic enzymes, and elevated plasma adrenaline levels in both strains, especially in WKY rats. Guanethidine also increased the plasma levels of aldosterone and corticosterone in WKY rats only. In conclusion, sympathectomy produced a transient decrease in BP, a chronic decrease in HR and improvement in baroreflex sensitivity. The effect of sympathectomy on BP was counteracted by increased vascular sensitivity to catecholamines in WKY rats and SHRs and/or by the enhanced secretion of adrenal hormones, which was more pronounced in WKY rats.

Alterations of sympathoadrenal and sympathoneural systems have been suggested to be involved in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). To evaluate the ontogenetic changes of these systems, mRNA and protein expressions of catecholaminergic system genes were measured in adrenal glands and sympathetic ganglia, and the catecholamine levels were determined in adrenal glands, sympathetic ganglia and plasma of prehypertensive (4-week-old) and hypertensive (24-week-old) SHR. Vascular sympathetic innervation was visualized in the femoral artery by glyoxylic acid. In the adrenal glands of prehypertensive SHR, the expression of catecholamine biosynthetic enzymes Ddc, Dbh and Pnmt was lower than in aged-matched Wistar-Kyoto rats. In contrast, the adrenal content of dopamine, noradrenaline and adrenaline was higher in prehypertensive SHR (141%, 123% and 120% of Wistar-Kyoto rats, respectively, p < 0.01). In the adrenal glands of adult SHR, the expression of catecholamine biosynthetic enzymes Th, Ddc, Dbh and Pnmt was decreased along the amounts of dopamine and noradrenaline (50% and 38%, respectively, p < 0.001). The expression levels of Ddc and Dbh enzymes were also downregulated in the sympathetic ganglia of both prehypertensive and adult SHR. At both ages, the density of sympathetic innervation was twofold higher in SHR compared to Wistar-Kyoto rats (p < 0.001). In conclusion, adrenal catecholamine content was increased in prehypertensive SHR, whereas it was reduced in SHR with established hypertension. Surprisingly, downregulation of catecholamine biosynthetic enzymes was observed in both the adrenal medulla and sympathetic ganglia of SHR at both ages. Thus, this downregulation might be a compensatory mechanism that counteracts the vascular sympathetic hyperinnervation seen in SHR of both ages.

Ligands of auxiliary α 2 δ subunit of voltage-dependent calcium channels (VDCCs) decrease elevated L-type VDCCs surface expression in arterial myocytes and arterial constriction in spontaneously hypertensive rats (SHR). However, their effect on blood pressure (BP) is unclear. In this study, we investigated the hemodynamic response to acute and chronic administration of gabapentin, a ligand of auxiliary α 2 δ subunit of VDCCs, in adult SHR with established neurogenic hypertension. The acute gabapentin administration lowered BP and heart rate more in conscious SHR than Wistar-Kyoto rats. Both nifedipine (L-type VDCCs blocker) and ω-conotoxin GVIA (N-type VDCCs blocker) also decreased BP more in SHR, but only gabapentin and ω-conotoxin GVIA abolished the nitroprusside-induced reflex tachycardia of baroreceptor-heart rate control. Hypotensive effect of gabapentin was accompanied by a reduction of (1) plasma norepinephrine level, (2) depressor response to ganglionic blocker pentolinium, (3) power of low frequency component of systolic BP variability, and (4) pressor response of mesenteric vascular bed to periarterial nerve stimulation, suggesting the decrease of peripheral sympathetic nerve transmission. Moreover, gabapentin effects on BP and baroreflex were absent in sympathectomized rats. In conclusion, the acute (but not chronic) administration of gabapentin lowered BP more in SHR than in Wistar-Kyoto rats. Besides the known L-type VDCCs involvement in the vascular effect of gabapentin, our data revealed the important role of N-type VDCCs in acute gabapentin effect on sympathetic control of BP. Gabapentin-induced changes of sympathetic nerve transmission indicated major hemodynamic mechanism of the acute response to this drug.

The dentate gyrus of the hippocampus is one of the few places in the brain where neurogenesis occurs in adulthood. Nowadays, an increasing number of children and young adults are affected by hypertension, one of the factors in the development of cerebrovascular diseases and age-related cognitive deficits. Since these cognitive deficits are often hippocampus-dependent, it is possible that hypertension exerts this effect via decreasing adult neurogenesis which has been shown to be essential for a range of cognitive tasks. We used spontaneously hypertensive rats, which develop hypertension in the first weeks of life. Half of them were treated with the antihypertensive drug captopril. We found that the drug-induced lowering of blood pressure in this period did not affect the rate of adult neurogenesis. In a second experiment, we used another animal model of hypertension - salt-sensitive and salt-resistant strains of Dahl rats. A high-salt diet induces hypertension in the salt-sensitive strain, but not in the salt-resistant strain. The high-salt diet led to salt-induced hypertension, but did not affect the level of adult neurogenesis in the dentate gyrus of the hippocampus. We conclude that hypertension does not significantly affect the rate of hippocampal neurogenesis in young adult rats.

Calcium sensitization mediated by RhoA/Rho kinase pathway can be evaluated either in the absence (basal calcium sensitization) or in the presence of endogenous vasoconstrictor systems (activated calcium sensitization). Our aim was to compare basal and activated calcium sensitization in three forms of experimental hypertension with increased sympathetic tone and enhanced calcium entry-spontaneously hypertensive rats (SHR), heterozygous Ren-2 transgenic rats (TGR), and salt hypertensive Dahl rats. Activated calcium sensitization was determined as blood pressure reduction induced by acute administration of Rho kinase inhibitor fasudil in conscious rats with intact sympathetic nervous system (SNS) and renin-angiotensin system (RAS). Basal calcium sensitization was studied as fasudil-dependent difference in blood pressure response to calcium channel opener BAY K8644 in rats subjected to RAS and SNS blockade. Calcium sensitization was also estimated from reduced development of isolated artery contraction by Rho kinase inhibitor Y-27632. Activated calcium sensitization was enhanced in all three hypertensive models (due to the hyperactivity of vasoconstrictor systems). In contrast, basal calcium sensitization was reduced in SHR and TGR relative to their controls, whereas it was augmented in salt-sensitive Dahl rats relative to their salt-resistant controls. Similar differences in calcium sensitization were seen in femoral arteries of SHR and Dahl rats., Competing Interests: The authors declare that they have no conflicting interests.

Vascular smooth muscle cells (VSMC) display considerable phenotype plasticity which can be studied in vivo on vascular remodeling which occurs during acute or chronic vascular injury. In differentiated cells, which represent contractile phenotype, there are characteristic rapid transient changes of intracellular Ca(2+) concentration ([Ca(2+)]i), while the resting cytosolic [Ca(2+)]i concentration is low. It is mainly caused by two components of the Ca(2+) signaling pathways: Ca(2+) entry via L-type voltage-dependent Ca(2+) channels and dynamic involvement of intracellular stores. Proliferative VSMC phenotype is characterized by long-lasting [Ca(2+)]i oscillations accompanied by sustained elevation of basal [Ca(2+)]i. During the switch from contractile to proliferative phenotype there is a general transition from voltage-dependent Ca(2+) entry to voltage-independent Ca(2+) entry into the cell. These changes are due to the altered gene expression which is dependent on specific transcription factors activated by various stimuli. It is an open question whether abnormal VSMC phenotype reported in rats with genetic hypertension (such as spontaneously hypertensive rats) might be partially caused by a shift from contractile to proliferative VSMC phenotype.

Increased systemic vascular resistance is responsible for blood pressure (BP) elevation in most forms of human or experimental hypertension. The enhanced contractility of structurally remodeled resistance arterioles is mediated by enhanced calcium entry (through L type voltage-dependent calcium channels - L-VDCC) and/or augmented calcium sensitization (mediated by RhoA/Rho kinase pathway). It is rather difficult to evaluate separately the role of these two pathways in BP control because BP response to the blockade of either pathway is always dependent on the concomitant activity of the complementary pathway. Moreover, vasoconstrictor systems enhance the activity of both pathways, while vasodilators attenuate them. The basal fasudil-sensitive calcium sensitization determined in rats deprived of endogenous renin-angiotensin system (RAS) and sympathetic nervous system (SNS) in which calcium entry was dose-dependently increased by L-VDCC opener BAY K8644, is smaller in spontaneously hypertensive rats (SHR) than in normotensive Wistar-Kyoto (WKY) rats. In contrast, if endogenous RAS and SNS were present in intact rats, fasudil caused a greater BP fall in SHR than WKY rats. Our in vivo experiments indicated that the endogenous pressor systems (RAS and SNS) augment calcium sensitization mediated by RhoA/Rho kinase pathway, whereas the endogenous vasodilator systems (such as nitric oxide) attenuate this pathway. However, the modulation of calcium entry and calcium sensitization by nitric oxide is strain-dependent because NO deficiency significantly augments low calcium entry in WKY and low calcium sensitization in SHR. Further in vivo and in vitro experiments should clarify the interrelationships between endogenous vasoactive systems and the contribution of calcium entry and/or calcium sensitization to BP maintenance in various forms of experimental hypertension.

Most anesthetics induce characteristic hemodynamic changes leading to blood pressure (BP) reduction but the role of renin-angiotensin system (RAS), sympathetic nervous system (SNS) and nitric oxide (NO) synthesis in this BP reduction is unknown. We therefore studied the influence of four widely used anesthetics - pentobarbital (P), isoflurane (ISO), ketamine-xylazine (KX) and chloralose-urethane (CU) - on the participation of these vasoactive systems in BP maintenance. BP effects elicited by the acute sequential blockade of RAS (captopril), SNS (pentolinium) and NO synthase (L-NAME) were compared in conscious and anesthetized Wistar or spontaneously hypertensive rats (SHR). Except for pentobarbital all studied anesthetics evidenced by diminished BP responses to pentolinium. The absolute pentolinium-induced BP changes were always greater in SHR than Wistar rats. KX anesthesia eliminated BP response to pentolinium and considerably enhanced BP response to NO synthase inhibition in SHR. In both rat strains the anesthesia with ISO or CU augmented BP response to captopril, decreased BP response to pentolinium and attenuated BP response to NO synthase inhibition. In conclusion, pentobarbital anesthesia had a modest influence on BP level and its maintenance by the above vasoactive systems. Isoflurane and chloralose-urethane anesthesia may be used in cardiovascular experiments if substantial BP decrease due to altered contribution of RAS, SNS and NO to BP regulation does not interfere with the respective research aim. Major BP reduction (namely in SHR) due to a complete SNS absence is a major drawback of ketamine-xylazine anesthesia.