ResearchApr 17, 20260 views

Effects of tirzepatide, a dual GIP and GLP-1 receptor agonist, on blood pressure, cardiac function, and sympathetic nervous system in stroke-prone spontaneously hypertensive rats.

Tirzepatide cranked up blood pressure and nervous system activity in a new rat study. Researchers at Kyushu University put tirzepatide, a dual GIP/GLP-1 receptor agonist, under the microscope in stroke-prone spontaneously hypertensive rats. This is a wild ride compared to the usual results seen in humans, where tirzepatide often lowers blood pressure and improves metabolic markers.

Hypertens Res

by Ono Y, Shinohara K, Nakashima H et al.

“Effects of tirzepatide, a dual GIP and GLP-1 receptor agonist, on blood pressure, cardiac function, and sympathetic nervous system in stroke-prone spontaneously hypertensive rats. Ono Y(1)(2), Shinohara K(3)(4), Nakashima H(1)(2), Miyamoto R(1)(2), Hara A(1)(2), Ikeda S(1)(2), Matsumoto S(1)(2), Yoshida D(1)(2), Nakashima R(1)(2), Matsushima S(1)(2), Hashimoto T(1)(2), Katsuki S(1)(2), Yoshida K(1)(2), Kinugawa S(1)(2), Tsutsui H(1)(2)(5), Abe K(1)(2). Author information: (1)Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. (2)Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. (3)Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. shinohara.keisuke.727@m.kyushu-u.ac.jp. (4)Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. shinohara.keisuke.727@m.kyushu-u.ac.jp. (5)International University of Health and Welfare, Fukuoka, Japan. Tirzepatide, a dual agonist for glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has shown robust efficacy in treating diabetes and obesity, and in obese patients with heart failure with preserved ejection fraction (HFpEF), it reduced weight, lowered blood pressure, and improved outcomes. However, its cardiovascular effects in non-obese, non-diabetic hypertension remain unclear. We investigated the impact of tirzepatide on blood pressure, cardiac function, and sympathetic nervous system activity in stroke-prone spontaneously hypertensive rats. Starting at 8 weeks of age, rats received tirzepatide (TZP, 25 nmol/kg, every two days), vehicle (VEH), or pair-fed vehicle (VEH-PF) to control for differences in food intake for 4 weeks. Tirzepatide significantly reduced food intake and body weight. Contrary to prior clinical observations, tirzepatide elevated mean blood pressure (197.4 ± 16.6 vs. 153.7 ± 5.4 mmHg at Day 28; TZP vs. VEH-PF, n = 9 vs. 8; p < 0.05) and increased heart rate, accompanied by left ventricular hypertrophy, myocardial fibrosis, and impaired diastolic function. Sympathetic activation was evident, with higher plasma norepinephrine levels and increased ΔFosB expression-a marker of sustained neuronal excitation-in the parvocellular paraventricular nucleus and the rostral ventrolateral medulla. Moreover, ΔFosB expression was increased in anorexigenic proopiomelanocortin neurons within the hypothalamic arcuate nucleus, which reduce feeding and have been implicated in promoting sympathetic excitation. These findings point to a central mechanism underlying increased sympathetic outflow. In conclusion, tirzepatide increased blood pressure and sympathetic activity in hypertensive rats without cardiac protection, highlighting context-dependent cardiovascular actions. Tirzepatide increased blood pressure, impaired LV diastolic function, and induced cardiac hypertrophy and fibrosis, as well as sympathetic overactivation in SHRSP. © 2026. The Author(s), under exclusive licence to The Japanese Society of Hypertension. Conflict of interest statement: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests.”

Here’s what they did: rats got tirzepatide every two days for four weeks. The team tracked blood pressure, heart function, and sympathetic nervous system activity. Two control groups kept things honest: one got just the vehicle, the other got the same amount of food as the tirzepatide group (to rule out weight loss as the only factor).

Key takeaway: tirzepatide cut body weight, but blood pressure shot up—by over 40 mmHg compared to controls. Heart rate climbed, and the rats developed left ventricular hypertrophy and myocardial fibrosis. Diastolic function took a hit. The sympathetic nervous system lit up, shown by both higher norepinephrine levels and increased ΔFosB—a marker for ongoing neural activation—in key brain areas.

Here’s the punchline for researchers:

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Tirzepatide’s cardiovascular effects are not one-size-fits-all—context matters.

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In this hypertensive, non-obese, non-diabetic animal model, tirzepatide revved up sympathetic activity and had pro-hypertensive effects.

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Central brain mechanisms (specifically, hypothalamic neurons involved in appetite and sympathetic tone) seem to be involved.

This study is a good reminder: animal models tell you what’s possible, not what always happens in humans. If you’re working with tirzepatide, dig into the details and ask tough questions about your model. You can always find more on tirzepatide or check the vendor directory for sourcing options. Stay curious—context is everything in peptide research.

Back to News Read original on Hypertens Res

Effects of tirzepatide, a dual GIP and GLP-1 receptor agonist, on blood pressure, cardiac function, and sympathetic nervous system in stroke-prone spontaneously hypertensive rats.

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